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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA Tampa, Florida Saturday, February 14, 2009, 12:15 pm - 2:15 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: Jorge Sierra, MD, Hospital de la Santa Creu i Sant Pau Phone: ; Fax: ; jsierra@hsp.santpau.es Martin Tallman, MD, Northwestern University Phone: ; Fax: ; m-tallman@northwestern.edu John F. Dipersio, MD, PhD, Washington University School of Medicine Phone: ; Fax: ; jdipersi@im.wustl.edu Waleska S. Pérez MPH, CIBMTR Statistical Center Phone: ; Fax: ; wperez@mcw.edu Mei-Jie Zhang, PhD, CIBMTR Statistical Center Phone: ; Fax: ; meijie@mcw.edu Daniel Weisdorf, MD, University of Minnesota Phone: ; Fax: ; weisd001@umn.edu 1. Introduction a. Minutes of February, 2008 meeting (Attachment 1) b. Newly appointed chair: Donald Bunjes, MD; University Hospital Ulm, Ulm, Germany; Phone: ; Fax: ; donald.bunjes@uniklinik.ulm.de 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers a. R03-50 Marks DI, Pérez WS, He W, Zhang M-J, Bishop MR, Bolwell BJ, Bredeson CN, Copelan EA, Gale RP, Gupta V, Hale GA, Isola LM, Jakubowsi AA, Keating A, Klumpp TR, Lazarus HM, Liesveld JL, Maziarz RT, McCarthy PL, Sabloff M, Schiller G, Sierra J, Tallman MS, Waller EK, Wiernik PH, Weisdorf DJ. Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission. Blood 112: , b. LK04-02/GV01-01 S Luger, O Ringdén, WS Peréz, M-J Zhang, JF DiPersio, J Sierra, M Tallman, DJ Weisdorf and M Pulsipher on behalf of the Acute Leukemia Writing Committee, CIBMTR, Milwaukee, WI, USA. Similar outcomes using myeloablative versus reduced intensity and nonmyeloablative allogeneic transplant preparative regimens for AML or MDS: From the Center for International Blood and Marrow Transplant Research. Presented at the American Society of Hematology in San Francisco, California, December

2 Not for publication or presentation c. LK04-03 A Keating, M. Kukreja, G Silva, V Gupta, C Cutler, M Tallman, J Sierra, JF DiPersio, M Horowitz, DJ Weisdorf on behalf of the Acute Leukemia Writing Committee, CIBMTR, Milwaukee, WI, USA. Similar 5-year survival after peripheral blood autotransplants versus HLA matched sibling myeloablative transplants for Acute Myeloid Leukemia in first complete remission. Presented at the American Society of Hematology in San Francisco, California, December d. LK07-03 B McClune, DJ Weisdorf, JF DiPersio, A Keating, T Pedersen, G Silva, J Sierra, M Tallman and S Giralt on behalf of the Acute Leukemia Writing Committee, CIBMTR, Minneapolis, WI, USA. Non-myeloablative hematopoietic stem cell transplantation in older patients with AML and MDS: Results from the Center for International Blood and Marrow Transplant Research. Presented at the American Society of Hematology in San Francisco, California, December Studies in progress (Attachment 3) a. LK02-02 Allogeneic transplants for tmds/aml (M Litzow) Manuscript Preparation b. LK03-03 Allogeneic transplants for refractory leukemia Manuscript Preparation (M Duval) (Attachment 4) c. LK04-01 Allogeneic and autologous transplants for APML in Data Collection CR2 (M Rubinger /M Tallman) d. LK04-02/GV01-01 Ablative vs. NST vs. RIC for AML/MDS Manuscript Preparation (S Luger/ M Pulsipher/ O Ringdén) (Attachment 5) e. LK04-03 PBSC autologous vs. HLA-id allogeneic for AML Manuscript Preparation (A Keating) (Attachment 6) f. R02-05 URD after failed autologous transplant (J Foran) Data File Preparation (Attachment 7) g. R02-09 DLI after relapse (A Loren) (Attachment 8) Protocol Development h. LK05-01 URD vs. HLA-id for poor risk AML in CR1 (V Gupta) Data File Preparation (Attachment 9) i. LK06-01 AlloHCT vs. chemo for AML-CR1 elderly (S Farag) Analysis j. LK07-01 Cytogenetic risk groups in AML/MDS (P Armand/ Data Collection R Soiffer) k. LK07-02 Scoring System as Predictor in AML after HCT Data File Preparation (J Sierra) (Attachment 10) l. LK07-03 Allo HCT in older patients with AML, MDS, NHL and Manuscript Preparation CML (B McClune) (Attachment 11) m. LK08-01 Landmark analysis for updated relapse/lfs estimates Data File Preparation for patients (S Lee) (Attachment 12) n. LK08-02 RIC in allohct for older patient with denovo MDS - Protocol Development decision analysis (J Koreth) (Attachment 13) o. LK08-03 Ablative vs. NST for Ph- ALL in adults (D Marks) Data File Preparation (Attachment 14) p. LK08-04 LTA alleles in AML relapse (P Posch) Protocol Development 2

3 Not for publication or presentation 5. Future/ Proposed studies a. PROP Relapsed good risk AML: Outcome of patients with core binding factor t(8,21) or inv(16) cytogenetic abnormalities treated with allogeneic or autologous transplantation after relapse (L Akard) (Attachment 15) b. PROP Role of CNS therapy for outcome of patients undergoing allogeneic hematopoietic progenitor cell transplant (N Esiashvili) (Attachment 16) c. PROP The impact of chromosome 7 abnormalities in allogeneic HSCT for AML/MDS and the role of growth factors on relapse (M Battiwalla) (Attachment 17) d. PROP Is there a graft-versus-leukemia effect in the central nervous system after hematopoietic stem cell transplant for acute myelogenous leukemia? (B Wirk) (Attachment 18) e. PROP Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation for acute myeloid leukemia (M Pasquini) (Attachment 19) f. PROP Impact of pre-transplant Azacytidine induction therapies on post-transplant outcomes in patients with myelodysplastic syndromes (C Cogle) (Attachment 20) g. PROP The outcome of adults with philadelphia positive acute lymphoblastic leukemia comparing reduced intensity conditioning and myeloablative conditioning allogeneic stem cell transplantation (V Bachanova) (Attachment 21) h. PROP Comparison of myeloablative vs. reduced intensity vs. non-myeloablative allogeneic transplantation in patients with AML or MDS eligible for either approach (M Pulsipher) (Attachment 22) i. PROP A comparison of autologous peripheral blood versus autologous bone marrow transplants (M Litzow) (Attachment 23) 6. Other business 3

4 Not for publication or presentation Attachment 1 MINUTES CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA San Diego, California Saturday, February 16, 2008, 12:15 pm - 2:15 pm Co-Chair: Armand Keating, MD, University of Toronto Phone: ; Fax: ; armand.keating@uhn.on.ca Co-Chair: Jorge Sierra, MD, Hospital de la Santa Creu i Sant Pau Phone: ; Fax: ; jsierra@hsp.santpau.es Co-Chair: Martin Tallman, MD, Northwestern University Phone: ; Fax: ; m-tallman@northwestern.edu Statisticians: Waleska S. Pérez, MPH, CIBMTR Statistical Center Phone: ; Fax: ; wperez@mcw.edu Mei-Jie Zhang, PhD, CIBMTR Statistical Center Phone: ; Fax: ; meijie@mcw.edu Scientific Dir: Daniel Weisdorf, MD, University of Minnesota Phone: ; Fax: ; weisd001@umn.edu 1. Introduction The CIBMTR Working Committee for Acute Leukemia was called to order at 12:20 pm on Saturday February 16, 2008 by Dr. Armand Keating. The chairs, scientific director and statisticians were presented. The newly appointed chair, Dr. John F. DiPersio, was introduced and a special acknowledge was given to Dr. Keating for his contributions to the Working Committee. Attendees were asked to sign the attendance sheet in order to maintain the committee membership and to fill out the Working Committee evaluations. Young investigators were encouraged to participate and propose new studies to the Working Committee. As the Committee had a full agenda, it was suggested to limit each presentation to 3 minutes so that there would be adequate time for discussion for the new proposals. Dr. Keating explained the voting process for the studies in progress and proposals. The minutes of the previous meeting from February 2007 were approved without modifications. 2. Accrual summary Due to the full agenda, the accrual summary of registration and research cases between 1995 and 2007 were not presented to the committee but was available as part of the Working Committee attachments. 3. Presentations, published or submitted papers Dr. Keating presented the published, submitted papers and presentations of the Working Committee. One paper was published, two are in press, one submitted and two ASH presentations were given during the past year. These include: 4

5 Not for publication or presentation Attachment 1 a. D00-52 Tallman MS, Dewald GW, Gandham S, Logan BR, Keating A, Lazarus HM, Litzow MR, Mehta J, Pedersen T, Pérez WS, Rowe JM, Wetzler M, Weisdorf, DJ. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Blood 110: , b. R02-28 Bishop MR, Logan BR, Gandham S, Bolwell BJ, Cahn J-Y, Lazarus HM, Litzow MR, Marks DI, Wiernik PH, McCarthy PL, Russell JA, Miller C, Sierra J, Milone G, Keating A, Loberiza, FR, Jr, Giralt SA, Horowitz MM, Weisdorf DJ. Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research. Bone Marrow Transplant, c. LK03-02 Schlenk RF, Pasquini MC, Pérez WS, Zhang M-J, Krauter J, Antin JH, Bashey A, Bolwell BJ, Büchner T, Cahn J-Y, Cairo MS, Copelan EA, Cutler CS, Döhner H, Gale RP, Ilhan O, Lazarus HM, Liesveld JL, Litzow MR, Marks DI, Maziarz RT, McCarthy PL, Nimer SD, Sierra J, TallmanMS, Weisdorf DJ, Horowitz MM, Arnold Ganser A. HLA-identical sibling allogeneic transplants versus chemotherapy in acute myelogenous leukemia with t(8;21) in first complete remission: collaborative study between the German AML Intergroup and CIBMTR. Biol Blood Marrow Transplant, d. R03-50 Marks DI, Pérez WS, He W, Zhang M-J, Bishop MR, Bolwell BJ, Bredeson CN, Copelan EA, Gale RP, Gupta V, Hale GA, Isola LM, Keating A, Klumpp TR, Lazarus HM, Liesveld JL, Maziarz RT, McCarthy PL, Sabloff M, Schiller G, Sierra J, Tallman MS, Waller EK, Wiernik PH, Weisdorf DJ. Unrelated Donor Stem Cell Transplantation for Adults with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia in First Complete Remission: A Center of the International Blood and Marrow Transplant Research Analysis. Submitted to Blood. e. LK02-02 Litzow M, Pérez WS, Tarima S, Keating A, Sierra J, Tallman M and Weisdorf D on behalf of the Writing Committee, CIBMTR, Milwaukee, WI, USA. Allogeneic Stem Cell Transplantation (AlloSCT) for the Treatment of Therapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia: Results from the Center for International Blood and Marrow Transplant Research (CIBMTR). Presented at the American Society of Hematology in Atlanta, Georgia, December f. R03-50 Marks DI, Pérez WS, He V, Zhang M-J, Keating A, Tallman M, Sierra J and Weisdorf D on behalf of the Writing Committee, CIBMTR, Milwaukee, WI, USA. Unrelated Donor Hematopoietic Stem Cell Transplantation for Adults with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia in First Complete Remission: A Center for International Blood and Marrow Transplant Research Analysis. Presented at the American Society of Hematology in Atlanta, Georgia, December

6 Not for publication or presentation Attachment 1 4. Studies in progress Dr. Tallman led this section. The studies in progress were the followings: a. LK01-02: Transplant vs. chemotherapy for relapsed AML (M delima): This analysis compares allografts vs. secondary/salvage chemotherapy using CIBMTR data compared with treatments at MD Anderson. The study was discontinued as differences in the data file structure could not be resolved to yield a satisfactory analysis. b. LK02-02: Allotransplant for treatment related MDS/AML (M Litzow): This project analyzes outcomes and factors associated with prognosis following grafting for secondary AML. The analysis was presented at ASH 2007 and at the CIBMTR/ASBMT Tandem 2008 meeting. It is expected to have a 1 st draft manuscript by June c. LK03-03: Allogeneic transplants for refractory leukemia (M Duval): This project evaluates the results of patients undergoing allogeneic HSCT for refractory acute leukemia or leukemia in relapse at the time of transplantation. The data file preparation is underway. Dr. Duval emphasized that the study should be finalized this year since the EBMT have a similar study in manuscript stage looking at HLA-identical sibling in primary induction failure at the time of transplant. It was suggested to look at the number of EBMT patients to decide whether to do a joint study with the EBMT. Submission of an abstract of this study is planned for the ASH 2008 meetings. d. LK04-01: Allo vs. autotransplants for APL in CR2 (M Rubinger/M Tallman): This project analyzes outcome of APL in second CR including details of molecular remission prior to transplant. Secondary data collection is required. The draft protocol and the final data collection supplemental form are available for review. Because of the merge of the two different databases (IBMTR and NMDP) and the initiation of the SCTOD, we haven t been able to send out to the centers the request of the supplemental data. It is expected to send this request in the next two months. e. LK04-02/GV01-01: Ablative vs. NST for AML/MDS (S Luger/ M Pulsipher/ O Ringdén): This revised protocol incorporates elements of three previous projects comparing the outcomes using non-myeloablative or reduced intensity vs. myeloablative transplants in patients 18 years of age undergoing HSCT for AML or MDS. The revised protocol is available for review. The data file preparation is underway (4421 myeloablative and 1514 non-myeloablative). Submission of an abstract of this study is planned for the ASH 2008 meetings. f. LK04-03: PBSC autologous vs. matched sibling allografts for AML (A Keating): This comparative analysis will assess the utility of allogeneic and PB autografts in AML CR1. The revised protocol is available for review. The data file preparation is underway (528 allo BM; 572 allo PB; 42 auto BM and 231 auto PB). Submission of an abstract of this study is planned for the ASH 2008 meetings. g. R02-05: URD HCT after failed autograft (J Foran): This study proposes to examine ALL and AML patients receiving URD HCT after relapse from a previous autograft and to identify patients likely to have the best outcome. The draft protocol is available for review and it now includes all types of transplants (traditional and NST/RIC) as suggested by the members of the 2007 Working Committee meeting. 6

7 Not for publication or presentation Attachment 1 h. R02-09: DLI after relapse for acute leukemia (A Loren): The value of related and unrelated donor DLI in treatment of acute leukemia relapsed after allografting will be examined, including the impact of disease status, timing, dose response, and comparative efficacy of the two donor sources. The draft protocol is available for review and it was suggested to extend the study criteria to include patients transplanted up to i. LK05-01: Unrelated vs. matched sibling transplants for high risk AML in CR1 (V Gupta): A descriptive outcome of high risk karyotype type CR1 AML patients receiving related mismatched or unrelated donor transplants is proposed. 180 unrelated, 191 matched siblings, and 30 other related patients are available for analysis. The draft protocol is available for review. The date of achieving CR will be the starting point for both the groups to adjust for two sources of bias: differences in time to transplant and differences in the baseline patient characteristics. j. LK06-01: AlloHCT vs chemo for AML-CR1 elderly (S Farag): This study proposes to compare the outcomes of TRM, relapse, LFS and overall survival among patients who underwent allogeneic HSCT in first CR vs. conventional chemotherapy in AML patients 60 years of age. A draft protocol is available for review. The study has been delayed due to the difficulty of identifying the CALGB patients who later had a transplant. It is expected to receive the CALGB data set by the end of March. k. LK07-01: Cytogenetic risk groups in AML/MDS (P Armand/ R Soiffer): This study proposes to confirm the prognostic importance of cytogenetics and establish a transplantation-specific cytogenetic risk grouping scheme for patients with AML, MDS, or AML arising from MDS undergoing allogeneic transplantation. The revised protocol is available for review and cytogenetic report collection from the centers is underway. The principal investigator will review the cytogenetic reports. l. LK07-02: Scoring System as predictor in AML after HCT (J Sierra): This study proposes to identify the factors that will impact leukemia-free survival after allogeneic HCT following myeloablative conditioning as treatment for primary AML. Based on the factors identified, a scoring system predicting the outcome will be generated. A draft protocol is available for review. m. LK07-03: Allo HCT in older patients with AML, MDS, NHL and CML (B McClune): This study proposes to compare the clinical outcomes of older adults with MDS, de novo AML, AML evolving from preceding MDS, CML and lymphoma after allogeneic hematopoietic cell transplantation (HCT) to younger adults. A protocol is available for review and comments. Based on the univariate outcomes of overall survival, age does not impact overall survival across all diseases. A final analysis is expected by June Future/ Proposed studies Dr. Sierra led this section. The proposals are the followings: a. PROP The outcome of reduced intensity matched sibling and unrelated donor stem cell transplantation for acute lymphoblastic leukaemia in CR1 and CR2 in adults (D Marks) Dr. Marks presented this proposal. The purpose of this proposal is (1) to determine the outcome of reduced intensity allogeneic SCT for adults with ALL in CR1 and CR2 using matched sibling and unrelated donors; (2) to examine the prognostic factors that determines that outcome; and (3) to evaluate the optimum conditioning regimen and the role of in vivo T cell depletion. The committee discussed the issue of comparing 7

8 Not for publication or presentation Attachment 1 this population (non-myeloablative, n=180) to traditional transplants (n=2210). b. PROP Outcomes of second transplant in patients relapsed after allogeneic stem cell transplantation for AML (B Savani) Dr. Savani presented this proposal. The purpose of this proposal is to compare the outcomes of patients with relapsed acute myeloid leukemia (AML) after myeloablative vs. reduced intensity allo-sct (related and unrelated donor grafts). The primary outcomes to be studied include response rates, GVHD, treatment-related mortality, disease-free survival and overall survival. The secondary outcome is to analyze factors associated with outcomes. Dr. Savani mentioned that a previous CIBMTR study (Eapen M, Giralt SA, Horowitz MM, Klein JP, Wagner JE, Zhang MJ, et al. Second transplant for acute and chronic leukemia relapsing after first HLAidentical sibling transplant. Bone Marrow Transplant 2004 Oct; 34(8):721-7) reported these outcomes but he emphasized the importance of looking at AML separately. c. PROP Evaluation of lymphotoxin alpha (LTA) alleles in relation to relapse in AML (PE Posch) Steve Spellman, Assistant Scientific Director of the Immunobiology Working Committee, presented this proposal in Dr. Posch s absence. This is a joint proposal with the Immunobiology Working Committee and the purpose is (1) to determine whether LTA alleles correlate with relapse in AML and CML; and (2) to determine if the correlation is associated with high or low LTA production. The Immunobiology Working Committee approved the proposal. d. PROP Using Landmark analysis to provide updated relapse and leukemiafree survival estimates to patients (S Lee) Dr. Weisdorf presented this proposal in Dr. Lee s absence. The purpose of this proposal is (1) to provide clinically understandable estimates of the likelihood of future events to patients surviving disease-free after allogeneic transplantation, that are based on the duration of leukemia-free survival already experienced, specifically, to provide estimates of the risks for relapse within the next year, leukemia-free survival for the next 3 and 5 years. Additional factors that impact long-term survival, such as patient age, cytogenetics and whether or not chronic GVHD has developed, will be incorporated into the estimates if possible. Dr. Zhang explained to the Committee the basis for using a multi-state model analysis. e. PROP A decision analysis of reduced intensity conditioning allogeneic stem cell transplantation for older patients with de-novo myelodysplastic syndrome (J Koreth) Dr. Koreth presented this proposal. The purpose of this proposal is to use decision analysis and the best available databases to determine the optimal role and timing of RIC allosct for de-novo MDS patients 60 years. f. PROP # The impact of post-induction chemotherapy on the outcomes of adult patients with acute lymphoblastic leukemia who receive allogeneic stem cell transplants in first complete remission (T Kovacsovics) Dr. Kovacsovics presented this proposal. The purpose of this proposal is (1) to determine the benefit of consolidation chemotherapy, prior to related allogeneic stem cell transplantation, in adult patients with acute lymphoblastic leukemia (ALL) who are transplanted in complete remission (CR1); (2) to determine the benefit of consolidation chemotherapy, prior to unrelated allogeneic stem cell transplantation, in 8

9 Not for publication or presentation Attachment 1 adult patients with ALL who are transplanted in CR1; and (3) to determine the pretransplant (disease related) and transplant related prognostic factors that effect the probability of long-term survival. If approved, a supplemental form will be needed to capture the different types of consolidation, number of consolidation cycles and time points given since this is not captured in the current CIBMTR research forms. 6. Other business After the studies in progress and the new proposals were presented, each participant in the meeting had the opportunity to rate each study in progress and each proposal using paper ballots. Based on the voting results, the goals for next fiscal year is as follows: Study # and PI Status at tandem 02/08 Anticipated status by 06/08 Studies in progress: LK02-02 (Litzow) Ms prep Ms prep Submit Data file prep Data file prep Submit LK04-02/GV01-01 (Luger/Pulsipher/Ringden ) Anticipated status by 06/09 LK03-03 (Duvall) Data file prep Data file prep Submit LK04-01 (Rubinger) Prot devel/form Prot devel/form Data file prep LK04-03 (Keating) Data file prep Analysis Submit LK06-01 (Farag) Prot devel Data file prep Submit R02-05 (Foran) Prot devel Data file prep Analysis R02-09 (Loren) Prot devel Prot devel Analysis LK05-01 (Gupta) Prot devel Data file prep Ms prep LK07-01 (Armand) Data collect Data collect Ms prep LK07-02 (Sierra) Prot devel Prot devel Analysis LK07-03 (McClune) Data file prep Submit Status at tandem 02/08 Anticipated status by 06/08 Anticipated status by 06/09 Study # and PI Proposals: (Marks) Prot devel Data file prep (Savani) Drop (Posch) Prot devel Data file prep (Lee) Prot devel Data file prep (Koreth) Prot devel Data file prep (Kovacsovics) Drop An additional expression of gratitude was given to Dr. Keating for his contributions to the Working Committee in the past 20 years. Without additional comments, the meeting was adjourned at 2:10 pm. 9

10 Not for publication or presentation Attachment 2 Accrual Summary for Acute Leukemia Working Committee Characteristics of recipients of allogeneic transplants for AML reported to the CIBMTR between 1995 and 2008 Variable Registration N (%) a Median (range) b Research N (%) a Median (range) b Number of patients Number of centers Age at transplant, years 39 (<1-93) 39 (<1-83) Age in decades, years < ( 9) 1159 (10) (11) 1409 (12) (14) 1606 (14) (18) 1885 (16) (22) 2399 (21) (18) 2196 (19) ( 8) 1040 ( 9) Sex Male (53) 6200 (53) Female 3248 (47) 5490 (47) Missing 69 (<1) 4 (<1) Stage of disease 1 st complete remission (45) 5021 (43) 2 nd complete remission 5726 (20) 2692 (23) Not in remission 7573 (27) 3551 (30) Unknown/Other 2260 ( 8) 430 ( 4) Donor type HLA-identical sibling (54) 4439 (38) Identical twin 192 ( 1) 61 ( 1) Other related 1945 ( 7) 638 ( 5) Unrelated (36) 6492 (56) Missing/other 623 ( 2) 64 ( 1) Year of transplant (11) 1640 (14) (13) 1438 (12) (14) 1403 (12) (16) 1785 (15) (18) 2097 (18) (20) 2471 (21) c 2397 ( 8) 860 ( 7) Follow-up of surviving patients, months 34 (<1-154) 40 (<1-154) a b c For categorical variables For continuous variables Cases continue to be reported in this interval 10

11 Not for publication or presentation Attachment 2 Accrual Summary for Acute Leukemia Working Committee Characteristics of recipients of allogeneic transplants for ALL reported to the CIBMTR between 1995 and 2008 Registration N (%) a Median (range) b Research N (%) a Median (range) b Variable Number of patients Number of centers Age at transplant, years 20 (<1-88) 19 (<1-88) Age in decades, years < (24) 1931 (26) (25) 1964 (26) (19) 1335 (18) (14) 961 (13) (11) 752 (10) ( 6) 419 ( 6) ( 1) 84 ( 1) Sex Male (62) 4582 (62) Female 6578 (38) 2862 (38) Missing 37 (<1) 3 (<1) Stage of disease 1 st complete remission 6577 (38) 2536 (35) 2 nd complete remission 6917 (40) 3236 (45) Not in remission 3013 (17) 1354 (19) Unknown/Other 730 ( 4) 122 ( 1) Donor type HLA-identical sibling 8007 (46) 2394 (32) Identical twin 104 ( 1) 41 ( 1) Other related 1314 ( 8) 431 ( 6) Unrelated 7444 (43) 4530 (61) Missing/other 368 ( 2) 51 ( 1) Year of transplant (14) 1311 (18) (14) 1119 (15) (16) 1058 (15) (17) 1111 (15) (16) 1142 (15) (17) 1272 (17) c 1198 ( 7) 434 ( 6) Follow-up of surviving patients, months 36 (<1-150) 45 (<1-150) a For categorical variables b For continuous variables c Cases continue to be reported in this interval 11

12 Not for publication or presentation Attachment 2 Accrual Summary for Acute Leukemia Working Committee Characteristics of recipients of autotransplants for AML reported to the CIBMTR between 1995 and 2008 Registration N (%) a Median (range) b Research N (%) a Median (range) b Variable Number of patients Number of centers Age at transplant, years 46 (<1-79) 42 (<1-74) Age in decades, years < ( 5) 80 ( 8) ( 6) 77 ( 8) (11) 130 (13) (16) 159 (16) (22) 189 (20) (26) 192 (20) (14) 140 (14) Sex Male 2601 (51) 494 (51) Female 2457 (48) 473 (49) Missing 17 (<1) 0 Stages of disease 1 st complete remission 3047 (60) 566 (59) 2 nd complete remission 988 (19) 219 (23) Not in remission 388 ( 8) 84 ( 9) Unknown/Other 652 (13) 98 (10) Graft type Bone marrow 697 (14) 177 (18) Peripheral blood 3728 (73) 646 (67) Bone marrow + peripheral blood 245 ( 5) 81 ( 8) Other/Missing 405 ( 8) 63 ( 7) Year of transplant (15) 307 (32) (17) 256 (26) (18) 128 (13) (17) 107 (11) (16) 72 ( 7) (13) 83 ( 9) c 208 ( 4) 14 ( 1) Follow-up of surviving patients, months 36 (<1-157) 61 (1-157) a For categorical variables b For continuous variables c Cases continue to be reported in this interval 12

13 Not for publication or presentation Attachment 2 Accrual Summary for Acute Leukemia Working Committee Characteristics of recipients of autotransplants for ALL reported to the CIBMTR between 1995 and 2008 Registration N (%) a Median (range) b Research N (%) a Median (range) b Variable Number of patients Number of centers Age at transplant, years 29 (<1-73) 26 (1-66) Age in decades, years <10 85 (10) 27 (15) (18) 40 (22) (24) 44 (23) (17) 17 ( 9) (15) 34 (18) (12) 22 (10) ( 4) 6 ( 3) Sex Male 509 (60) 121 (64) Female 344 (40) 69 (36) Stage of disease 1 st complete remission 375 (44) 104 (55) 2 nd complete remission 249 (29) 48 (25) Not in remission 79 ( 9) 18 ( 9) Unknown/Other 150 (16) 20 (11) Graft type Bone marrow 136 (16) 30 (16) Peripheral blood 516 (61) 125 (66) Bone marrow + peripheral blood 51 ( 6) 17 ( 9) Other 150 (17) 18 ( 9) Year of transplant (25) 76 (39) (20) 61 (32) (18) 20 (11) (16) 16 ( 8) (11) 5 ( 3) ( 8) 10 ( 5) c 18 ( 2) 3 ( 2) Follow-up of surviving patients, months a For categorical variables 38 (<1-149) 77 (1-149) b For continuous variables c Cases continue to be reported in this interval 13

14 Not for publication or presentation Attachment 3 TO: FROM: RE: Acute Leukemia Working Committee Members Daniel Weisdorf, MD, Scientific Director for the Acute Leukemia WC Studies in Progress Summary LK02-02: Allotransplant for treatment related MDS/AML (M Litzow): This project analyzes outcomes and factors associated with prognosis following grafting for secondary AML. A final version of the manuscript is underway and it is expected to be submitted by the end of February LK03-03: Allogeneic transplants for refractory leukemia (M Duval): This project evaluates the results of patients undergoing allogeneic HSCT for refractory acute leukemia or leukemia in relapse at the time of transplantation. The draft manuscript is underway and it is expected to be submitted after Tandem. LK04-01: Allo vs. autotransplants for APL in CR2 (M Rubinger/M Tallman): This project analyzes outcome of APL in second CR including details of molecular remission prior to transplant. Secondary data collection is required and is underway. The PIs and Acute Leukemia Chairs will communicate with the centers directors to encourage supplemental data submission. LK04-02/GV01-01: Ablative vs. NST for AML/MDS (S Luger/ M Pulsipher/ O Ringdén): This project incorporates elements of three previous projects comparing the outcomes using nonmyeloablative vs. reduced intensity vs. myeloablative transplants in patients 18 years of age undergoing HSCT for AML or MDS. The analysis was presented at the 2008 American Society of Hematology meeting in San Francisco, California. A draft manuscript is underway and it is expected to be submitted after Tandem. LK04-03: PBSC autologous vs. matched sibling allografts for AML (A Keating): This comparative analysis will assess the utility of allo and PB autografts in AML CR1. The analysis was presented at the 2008 American Society of Hematology meeting in San Francisco, California. A draft manuscript is underway and it is expected to be submitted after Tandem. R02-05: URD HCT after failed autograft (J Foran): This study proposes to examine ALL and AML patients receiving URD HCT after relapse from a previous autograft and to identify patients likely to have the best outcome. The revised protocol is available for review and it is expected to have a final dataset ready for analysis by June

15 Not for publication or presentation Attachment 3 R02-09: DLI after relapse for acute leukemia (A Loren): The value of related and unrelated donor DLI in treatment of acute leukemia relapsed after allografting will be examined, including the impact of disease status, timing, dose response, and comparative efficacy of the two donor sources. The draft protocol is available for review and it is expected to have a final dataset ready for analysis by June LK05-01: Unrelated vs. matched sibling transplants for high risk AML in CR1 (V Gupta): This study proposes to evaluate the outcomes of allogeneic stem cell transplantation for acute myeloid leukemia with adverse-risk karyotype in first complete remission using matched sibling or unrelated donors. The protocol is available for review and the data file preparation is underway. LK06-01: AlloHCT vs chemo for AML-CR1 elderly (S Farag): This study proposes to compare the outcomes of TRM, relapse, LFS and overall survival among patients who underwent allogeneic HSCT in first CR vs. conventional chemotherapy in AML patients 60 years of age. The analysis is underway and the manuscript is expected to be submitted by June LK07-01: Cytogenetic risk groups in AML/MDS (P Armand/ R Soiffer): This study proposes to confirm the prognostic importance of cytogenetics and establish a transplantation-specific cytogenetic risk grouping scheme for patients with AML, MDS, or AML arising from MDS undergoing allogeneic transplantation. The cytogenetic report collection from the centers is underway and the principal investigator will review these reports. LK07-02: Scoring System as predictor in AML after HCT (J Sierra): This study proposes to identify the factors that will impact leukemia-free survival after allogeneic HCT following myeloablative conditioning as treatment for primary AML. Based on the factors identified, a scoring system predicting the outcome will be generated. The protocol is available for review. LK07-03: Allo HCT in older patients with AML, MDS, NHL and CML (B McClune): This study proposes to compare the clinical outcomes of older adults with MDS, de novo AML, AML evolving from preceding MDS, CML and lymphoma after allogeneic hematopoietic cell transplantation (HCT) to younger adults. A protocol is available for review and comments. The analysis for the AML and MDS population was presented at the 2008 American Society of Hematology meeting in San Francisco, California. A draft manuscript of the AML and MDS population is underway and it is expected to be submitted after Tandem. The data file preparation for the Lymphoma and CML population is underway. LK08-01: Landmark analysis for updated relapse/lfs estimates for pts (S Lee) This study proposes to provide clinically understandable estimates of the likelihood of future events to patients surviving disease-free after allogeneic transplantation, that are based on the duration of leukemia-free survival already experienced, specifically, to provide estimates of the risks for relapse within the next year, leukemia-free survival for the next 3 and 5 years. Additional factors that impact long-term survival, such as patient age, cytogenetics and whether or not chronic GVHD has developed, will be incorporated into the estimates. The protocol is available for review. 15

16 Not for publication or presentation Attachment 3 LK08-02: RIC in allohct for older patient with denovo MDS - decision analysis (J Koreth) This study purpose of this proposal is to use decision analysis and the best available databases to determine the optimal role and timing of RIC allosct for de-novo MDS patients 60 years. A draft protocol is available for review. LK08-03: Ablative vs. NST for Ph- ALL in adults (D Marks) This study proposes to determine the outcome of reduced intensity allogeneic SCT for adults with Ph-neg ALL in CR1 and CR2 using matched sibling and unrelated donors and to compare this with the outcome in patients who received myeloablative regimens. The protocol is available for review. LK08-04: LTA alleles in AML relapse (P Posch) This is a joint study with the Immunobiology Working Committee and it proposes to determine whether LTA alleles correlate with relapse in AML and CML and to determine if the correlation is associated with high or low LTA production. A protocol will be available by June

17 Not for publication or presentation Attachment 4 TO: FROM: Writing Committee for study LK03-03: A Bashey, BJ Bolwell, CN Bredeson, J-Y Cahn, MS Cairo, BM Camitta, RE Champlin, E Copelan, M delima, JF DiPersio, I Fernandez, J Finke, RP Gale, V Gupta, R Kamble, A Keating, J Kurtzberg, H Lazarus, J Liesveld, M Litzow, AW Loren, D Maharaj, DI Marks, RT Maziarz, PL McCarthy, WH Navarro, DA Rizzieri, G Schiller, KR Schultz, J Sierra, MS Tallman, PH Wiernik, AR Zander Michel Duval, MD, Vincent He, MS, and Daniel Weisdorf, MD DATE: December 2, 2008 RE: Final analyses for CIBMTR study #LK03-03: Outcome of HSCT in patients with active leukemia at the time of transplant Enclosed is a description of the patient population and results of univariate and multivariate analyses of GVHD, treatment-related mortality, relapse, leukemia-free survival, overall survival for patients undergoing allogeneic transplants for refractory acute leukemia or leukemia in relapse between 1995 and 2004, reported to the CIBMTR. Only patients received TBI or Busulfan- based conditioning regimens were included in the analyses. Patients with Identical-twin transplants and cord blood transplants were excluded from the analyses AML and 582 ALL patients met the on-study criteria. The AML cases identified came from 221 reporting centers from 34 different countries. The ALL cases identified came from 180 reporting centers from 33 different countries. Median follow-up of survivors was 61 (2 137) months for AML patients, and 61 (3-132) months for ALL patients. Table 1 shows the patient, disease, and transplant characteristics of the patients included in the study. Table 2 shows univariate analyses of the outcomes of interests. Probability of leukemia-free survival and overall survival was calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood s formula. Values for other endpoints were calculated using cumulative incidence curves to accommodate competing risks. The multivariate analyses were performed separately for AML and ALL. The outcomes studied were acute and chronic GVHD, treatment-related mortality, leukemia-free survival, overall survival. Assessments of potential risk factors for outcomes of interest at predetermined time points were evaluated in multivariate analysis using the pseudo-value technique. Risk factors for acute GVHD were assessed at 100 days post transplant. Risk factors for chronic GVHD were assessed at 2 years post transplant. For treatment-related mortality, leukemia-free survival, overall 17

18 Not for publication or presentation Attachment 4 survival, the risk factors were assessed at two fixed time points (6 months and 3 years post transplant). Table 3 shows the variables that were tested in the multivariate model building. Variables not listed in the final models did not meet the 5% level of significance. Tables 4-8 show results of the multivariate analyses for disease AML. Tables 9-13 show results of the multivariate analyses for disease ALL. Table 14 shows causes of death. Please review this summary critically and send your comments to: Michel Duval, MD, Service d'hématologie-oncologie, Hôpital Sainte-Justine, 3175, chemin de la Côte-Sainte-Catherine, Montréal, QC, Canada, H3T 1C5; Telephone: (514) ; Fax (514) ; michel.duval@umontreal.ca with a copy via Fax or to Vincent He, MS at the CIBMTR Statistical Center [Fax: , vhe@mcw.edu] by December 16, You should note that any member of a Writing Committee who does not make a substantive contribution to the design, analysis, interpretation or manuscript would be expected to withdraw as a co-author or, alternatively, the lead author could remove names of non-contributors. If we do not hear from you by December 16, 2008 we may assume you no longer wish to participate in the study. The rules of the CIBMTR require inclusion of the following statement: "The enclosed raw data are confidential. If used publicly, the following statement must be included: The data presented here were obtained from the Center for International Blood and Marrow Transplant Research. The analysis has not been reviewed or approved by the Advisory Committee of the CIBMTR. The data may not be published without prior approval of the Advisory Committee." If the data are used in an oral presentation, please send us the name, place and dates of the meeting where the data are presented, and the title of your presentation. enclosures 18

19 Not for publication or presentation Attachment 4 Table 1. Characteristics of patients who underwent myeloablative allogeneic transplantation for AML or ALL in relapse or primary induction failure from 1995 to 2004, reported to the CIBMTR. AML ALL Characteristics of patients N(%) N(%) Number of patients Number of centers Age 38 (<1-70) 29 (<1-60) Median (range), years < ( 8) 55 ( 9) (10) 102 (18) (15) 146 (25) (22) 127 (22) (27) 105 (18) (17) 46 ( 8) ( 2) 1 (<1) Male sex 880 (53) 371 (64) Karnofsky score prior to HCT < 90% 759 (48) 262 (47) Missing WBC at diagnosis, x10 9 /L median, range 11 (<1 1803) 21 (<1 990) < 50 x10 9 /L 1079 (75) 329 (68) > 50 x10 9 /L 364 (25) 155 (32) Missing Extramedullary disease 233 (14) 192 (33) CNS disease prior to transplant Yes 80 ( 9) 104 (26) No 782 (91) 290 (74) Missing Therapy-related leukemia 109 ( 7) NA Missing 4 Prior myelodysplasia 343 (21) NA Blasts in BM prior to HCT median (range) 21 (0-100) 17 (0-100) < (53) 277 (57) > (47) 211 (43) Missing Blasts in blood prior to HCT, Median (range) 4.2 ( ) 0 ( ) (43) 320 (62) > (57) 198 (38) Missing

20 Not for publication or presentation Attachment 4 Table 1. Continued. AML ALL Characteristics of patients (N%) (N%) Cytogenetics prior to HCT (AML) Good 117 ( 7) NA Intermediate/no abnormalities 988 (59) Poor 273 (16) Unknown 295 (18) Cytogenetics prior to HCT (ALL) High risk (t(4,11), t(9,22), hypodiploidy/near triploloidy, >5 abnormalities) NA 151 (26) Others 138 (24) No abnormalities 145 (25) Unknown 148 (25) Disease status prior to HCT PIF 636 (38) 144 (25) 1 st relapse, untreated 322 (19) 67 (12) 1 st refractory relapse 428 (26) 251 (43) 1 st relapse, unknown treatment 9 ( 1) 9 ( 2) 2nd relapse 278 (17) 111 (19) Time from relapse to HCT (for patients transplanted in 1 st refractory relapse only), months Median (range) 2.5 (<1-23) 3.0 (<1-16) < (60) 127 (51) (40) 124 (49) Duration of 1 st CR ( for patients in relapse), months 5 (<1 113) 8 (<1-97) Median (range) < (55) 140 (39) (45) 217 (61) Missing Fungal infection anytime prior to HCT 250 (15) 70 (12) Missing Conditioning regimen CyTBI + others 456 (27) 241 (41) CyTBI alone 489 (29) 167 (29) BuCy + others 285 (17) 59 (10) BuCy alone 320 (19) 40 ( 7) Bu or TBI ± others 123 ( 7) 75 (13) Donor-recipient sex match M M 549 (33) 227 (39) M F 440 (26) 117 (20) F M 331 (20) 144 (25) F F 353 (21) 94 (16) 20

21 Not for publication or presentation Attachment 4 Table 1. Continued. AML ALL Characteristics of patients (N%) (N%) Donor-recipient CMV status -/- 447 (28) 151 (27) +/- 223 (14) 76 (13) -/+ 426 (26) 145 (26) +/+ 519 (32) 192 (34) Missing Donor-recipient HLA match HLA-identical sibling 552 (33) 224 (38) Other related 117 ( 7) 49 ( 8) Well-matched unrelated 354 (21) 116 (20) Partially-matched unrelated 419 (25) 126 (22) Mismatched unrelated 231 (14) 67 (12) Graft type BM 1095 (65) 376 (65) BM ± PBSC 578 (35) 206 (35) Year of transplant (26) 163 (28) (23) 122 (21) (17) 105 (18) (17) 106 (18) (17) 86 (15) GVHD prophylaxis T-cell depletion 213 (13) 51 ( 9) (FK506 or CsA)+ MTX ± other 1198 (72) 436 (75) (FK506 or CsA) ± other 224 (13) 80 (14) Other 38 ( 2) 15 ( 3) Median (range) follow-up of survivors, months 61 (2 137) 61 (3-132) Abbreviations: TBI = total body irradiation; CNS = central nervous system; CY = cyclophosphamide; CsA = cyclosporine; MTX = methotrexate; CR = complete remission; WBC = white blood cell; CMV = cytomegalovirus; GVHD = graft-versus-host disease; FK506 = tacrolimus; BM=bone marrow First refractory relapse is defined as transplantation in first relapse with chemotherapy between relapse and conditioning for relapse patients Completeness index FU = 91%; Data has been cap-modeled 21

22 Not for publication or presentation Attachment 4 Table 2. Univariate probabilities of outcomes AML ALL Outcome event N eval. Prob (95% CI) a N eval. Prob (95% CI) a ANC > 0.5 x 10 9 /L days 90 (87-92) 89 (83-93) Platelets > 20 x 10 9 /L 1627 days 66 (63-69) 66 (61-71) Acute GvHD, Grades days 48 (45-51) 52 (47-56) Chronic GvHD year 25 (23-28) 26 3 years 27 (25-29) 27 5 years 27 (25-30) 27 (23 32) Relapse months 37 (34-40) 33 1 year 45 (42-47) 40 3 years 48 (45-51) 46 5 years 49 (46-52) 47 (42-52) TRM 1673 months 29 (26-31) 32 1 year 32 (29-34) 36 3 years 34 (32-37) 38 5 years 35 (33-38) 39 (34-43) Disease-free survival 1673 months 34 (32-37) 35 1 year 23 (22-26) 24 3 years 18 (16-20) 16 5 years 16 (14-18) 14 (11-17) Overall survival 1673 months 45 (42-47) 45 1 year 30 (28-32) 32 3 years 20 (18-22) 20 5 years 18 (16-20) 17 (13-20) a Probabilities of ANC>0.5 x 10 9 /L, Platelets > 20 x 10 9 /L, acute GvHD, chronic GvHD, TRM, relapse were calculated using the cumulative incidence estimate. Probabilities of disease free survival and overall survival were calculated using the Kaplan-Meier product limit estimate. 22

23 Not for publication or presentation Attachment 4 Table 3. Variables tested in Cox proportional hazards regression models. Patient-related variables: Age at transplant: by decades Gender: female* vs. male Karnofsky performance score: <90%* vs. 90% vs. missing Disease-related variables Blasts in BM prior to transplant: <25 vs 25 vs.missing Time from relapse to transplant (for patients in first refractory only): <3 months* vs. 3 months Duration of 1st CR (for patients in relapse only): 6 months* vs. 6 months Extramedullary disease: no* vs. yes CNS disease prior to tx: no* vs. yes vs. missing Prior Myelodysplasia (AML): no* vs. yes Cytogenetics: ALL: no abnormalities* vs. high risks vs. others vs. Unknown AML: good vs. intermediate vs. poor vs. unknown Disease status prior to transplant: PIF* vs 1 st relapse, untreated vs. other relapse Fungal infection prior to transplant: no* vs. yes Treatment-related: Conditioning regimen: Cy+TBI± other* vs. Cy +TBI vs. BuCy + other vs. BuCy alone vs. other Donor-recipient sex match: M-M* vs. M-F vs. F-M vs. F-F Donor-recipient CMV status: -/-* vs. +/- vs.-/+ vs. +/+ Donor-recipient HLA match: HLA-identical sibling* vs. other related vs. well matched URD vs. partially matched URD vs. mismatched URD Graft type: BM* vs. PBSC Year of transplant: vs GVHD prophylaxis: T-cell depletion* vs. (CsA- or FK506) ± other vs. (CsA- or FK506 + MTX) ± other vs. others * Reference group 23

24 Not for publication or presentation Attachment 4 Table 4. Multivariate analysis of acute GVHD at 100 days post transplant for AML Variables: N Relative Risk (95% CI) P-value GVHD prophylaxis P overall = T-cell depletion a (CSA or FK506) + MTX ± other ( ) (CSA or FK506) ± other ( ) Others ( ) Donor-recipient HLA match P overall < HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) < Partially-matched unrelated ( ) < Mismatched unrelated ( ) < Cytogenetics prior to transplant P overall = Good a Intermediate ( ) Poor ( ) Unknown ( ) a Reference group; Significant pair wise comparison at α =.05: Cytogenetics: Intermediate vs. Unknown, p=0.0041; Poor vs. Unknown, p=0.0059; GVHD prophylaxis: (CSA or FK506) + MTX ± other vs. Others, p=0.0191; (CSA or FK506) ± other vs. Others, p=

25 Not for publication or presentation Attachment 4 Table 5. Multivariate analysis of chronic GVHD at 2 years post transplant for AML Variables: N Relative Risk(95% CI) P-value Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Disease status/duration 1st CR P overall = PIF a 1 st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown ( ) Conditioning regimen P overall = CyTBI + others a CyTBI alone ( ) BuCy + others ( ) BuCy alone ( ) (Bu or TBI) ± others ( ) Age < a P overall = ( ) ( ) ( ) ( ) > ( ) Donor-recipient sex match P overall = M-M a M-F ( ) F-M ( ) F-F ( ) Karnofsky score prior to HCT < a ( ) Missing ( ) Donor-recipient CMV match P overall = / a -/ ( ) / ( ) / ( ) missing ( )

26 Not for publication or presentation Attachment 4 Table 5. Continued. Variables: N Relative Risk(95% CI) P-value Prior Myelodysplasia No a Yes ( ) GVHD prophylaxis P overall = T-cell depletion a (CSA or FK506) + MTX ± other ( ) (CSA or FK506) ± other ( ) Others ( ) Year of transplant a ( ) a Reference group; Significant Contrasts at α =.05: Donor-recipient CMV match: -/+ vs. Missing, p=0.0057; +/+ vs. Missing, ; Donor-recipient sex match: M-F vs F-M, p=0.0025; F-M vs. F-F, p=0.0042; Age: vs , p=0.0206; 1st relapse Untreated and 6 mo vs. 1st relapse Untreated and > 6 mo, p=0.0005; 1st relapse Untreated and > 6 mo vs. 1st relapse Untreated and unknown, p=0.0075; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and < 6 mo, p=0.0001; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and >6 mo, p=0.0337; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and unknown, p=0.0131; 1st relapse Untreated and > 6 mo vs. > 2nd relapse and < 6 mo, p<0.0001; 1st refractory Relapse and >6 mo vs. > 2nd relapse and < 6 mo, p=0.0423; > 2nd relapse and < 6 mo vs. > 2nd relapse and > 6 mo, p=0.0342; Conditioning regimen: CyTBI alone vs. (Bu or TBI) ± others, p=0.0406; BuCy + others vs. BuCy alone, p= ; BuCy + others vs. (Bu or TBI ) ± others, p=

27 Not for publication or presentation Attachment 4 Table 6. Multivariate analysis of transplant-related mortality for AML Variables: N Relative Risk (95% CI) 6 months b Karnofsky score prior to HCT P overall = < a ( ) Missing ( ) Disease status/duration 1st CR PIF st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown Donor-recipient HLA match P overall = HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) Mismatched unrelated ( ) 3 years c Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Disease status/duration 1st CR PIF a P overall = st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown ( )

28 Not for publication or presentation Attachment 4 Table 6. Continued. Variables: N Relative Risk (95% CI) P-value Conditioning regimen P overall = CyTBI + others a CyTBI alone ( ) BuCy + others ( ) BuCy alone ( ) Bu or TBI ± others ( ) Age P overall = < a ( ) ( ) ( ) ( ) ( ) a Reference group; Significant pair wise comparison at α 6 months : 1st relapse Untreated and 6 mo vs 2nd relapse and < 6 mo, p=0.0455; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and < 6 mo, p=0.002; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and > 6 mo, p=0.0127; 1st relapse Untreated and > 6 mo vs 2nd relapse and < 6 mo, p=0.0025; 1st relapse Untreated and > 6 mo vs 2nd relapse and > 6 mo, p=0.0098; 1st refractory Relapse and >6 mo vs. > 2nd relapse and < 6 mo, p= > 2nd relapse and < 6 mo vs > 2nd relapse and > 6 mo, p= Donor-recipient HLA match: Other related vs Well-matched URD, p=0.02; c Significant pair wise comparison at α 3 years : 1st relapse Untreated and 6 mo vs 1st relapse Untreated and > 6 mo, p=0.0411; 1st relapse Untreated and 6 mo vs 1st relapse Untreated and unknown interval, p=0.0411; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and < 6 mo, p=0.0008; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and >6 mo, p=0.0061; 1st refractory Relapse and >6 mo vs 1st refractory Relapse and unknown interval, p=0.0116; 1st refractory Relapse and unknown vs. > 2nd relapse and unknown interval, p= ; 1st relapse Untreated and unknown vs. 1st refractory Relapse and < 6 mo, p = ; 1st relapse Untreated and unknown vs 1st refractory Relapse and unknown interval, p= ; 1st relapse Untreated and unknown vs. > 2nd relapse and < 6 mo, p=0.0399; 1st relapse Untreated and unknown vs. > 2nd relapse and unknown interval, p=0.0077; 1st refractory Relapse and < 6 mo vs. > 2nd relapse and > 6 mo, p=0.0284; Age: vrs 40-49, p=0.0051; vrs 50-59, p=0.0101; vrs 40-49, p=0.0205; vrs 50-59, p=

29 Not for publication or presentation Attachment 4 Table 7. Multivariate analysis of treatment failure for AML Variables: N Relative Risk (95% CI) 6 months b Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Karnofsky score prior to HCT P overall <.0001 < a ( ) Missing ( ) Disease status/duration 1st CR P overall <.0001 PIF a 1 st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown () Donor-recipient HLA match P overall =.0023 HLA-identical sibling 552 Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) Mismatched unrelated ( ) 3 years c Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Karnofsky score prior to HCT P overall <.0001 < a ( ) Missing ( )

30 Not for publication or presentation Attachment 4 Table 7. Continued. Variables: N Relative Risk (95% CI) P-value Disease status/duration 1st CR P overall <.0001 PIF a 1 st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown ( ) Donor-recipient HLA match P overall = HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) Mismatched unrelated ( ) Conditioning regimen CyTBI + others a CyTBI alone ( ) BuCy + others ( ) BuCy alone ( ) Bu or TBI ± others ( ) a Reference group; Significant pair wise comparison at α 6 months : 1st relapse Untreated and 6 mo vs 1st relapse Untreated and > 6 mo, p<0.0001; 1st relapse Untreated and 6 mo vs 1st refractory Relapse and < 6 mo, p<0.0221; 1st relapse Untreated and 6 mo vs > 2nd relapse and < 6 mo, p< st relapse Untreated and > 6 mo vs. 1st relapse Untreated and unknown, p=0.0057; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and < 6 mo, p<0.0001; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and >6 mo, p=0.007; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and unknown, p=0.0003; 1st relapse Untreated and > 6 mo vs > 2nd relapse and < 6 mo, p<0.0001; 1st relapse Untreated and > 6 mo vs > 2nd relapse and > 6 mo, p=0.0094; 1st relapse Untreated and > 6 mo vs > 2nd relapse and unknown, p=0.0002; 1st refractory Relapse and < 6 mo vs. > 2nd relapse and > 6 mo, p<0.0001; 1st refractory Relapse and >6 mo vs. > 2nd relapse and < 6 mo, p=0.0008; > 2nd relapse and < 6 mo vs. > 2nd relapse and > 6 mo, p=

31 Not for publication or presentation Attachment 4 Table 7. Continued. c Significant pair wise comparison at α 3 years : 1st relapse Untreated and 6 mo vs 1st relapse Untreated and > 6 mo, p<0.0001; 1st relapse Untreated and 6 mo vs 1st refractory Relapse and >6 mo, p=0.0488; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and < 6 mo, p<0.0001; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and >6 mo, p=0.013; 1st relapse Untreated and > 6 mo vs st refractory Relapse and unknown, p=0.017; 1st relapse Untreated and > 6 mo vs 2nd relapse and < 6 mo, p<0.0001; 1st relapse Untreated and > 6 mo vs 2nd relapse and > 6 mo, p=0.0005; 1st relapse Untreated and > 6 mo vs 2nd relapse and unknown, p=0.011; 1st relapse Untreated and unknown vs 1st refractory Relapse and < 6 mo, p=0.0068; 1st refractory Relapse and < 6 mo vs. 1st refractory Relapse and >6 mo, p=0.0003; 1st refractory Relapse and < 6 mo vs. 2nd relapse and > 6 mo, p=0.0266; 1st refractory Relapse and >6 mo vs. > 2nd relapse and < 6 mo, p=0.0412; Donor-recipient HLA match: Other related vs. Partially-matched URD, p=0.0326; Partially-matched URD vs. Mismatched URD, p=

32 Not for publication or presentation Attachment 4 Table 8. Multivariate analysis of Overall Mortality for AML Variables: N Relative Risk (95% CI) 6 months b Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Karnofsky score prior to HCT P overall <.0001 < a ( ) Missing ( ) Disease status/duration 1st CR P overall <.0001 PIF a 1 st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown ( ) Donor-recipient HLA match P overall <.0001 HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) <.0001 Mismatched unrelated ( ) <.0001 Year of transplant a ( ) Graft type BM a PBSC ( ) 3 years c Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Karnofsky score prior to HCT P overall <.0001 < a ( ) Missing ( )

33 Not for publication or presentation Attachment 4 Table 8. Continued. Variables: N Relative Risk (95% CI) P-value Disease status/duration of 1st CR P overall = PIF a 1 st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown ( ) Donor-recipient HLA match P overall < HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) Mismatched unrelated ( ) Cytogenetics prior to transplant P overall = Good a Intermediate ( ) Poor ( ) Unknown ( ) a Reference group; Significant pair wise comparison at α 6 months : 1st relapse Untreated and 6 mo vs 1st relapse Untreated and >6 mo, p<0.0001; 1st relapse Untreated and 6 mo vs. 1st refractory Relapse and < 6 mo, p=0.0500; 1st relapse Untreated and 6 mo vs. > 2nd relapse and < 6 mo, p=0.0087; 1st relapse Untreated and > 6 mo vs 1st relapse Untreated and unknown, p=0.024; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and < 6 mo, p<0.0001; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and >6 mo, p=0.0025; 1st relapse Untreated and > 6 mo vs 1st refractory Relapse and unknown, p=0.007; 1st relapse Untreated and > 6 mo vs > 2nd relapse and < 6 mo, p<0.0001; 1st relapse Untreated and > 6 mo vs > 2nd relapse and > 6 mo, p=0.0186; 1st relapse Untreated and > 6 mo vs > 2nd relapse and unknown, p=0.011; 1st relapse Untreated and unknown vs. > 2nd relapse and < 6 mo, p=0.0254; 1st refractory Relapse and < 6 mo vs. 1st refractory Relapse and >6 mo, p<0.0001; 1st refractory Relapse and < 6 mo vs. > 2nd relapse and > 6 mo, p<0.0001; 1st refractory Relapse and >6 mo vs. > 2nd relapse and < 6 mo, p<0.0001; 1st refractory Relapse and unknown vs. > 2nd relapse and < 6 mo, p=0.0466; > 2nd relapse and < 6 mo vs > 2nd relapse and > 6 mo, p=<0.0001; 33

34 Not for publication or presentation Attachment 4 Table 8. Continued. c Significant pair wise comparison at α 3 years : 1st relapse Untreated and 6 mo vs. 1st relapse Untreated and > 6 mo, p=0.0002; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and < 6 mo, p<0.0001; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and >6 mo, p=0.0127; 1st relapse Untreated and > 6 mo vs. 1st refractory Relapse and unknown, p=0.0127; 1st relapse Untreated and > 6 mo vs. > 2nd relapse and < 6 mo, p=0.0002; 1st relapse Untreated and > 6 mo vs. > 2nd relapse and > 6 mo, p=0.0114; 1st relapse Untreated and unknown vs. 1st refractory Relapse and < 6 mo, p=0.0164; 1st refractory Relapse and < 6 mo vs. 1st refractory Relapse and >6 mo, p=0.0105; 1st refractory Relapse and < 6 mo vs. > 2nd relapse and > 6 mo, p<0.0001; Donor-recipient HLA match: Other related vs. Well-matched unrelated, p=0.0063; Other related vs. Partially-matched unrelated, p=0.0011; Partially-matched unrelated vs. Mismatched unrelated, p=0.0175; Cytogenetics prior to transplant: Intermediate vs. Poor, p=

35 Not for publication or presentation Attachment 4 Table 9. Multivariate analysis of acute GVHD at 100 days post transplant for ALL Variables: N Relative Risk (95% CI) P-value Donor-recipient HLA match P overall = HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) Mismatched unrelated ( ) Fungal infection prior to transplant P overall = No a Yes ( ) Unknown ( ) Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) GVHD prophylaxis P overall = T-cell depletion a (CSA or FK506) + MTX ± other ( ) (CSA or FK506) ± other ( ) Others ( ) a Reference group; Significant Contrasts at α =.10: None 35

36 Not for publication or presentation Attachment 4 Table 10. Multivariate analysis of chronic GVHD at 2 years post transplant for ALL Variables: N Relative Risk (95% CI) P-value GVHD prophylaxis P overall = T-cell depletion a (CSA or FK506) + MTX ± other ( ) (CSA or FK506) ± other ( ) Others ( ) Disease status/duration 1st CR P overall = PIF a 1 st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown ( ) a Reference group; Significant Contrasts at α =.10: 1st relapse Untreated and > 6 mo vrs 1st refractory Relapse and < 6 mo, p=0.0101; 1st relapse Untreated and > 6 mo vrs > 2nd relapse and < 6 mo, p=0.0510; 1st relapse Untreated and > 6 mo vrs > 2nd relapse unknown interval, p=0.0384; 1st refractory Relapse and < 6 mo vrs 1st refractory Relapse and >6 mo, p=.0034; 1st refractory Relapse and < 6 mo vrs > 2nd relapse and > 6 mo, p=0.0019; > 2nd relapse and < 6 mo vs > 2nd relapse and unknown interval, p=

37 Not for publication or presentation Attachment 4 Table 11. Multivariate analysis of transplant-related mortality for ALL Variables: N Relative Risk (95% CI) 6 months b CNS disease P overall = No a Yes ( ) Missing ( ) Donor-recipient HLA match P overall = HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) Mismatched unrelated ( ) Age P overall = < a ( ) ( ) ( ) ( ) ( ) 3 years c CNS disease P overall = No a Yes ( ) Missing ( ) <.0001 Donor-recipient HLA match P overall = HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) Mismatched unrelated ( ) Age P overall = < a ( ) ( ) ( ) ( ) < ( ) a Reference group; 37

38 Not for publication or presentation Attachment 4 Table 11. Continued. b Significant Contrasts at α 6 months : Age: vrs 40-49, p=0.0053; vrs 30-39, p=0.0318; vrs 40-49, p=<.0001; vrs 50-59, p=0.0412; vrs 40-49, p= Donor-recipient HLA match: Other related vs Well-matched URD, p=0.0034; Well-matched URD vs Partially-matched URD, p=.0121; Well-matched URD vs Mismatched URD, p= C Significant Contrasts at α 3 years: Age: vrs 40-49, p=0.0030; vrs 40-49, p=0.0008; vrs 40-49, p=0.0546; Donor-recipient HLA match: Other related vs Well-matched URD p=0.0147; Well-matched URD vs Partially-matched URD p=.0137 Well-matched URD vs Mismatched URD p=

39 Not for publication or presentation Attachment 4 Table 12. Multivariate analysis of treatment failure for ALL Variables: N Relative Risk (95% CI) 6 months b Blasts in BM prior to transplant P overall < < a ( ) Missing ( ) GVHD prophylaxis P overall = T-cell depletion a (CSA or FK506) + MTX ± other ( ) (CSA or FK506) ± other ( ) Others ( ) Disease status/duration 1st CR P overall = PIF a 1 st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) < st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown ( ) 3 years c Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Donor recipient CMV status P overall = / a -/ ( ) / ( ) / ( ) Missing ( ) Disease status P overall = PIF a 1 st relapse, Untreated ( ) st refractory relapse ( ) Second and further relapse ( ) a Reference group; 39

40 Not for publication or presentation Attachment 4 Table 12. Continued. b Significant Contrasts at α 6 months : 1 st relapse Untreated and 6 mo vs 1 st refractory Relapse and < 6 mo, p=.0537; 1 st relapse Untreated and >6 mo vs 1st refractory Relapse and < 6 mo, p=0.0088; 1 st relapse Untreated and >6 mo vs > 2nd relapse and < 6 mo, p=0.0416; 1 st relapse Untreated and >6 mo vs > 2nd relapse and missing, p=0.0849; 1st refractory Relapse and < 6mo vs 1st refractory Relapse and >6 mo, p=0.0007; 1st refractory Relapse and < 6mo vs 1st refractory Relapse missing, p=0.0052; 1st refractory Relapse and < 6mo vs > 2nd relapse and < 6 mo, p=0.0003; > 2nd relapse and >6 mo vs > 2nd relapse and < 6 mo, p=0.0587; > 2nd relapse and unknown vs > 2nd vs relapse and < 6 mo, p=0.0566; > 2nd relapse and < 6 mo vs > 2nd relapse unknown, p=0.0350; c Significant Contrasts at α 3 years : CMV -/+ vs missing, p=.0865; +/+ vs missing, p=

41 Not for publication or presentation Attachment 4 Table 13. Multivariate analysis of overall mortality for ALL Variables: N Relative Risk (95% CI) 6 months b Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Donor-recipient HLA match P overall = HLA-identical sibling a Other related ( ) Well-matched unrelated ( ) Partially-matched unrelated ( ) Mismatched unrelated ( ) Disease status/duration 1st CR P overall = PIF a +1 st relapse Untreated and 6 mo ( ) st relapse Untreated and > 6 mo ( ) st relapse Untreated and unknown ( ) st refractory Relapse and < 6 mo ( ) < st refractory Relapse and >6 mo ( ) st refractory Relapse and unknown ( ) > 2nd relapse and < 6 mo ( ) > 2nd relapse and > 6 mo ( ) > 2nd relapse and unknown ( ) CNS disease P overall = No a Yes ( ) Missing ( ) 3 years c Blasts in BM prior to transplant P overall = < a ( ) Missing ( ) Donor recipient CMV status P overall = / a -/ ( ) / ( ) / ( ) Missing ( )

42 Not for publication or presentation Attachment 4 Table13. Continued. Variables: N Relative Risk (95% CI) P-value Disease status prior to transplant P overall = PIF a 1 st relapse, Untreated ( ) st refractory relapse ( ) Second and further relapse ( ) Age P overall = < a ( ) ( ) ( ) ( ) < ( ) a Reference group; b Significant Contrasts at α 6 months : 1st relapse Untreated and 6 mo vs 1st refractory Relapse and < 6 mo, p=0.0128; 1st relapse Untreated and 6 mo vs > 2nd relapse and < 6 mo, p=0.0434; 1st relapse Untreated and >6 mo vs 1st refractory Relapse and < 6 mo, p=0.0059; 1st relapse Untreated and >6 mo vs > 2nd relapse and < 6 mo p=0.0141; 1st relapse Untreated and >6 mo vs > 2nd relapse and unknown interval, p=0.0688; 1st refractory Relapse and < 6 mo vs 1st refractory Relapse and >6 mo, p<.0001; 1st refractory Relapse and < 6 mo vs 1st refractory Relapse and unknown interval, p=0.0119; 1st refractory Relapse and < 6 mo vs > 2nd relapse and < 6 mo, p=0.0007; 1st refractory Relapse and > 6 mo vs > 2nd relapse and < 6 mo, p=0.0115; 1st refractory Relapse and > 6 mo vs > 2nd relapse missing, p=0.0645; 1st refractory Relapse missing mo vs > 2nd relapse and < 6 mo, p=0.0350; > 2nd relapse and < 6 mo vs > 2nd relapse and > 6 mo, p=0.0080; > 2nd relapse and >6 mo vs > 2nd relapse and unknown interval, p=0.0461; HLA Other related vs Well Matched URD, p=0.0005; HLA Other related vs Partially Matched URD, p=0.0005; HLA Other related vs Mismatched URD, p=0.0805; HLA URD Well matched vs URD Mismatched, p=0.0306; HLA URD Patially matched vs URD Mismatched, p=0.0483; c Significant Contrasts at α 3 years : 1st relapse, untreated vs first refractory relapse, p=.0686; 1st relapse, untreated vs 2rd relapse, p=.0294; CMV: -/+ vrs +/-, p=0.0958; +/- vs +/+, p=0.0022; +/+ vrs missing, p=.0450; Age: vrs 40-49, p=0.0031; vrs 40-49, p=0.0017; vrs 40-49, p=0.0004; vrs 50-49, p=

43 Not for publication or presentation Attachment 4 Table 14. Cause of death AML ALL Cause of death N N (%) N N (%) Number of patients Number of death Primary disease/prior malignancy 641 (42) 208 (37) Graft failure 12 ( 1) 6 ( 1) Infection 232 (15) 72 (13) IpN/ARDS 120 ( 8) 48 ( 9) Organ failure 180 (12) 88 (16) Secondary malignancy 9 ( 1) 3 ( 1) Hemorrhage 43 ( 3) 15 ( 3) Graft-versus-host disease 111 ( 7) 45 ( 8) Accidental death 3 (<1) 0 Unknown 19 ( 1) 6 ( 1) 43

44 Not for publication or presentation Attachment 5 TO: FROM: Writing Committee for study LK04-02: K Ballen, M Bishop, M Bornhauser, CN Bredeson, WA Bujan, MS Cairo, E Copelan, JL Gajewski, RP Gale, SA Giralt, SC Goldstein, Z Gulbas, V Gupta, GA Hale, RH Herzig, J Horan, O Ilhan, LM Isola, HM Lazarus, VA Lewis, JL Liesveld, MC Lill, PL McCarthy, GA Milone, MA Pulsipher, O Ringdén, DA Rizzieri, JR Russell, M Sabloff, S Santarone, G Schiller, RJ Soiffer, E Waller, RS Weiner, PH Wiernik, Mei-Jie Zhang Selina M. Luger, MD, Waleska S. Pérez, MPH, Daniel J. Weisdorf, MD DATE: January 7, 2008 RE: Revised final analyses for CIBMTR study #LK04-02: Comparison of myeloablative vs. reduced intensity vs. non-myeloablative allogeneic transplants in patients with AML or MDS Enclosed is a description of the patient population and results of univariate and multivariate analyses of engraftment, acute GVHD, chronic GVHD, treatment-related mortality, relapse, leukemia-free survival, and overall survival for patients years of age who underwent allogeneic bone marrow and/or peripheral blood HLA-identical sibling or URD HCT for AML or MDS, reported to the CIBMTR between 1997 and The primary objective of the study is to compare the above outcomes between reduced intensity (RIC), non-myeloablative (NST) and myeloablative conditioning regimens in AML and MDS patients. Patients with the following characteristics were excluded from the final population: Exclusions: # of excluded cases CAP model 179 Age>70 years 41 (3-trad; 38 NST/RIC) Cord blood 128 (90-trad; 38 NST/RIC) FAB subtype = M3 204 (181-trad; 23 NST/RIC) Conditioning regimen= cyclophosphamide+vp16+tbi (TBI dose>500 cgy) 2 Conditioning regimen=fludarabine+ara-c+ida 8 Conditioning regimen=busulfan+melphalan (unknown dose) 18 Conditioning regimen=cbv 1 Conditioning regimen=vp16+cyclophosphamide 8 Conditioning regimen=ara-c+fludarabine 8 Conditioning regimen=ara-c +other drug (not specify) 8 Conditioning regimen=ara-c+vp16 1 Conditioning regimen=atg+anth+ara-c+fludarabine+itchemo 1 Conditioning regimen=atg+ara-c+fludarabine 9 44

45 Not for publication or presentation Attachment 5 Conditioning regimen=atg+bleo+cortico+fludarabine 1 Conditioning regimen=atg+busulfan+cortico+fludarabine 1 Conditioning regimen=atg+cortico+fludarabine+other drug (not 1 specify) Conditioning regimen=atg+cyclophosphamide 4 Conditioning regimen=atg+cyclophosphamide+itchemo+mab 1 Conditioning regimen=atg+cyclophosphamide+thiotepa 1 Conditioning regimen=atg+fludarabine 3 Conditioning regimen=atg+fludarabine+melphalan 3 Conditioning regimen=atg+fludarabine+mab 1 Conditioning regimen=atg+fludarabine+nitro 1 Conditioning regimen=atg+fludarabine+other drug (not specify) 3 Conditioning regimen=atg+fludarabine+thiotepa 1 Conditioning regimen=bleomycin+cyclophosphamide 1 Conditioning regimen=corticosteroids+cyclophosphamide+thiotepa 1 Conditioning regimen=corticosteroids+fludarabine+mito+mab 1 Conditioning regimen=cyclophosphamide 8 Conditioning regimen=cyclophosphamide+ara-c 4 Conditioning regimen=cyclophosphamide+itchemo 7 Conditioning regimen=cyclophosphamide+mab 1 Conditioning regimen=cyclophosphamide+other drug (not specify) 4 Conditioning regimen=cyclophosphamide+thiotepa 4 Conditioning regimen=fludarabine 5 Conditioning regimen=fludarabine+ifos+itchemo 1 Conditioning regimen=fludarabine+melphalan 1 Conditioning regimen=fludarabine+mab 1 Conditioning regimen=fludarabine+nitro 2 Conditioning regimen=tbi 5 Conditioning regimen=tbi+atg+corticosteroids+cyclophosphamide 1 Conditioning regimen=tbi+bleomycin+fludarabine 1 Conditioning regimen=tbi(unknown dose)+cyclophosphamide 3 Conditioning regimen=tbi(unknown dose)+fludarabine 1 Conditioning regimen=tli+atg 2 Conditioning regimen=atg+busulfan+cyclophosphamide 1 Conditioning regimen=atg+busulfan+fludarabine 2 Conditioning regimen=atg+corticosteroids+fludarabine 2 Conditioning regimen=busulfan<9 mg/kg+cyclophosphamide 18 Conditioning regimen=busulfan+fludarabine 3 Conditioning regimen=not reported 97 Centers (n=7) with <10% completeness index follow-up excluded 52 Centers (n=10) with 10-19% completeness index follow-up excluded 34 Centers (n=15) with 20-29% completeness index follow-up excluded 15 Prior autologous transplant information missing 5 Donor-recipient sex match information missing 15 (8-trad; 7 NST/RIC) GVHD prophylaxis missing 10 (9-trad; 1 NST/RIC) GVHD prophylaxis= T-cell depletion (per stats mtg.) 459 (430-trad; 29 NST/RIC) 45

46 Not for publication or presentation Attachment 5 GVHD prophylaxis= none (per stats mtg.) 12 GVHD prophylaxis=other (per stats mtg.) myeloablative, 1041 reduced-intensity (273 BM; 768 PBSC: combined for analysis) and 407 non-myeloablative conditioning met the on-study criteria. The cases identified came from 223 reporting centers from 37 different countries. Median follow-up of survivors was as follows: 58 (3-128) months for the myeloablative group, 38 (4-124) months for the reduced-intensity bone marrow group, 38 (3-90) months for the reduced-intensity peripheral blood group and 48 (3-87) months for the non-myeloablative group. The following regimens (n>30) were included in the final population: - Myeloablative: o CY+TBI (TBI dose> 500 cgy single dose or TBI dose> 800 cgy fractionated) o Busulfan+cyclophosphamide o TBI dose 500 cgy single dose or TBI dose >800 cgy fractionated) o Melphalan dose 150 mg/m 2 o Busulfan dose > 9 mg/kg - Reduced-intensity (RIC): o TBI dose < 500 cgy single dose or TBI dose <800 cgy fractionated o Melphalan dose 150 mg/m 2 o Busulfan dose 9 mg/kg - Non-myeloablative (NST): o TBI dose = 200 cgy o Fludarabine + TBI dose = 200 cgy o Fludarabine+cyclophosphamide Table 1 shows the patient, disease, and transplant characteristics of the 5179 patients included in the study. Table 2 shows univariate analyses of engraftment, acute GVHD, chronic GVHD, relapse, treatment-related mortality, leukemia-free survival and overall survival. The primary goal of this study was to compare engraftment, acute GVHD, chronic GVHD, treatment-related mortality, relapse, leukemia-free survival, and overall survival among the conditioning regimen groups. The Cox proportional hazards model was used in multivariate analyses. The backward stepwise selection with p>0.05 was used to remove each risk factor from the model. The main effect (conditioning regimen group) was included in each step of the model building since it was the main interest of the study. The potential interaction between conditioning regimen and graft type and all significant risk factors were examined. Risks associated with NST BM and NST PBSC were virtually identical for overall survival (p=0.11), so final models show only the relative risk for NST. The proportionality assumption of the Cox model was tested by adding a time-dependent covariate. When proportionality assumption was violated, a stepwise constant coefficient Cox model was used to adjust the time-changing effect. The proportionality assumption was further tested. The cumulative incidence probabilities of engraftment, acute GVHD, chronic GVHD, TRM and relapse were calculated to accommodate 46

47 Not for publication or presentation Attachment 5 competing risks. Finally, adjusted probabilities of LFS and survival were calculated using the multivariate models, stratified by main treatment group and weighted by the pooled sample proportion value for each prognostic factor. These adjusted probabilities estimate likelihood of outcomes in populations with similar prognostic factors. Table 3 shows all the variables considered in the model building. Variables not listed in the final models did not meet the 5% level of significance. Tables 4 show results of the multivariate analyses. Table shows the multivariate results for engraftment, acute GVHD, chronic GVHD, treatment-related mortality, relapse, treatment failure and overall mortality. Table 11 shows the adjusted survival probability of LFS and overall survival based on multivariate regression model adjusting significant risk factors given in Table 9 and 10. Table 12 shows causes of death. Attached are the curves illustrating the primary outcomes. Please review this summary critically and send your comments to: Selina Luger, MD, University of Pennsylvania Health System, 3400 Spruce Street, Philadelphia, PA 19104, Telephone: , Fax: , selina.luger@uphs.upenn.edu with a copy via Fax or to Waleska S. Pérez, MPH at the CIBMTR Statistical Center [Fax: , wperez@mcw.edu]. You should note that any member of a Writing Committee who does not make a substantive contribution to the design, analysis, interpretation or manuscript would be expected to withdraw as a co-author or, alternatively, the lead author could remove names of non-contributors. If we do not hear from you by December 15, 2008 we may assume you no longer wish to participate in the study. The rules of the CIBMTR require inclusion of the following statement: "The enclosed raw data are confidential. If used publicly, the following statement must be included: The data presented here were obtained from the Statistical Center of the International Bone Marrow Transplant Registry. The analysis has not been reviewed or approved by the Advisory Committee of the CIBMTR. The data may not be published without prior approval of the Advisory Committee." If the data are used in an oral presentation, please send us the name, place and dates of the meeting where the data are presented, and the title of your presentation. 47

48 Not for publication or presentation Attachment 5 Table 1. Characteristics of patients years of age who underwent allogeneic bone marrow and/or peripheral blood HLA-identical sibling or URD SCT for AML or MDS, reported to the CIBMTR between 1997 and Characteristics of patients Myeloablative RIC NST P Number of patients Number of centers Age, median (range), yrs 42 (18-68) 55 (18-70) 57 (18-70) <0.001 Age at transplant <0.001 <30 y 827 (22) 77 ( 7) 21 ( 5) y 835 (22) 101 (10) 24 ( 6) y 1187 (32) 193 (19) 55 (14) y 785 (21) 411 (39) 160 (39) y 97 ( 3) 259 (25) 147 (36) Male sex 1991 (53) 604 (58) 253 (62) <0.001 Disease AML 2814 (75) 731 (70) 289 (71) MDS 917 (25) 310 (30) 118 (29) FAB subtype --- AML M0 71 ( 2) 37 ( 4) 7 ( 2) M1 433 (12) 97 ( 9) 50 (12) M2 729 (20) 157 (15) 58 (14) M4 572 (15) 129 (12) 56 (14) M5 326 ( 9) 71 ( 7) 24 ( 6) M6 93 ( 2) 24 ( 2) 8 ( 2) M7 46 ( 1) 14 ( 1) 2 ( 1) Transformed from MDS 54 ( 1) 53 ( 5) 17 ( 4) Unclassified AML 334 ( 9) 86 ( 8) 48 (12) Other AML 156 ( 4) 63 ( 6) 19 ( 5) MDS RA 200 ( 5) 90 ( 9) 35 ( 9) RARS 29 ( 1) 9 ( 1) 2 (<1) RAEB 274 ( 7) 108 (10) 41 (10) RAEB-t 137 ( 4) 35 ( 3) 7 ( 2) CMML 86 ( 2) 14 ( 1) 10 ( 2) Unclassified MDS 61 ( 2) 15 ( 1) 4 ( 1) Other MDS 130 ( 3) 39 ( 4) 19 ( 5) Karnofsky score at transplant 90% 2341 (66) 655 (67) 210 (56) <0.001 Missing Therapy-related leukemia 312 ( 8) 128 (12) 60 (15) <0.001 Missing

49 Not for publication or presentation Attachment 5 Table 1. Continued. Characteristics of patients Myeloablative RIC NST P Conditioning regimen --- Cy+TBI (TBI dose>500 cgy single dose 1635 (44) 0 0 or TBI dose >800 cgy fractionated) Busulfan+cyclophosphamide 1575 (42) 0 0 TBI dose 500 cgy single dose or TBI 144 ( 4) 0 0 dose >800 cgy fractionated Melphalan dose 150 mg/m 2 57 ( 2) 0 0 Busulfan dose > 9 mg/kg 320 ( 9) 0 0 TBI dose<500 cgy single dose or TBI 149 (14) 0 dose<800 cgy fractionated Melphalan dose 150 mg/m (36) 0 Busulfan dose 9 mg/kg (49) 0 TBI dose = 200 cgy ( 8) FLUD+TBI dose=200 cgy (60) FLUD+cyclophosphamide (32) Cytogenetics 0.07 Good prognosis 189 ( 5) 53 ( 5) 14 ( 4) Intermediate prognosis 2232 (60) 601 (58) 249 (61) Poor prognosis 691 (17) 227 (22) 90 (22) Unknown 619 (17) 160 (15) 54 (13) IPSS score at transplant (for MDS) 0.85 Low 45 ( 7) 18 ( 8) 9 (11) Intermediate (46) 93 (43) 37 (46) Intermediate (30) 68 (32) 24 (30) High 108 (17) 35 (16) 11 (14) Missing Disease status at transplant < st complete remission 1200 (33) 237 (23) 124 (31) 2 nd complete remission 565 (15) 171 (17) 85 (21) Relapse 606 (16) 172 (17) 51 (13) Primary induction failure 410 (11) 130 (13) 27 ( 7) MDS treated 474 (13) 181 (18) 75 (19) MDS untreated 429 (12) 123 (12) 40 (10) Missing Duration of CR1 (AML in CR2) 0.39 Median (range), months 11 (<1-79) 11 (1-60) 11 (<1-60) 6 months 112 (24) 22 (17) 14 (22) 6-12 months 159 (35) 44 (35) 20 (31) 12 months 187 (41) 62 (48) 30 (47) Missing

50 Not for publication or presentation Attachment 5 Table 1. Continued. Characteristics of patients Myeloablative RIC NST P Time from remission to transplant, months (for AML patients in CR1) months 600 (51) 115 (50) 43 (35) >3 months 569 (49) 114 (50) 81 (65) Missing Blast in BM at transplant Median (range), months 0 (0-99) 0 (0-99) 0 (0-92) <5% 2842 (83) 770 (82) 346 (91) 5-10% 168 ( 5) 57 ( 6) 13 ( 3) >10% 413 (12) 117 (12) 22 ( 6) Missing Type of donor <0.001 HLA-identical sibling 1560 (42) 376 (36) 143 (35) Unrelated well matched 999 (27) 307 (29) 173 (43) Unrelated partially matched 726 (19) 216 (21) 56 (14) Unrelated mismatched 313 ( 8) 80 ( 8) 24 ( 6) Unrelated matching unknown 133 ( 4) 62 ( 6) 11 ( 3) Donor age, years <0.001 Median (range), months 37 (<1-82) 40 (1-78) 41 (19-75) <30 y 1010 (28) 211 (21) 85 (21) y 1181 (32) 298 (29) 111 (28) y 979 (27) 252 (25) 95 (24) y 384 (11) 162 (16) 65 (16) y 83 ( 2) 75 ( 7) 41 (10) 70 y 10 (<1) 14 ( 1) 5 ( 1) Missing Donor-recipient sex match M-M 1272 (34) 391 (38) 169 (42) M-F 945 (25) 257 (25) 94 (23) F-M 719 (19) 213 (20) 84 (21) F-F 795 (21) 180 (17) 60 (15) Donor-recipient CMV match < / (34) 373 (38) 120 (30) +/- 426 (12) 102 (10) 48 (12) -/+ 960 (27) 305 (31) 110 (28) -/- 990 (27) 208 (21) 119 (30) Missing Prior autologous transplant (10)

51 Not for publication or presentation Attachment 5 Table 1. Continued. Characteristics of patients Myeloablative RIC NST P Graft type <0.001 BM 2011 (54) 273 (26) 49 (12) PBSC 1720 (46) 768 (74) 358 (88) Year of transplant < (12) 14 ( 1) 3 ( 1) (12) 21 ( 2) 2 (<1) (11) 45 ( 5) 4 ( 1) (12) 104 (10) 49 (12) (12) 124 (12) 77 (19) (13) 179 (17) 90 (22) (12) 249 (24) 73 (18) (16) 305 (29) 109 (27) ATG 631 (17) 381 (37) 57 (14) <0.001 Missing GVHD prophylaxis <0.001 FK506+MTX±other 851 (23) 233 (23) 35 ( 9) FK506±other 202 ( 5) 178 (17) 43 (11) CsA+MTX±other 2442 (65) 305 (29) 57 (14) CsA±other 236 ( 6) 325 (31) 272 (67) Median follow-up of survivors, m 58 (3-128) 38 (3-124) 48 (3-87) Abbreviations: CMV = cytomegalovirus; CsA = cyclosporine; MTX = methotrexate; FK506=tacrolimus; FLUD = fludarabine. Completeness FU: 90% as of 12/31/05; 85% as of 12/31/06; 82% as of 06/01/07 51

52 Not for publication or presentation Attachment 5 Table 2. Cumulative incidence probability of relapse and TRM and univariate survival probabilities of LFS and overall survival for patients years of age who underwent allogeneic bone marrow and/or peripheral blood HLA-identical sibling or URD SCT for AML or MDS between 1997 and 2004, by type of conditioning regimen. Outcome Myeloablative (1) RIC BM (2) RIC PB (3) NST (4) P 1 vs. 2 P 1 vs. 3 P 1 vs. 4 P 2 vs. 3 P 2 vs. 4 P 3 vs d 93 (92-94) 92 (89-95) 95 (94-97) 94 (91-96) Acute 100d (grade II-IV) 47 (45-48) 41 (35-47) 45 (42-49) 47 (42-52) Chronic GVHD 1 yr 3 yrs 5 yrs TRM 1 yr 3 yrs 5 yrs 37 (35-38) 40 (39-42) 41 (39-42) 28 (26-29) 32 (30-33) 34 (32-36) 29 (24-35) 31 (25-36) 33 (27-39) 32 (26-38) 35 (29-41) 37 (31-43) 43 (39-47) 46 (42-49) 46 (42-49) 25 (22-28) 30 (26-33) 34 (30-38) 38 (33-43) 41 (36-46) 41 (36-46) 25 (21-30) 33 (28-38) 36 (31-41) <0.001 < Relapse 1 yr 3 yrs 5 yrs 25 (24-27) 31 (29-33) 32 (31-34) 38 (32-44) 39 (33-45) 42 (36-48) 29 (25-32) 36 (32-40) 39 (35-43) 38 (33-43) 42 (37-47) 43 (38-48) < <0.001 <0.001 < LFS 1 yr 3 yrs 5 yrs 47 (45-49) 37 (36-39) 34 (32-35) 30 (25-36) 26 (20-31) 21 (16-27) 47 (43-50) 34 (31-38) 27 (22-31) 37 (32-41) 25 (21-30) 21 (17-26) <0.001 <0.001 < <0.001 <0.001 <0.001 < OS 1 yr 3 yrs 5 yrs 51 (50-53) 40 (38-41) 35 (34-37) 36 (31-42) 27 (21-32) 25 (20-31) 52 (49-56) 36 (33-40) 29 (25-33) 42 (37-47) 30 (25-34) 24 (19-28) <0.001 <0.001 < <0.001 <0.001 <0.001 <

53 Not for publication or presentation Attachment 5 Table 3. Variables tested in Cox proportional hazards regression models. Main effect variable a : Type of conditioning regimen: myeloablative * vs. RIC BM vs. RIC PBSC vs. NST Patient-related variables: Age at transplant: to be determined Gender: female * vs. male Karnofsky performance score: <90% * vs. 90% vs. unknown Disease-related variables Disease: AML * vs. MDS FAB subtype at diagnosis: M0-M2 * vs. M4-M7 vs. other/unclassified (for AML); RA or RARS vs. other MDS (for MDS) Therapy-related leukemia: no * vs. yes vs. unknown Cytogenetics: no abnormalities or intermediate * vs. good vs. poor prognosis vs. unknown Blast percentage at transplant: <5% vs. 5-10% vs. >10% vs. unknown Duration of first complete remission (for AML patients transplanted in CR2): <6 * vs vs. >12 months vs. unknown Disease status at HCT: PIF * vs. CR1 vs. CR2 vs. relapse (for AML) vs. treated vs. untreated (for MDS) Treatment-related: Time from remission to transplant, months (for AML patients transplanted in CR1): 3 months vs. >3 months vs. unknown Type of donor: HLA-identical sibling * vs. URD well-matched vs. URD partially matched vs. URD mismatched vs. URD matching unknown Donor age: to be determined Donor-recipient sex match: F-M * vs. others Donor-recipient CMV status: D-/R- * vs. D+/R- vs. recipient positive vs. unknown Graft type: BM* vs. PBSC Year of transplant: to be determined Previous autologous transplant: no * vs. yes ATG: no * vs. yes GVHD prophylaxis:fk506+mtx±other * vs. FK506±other vs. CsA+MTX±other vs. CsA±other a Included in all models. 53

54 Not for publication or presentation Attachment 5 Table 4. Multivariate analysis of hematopoietic recovery at 100 days Variable N OR (95% CI) P-value Main Effect: Myeloablative a P overall = 0.26 RIC BM ( ) 0.49 RIC PB ( ) 0.06 NST ( ) 0.29 Other significant covariates: Age at transplant <40 years a 40 years ( ) Karnofsky score <90% a P overall < % ( ) <0.001 Unknown ( ) Blast percentage at transplant <5% a P overall < % ( ) 0.55 >10% ( ) <0.001 Unknown ( ) 0.92 Type of donor HLA-identical sibling a P overall <0.001 URD, well-matched ( ) URD, partially matched ( ) <0.001 URD, mismatched ( ) <0.001 URD, matching unknown ( ) 0.86 Previous autologous transplant No a Yes ( ) Year of transplant a ( ) a Reference group Pairwise comparisons: RR (95% CI) P-value RIC PB vs. RIC BM 1.22 ( ) 0.50 NST vs. RIC BM 1.08 ( ) 0.81 RIC PB vs. NST 1.13 ( )

55 Not for publication or presentation Attachment 5 Table 5. Multivariate analysis of acute GVHD at 100 days Variable N OR (95% CI) P-value Main Effect: Myeloablative a P overall = RIC BM ( ) RIC PB ( ) 0.72 NST ( ) 0.76 Other significant covariates: Type of donor HLA-identical sibling a P overall <0.001 URD, well-matched ( ) <0.001 URD, partially matched ( ) <0.001 URD, mismatched ( ) <0.001 URD, matching unknown ( ) <0.001 Donor-recipient CMV serostatus D-, R a P overall = D+,R ( ) 0.28 R ( ) Unknown ( ) 0.14 a Reference group Pairwise comparisons: RR (95% CI) P-value RIC PB vs. RIC BM 1.48 ( ) NST vs. RIC BM 1.47 ( ) RIC PB vs. NST 1.00 ( )

56 Not for publication or presentation Attachment 5 Table 6. Multivariate analysis of chronic GVHD Variable N RR (95% CI) P-value Main Effect: Myeloablative a P overall = RIC BM ( ) RIC PB ( ) NST ( ) 0.08 Other significant covariates: Age at transplant <40 years a 40 years ( ) <0.001 Disease AML a MDS ( ) Type of donor HLA-identical sibling a P overall <0.001 URD, well-matched ( ) <0.001 URD, partially matched ( ) <0.001 URD, mismatched ( ) <0.001 URD, matching unknown ( ) 0.55 Donor-recipient sex match Others a F-M ( ) <0.001 GVHD prophylaxis FK506+MTX±others a P overall <0.001 FK506±others ( ) <0.001 CsA+MTX±others ( ) 0.61 CsA±others ( ) 0.05 a Reference group Pairwise comparisons: RR (95% CI) P-value RIC PB vs. RIC BM 1.49 ( ) NST vs. RIC BM 1.51 ( ) RIC PB vs. NST 0.99 ( )

57 Not for publication or presentation Attachment 5 Table 7. Multivariate analysis of treatment-related mortality Variable N RR (95% CI) P-value Main Effect: Myeloablative a P overall <0.001 RIC BM 3m ( ) RIC BM > 3m 1.36 ( ) 0.04 RIC PB 3m ( ) <0.001 RIC PB > 3m 1.27 ( ) NST 3m ( ) NST > 3m 1.55 ( ) Other significant covariates: Age at transplant <40 years a 40 years ( ) <0.001 Karnofsky score <90% a P overall < % ( ) <0.001 Unknown ( ) <0.001 Therapy-related leukemia No a P overall = Yes ( ) Unknown ( ) 0.23 Blast percentage at transplant <5% a P overall = % ( ) 0.61 >10% ( ) <0.001 Unknown ( ) 0.06 Disease status at transplant PIF a P overall = CR ( ) 0.09 CR2, duration of CR1 12m ( ) 0.30 CR2, duration of CR1>12m ( ) 0.81 CR2, duration of CR ( ) 0.67 unknown Relapse ( ) 0.42 MDS, treated ( ) 0.15 MDS, untreated ( ) 0.15 Unknown ( ) 0.68 Cytogenetics Good prognosis a P overall < Intermediate prognosis ( ) 0.24 Poor prognosis ( ) Unknown ( )

58 Not for publication or presentation Attachment 5 Table 7. Continued. Variable N RR (95% CI) P-value Type of donor HLA-identical sibling a P overall <0.001 URD, well-matched ( ) <0.001 URD, partially matched ( ) <0.001 URD, mismatched ( ) <0.001 URD, matching unknown ( ) Donor age <50 years a P overall = years ( ) Unknown ( ) 0.86 Donor-recipient sex match Others a F-M ( ) Year of transplant a ( ) <0.001 a Reference group RIC BM: P early vs. late = RIC PB: P early vs. late <0.001 NST: P early vs. late <0.001 Pairwise comparisons: RR (95% CI) P-value RIC PB<3m vs. RIC BM<3m 0.89 ( ) 0.52 RIC PB>3m vs. RIC BM<3m 1.81 ( ) NST<3m vs. RIC BM<3m 1.01 ( ) 0.95 NST>3m vs. RIC BM<3m 2.21 ( ) <0.001 RIC PB<3m vs. RIC BM>3m 0.46 ( ) <0.001 RIC PB>3m vs. RIC BM>3m 0.94 ( ) 0.69 NST<3m vs. RIC BM>3m 0.52 ( ) NST>3m vs. RIC BM>3m 1.14 ( ) 0.48 NST <3m vs. RIC PB<3m 1.15 ( ) 0.45 NST >3m vs. RIC PB<3m 2.50 ( ) <0.001 NST<3m vs. RIC PB>3m 0.56 ( ) NST>3m vs. RIC PB>3m 1.22 ( )

59 Not for publication or presentation Attachment 5 Table 8. Multivariate analysis of relapse Variable N RR (95% CI) P-value Main Effect: Myeloablative a P overall <0.001 RIC BM ( ) <0.001 RIC PB ( ) 0.27 NST ( ) <0.001 Other significant covariates: Karnofsky score <90% a P overall < % ( ) <0.001 Unknown ( ) FAB subtype M0-M a P overall <0.001 M4-M ( ) Other AML ( ) 0.55 RA/RARS ( ) 0.50 Other MDS ( ) 0.54 Blast percentage at transplant <5% a P overall < % ( ) <0.001 >10% ( ) <0.001 Unknown ( ) 0.57 Disease status at transplant PIF a P overall <0.001 CR ( ) <0.001 CR2, duration of CR1 12m ( ) <0.001 CR2, duration of CR1>12m ( ) <0.001 CR2, duration of CR ( ) unknown Relapse ( ) 0.08 MDS, treated ( ) 0.05 MDS, untreated ( ) Unknown ( ) Cytogenetics Good prognosis a P overall <0.001 Intermediate prognosis ( ) Poor prognosis ( ) <0.001 Unknown ( ) <0.001 Donor age <50 years a P overall = years ( ) Unknown ( ) 0.31 a Reference group Pairwise comparisons: RR (95% CI) P-value RIC PB vs. RIC BM 0.68 ( ) NST vs. RIC BM 1.18 ( ) 0.20 RIC PB vs. NST 0.63 ( ) <

60 Not for publication or presentation Attachment 5 Table 9. Multivariate analysis of treatment failure (inverse of LFS) Variable N RR (95% CI) P-value Main Effect: Myeloablative a P overall <0.001 RIC BM ( ) 0.07 RIC PB 3m ( ) RIC PB > 3m 1.03 ( ) 0.66 NST ( ) <0.001 Other significant covariates: Age at transplant <40 years a 40 years ( ) <0.001 Karnofsky score <90% a P overall < % ( ) <0.001 Unknown ( ) <0.001 Therapy-related leukemia No a P overall = Yes ( ) Unknown ( ) 0.16 Blast percentage at transplant <5% a P overall < % ( ) >10% ( ) <0.001 Unknown ( ) 0.14 Disease status at transplant PIF a P overall <0.001 CR ( ) <0.001 CR2, duration of CR1 12m ( ) CR2, duration of CR1>12m ( ) <0.001 CR2, duration of CR1 unknown ( ) Relapse ( ) MDS, treated ( ) <0.001 MDS, untreated ( ) <0.001 Unknown ( ) Cytogenetics Good prognosis a P overall <0.001 Intermediate prognosis ( ) Poor prognosis ( ) <0.001 Unknown ( ) <

61 Not for publication or presentation Attachment 5 Table 9. Continued. Variable N RR (95% CI) P-value Type of donor HLA-identical sibling a P overall <0.001 URD, well-matched ( ) <0.001 URD, partially matched ( ) <0.001 URD, mismatched ( ) <0.001 URD, matching unknown ( ) Donor age <50 years a P overall = years ( ) <0.001 Unknown ( ) 0.74 a Reference group Pairwise comparisons: RR (95% CI) P-value RIC PB 3m vs. RIC BM 0.70 ( ) RIC PB>3m vs. RIC BM 0.90 ( ) 0.27 NST vs. RIC BM 1.11 ( ) 0.27 RIC PB 3m vs. NST 0.63 ( ) <0.001 RIC PB>3m vs. NST 0.81 ( )

62 Not for publication or presentation Attachment 5 Table 10. Multivariate analysis of mortality (inverse of overall survival) Variable N RR (95% CI) P-value Main Effect: Myeloablative a P overall <0.001 RIC BM ( ) 0.21 RIC PB 3m ( ) <0.001 RIC PB > 3m 1.03 ( ) 0.64 NST ( ) Other significant covariates: Age at transplant <40 years a 40 years ( ) <0.001 Karnofsky score <90% a P overall < % ( ) <0.001 Unknown ( ) <0.001 Therapy-related leukemia No a P overall = Yes ( ) <0.001 Unknown ( ) 0.35 Blast percentage at transplant <5% a P overall < % ( ) >10% ( ) <0.001 Unknown ( ) 0.11 Disease status at transplant PIF a P overall <0.001 CR ( ) <0.001 CR2, duration of CR1 12m ( ) 0.12 CR2, duration of CR1>12m ( ) <0.001 CR2, duration of CR1 unknown ( ) 0.23 Relapse ( ) MDS, treated ( ) <0.001 MDS, untreated ( ) <0.001 Unknown ( ) Cytogenetics Good prognosis a P overall <0.001 Intermediate prognosis ( ) Poor prognosis ( ) <0.001 Unknown ( ) <

63 Not for publication or presentation Attachment 5 Table 10. Continued. Variable N RR (95% CI) P-value Type of donor HLA-identical sibling a P overall <0.001 URD, well-matched ( ) <0.001 URD, partially matched ( ) <0.001 URD, mismatched ( ) <0.001 URD, matching unknown ( ) Donor age <50 years a P overall = years ( ) <0.001 Unknown ( ) 0.52 Year of transplant a ( ) a Reference group RIC PB: P early vs. late = Pairwise comparisons: RR (95% CI) P-value RIC PB 3m vs. RIC BM 0.66 ( ) <0.001 RIC PB>3m vs. RIC BM 0.94 ( ) 0.48 NST vs. RIC BM 1.09 ( ) 0.38 RIC PB 3m vs. NST 0.60 ( ) <0.001 RIC PB>3m vs. NST 0.86 ( )

64 Not for publication or presentation Attachment 5 Table 11. Adjusted survival probability of LFS and overall survival based on multivariate regression model adjusting significant risk factors given in Table 9 and 10 for patients years of age who underwent allogeneic bone marrow and/or peripheral blood HLA-identical sibling or URD SCT for AML or MDS between 1997 and 2004, by type of conditioning regimen. Outcome Adjusted LFS 1 yr 3 yrs 5 yrs Myeloablative (1) 46 (44-47) 36 (34-37) 33 (31-34) RIC BM (2) 38 (33-43) 34 (28-39) 29 (23-35) RIC PB (3) 49 (46-53) 38 (34-41) 30 (26-34) NST (4) 39 (34-43) 28 (24-32) 24 (20-29) P overall P 1 vs. 2 P 1 vs. 3 P 1 vs. 4 P 2 vs. 3 P 2 vs. 4 P 3 vs. 4 < <0.001 <0.001 < <0.001 < Adjusted OS 1 yr 3 yrs 5 yrs 50 (49-52) 38 (37-40) 34 (33-36) 44 (39-49) 35 (29-40) 33 (27-38) 54 (51-57) 39 (36-43) 33 (29-36) 43 (39-48) 31 (27-36) 26 (21-30) < <

65 Not for publication or presentation Attachment 5 Table 12. Causes of death Myeloablative RIC BM RIC PB NST Number of patients Number of deaths Primary disease 870 (37) 69 (34) 180 (37) 125 (43) Infection 385 (16) 46 (23) 101 (21) 49 (17) GVHD 304 (13) 29 (14) 73 (15) 39 (12) Organ failure 249 (11) 13 ( 6) 42 ( 9) 25 ( 9) IpN 116 ( 5) 15 ( 7) 10 ( 2) 9 ( 3) Hemorrhage 96 ( 4) 5 ( 2) 15 ( 3) 7 ( 2) Toxicity 88 ( 4) 6 ( 3) 12 ( 3) 11 ( 4) Graft rejection 21 ( 1) 6 ( 3) 3 ( 1) 7 ( 2) ARDS 64 ( 3) 2 ( 1) 7 ( 1) 3 ( 1) 2 nd malignancy 29 ( 1) 7 ( 3) 5 ( 1) 2 ( 1) Vascular 23 ( 1) 0 6 ( 1) 4 ( 1) Prior malignancy 3 (<1) 0 2 (<1) 1 (<1) Accidental death 3 (<1) Other cause 60 ( 3) 3 ( 1) 21 ( 4) 10 ( 3) Unknown 27 ( 1) 1 ( 1) 4 ( 1) 1 (<1) 65

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70 Not for publication or presentation Attachment ASH ABSTRACT Similar Outcomes Using Myeloablative versus Reduced Intensity and Non-Myeloablative Allogeneic Transplant Preparative Regimens for AML or MDS: From the Center for International Blood and Marrow Transplant Research Selina Luger, Olle Ringdén, Waleska S. Pérez, Mei-Jie Zhang, John F. DiPersio, Jorge Sierra, Martin Tallman, Daniel Weisdorf and Michael Pulsipher on behalf of the Acute Leukemia Writing Committee, Center for International Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, USA. Use of reduced intensity conditioning (RIC) and nonmyeloablative (NMA) regimens in allogeneic transplantation (allo HCT) for AML and MDS has rapidly increased over the past decade. Efficacy of these approaches compared to myeloablative (MA) conditioning has not been clearly established. We compared disease status, donor, graft and recipient characteristics and outcomes of 3731 MA HCT with 1500 RIC/NMA procedures performed at 217 centers between 1997 and 2004 (median f/u 58 vs. 40m, MA vs. RIC/NMA). Patients in the MA group were younger (median age 42 (18-68) vs. 55 (18-69) years), more frequently in CR1, and more often were transplanted from matched sibling grafts, compared to recipients of RIC/NMA. NMA recipients were less often transplanted with >10% blasts and had a lower performance scores. RIC recipients received fully matched unrelated donor (URD) grafts and PBSC as hematopoietic source more often than MA patients. Proportion with adverse cytogenetics, IPSS categories for MDS patients, median time to first relapse in AML CR2 patients, and marrow blasts at HCT were similar in the conditioning groups. 5-years univariate probabilities and multivariate relative risk (RR) outcomes of relapse, transplant-related mortality (TRM), leukemia-free (LFS) and overall survival (OS) are shown below: Outcome: MA RIC PBSC RIC BM NMA Univariate: Relapse, % 32 (31-34) 39 (35-43) 42 (36-48) 43 (38-48) TRM,% 34 (32-36) 34 (30-38) 37 (31-43) 36 (31-41) Adjusted LFS, % 33 (31-34) 30 (26-35) 28 (23-34) 24 (20-29) Adjusted OS, % 34 (33-36) 33 (29-37) 32 (27-38) 26 (21-30) Multivariate: Relapse* ( ) 1.51 ( ) 1.64 ( ) TRM* ( ) 1.36 ( ) 1.55 ( ) Treatment failure* ( ) 1.17 ( ) 1.28 ( ) Mortality* ( ) 1.12 ( ) 1.20 ( ) * overall p<0.001 MA regimens were associated with significantly less relapse (RR with RIC/NST 1.32 ( ), p <0.001). While early TRM was substantially less with RIC/NMA approaches, 5 year TRM is equivalent (p=0.48). This leads to marginally better 5 year LFS (RR 1.08, p=0.05) but similar OS (RR 1.05, p=0.25) with MA vs. RIC/NST. These data indicate that late TRM negates any early advantage offered by RIC and NMA regimens, resulting in similar but slightly better 5 year LFS in recipients of MA conditioning. Similar outcomes with these RIC/NMA vs. MA regimens suggest the need for prospective trials comparing these transplant intensities in patients eligible for either approach. 70

71 Not for publication or presentation Attachment 6 TO: FROM: Writing Committee for study LK04-03: Vikas Gupta, Corey Cutler, K Ballen, A Bashey, M Cairo, B Camitta, R Champlin, RP Gale, J Gajewski, G Hale, W Hogan, J Horan, H Lazarus, D Marks, Waleska S.Pérez, P McCarthy, MM Lill, G Milone, A Rubin, G Schiller, G Socie, J Szer, RS. Weiner, C Nabhan, Gisela Tunes da Silva, Jorge Sierra, Martin Tallman, John F. Dipersio, Mary Horowitz Armand Keating, MD, Manisha Kukreja, MBBS, MPH, and Daniel Weisdorf, MD DATE: August 12, 2008 RE: Final analyses for CIBMTR study # LK04-03: Comparison of Autologous Blood Cell and HLA-identical Sibling Myeloablative Transplants for Acute Myeloid Leukemia in First Complete Remission. Enclosed is a description of the patient population and results of univariate and multivariate analyses of treatment-related mortality, relapse, leukemia-free survival, and overall survival of patients years of age in first complete remission who underwent blood cell auto transplants or HLA-identical myeloablative allogeneic transplants for AML from , reported to the CIBMTR. Patients with the following characteristics were excluded from the study population: Recipients of syngeneic transplants, T-cell depleted, umbilical cord blood and Non-myeloablative transplants. Additional patients will also be excluded, including those with M3 FAB, granulocytic sarcoma, patients with previous MDS, and patients with prior malignancy. Eleven hundred thirty three (1133) met the on-study criteria. The three groups of comparison are allogeneic bone marrow, allogeneic peripheral blood and autologous peripheral blood Transplants. The number of cases in each group is 475, 428, and 230 respectively. The cases identified came from 315 reporting centers from 40 different countries. Median follow-up of survivors for each of above mentioned groups are 82 (6-149), 60 (4-144), and 62 (1-139) months respectively. Table 1 shows the patient, disease, and transplant characteristics of the 1133 patients included in the study. Table 2 shows univariate analyses of the outcomes of interests for all three group included in the study. Probability of leukemia-free survival and overall survival was calculated using the Kaplan- Meier estimator, with the variance estimated by Greenwood s formula. Values for other endpoints were calculated using cumulative incidence curves to accommodate competing risks. Table 3 shows all the variables tested in the model. The primary outcomes studied were treatment-related mortality, relapse, leukemia-free survival and overall survival. Assessments of potential risk factors for outcomes of interest were evaluated in 71

72 Not for publication or presentation Attachment 6 multivariate analyses using the pseudo-value technique. These analyses fit models to determine which risk factors were related to a given outcome. The pseudo-value technique to analyze survival data on predetermined time points was used in this multivariate analysis because the proportional assumption needed for the Cox model does not hold for overall survival. Two time points were considered (one year and five years) and separate analysis were made for each time point. For overall survival and leukemia free survival, pseudo-values were computed using the Kaplan Meier estimator for the survival function and a generalized linear model with complementary log-log link function was used. For Relapse and treatment mortality, pseudo-values for the cumulative incidence function were computed and a generalized linear model with complementary log log function was fitted for each time point (one year and five years). The cutpoints for low/high risk groups for two continuous variables (time from diagnosis to transplant and time from CR1 to transplant) were determined by a multivariate analysis based on pseudo-values and Wald test statistic. Table below shows the cutpoints obtained. Values for Cutpoints Time from CR1 to transplant: <= 5 months vs >5 months. Time from diagnosis to transplant: <=6 months vs >6 months. Initially, an analysis was done with each model containing the main effect for type of transplant (Allo BM vs Allo PB vs Auto PB). However, risks associated with Allo BM and Allo PB were virtually identical in all analysis, so final models now show only the relative risk of each outcome for patients receiving any Allo Tx (Allo BM/PB) versus those receiving Auto PB. The p-values for the tests that Allo BM and Allo PB are equal; are shown as a footnote in each table. Variables not listed in the final models did not meet the 0.05 level of significance. The estimated hazard ratios of the final models are shown in Tables (4A,4B, 5A,5B,6A,6B,7A,7B). APPENDICES: FOR THE MULTIVARIATE ANALYSIS Overall survival; 1 Year, overall survival 5 years: Tables (4A,4B) Leukemia free survival 1 year; leukemia free survival 5 years Tables (5A,5B) TRM 1 yr and 5 yr Tables (6A,6B) Relapse 1 yr and 5 yr Tables (7A,7B). For overall survival: There is no difference in the risk of death among groups at one year, and 5 year (p-value= 1 year; and 5 year). The results for the leukemia free survival show that there are differences among groups in both 1 year and 5 years leukemia free survival. In both time points, auto PB have higher risk of death or 72

73 Not for publication or presentation Attachment 6 relapse when compared with the allo BM/PB group. Age is a significant covariate for both 1 and 5 years leukemia free survival. For relapse and treatment-related mortality For TRM at one year, wee can see that auto PB have lower incidence of TRM when compared with allo BM/PB. The same holds for the 5 year TRM, but at 5 years we also see an important effect of age and year of transplantation. Model of Relapse at 1 year, indicate that there is an interaction between the graft and extramedullary disease and other significant covariates are year of transplant and number of consolidation therapy. While the relapse at 5 years, we see that there is a significant interaction between graft and age of the patient at transplant and other significant covariates are year of transplant and extramedullary disease. Note: cytogenetic classifications were included as covariates to be tested in the multivariate model, but did not appear significant in multivariate analysis. Table 8 shows the causes of death. Attached are Kaplan-Meier and cumulative incidence curves illustrating the primary outcomes. Please review this summary critically and send your comments to: Armand Keating, MD, Epstein chair in cell therapy and transplantation, Dept. of Medical Hematology/ Oncology, Princess Margaret Hospital, 610 University Avenue, Suite 5-303,Toronto, Ontario, CANADA, M5G 2M9; Telephone: (416) ; Fax: (416) ; armand.keating@uhn.on.ca with a copy via Fax or to Manisha Kukreja, MBBS, MPH at the CIBMTR Statistical Center [Fax: , mkukreja@mcw.edu] by August 25, You should note that any member of a Writing Committee who does not make a substantive contribution to the design, analysis, interpretation or manuscript would be expected to withdraw as a co-author or, alternatively, the lead author could remove names of non-contributors. If we do not hear from you by August 25, 2008 we may assume, you no longer wish to participate in the study. The rules of the CIBMTR require inclusion of the following statement: "The enclosed raw data are confidential. If used publicly, the following statement must be included: The data presented here were obtained from the Center for International Blood and Marrow Transplant Research. The analysis has not been reviewed or approved by the Advisory Committee of the CIBMTR. The data may not be published without prior approval of the Advisory Committee." If the data are used in an oral presentation, please send us the name, place and dates of the meeting where the data are presented, and the title of your presentation. Enclosures 73

74 Not for publication or presentation Attachment 6 Table1. Characteristics of patients years of age in first complete remission who underwent blood cell autotransplants or HLA-identical Myeloablative Allogeneic transplants for AML, reported to the CIBMTR from a. Allo BM Allo PB Auto PB P-value d Number of patients a Number of centers Age, median (range), years 36 (19-60) 40 (19-60) 44 (19-60) <0.001 Age at transplant, years < (31) 90 (21) 41 (18) (35) 112 (26) 58 (25) (27) 153 (36) 61 (27) ( 7) 73 (17) 70 (30) Male sex 244 (51) 236 (55) 113 (49) 0.29 Karnofsky score 0.05 pretransplant <90 79 (17) 90 (21) 54 (24) > (82) 332 (78) 168 (73) Unknown 7 ( 1) 6 ( 1) 8 ( 3) FAB classification <0.001 M0 12 ( 3) 20 ( 5) 9 ( 4) M1 94 (20) 66 (16) 35 (15) M2 151 (31) 121 (28) 67 (29) M4 126 (26) 78 (18) 53 (23) M5 55 (12) 76 (18) 46 (20) M6 11 ( 2) 13 ( 3) 4 ( 2) M7 4 ( 1) 5 ( 1) 2 ( 1) AML unclassified 19 ( 4) 39 ( 9) 11 ( 5) Other AML 3 ( 1) 10 ( 2) 3 ( 1) WBC at diagnosis, median (range), x10 9 /L 14 (<1-900) 13 (<1-266) 18 (<1-470) 0.16 Missing

75 Not for publication or presentation Attachment 6 Table 1. Continued. Allo BM Allo PB Auto PB P-value WBC at diagnosis 0.24 <20 x10 9 /L 250 (58) 234 (59) 107 (52) x10 9 /L 79 (18) 73 (19) 36 (17) x10 9 /L 58 (13) 52 (13) 42 (20) >100 x10 9 /L 46 (11) 35 ( 9) 23 (11) Missing Cytogenetics b <0.001** No abnormalities 192 (40) 195 (46) 105 (46) Good 30 ( 6) 12 ( 3) 15 ( 7) Intermediate 106 (22) 129 (30) 53 (23) Poor 26 ( 6) 39 ( 9) 17 ( 7) Missing/Unknown 121 (26) 53 (12) 40 (17) Extramedullary disease 28 ( 6) 48 (10) 17 ( 7) 0.06 Missing Time from diagnosis to transplant, median (range), months 5 (2-31) 4 (2-15) 5 (1-38) <0.001 Time from CR1 to transplant, median (range), months 3 (<1-18) 3 (<1-15) 4 (1-35) <0.001 Missing Presence of CNS disease prior to transplant 8 ( 2) 13 ( 3) 10 ( 4) 0.11 Missing Number of chemotherapy 0.26 cycles to achieve CR 1 cycle 319 (72) 275 (73) 163 (78) > 2 cycles 122 (28) 104 (27) 46 (22) Missing Number of consolidation <0.001 treatments prior to transplant 1 cycle 192 (40) 169 (40) 110 (48) > 2 cycle 136 (29) 74 (17) 75 (32) No consolidation 77 (16) 107 (25) 12 ( 6) Missing 70 (15) 78 (18) 33 (14) 75

76 Not for publication or presentation Attachment 6 Table 1. Continued. <0.001 Allo BM Allo PB Auto PB P-value High dose Cytarabine consolidation c Standard dose 144 (30) 87 (20) 46 (20) High dose 194 (41) 193 (45) 151 (66) Other drug given 55 (12) 34 ( 8) 19 ( 8) No therapy 77 (16) 107 (25) 12 ( 5) Missing 5 ( 1) 7 ( 2) 2 ( 1) Purging NA NA 4 ( 2) NA Missing 3 Year of transplant < (25) 26 ( 6) 29 (13) (22) 61 (14) 33 (14) (14) 35 ( 8) 36 (16) (13) 28 ( 7) 45 (19) ( 8) 40 ( 9) 36 (16) ( 5) 55 (13) 9 ( 4) ( 3) 45 (11) 13 ( 5) ( 4) 41 (10) 18 ( 8) ( 3) 40 ( 9) 5 ( 2) ( 3) 57 (13) 6 ( 3) Median follow-up of survivors, months 82 (6-149) 60 (4-144) 62 (1-139) Abbreviations: WBC = white blood cells; RIC = reduced-intensity conditioning; PB = peripheral blood; CR = complete remission; BM = bone marrow. a Selection criteria: Patients years of age who underwent an autologous BM or PBSC or HLA-identical sibling Myelogeneic allogeneic BM or PBSC transplant for acute myeloid leukemia in first complete remission transplanted between Patients with granulocytic sarcoma, AML transformed from MDS, M3 FAB subtype, prior malignancy, syngeneic transplants or cord blood transplants were excluded. b Cytogenetics classification is defined as follow: Good prognosis includes: 16q; t(8;21); t(15;17). Intermediate prognosis includes: +8; +21; t(1;7); t(8;16); other abnormalities. Poor prognosis includes: -5/5q-; -7/7q-; -20/20q-; 3q; 11q; t(5;7); t(9;22); t(6;9); ** p values=0.03 to detect the level of difference in each group s cytogenetic abnormality (excluding unknown/untested category) c Cytarabine dose defined: cytarabine<1 gm/m 2 /d=standard dose cytarabine, : cytarabine 1 gm/m 2 /d=high dose cytarabine. d The chi-square test was used for discrete covariates; the Kruskal-Wallis test was used for continous covariates. Completeness index=87% 76

77 Not for publication or presentation Attachment 6 Table 2. Univariate probabilities of transplant outcomes among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLAidentical Myeloablative Allogeneic transplants for AML, reported to the CIBMTR from Allo BM Allo PB Auto PB Outcome event a N Prob (95% CI) N Prob (95% CI) N Prob (95% CI) P-value Relapse year 12 ( 9-15) 15 (12-19) 33 (27-39) < years 19 (16-23) 21 (17-25) 42 (35-48) < years 20 (17-24) 26 (21-30) 45 (38-52) <0.001 b TRM year 16 (13-20) 14 (11-18) 5 (2-8) < years 19 (15-22) 19 (16-23) 7 (4-11) < years 19 (16-23) 20 (17-24) 8 (5-12) <0.001 b LFS year 72 (67-75) 71 (66-75) 62 (55-68) years 62 (58-67) 60 (55-65) 51 (44-57) years 61 (56-65) 54 (49-59) 47 (40-54) 0.13 b Overall survival year 76 (71-79) 75 (71-79) 74 (68-79) years 65 (61-70) 63 (58-68) 58 (52-65) years 64 (59-68) 59 (54-64) 54 (47-60) 0.19 b Abbreviations: TRM = treatment-related mortality; LFS = leukemia-free survival; PROB = probability; CI = confidence interval. a Probabilities of treatment-related mortality and progression/relapse were calculated using the cumulative incidence estimate. Leukemia - free survival and overall survival was calculated using the Kaplan-Meier product limit estimate. b Point wise p-value 77

78 Not for publication or presentation Attachment 6 Table 3. Variables tested in models for multivariate analysis. Main effect variable a Type of Transplant: Allo BM vs. Allo PB vs. Auto PB Patient-related variables: Age at transplant: 40 years* vs. >40 years Gender: female* vs. male Karnofsky performance score: 90%* vs. <90% vs. unknown Disease-related variables FAB subtype at diagnosis: M0-M2* vs. M4-M7 vs. other/unclassified (for AML) WBC at diagnosis: <20* vs vs vs >100 vs. unknown Cytogenetics: no abnormalities or intermediate* vs. good vs. poor prognosis vs. unknown Extramedullary disease: no* vs. yes Time from diagnosis to transplant: TBD Time from CR1 to transplant: TBD Treatment-related: Number of chemotherapy cycles to achieve CR: 1* vs. >1 Number of consolidation therapy prior to transplant: none* vs. 1 vs. 2 vs. unknown Type of consolidation therapy prior to transplant: standard dose* cytarabine vs. high dose cytarabine vs. other drugs vs. no therapy Year of transplant: * vs a Included in all models. *Reference group 78

79 Not for publication or presentation Attachment 6 Table 4A. Multivariate analysis comparing survival at 1 yr among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLAidentical Myeloablative Allogeneic transplants for AML from Variables: N Relative Risk of death (95% CI) P-value Main effect: Allo BM/PB* a Auto PB ( ) b Abbreviations: CI = confidence interval. a Reference group b One degrees of freedom * P-value for test allo PB: allo BM= Table 4B. Multivariate analysis comparing survival at 5 yr among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLAidentical Myeloablative Allogeneic transplants for AML from Variables: N Relative Risk of death (95% CI) P-value Main effect: Allo BM/ PB* a Auto PB ( ) b Other significant covariates: Age <= 40 years a > 40 years ( ) b Karnofsky score c >=90% a <90% ( ) Unknown ( ) Abbreviations: CI = confidence interval. a Reference group b One degrees of freedom c Two degrees of freedom * P-value for test allo PB: allo BM=

80 Not for publication or presentation Attachment 6 Table 5A. Multivariate analysis comparing leukemia free survival at 1 yr among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLA-identical Myeloablative Allogeneic transplants for AML from Variables: N Relative Risk of death or relapse (95% CI) P-value Main effect: Allo BM/ PB* a Auto PB ( ) b Other significant covariates: Age <= 40 years a > 40 years ( ) b Abbreviations: CI = confidence interval. a Reference group b One degrees of freedom * P-value for test allo PB: allo BM= Table 5B. Multivariate analysis comparing leukemia free survival at 5 yr among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLA-identical Myeloablative Allogeneic transplants for AML from Variables: N Relative Risk of death or relapse (95% CI) P-value Main effect: Allo BM/ PB* a Auto PB ( ) b Other significant covariates: Age <= 40 years a > 40 years ( ) b Abbreviations: CI = confidence interval. a Reference group b One degrees of freedom * P-value for test allo PB: allo BM=

81 Not for publication or presentation Attachment 6 Table 6A. Multivariate analysis comparing TRM at 1 yr among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLAidentical Myeloablative Allogeneic transplants for AML from Variables: N Relative Risk of TRM (95% CI) P-value Main effect: Allo BM/PB* a Auto PB ( ) b Abbreviations: CI = confidence interval. a Reference group b One degrees of freedom * P-value for test allo PB: allo BM= Table 6B. Multivariate analysis comparing TRM at 5 yr among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLAidentical Myeloablative Allogeneic transplants for AML from Variables: N Relative Risk of TRM (95% CI) P-value Main effect: Allo BM/PB* a Auto PB ( ) b Other significant covariates: Age <= 40 years a > 40 years ( ) b Year of transplant a ( ) b Abbreviations: CI = confidence interval. a Reference group b One degrees of freedom * P-value for test allo PB: allo BM=

82 Not for publication or presentation Attachment 6 Table 7A. Multivariate analysis comparing Relapse at 1 yr among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLAidentical Myeloablative Allogeneic transplants for AML from Variables: N Relative Risk of Relapse (95% CI) P-value Main effect: (Group*extramedullary disease) <.0001 d Allo BM/PB, no extr a Allo BM/PB, yes extr ( ) Auto PB, no extr ( ) <.0001 Auto PB, yes extr ( ) <.0001 Other significant covariates: Year of transplant a ( ) b Number consolidation Therapy d none a ( ) >= ( ) Unknown ( )

83 Not for publication or presentation Attachment 6 Table 7B. Multivariate analysis comparing Relapse at 5 yr among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLAidentical Myeloablative Allogeneic transplants for AML from Variables: N Relative Risk of Relapse (95% CI) P-value Main effect: (Group*age) <.0001 d Allo BM, <= 40 years a Allo BM, > 40 years ( ) Auto PB, <= 40 years ( ) Auto PB, > 40 years ( ) <.0001 Other significant covariates: Extramedullary disease No a Yes ( ) b Year of transplant a ( ) <.0001 b Abbreviations: CI = confidence interval. a Reference group b One degrees of freedom d Three degrees of freedom 83

84 Not for publication or presentation Attachment 6 Table 8. Causes of death among patients years of age in first complete remission who underwent blood cell autotransplants (ABCT) or HLA-identical Myeloablative Allogeneic transplants for AML, reported to the CIBMTR from Allo BM Allo PB Auto PB Causes of death Number of patients Number of deaths Graft rejection 5 ( 3) 0 0 Primary disease 66 (37) 64 (35) 68 (67) GVHD 20 (11) 30 (17) 0 IpN 9 ( 5) 10 ( 5) 3 ( 3) Infection 32 (18) 35 (19) 12 (11) ARDS 4 ( 2) 3 ( 2) 0 Organ Failure 19 (11) 8 ( 5) 9 ( 8) New malignancy 3 ( 2) 2 ( 1) 1 ( 1) Hemorrhage 9 ( 5) 7 ( 4) 2 ( 2) Vascular 2 ( 1) 1 ( 1) 0 Other** 7 ( 4) 12 ( 7) 2 ( 2) Missing 2 ( 1) 9 ( 4) 6 ( 6) Abbreviations: GVHD = Graft-vs-Host Disease; IpN = interstitial pneumonia; ARDS = adult respiratory distress syndrome. **Others include (N=21): Cardio pulmonary arrest (n=3); non hematological reason (n=1); TTP (n=2); unknown (n=18) 84

85 Not for publication or presentation Attachment 6 85

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87 Not for publication or presentation Attachment ASH ABSTRACT Similar 5-Year Survival after Peripheral Blood Autotransplants (AutoPB) versus HLA Matched Sibling Myeloablative Transplants (AlloBMT) for Acute Myeloid Leukemia (AML) in First Complete Remission (CR1) A Keating, M. Kukreja, G. Silva, V. Gupta, C. Cutler, M. Tallman, J. Sierra, J. DiPersio, M. Horowitz, D. Weisdorf on behalf of the Writing Committee. Center for International Blood and Marrow Transplant Research, Milwaukee, WI. Optimum post-remission strategies for AML CR1 remain uncertain. Previous studies comparing autotransplants with allobmt favored the latter because of less relapse despite treatment-related mortality (TRM) rates of 20-30%. In those studies, the autotransplants were exclusively with bone marrow (BM) and reported TRM of 12-20%. We were interested in determining the effect of lower TRM with AutoPB shown in many series to be 5-10%. We compared TRM, relapse, leukemia-free survival (LFS), and overall survival (OS) of 1133 patients years of age in CR1 who underwent HLA-identical myeloablative BM or peripheral blood (PB) allogeneic transplants or AutoPB for AML reported to the CIBMTR from For allobm, allopb and autopb, median ages were 36, 40 and 44 yrs; cytogenetics were missing/unknown in 26%, 12% and 17%; proportion with poor risk cytogenetics was 6%, 9% and 7%; and median follow-up of survivors was 82 (6-149), 60 (4-144), and 62 (1-139) mo., respectively. Outcomes were evaluated in univariate and by multivariate analyses using the pseudo-value technique. Results: 5 year transplant outcomes by univariate analysis are as follows: Allo BM Allo PB Auto PB N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Relapse (17-24) (21-30) (38-52) <0.001 TRM (16-23) (17-24) (5-12) <0.001 LFS (56-65) (49-59) (40-54) 0.13 Survival (59-68) (54-64) (47-60) 0.19 All analyses showed that risks associated with allobm and AlloPB were identical, hence relative risk (RR) was modeled for any allotransplant (allobmt) vs autopb. Multivariate analysis of allobmt vs autopb cohorts revealed that age >40 yrs was associated with increased RR for TRM, LFS and OS at 5yrs:1.39 ( ;n=518;p=0.019);1.25( ;n=521;p=0.015);1.28( ;n=521;p= 0.012), respectively. For relapse at 5 yrs, the presence of extramedullary disease was a poor prognostic factor: [RR: 1.60 ( ); for no n=1036; yes n=88]. Cytogenetics risk category was not a significant co-variate for TRM (p=0.84), relapse (p=0.13), LFS (p=0.27) or OS (p=0.062) at 5 yrs. Conclusions: AutoPB may provide acceptable alternative post-remission therapy for AML CR1 in the absence of a matched sibling donor, and its role in this regard should be re-investigated prospectively. 87

88 Not for publication or presentation Attachment 7 CIBMTR R02-05 UNRELATED DONOR STEM CELL TRANSPLANTATION IN AML AND ALL PATIENTS WHO FAILED AN AUTOLOGOUS TRANSPLANT REVISED PROTOCOL Study Chairs: James Foran, MD Assistant Professor of Medicine Division of Hematology and Oncology University of Alabama at Birmingham th Avenue South, WTI 225 Birmingham, AL Telephone: Fax: james.foran@ccc.uab.edu Steven Z. Pavletic, MD National Cancer Institute National Institutes of Health 10 Center Drive, Room 12S241 Bethesda, MD Telephone: pavletis@mail.nih.gov Study Statistician: Manza-A. Agovi, MPH CIBMTR 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI Telephone: Fax: magovi@mcw.edu 88

89 Not for publication or presentation Attachment 7 Working Committee Chairs: Armand Keating, MD Chief of Medical Services Head of the Dept. of Medical Hematology/ Oncology Princess Margaret Hospital 610 University Avenue, Suite Toronto, Ontario, CANADA M5G 2M9 Telephone: Fax: armand.keating@uhn.on.ca Martin Tallman, MD Professor of Medicine Division of Heamatology-Oncology Department of Medicine, Northwestern Memorial Hospital Northwestern University 676 North St. Clair Street, Suite 850 Chicago, IL Telephone: Fax: m-tallman@northwestern.edu Jorge Sierra, MD Professor of Medicine Director, Clinical Hematology and BMT Program Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona Barcelona, SPAIN, Telephone: (34) Fax: (34) jsierra@hsp.santpau.es Scientific Director: Daniel J. Weisdorf, MD Division of Hematology University of Minnesota 420 Delaware Street, SE, Box 480, UMHC Minneapolis, MN USA Telephone: Fax: weisd001@umn.edu 89

90 Not for publication or presentation Attachment OBJECTIVES: 1.1 To determine the outcome of patients with acute lymphoblastic leukemia or acute myeloid leukemia who received an unrelated donor (URD) stem cell transplant after failing a previous autologous transplant as measured by treatment-related mortality, overall and disease-free survival. 1.2 To identify the subset of recipients with best outcome, and to identify prognostic factors related to the main clinical outcomes. 2.0 SCIENTIFIC JUSTIFICATION: The prognosis of hematologic malignancy patients relapsing after autologous blood stem cell transplantation is very poor. Allogeneic stem cell transplantation from matched sibling donors offers a possibility of curing some of these patients but at costs of high transplant related mortality. 1-7 Frequently, patients in whom autologous transplantation is performed do not have an HLA-matched related donor and become candidates for URD transplants. There is little literature information about the outcomes after URD transplantation in patients who failed autologous transplant and the value of this kind of salvage strategy is unknown. At the University of Nebraska Medical Center six lymphoma patients received a myeloablative matched URD bone marrow transplant for relapse after an autologous stem cell transplant. Five of them have died of transplant related toxicities within the first 100 days post-transplant and one patient died in remission at 12 months from hemolyticuremic syndrome (Steven Pavletic, non-published observation). Similar high transplantrelated mortality in unrelated donor transplant patients after a failed autologous transplant have been recorded by others. 2-4 However, some reports suggest a possibility that some patients who relapse after autologous transplantation may achieve long-term survival benefit from a second allogeneic unrelated donor transplant. 5-7 In an EBMT study, Ringden et al reported 2-year survival of 37% in a group of 62 acute leukemia patients who received allogeneic transplant from HLA matched related (n=29) and unrelated (n=33) donors. 5 Blau et al reported on 5/10 patients who become long-term survivors ( days) after a post-autologous URD allotransplant. 6 In a most elaborate report on the topic, Radich et al evaluated 59 leukemia and lymphoma patients aged 1-57 years who relapsed after initial autologous transplantation. 7 Twenty patients in that study received grafts from matched unrelated donors and 2-year disease-free survival in that subset was 19%. Univariate analysis of all 59 patients showed that superior disease-free survival was associated with age <17 years, remission at the time of second transplantation, TBI-based regimen for second transplant, and the diagnosis of AML. Type of donor (related vs. unrelated) was not statistically significantly associated with disease-free survival. The 2- year disease-free estimates for AML, ALL, and lymphoma were 46%, 23%, and 0% respectively. 7 No study to date has specifically analyzed URD transplantation as a salvage strategy for patients who failed an autologous transplant, although some additional recent reports suggest that it is feasible in selected patients This question is even more important today since an alternative treatment approach exists with using a nonmyeloablative regimen rather than a high-intensity regimen. Non-myeloablative transplants have somewhat less short-term transplantation related toxicity but the 90

91 Not for publication or presentation Attachment 7 8, 9, cytoreductive effect of such regimens may be insufficient for adequate disease control. 11, 13, 14 Particularly in patients with more rapidly progressive malignancy, high-dose regimens may still have an advantage. Therefore, for defining best salvage strategies after an autologous transplant it would be important to identify patients who may benefit from high-dose URD transplant therapy. The CIBMTR database is a unique resource and the results of such a study should ultimately help in increasing the utilization of URD transplantation by determining the optimal patient and the most appropriate transplantation regimen. 3.0 STUDY POPULATION: Inclusion criteria: - Unrelated donor transplant for recurrent malignancy or persistent disease between Prior autologous transplant for AML or ALL - Diagnosis of AML or ALL Exclusion criteria: - Cord blood transplant - Prior allogeneic transplant - More than one prior high-dose regimen (i.e., more than one prior tx) - Prior autologous transplant for other diagnosis such as breast cancer, NHL and HL. 4.0 OUTCOMES: Primary outcomes: 4.1 Disease-free survival: An event is death without hematologic relapse post- HCT. 4.2 Overall survival: Deaths from any cause are events. Surviving patients are censored at the date of last contact. 4.3 Non-relapse mortality: Any patient s death prior to relapse of the underlying disease. Secondary outcomes: 4.4 Hematopoietic recovery: Patients without hematopoietic recovery will be censored at the time of death or last follow-up. Patients that survive <21 days without recovery will be considered not evaluable. 4.5 Acute GVHD: The occurrence of skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of Grades II, III and/or IV acute GVHD are considered events. Patients without acute GVHD will be censored at the time of death or last follow-up. Patients receiving a second transplant will be censored format the time of second transplant. 91

92 Not for publication or presentation Attachment Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the criteria of limited or extensive chronic GVHD, among patients surviving > 80 days with evidence of engraftment. Patients without chronic GVHD will be censored at time of death or last follow-up. 4.7 Day-100 Survival: Deaths from any cause up to 100 days post-transplant are events. Surviving patients are censored at the date of last contact date or day 100, whichever is sooner. 4.8 Time to relapse: Time from URD transplant to occurrence of relapse or recurrence of underlying disease. Patients dying before relapse will be evaluated separately from the time of death. 5.0 VARIABLES TO BE ANALYZED (TBD): Patient-related: - Age - Gender: male vs. female - Race - CMV status: positive vs. negative - Lansky/Karnofsky performance score pre-transplant: <90 vs Serum bilirubin prior to conditioning - Serum creatinine prior to conditioning - Cardiac ejection fraction - Pulmonary diffusion capacity (% predicted) - For these 4 latter variables; if excess missing data (>20% of subjects), these variables will not be considered Disease-related factors: - Date of diagnosis - Disease status at transplant: Complete remission vs. no CR - Bone marrow cytogenetics at any time prior to URD HCT (for AML, ALL) Transplant-related factors (autologous): - Date of transplant - Interval from diagnosis to autologous transplant - Date of relapse/progression post autologous HCT Transplant-related factors (unrelated): - Donor age - Donor gender: male vs. female - Donor race - Donor parity - Donor CMV status: positive vs. negative - Blood vs. marrow 92

93 Not for publication or presentation Attachment 7 - Interval from relapse to URD transplant - Interval from autologous transplant to URD transplant - HLA matching at A, B, C, DRB1: well matched vs. partially matched vs. mismatch - ABO compatibility o Conditioning regimen: Myeloablative: or Reduced intensity/nonmyeloablative conditioning (RIC/NMA) o GVHD prophylaxis: T-cell depletion vs. non T-cell depleted prophylaxis o Total nucleated cell for marrow, total mononuclear cell count for PBSC and CD34 cell dose for PBSC, if available - Growth factor use post-transplant - Acute GVHD, stage (II-IV and III-IV) as a time-dependent variable o Chronic GVHD any severity 6.0 STATISTICAL METHODS: To summarize the characteristics of the dataset, descriptive tables of patient- diseasedonor- and transplant-related factors will be reported. For discrete factors, the number of cases and their respective percentages will be calculated. For continuous factors, the median and ranges will be calculated. Probabilities for overall survival, day-100 survival and disease-free survival will be calculated using the Kaplan-Meier estimator with variance estimated by Greenwood's formula. Values for hematopoietic recovery, acute GVHD, chronic GVHD, time to relapse and non-relapse mortality will be calculated according to cumulative incidence function to accommodate the competing risks data. Due to the small sample size of patients with ALL, the assessment of outcomes of interest will not be evaluated in the multivariate analysis. The multivariate analysis, which will focus on AML patients only, will be performed using the proportional hazards model. Models will be fit to determine which risk factors affect outcome. All variables (to be determined) will be examined to ensure that they comply with the proportional hazards assumption. Factors found to have non-proportional hazards will be adjusted for in subsequent analyses. A stepwise model building approach will then be used to develop models for overall survival and disease-free survival, time to relapse and non-relapse mortality. 7.0 REFERENCES: 1. Lima M, van Besien KW, Giralt SA et al. Bone marrow transplantation after failure of autologous transplant for non-hodgkin s lymphoma. Bone Marrow Transplant 1997; 19: Martinez C, Carreras E, Montserrat R et al. Allogeneic stem cell transplantation as salvage therapy for patients relapsing after autologous transplantation: experience from a single institution. Leuk Res 2001; 25: Tsai T, Goodman S, Saez R et al. Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation. Bone Marrow Transplant 1997; 20:859-93

94 Not for publication or presentation Attachment Chiang KY, Weisdorf DJ, Davies SM et al. Outcome of second bone marrow transplantation following a uniform conditioning regimen as therapy for malignant relapse. Bone Marrow Transplant 1996; 17: Ringden O, Labopin M, Gorin NC et al. The dismal outcome in patients with acute leukemia who relapse after an autograft is improved if a second autograft or a matched allograft is performed. Bone Marrow Transplant, 2000; 25; Blau IW, Basara N, Bischoff M et al. Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following first transplant. Bone Marrow Transplant, 2000; 25: Radich JP, Gooley T, Sanders JE et al. Second allogeneic transplantation after failure of first autologous transplantation. Biol Blood Marrow Transplant, 2000; Feinstein LC, Sandmeier BM, Maloney DG et al. Allografting after nonmyeloablative conditioning as a treatment after a failed conventional hematopoietic cell transplant. Biol Blood and Marrow Transplant 2003; 9: Grüllich C, Bertz H, Spyridonidis A, Müller CI, Finke J. A fludarabine, thiotepa reduced toxicity conditioning regimen designed specifically for allogeneic second haematopoietic cell transplantation after failure of previous autologous or allogeneic transplantation. Bone Marrow Transplant 2008 Jan 21 [Epub ahead of print] 10. Al-Qurashi F, Ayas M, Al Sharif F, Ibrahim E, Sahovic E, Al Mahr M, Chaudhri N, Al Mohareb F, Al Zahrani H, Al Jefri A, Al Omar H, Al Shanqeeti A, Seth P, Aslam M, El Solh H, Aljurf M. Second allogeneic bone marrow transplantation after myeloablative conditioning analysis of 43 cases from single institution. Hematology 2004; 9: Corradini P, Zallio F, Mariotti J, Farina L, Bregni M, Valagussa P, Ciceri F, Bacigalupo A, Dodero A, Lucesole M, Patriarca F, Rambaldi A, Scimè R, Locasciulli A, Bandini G, Gianni AM, Tarella C, Olivieri A. Effect of age and previous autologous transplantation on nonrelapse mortality and survival in patients treated with reducedintensity conditioning and allografting for advanced hematologic malignancies. J Clin Oncol 2005; 23: Meshinchi S, Leisenring WM, Carpenter PA, Woolfrey AE, Sievers EL, Radich JP, Sanders JE. Survival after second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia. Biol Blood Marrow Transplant 2003; 9: Baron F, Storb R, Storer BE, Maris MB, Niederwieser D, Shizuru JA, Chauncey TR, Bruno B, Forman SJ, McSweeney PA, Maziarz RT, Pulsipher MA, Agura ED, Wade J, Sorror M, Maloney DG, Sandmaier BM. Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopoietic cell transplantation. J Clin Oncol 2006; 24: Fung HC, Cohen S, Rodriguez R, Smith D, Krishnan A, Somlo G, Sahebi F, Senitzer D, O'Donnell MR, Stein A, Snyder DS, Spielberger R, Bhatia R, Falk P, Molina A, Nademanee A, Parker P, Kogut N, Popplewell L, Vora N, Margolin K, Forman SJ. Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed. Biol Blood Marrow Transplant 2003; 9:

95 Not for publication or presentation Attachment 7 Table 1. Characteristics of patients who underwent an allogeneic transplant for acute myelogenous leukemia or acute lymphoblastic leukemia after failing a previous autologous transplant from 1995 to 2005, reported to the CIBMTR. AML ALL Characteristics of patients N (%) N (%) Number of patients Number of centers Age at transplant, median (range), years 38 (1-67) 21 (1-56) <10 22 ( 7) 8 (13) ( 9) 20 (32) (18) 16 (26) (21) 11 (18) (18) 5 ( 8) (21) 2 ( 3) ( 6) -- Male sex 155 (48) 49 (79) Karnofsky score < (38) 27 (43) (59) 34 (55) Missing 10 ( 3) 1 ( 2) Reason for 2 nd transplant Relapse 315 (97) 61 (98) Disease status prior to conditioning a >1 st complete remission 228 (70) 35 (56) Relapse 89 (27) 22 (35) Donor-recipient HLA match b status Well-matched 107 (33) 7 (11) Partially matched 104 (32) 20 (32) Mismatched 51 (16) 7 (11) To be determined 63 (19) 28 (45) Donor age, median (range) years 36 (19-57) 36 (21-56) Missing 13 8 Donor-recipient sex match M-M 98 (30) 29 (47) M-F 56 (17) 18 (29) F-M 93 (29) 9 (15) F-F 72 (22) 4 ( 6) Missing 6 ( 2) 2 ( 3) Graft type Bone marrow 201 (62) 51 (82) Peripheral blood stem cells 124 (38) 11 (18) 95

96 Not for publication or presentation Attachment 7 Table 1. Continued. AML ALL Characteristics of patients N (%) N (%) Interval between 1 st auto transplant and 2 nd allo transplant median (range) months 14 (1-187) 13 (1-89) 6 months 46 (14) 5 ( 8) > 6 months 278 (86) 56 (92) Donor recipient CMV status Positive/ positive 83 (25) 15 (24) Positive/ negative 48 (15) 10 (16) Negative/ positive 103 (32) 15 (24) Negative/ negative 84 (26) 21 (34) Missing 7 ( 2) 1 ( 2) Year of transplant (15) 13 (21) (18) 19 (31) (17) 16 (26) (18) 11 (18) (22) 1 ( 2) (11) 2 ( 3) Conditioning regimen type Myeloablative 313 (81) 70 (90) RIC/NMA 76 (20) 8 (10) Conditioning regimen Cy + TBI ± other 131 (40) 20 (32) Cy + Bu ± other 50 (15) 26 (42) TBI ± other 43 (14) 2 ( 3) Cy ± other 8 ( 3) 5 ( 9) Bu ± other 27 ( 9) 3 ( 5) Fludara + LPAM ± other 56 (17) 2 ( 4) Fludara ± other 2 ( 1) 2 ( 4) Lpam ± other 6 ( 2) 2 ( 2) Other c 2 ( 1) -- GVHD prophylaxis None 2 ( 1) -- T-cell depletion 42 (13) 10 (16) CSA + MMF ± other 46 (15) 1 ( 2) CSA + MTX ± other 114 (35) 38 (61) CSA ± other (not MTX) 26 ( 8) 7 (11) FK506 + MMF ± other 22 ( 7) 1 ( 2) FK506 + MTX ± other 56 (17) 4 ( 6) FK506 ± other (not MTX) 14 ( 4) 1 ( 2) MTX ± other 3 ( 1) -- Median follow-up of survivors, months 49 (2-148) 79 (36-100) Abbreviations: CSA= cyclosporine; MTX = methotrexate; FK506=tacrolimus; CSA= cyclosporine; MMF= mycophenolate; MTX=methotrexate; TBI= total body irradiation; Bu=busulfan; Cy=cyclophosphamide; GVHD= graft vs host disease; Fludara= fludarabine; LPAM=melphalan; Cort=corticosteroids; RIC=reduced intensity conditioning; NMA=non myeloablative; CMV=cytomegalovirus; HLA=human leukocyte antigen. 96

97 Not for publication or presentation Attachment 7 Table 1. Continued. a Patients with disease status= 1 st CR or PIF at time of allo transplant will be confirmed with the teams. b Type of donor defined as: Well-matched includes: 1,7,10,16 (see below) Partially matched includes: 2,3,8,11,13,17,21 (see below) Mismatched includes 4,5,6,9,12,14,18,22,23,24 (see below) c Other conditioning regimen: Busulfan + TBI(n=1); Carboplatin + Thiopeta + other (n=1). HLA Groups N 1 Matched 8/8 at high-res HLA-A, -B, -C and DRB Single allele MM (7/8) at high res HLA-A, -B, -C and DRB Single antigen MM (7/8) at high-res HLA-A, -B, -C and DRB allele MM (<7/8) at high-res HLA-A, -B, -C and DRB MM with 1 antigen MM (<7/8) at high-res HLA-A, -B, -C and DRB MM with 2 or more antigen MM (<7/8) at high-res HLA-A, -B, -C and DRB Matched 8/8 at high-res HLA-A, -B, and DRB1 and low-res at HLA-C 9 8 Single MM (7/8) at high-res HLA-A, -B, and DRB1 and low-res at HLA-C MM (<7/8) at high-res HLA-A, -B, and DRB1and low-res HLA-C 1 10 Matched 8/8 at low-res HLA-A, -B, -C and high-res at HLA-DRB Single MM (7/8) at low-res HLA-A, -B, -C and high-res at HLA-DRB MM (<7/8) at low-res HLA-A, -B, -C and high-res at HLA-DRB Matched 8/8 at low-res HLA-A, -B, -C and -DRB Single MM (7/8) at low-res HLA-A, -B, -C and -DRB MM (<7/8) at low-res HLA-A, -B, -C and -DRB Matched 6/6 at high-res HLA-A, -B, DRB1 (HLA-C unknown) 2 17 Single allele MM (5/6) at high-res HLA-A, -B, DRB1 (HLA-C unknown) 0 18 Single antigen MM (5/6) at high-res HLA-A, -B, DRB1 (HLA-C unknown) allele MM (<5/6) ) at high-res HLA-A, -B, DRB1 (HLA-C unknown) MM with 1 antigen MM (<5/6) at high-res HLA-A, -B, DRB1 (HLA-C unknown) 0 21 Matched 6/6 at low-res HLA-A and B and high-res at HLA-DRB1 (HLA-C unknown) Single MM (5/6) at low-res HLA-A and B and high-res at HLA-DRB1 (HLA-C unknown) MM (<5/6) at low-res HLA-A and B and high-res at HLA-DRB1 (HLA-C unknown) 0 24 Matched (6/6) at low-res HLA-A, -B, and -DRB1 (HLA-C unknown) 2 25 Single MM (5/6) at low-res HLA-A, -B, and -DRB1 (HLA-C unknown) 0 26 Two MM (4/6) at low-res HLA-A, -B, and -DRB1 (HLA-C unknown) 0 Patient selection/exclusion criteria: All patients who received a second transplant (allo) for ALL or AML between 1995 and N=1870 Full report forms (n=157 excluded) N=1713 Selected for patients with previous auto transplant N=606 Reason for second transplant= relapse/persistent disease N=495 Excluded 28 cord blood patients N=467 Selected for unrelated donor patients only N=390* * Excluded 3 patients whose autologous transplant was for a NHL (n=2) or Teratoma (n=1). ** 4 other patients suspected of receiving auto transplant as treatment for NHL or breast cancer will be confirmed with the reporting center. Even though recurrent (relapse) disease was checked as reason for second transplant by these patients at the time of allo transplant, if confirmed that the previous auto transplant was for treatment of breast cancer or NHL or HL, these patients will be excluded from the study. *** 77 patients who received other allogeneic transplant (39 HLA- id sibs, 36 other related, 2 other patients) were excluded from the study. These numbers are too small to be considered as a comparable if included in the analysis. 97

98 Not for publication or presentation Attachment 8 CIBMTR R02-09 EVALUATION OF DONOR LEUKOCYTE INFUSIONS TO TREAT RELAPSED HEMATOLOGIC MALIGNANCIES AFTER RELATED AND UNRELATED DONOR MYELOABLATIVE ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION DRAFT PROTOCOL Study Chair: Study Co-Chairs: Alison Wakoff Loren, MD, MS University of Pennsylvania Cancer Center 16 Penn Tower, 3400 Spruce Street Philadelphia, PA Telephone: Fax: awakoff@mail.med.upenn.edu David L. Porter, MD University of Pennsylvania Cancer Center 16 Penn Tower, 3400 Spruce Street Philadelphia, PA Telephone: Fax: david.porter@uphs.upenn.edu Jose Leis, MD Oregon Health and Sciences University 3181 SW Sam Jackson Park Road, UHN 73C Portland, OR Telephone: Fax: leisj@ohsu.edu 98 1

99 Not for publication or presentation Attachment 8 Study Statistician: Acute Leukemia Working Committee Chairs: Zhiwei Wang, MS CIBMTR 9200 W Wisconsin Ave., CLCC Suite C5500 Milwaukee, WI USA Telephone: Fax: zwang@mcw.edu Martin Tallman, MD Division of Heamatology-Oncology Department of Medicine, Northwestern Memorial Hospital Northwestern University 676 North St. Clair Street, Suite 850 Chicago, IL Telephone: Fax: m-tallman@northwestern.edu Jorge Sierra, MD Hospital Sant Pau Creau 1 Sant Pau Sant Antoni M Claret, 167 Barcelona, SPAIN, Telephone: (34) Fax: (34) jsierra@hsp.santpau.es Acute Leukemia Scientific Director: John F. DiPersio, MD, PhD Division of Oncology Washington University School of Medicine Campus Box South Euclid Avenue St. Louis, MO Phone: Fax: jdipersi@im.wustl.edu Daniel J. Weisdorf, MD Division of Hematology University of Minnesota 420 Delaware Street, SE, Box 480, UMHC Minneapolis, MN USA Telephone: Fax: weisd001@maroon.tc.umn.edu 99

100 Not for publication or presentation Attachment HYPOTHESIS: Donor leukocyte infusion (DLI) is increasingly used to treat patients with relapsed hematologic malignancies after myeloablative allogeneic hematopoietic stem cell transplantation (SCT). For patients with relapsed CML after related-donor transplants, cell dose, efficacy and toxicity of DLI are well-defined; however, these parameters are less clear for patients with other malignancies, or for patients receiving transplants from unrelated donors. Based on older analyses with small numbers of patients, we hypothesize that response rates to unrelated-donor DLI (U-DLI) are similar to relateddonor DLI (R-DLI) for CML, and are higher than R-DLI for acute leukemias. We further hypothesize that toxicity from U-DLI is not significantly different from R-DLI. 2.0 OBJECTIVES: Primary: To compare the outcomes of patients with relapsed hematologic malignancies after myeloablative SCT who receive R-DLI and U-DLI, controlling for other important covariables. Outcomes to be studied include: Response rates Disease-free survival (DFS) Cumulative incidence of acute graft-versus-host disease (GVHD) Cumulative incidence of chronic GVHD Cumulative incidence of marrow aplasia Treatment-related mortality (TRM) Overall survival (OS) Secondary: To describe a dose-response (i.e., a minimum effective threshold dose) relationship for DLI, with exploratory comparisons by disease subtype. To explore a dose-toxicity (i.e., a maximum tolerated dose) relationship for DLI. In patients with relapsed CML, to compare DFS and toxicity experienced by patients receiving imatinib mesylate or other tyrosine kinase inhibitors to those receiving DLI. In patients with relapsed acute leukemia or RAEB, to describe the role of induction chemotherapy administered prior to DLI. 3.0 SCIENTIFIC JUSTIFICATION: The graft-versus-tumor (GVT) effect is a critical component of the ability of allogeneic SCT to cure hematologic malignancies, and there is extensive literature demonstrating the efficacy of DLI to treat relapsed disease after transplantation. 1-6 A major limitation of previous studies of DLI is the small number of patients included, compounded when analyzing specific diseases and when attempting to control for important co-variables. It has therefore been difficult to draw definitive conclusions regarding the role of DLI and in particular the relative risks and benefits of U-DLI vs. R-DLI. One study focused 100

101 Not for publication or presentation Attachment 8 primarily on the role of U-DLI compared to R-DLI for CML, but only included 12 recipients of U-DLI. 7 Our series of 58 patients who received U-DLI demonstrated a somewhat lower than expected response rate for relapsed CML (46%), while response rates in patients with AML and ALL were higher than those anticipated in the matched sibling setting (42% and 50% respectively). 4 The conclusions in this study were limited by the small numbers of U-DLI recipients, including 23 AML patients and 7 ALL patients. Although a dose:response effect has been suggested for R-DLI, 8,9 no such relationship was demonstrated for U-DLI in our study. A dose:toxicity relationship for DLI has not been established in either setting. Thus, there remains limited data regarding the role for and outcomes after U-DLI for relapsed disease, 10 and there have been no comprehensive comparative analyses to the R-DLI experience. Given the improving outcomes after myeloablative SCT with more long-term survivors, the use of DLI in both the related and unrelated donor setting is increasingly required for relapse, mixed chimerism, or graft failure. We will better define the appropriate indications, cell doses, and toxicities for R-DLI and U-DLI. In addition, we will address specific disease-related questions. In CML, new treatment options for relapse, such as imatinib mesylate, 11,12 are likely to alter the therapeutic algorithm, and an analysis of response, toxicity, and long-term outcomes after DLI in a larger cohort of patients is appropriate. In acute leukemia, the role of induction chemotherapy prior to DLI may increase the efficacy of the graft-versus-leukemia effect by reducing leukemic burden, but also carries the risk of increased toxicity STUDY POPULATION: The study will include patients reported to the CIBMTR who received DLI between 1993 and 2005 after a myeloablative allogeneic HSCT for hematologic malignancy. Eligible diseases will include: CML, AML, ALL, and myelodysplasia (RAEB and RAEB-T only). Both related- and unrelated-donor transplants will be included. Potential numbers of subjects are given in Table OUTCOMES: 5.1 Response rate: Estimated for the entire cohort of patients, and stratified based on (1) donor type and (2) disease type. Results will be reported as complete, partial, or no response, or not evaluable. If data is available, time to response will be determined. 5.2 DFS: Time to treatment failure (death or relapse). Patients remaining alive and in complete remission will be censored at last follow-up. 13 Estimated for the entire cohort of patients, and stratified based on (1) donor type and (2) disease type. Patients who do not respond to DLI will be considered to have relapsed at day 1 post-infusion. 101

102 Not for publication or presentation Attachment Acute GVHD: Cumulative incidence will be estimated, with death as a competing risk. 14,15 Acute GVHD will be coded as absent (none or grade I) vs. present (grade II or greater). 5.4 Chronic GVHD: Cumulative incidence, with death as a competing risk. 14,15 Chronic GVHD will be coded as absent (none or limited) vs. present (extensive). 5.5 Marrow aplasia: Defined by marrow cellularity < 5% and either ANC < 500/µL or platelets < 20,000/µL persisting for > 28 days post-infusion. 5.6 TRM: Time to death without evidence of leukemia recurrence. Patients alive in continuous complete remission and patients who relapse after DLI will be censored at date of last follow-up or date of relapse, respectively. 13 Cause of death will be described for U-DLI and R-DLI recipients. 5.7 Overall survival: Time to death. Patients are censored at last follow-up. 5.8 Dose-response and dose-toxicity: To establish relationships between cell dose and biologic outcomes, we will describe the distribution of cell doses received using the median and range of mononuclear cell dose and the CD3+ T-cell dose. The relationship between cell dose and response or toxicity will be determined as described below (see Methods). 5.9 Tyrosine kinase inhibitors vs. DLI: Patients with relapsed CML will be further stratified by treatment (DLI vs. imatinib mesylate or other tyrosine kinase inhibitors), and DFS and toxicity will be compared according to the methods described below LI with vs. without prior induction chemotherapy: The role of induction chemotherapy for patients with relapsed acute leukemia/raeb will be evaluated by stratifying by treatment (induction chemotherapy vs. none) prior to DLI, and DFS and toxicity will be compared according to the methods described below. 6.0 VARIABLES TO BE ANALYZED: Patient- and donor-related: Age (by decades) Gender (M vs. F) CMV status (-/- vs. all others) Donor type (related vs. unrelated) HLA matching (related donor: 6/6 vs. other; unrelated donor: best available typing) Disease-related: Disease type (CML, AML, ALL, MDS) Disease risk at the time of transplant (low vs. intermediate vs. high) 102

103 Not for publication or presentation Attachment 8 o Low-risk: 1st complete remission (CR) or 1st chronic phase (CP) o Intermediate-risk: 2nd CR or CP, RAEB o High-risk: 3rd CR or CP, accelerated phase/blast crisis, relapsed or refractory disease, primary induction failure, RAEB-T Transplant-related: T-cell depleted (yes vs. no) Conditioning regimen (TBI vs. none) Time from diagnosis to transplant (days, continuous) Relapse-related: Time from transplant to relapse (days, continuous) Disease risk at the time of relapse (low vs. high) o Low risk: Molecular, cytogenetic, or chronic phase relapse of CML o High risk: Relapse of AML, ALL, RAEB/RAEB-T For CML: Post-relapse therapy with tyrosine kinase inhibitors (in patients not receiving DLI) For acute leukemia/raeb: Induction chemotherapy given prior to DLI (yes vs. no) DLI-related: Time from relapse to DLI (days, continuous) Number of infusions received Mononuclear and CD3+ cell doses received (per infusion and total) - Cumulative totals of cells will be calculated. Cells administered within a 28 day period will be combined as 1 infusion. Transplant centers reporting Other therapy for patients with relapsed CML (Q.10 on Form 095-CMLFU) will be contacted to characterize this therapy, in order to identify patients who are treated with imatinib or other tyrosine kinase inhibitors. 7.0 STUDY DESIGN: This is a descriptive study, but exploratory subgroup analyses by disease type and donor type will be performed. Patient-, disease-, transplant-, relapse- and DLI-related factors will be compared between the two conditioning regimen groups using the chi-square test for categorical and the Kruskal-Wallis or Wilcoxon rank-sum test for continuous variables DFS, TRM, and OS will be estimated using the Kaplan-Meier method, with the log-rank test used to compare subgroups. The probability of response will be estimated for each diagnosis (all patients and R-DLI vs U-DLI). The cumulative incidence of marrow aplasia, and of acute and chronic GVHD, will be estimated, with death as a competing risk for each endpoint. 14,15 Multivariable Cox proportional hazards regression will be used to control for confounding and to estimate the impact of donor type and disease type on these outcomes. Cox proportional hazards regression will also be used to assess the 103

104 Not for publication or presentation Attachment 8 impact of cell dose on DFS and toxicity. In these models, cell dose (both mononuclear and CD3+) will be included as a continuous variable. If cell dose remains an important contributor to these outcomes after controlling for co-variables, we will perform exploratory analyses to determine a therapeutic and/or toxic threshold dose or dose range. 8.0 REFERENCES: 1. Collins RH, Jr., Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15: Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood. 1995;86: Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. 2000;26: Porter DL, Collins RH, Jr., Hardy C, et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood. 2000;95: Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol. 2002;20: Porter DL, Stadtmauer EA, Lazarus HM. 'GVHD': graft-versus-host disease or graft-versus-hodgkin's disease? An old acronym with new meaning. Bone Marrow Transplant. 2003;31: van Rhee F, Savage D, Blackwell J, et al. Adoptive immunotherapy for relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: equal efficacy of lymphocytes from sibling and matched unrelated donors. Bone Marrow Transplant. 1998;21: Dazzi F, Szydlo RM, Craddock C, et al. Comparison of single-dose and escalatingdose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood. 2000;95: Guglielmi C, Arcese W, Dazzi F, et al. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood. 2002;100: Leis J, Porter DL. Unrelated donor leukocyte infusions to treat relapse after unrelated donor bone marrow transplantation. Leuk Lymphoma. 2002;43: Kantarjian HM, O'Brien S, Cortes JE, et al. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood. 2002;100: Olavarria E, Craddock C, Dazzi F, et al. Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation. Blood. 2002;99: Clift R, Goldman J, Gratwohl A, Horowitz M. Proposals for standardized reporting of results of bone marrow transplantation for leukaemia. Bone Marrow Transplant. 1989;4:

105 Not for publication or presentation Attachment Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18: Klein JP, Rizzo JD, Zhang MJ, Keiding N. Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part I: unadjusted analysis. Bone Marrow Transplant. 2001;28:

106 Not for publication or presentation Attachment 8 Table 1. Characteristics of patients with AML, ALL, CML, and MDS (RAEB and RAEB-t) who received DLI after a myeloablative allogeneic HSTC reported to CIBMTR between a Related Donor Unrelated Donor c N (%) N (%) Characteristics of patients N Median (range) N Median (range) P-value b Number of patients Number of centers Age at DLI, yr median (range) 35 (1-66) 35 (1-69) yr 26 ( 6) 8 (10) yr 70 (15) 12 (15) yr 81 (17) 9 (11) yr 118 (25) 25 (30) yr 101 (21) 20 (24) yr 64 (14) 6 ( 7) yr 10 ( 2) 2 ( 2) Male sex (58) (52) Disease AML 174 (37) 25 (30) ALL 71 (15) 20 (24) CML 200 (42) 33 (40) MDS 26 ( 6) 4 ( 5) Disease risk at time of 1st transplant d Low risk 256 (55) 41 (51) Intermediate risk 64 (14) 18 (22) High risk 147 (31) 22 (27) Conditioning regimen at 1st transplant <0.001 Cy+TBI dose>500 cgy single dose or >800 cgy fractionated 192 (41) 60 (73) Cy+TBI+Etoposide 0 1 ( 1) Busulfan+Cy 219 (46) 16 (20) TBI dose 500 cgy single dose or TBI dose >800 cgy fractionated 29 ( 6) 2 ( 2) Melphalan dose 150 mg/m 2 3 ( 1) 0 Busulfan dose > 9 mg/kg 24 ( 5) 3 ( 4) Busulfan+melphalan 1 (<1) 0 Other 3 ( 1) 0 Use of TBI (47) (77) <0.001 GVHD prophylaxis T-cell depletion 83 (18) 12 (15) FK506+MTX±other 28 ( 6) 8 (10) FK506±other 8 ( 2) 3 ( 4) CsA+MTX±other 304 (65) 53 (65) CsA±other 44 ( 9) 4 ( 5) Other 2 (<1) 2 ( 2) None 2 (<1) 0 106

107 Not for publication or presentation Attachment 8 Table 1. Continued. Related Donor Unrelated Donor N (%) N (%) Characteristics of patients N Median (range) N Median (range) P-value b T Cell depletion (6) 82 8 (10) Time from dx to tx, mo (1-114) (3-118) <0.001 Donor type HLA-matched Sibs 416 (88) 0 Identical twins 2 (<1) 0 Other related 53 (11) 0 Unrelated 0 82 (100) Graft type BM 334 (71) 63 (77) PBSC 137 (29) 19 (23) Reason for cellular infusion Persistent disease e 20 ( 4) 5 ( 6) Recurrent disease 333 (71) 57 (70) To be determined f 118 (25) 20 (24) CMV status (donor/recipient) < /- 132 (30) 31 (39) -/+ 65 (15) 16 (20) +/- 49 (11) 18 (23) +/+ 196 (44) 14 (18) HLA match <0.001 HLA-matched siblings 416 (88) 0 Well matched 1 (<1) 20 (24) Partially matched 4 ( 1) 23 (28) Mismatched 39 ( 8) 15 (18) Unknown 11 ( 2) 25 (30) Time from 1 st tx to relapse, mo (<1-177) 51 9 (<1-67) Disease risk at time of relapse g Low risk 75 (17) 12 (17) High risk 368 (83) 60 (83) Year of DLI ( 3) ( 7) 3 ( 4) ( 9) 4 ( 5) (14) 4 ( 5) (11) 5 ( 6) ( 8) 9 (11) (10) 9 (11) ( 9) 6 ( 7) ( 5) 6 ( 7) ( 7) 10 (12) ( 5) 8 (10) ( 7) 8 (10) ( 6) 10 (12) 107

108 Not for publication or presentation Attachment 8 Table 1. Continued. Related Donor Unrelated Donor N (%) N (%) Characteristics of patients N Median (range) N Median (range) P-value b Time from 1st tx to DLI, mo (1-182) (1-147) < th percentile th percentile Time from relapse to DLI, mo (<1-96) 51 2 (<1-31) th percentile th percentile 3 3 Follow up of the survivors since DLI, mo (2-152) (8-152) Abbreviations: DLI=donor leukocyte infusion; CMV = cytomegalovirus; CsA = cyclosporine; MTX = methotrexate; FK506=tacrolimus; Cy=Cycolphosphamide; mo=month; tx=transplant. a Population selection : Excluded N Patients with AML, ALL, CML, MDS (RAEB and RAEB-T) reported to CIBMTR with two consecutive transplant information 4121 DLI due to presistent or recurrent disease DLI confirmed by CRC check (N=24) DLI indicated on forms (N=348) DLI determined by checking algorithm (N=371) * DLI between year 1993 and After a myeloablative allo transplant * The checking algorithm determines a second transplant to be DLI if 1) the subsequent transplant was after year 1990, 2) Allo transplant, 3) the subsequent transplant did not have conditioning regimen, 4) No cord blood transplants, 5) Two transplant was from the same donor. b The chi-square test was used for discrete covariates; the Kruskal-Wallis test was used for continuous covariates. c Additional cases under review, eligible cases will be added. d Low-risk: 1st complete remission (CR1) or 1st chronic phase (CP1); Intermediate-risk: 2nd CR or 2nd CP, RAEB; High-risk: 3rd CR or CP, accelerated phase, blast phase, relapsed or refractory disease, primary induction failure, RAEB-T. e Time from transplant to DLI, Median (range). months: 4 (<1-49). Diagnosis: AML (N=11), ALL (N=4), CML (N=8), MDS (N=2). f Time from transplant to DLI, Median (range). months: 14 (<1-182). Diagnosis: AML (N=60), ALL (N=19), CML (N=49), MDS (N=10). g Low risk : Molecular, cytogenetic or chronic phase relapse of CML ; High risk : Relapse of AML, ALL, RAEB/RAEB-T 108

109 Not for publication or presentation Attachment 9 CIBMTR LK05-01 OUTCOME OF ALLOGENEIC STEM CELL TRANSPLANTATION IN ACUTE MYELOID LEUKEMIA WITH ADVERSE-RISK KARYOTYPE IN FIRST COMPLETE REMISSION USING MATCHED SIBLING OR ALTERNATIVE DONORS PROTOCOL SENT TO WORKING COMMITTEE Study Chairs: Vikas Gupta, MD Blood and Marrow Transplant Program Princess Margaret Hospital Suite 5-217, 610- University Avenue Toronto, Canada, M5G 2M9 Tel: Fax vikas.gupta@uhn.on.ca Martin Tallman, MD Professor of Medicine Department of Medicine, Northwestern Memorial Hospital Northwestern University 676 North St. Clair Street, Suite 850 Chicago, IL Telephone: Fax: m-tallman@northwestern.edu Study Statistician: Vincent He, MS CIBMTR Statistical Center 9200 W. Wisconsin Ave. CLCC. Suite C5500 Milwaukee, WI USA Telephone: Fax: vhe@mcw.edu 109

110 Not for publication or presentation Attachment 9 Scientific Director: Working Committee Chairs: Daniel J. Weisdorf, MD Division of Hematology, Oncology & Transplantation University of Minnesota 420 Delaware Street, SE, Box 480, UMMC Minneapolis, MN USA Telephone: Fax: weisd001@umn.edu Martin Tallman, MD Professor of Medicine Division of Heamatology-Oncology Department of Medicine, Northwestern Memorial Hospital Northwestern University 676 North St. Clair Street, Suite 850 Chicago, IL Telephone: Fax: m-tallman@northwestern.edu Jorge Sierra, MD Professor of Medicine Director, Clinical Hematology and BMT Program Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona Barcelona, SPAIN, Telephone: (34) Fax: (34) jsierra@hsp.santpau.es John F. DiPersio, MD, PhD Division of Oncology Washington University School of Medicine Campus Box South Euclid Avenue St. Louis, MO Phone: Fax: jdipersi@im.wustl.edu 110

111 Not for publication or presentation Attachment OBJECTIVES: 1.1 To evaluate the outcomes of allogeneic stem cell transplantation for acute myeloid leukemia with adverse-risk karyotype in first complete remission (CR1) using matched sibling or unrelated donors. The primary end point of the study is leukemia-free survival. Other endpoints of interests are: - Relapse; - Treatment-related mortality; - Overall survival; - Causes of death. 1.2 Comparison of outcomes of MSD transplants to the patients receiving transplant from alternative donors (URD). 1.3 To study the impact of acute and chronic GVHD on relapse. 2.0 SCIENTIFIC JUSTIFICATION: Cytogenetics analysis performed at diagnosis is considered the most robust prognostic factor in AML. 1-6 Pre-treatment cytogenetics abnormalities not only are predictive of success of induction therapy, but also provide an important basis for selection of postremission strategies. Several studies have confirmed the importance of cytogenetics changes in the leukemic clones to predict relapse. Based on cytogenetics at diagnosis, most of the studies have subdivided AML patients into 3 genetically defined risk groups: favourable, intermediate and adverse risk groups. The definition of these risk groups in these studies, although not identical, is nearly same with minor differences. A large study from medical research council of UK evaluated 1612 patients with AML and showed that at 5-years relapse-risk of favourable, intermediate and adverse-risk group was 35%, 51% and 76%, respectively. 3 Similar outcomes have been reported from the studies from other co-operative groups. 5 Fewer available data indicate that the outcome of AML patients with adverse-risk karyotype treated with allogeneic transplant is better compared to chemotherapy or autologous stem cell transplant (ASCT). A study from SWOG group on 58 patients with unfavourable risk cytogenetics showed that that 5-year survival of patients treated with allogeneic SCT, ASCT and chemotherapy was 44%, 13% and 15%, respectively (p=0.043, when allosct compared with ASCT and chemotherapy combined). 5 In this study, allocation to allogeneic arm was done on the basis of availability of a matched sibling donor (MSD). Those without a donor were randomized to receive ASCT or chemotherapy. Small studies from Vancouver and Belgian groups showed that long-term survival of favourable, intermediate and adverse-risk group were identical when patients were transplanted in CR1. 7, 8 Large retrospective studies from IBMTR and EBMT 9, 10 groups confirmed the predictive value of cytogenetics in patients undergoing BMT. More recently, the EORTC group showed that the outcome of young patients with poor cytogenetics abnormalities was superior for the patients with a donor (43% vs. 18%). 11 A recent study from CIBMTR reported 5-year estimate for DFS and OS at 31% in patients with AML in CR1 undergoing unrelated donor transplantation

112 Not for publication or presentation Attachment 9 Given the high-relapse risk associated with AML with adverse-risk karyotype, most of the leukemia and BMT physicians agree that these patients should be considered for allogeneic transplants from a MRD or alternative donor provided they are fit for such an intervention. However, the practices of offering alternative donor transplants to these patients in CR1 are variable and centre dependent. Recent studies from CIBMTR and EBMT have also shown that the outcome of cord blood transplants for patients with acute leukemia are at least equivalent to those with unrelated donor transplants. 13, 14 Given the increasing experience of CBT in adults, it may be reasonable to offer this option AML patiensts with poor risk karyotype in CR1, who do not have a suitable donor. However, there are no data available on use of CBT for AML with poor risk karyotype in CR1. In view of paucity of data in this area and inability of single-centres to do such a study, it seems reasonable to do such a study through CIBMTR. Such a study will help in facilitating the clinical decision making, and help in defining the role of alternative donor transplants in the management of AML with poor risk cytogenetics in first CR. 3.0 STUDY POPULATION: The study population will include patients undergoing first allogeneic transplant and meeting the following criteria: 1. AML in first complete remission 2. adverse karyotype according to SWOG/ECOG* 3. Stem cells from one of the following donors: a. Matched sibling donors b. Unrelated donors Syngeneic and cord blood transplants will be excluded. * The adverse-risk karyotype will be defined as previously described by the study of SWOG/ECOG. 5 According to this study unfavourable or adverse-risk karyotypes in AML are: del(5q)/-5, -7/del(7q), abn 3q,9q,11q,20q, 21q,17p,t(6;9),t(9;22) and complex karyotype ( 3 unrelated abn) 4.0 OUTCOMES: 4.1 Engraftment: Time to neutrophils (ANC) >0.5 x 10 9 /L (first of 3 consecutive days) and time to platelets 20 x 10 9 /L (first of 3 consecutive days and no platelet transfusions 7 days prior) 4.2 Acute GVHD: Occurrence of grade II, III and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD. 4.3 Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the criteria of chronic GVHD 4.4 Relapse: time to onset of leukemia recurrence. This event will be summarized by cumulative incidence estimate with TRM as the competing risk 112

113 Not for publication or presentation Attachment Treatment-related mortality: time to death without evidence of disease relapse. This event will be summarized as cumulative incidence estimate with relapse as the competing risk. 4.6 Disease-free survival: will be defined as time to relapse or death from any cause. Patients are censored at last follow-up. 4.7 Overall survival: Time to death, patients censored at last follow-up 5.0 VARIABLES TO BE ANALYZED: Patient-related: (at the time of transplant): - Age at transplant: (continuous and <20 vs vs. >40) - Gender: female vs. male - Karnofsky performance status: <90% vs. 90% Disease-related: (at diagnosis): - Morphologic sub-type (FAB) - Malignancy (or non malignant disease) prior to diagnosis of AML treated with chemotherapy or radiotherapy (yes/no) - WBC at diagnosis x 10 9 /L (continuous and <20 vs. >20; <50 vs. >50, <100 vs. >100) - Previous history of myelodysplastic syndrome or myeloproliferative disorder (yes/no) - Extramedullary disease (yes/no) - Single, specificcytogenetic abnormalities including monosomy or translocations vs. multiple abnormalities Disease-related: (at transplant): - Time from diagnosis to transplant - Presence of CNS disease prior to transplant - Presence of proven or probable fungal infection any time prior to transplant Treatment prior to transplant: - Number of chemotherapy cycles to achieve CR (1 vs. >1) - Number of consolidation treatments prior to transplant (0, 1vs. >=2) Transplant related: - Conditioning regimen : TBI vs. non-tbi; myeloablative vs Non-ablative/reduced intensity - Donor age <10 y vs vs vs vs. >40y (or relvant grouping based upon distribution - Donor-recipient gender: M-M vs. M-F vs. F-M vs. F-F - HLA-matching: HLA-identical sibling vs. well-matched unrelated vs. partiallymatched unrelated vs. mismatched unrelated 113

114 Not for publication or presentation Attachment 9 - CMV status of donor and recipient: +/+ vs. +/- vs. -/- - Source of stem cells: BM vs. PBSC - CD34 cell dose, x 10 6 /kg: BM, above median vs. below median; PBSC, above median vs below median - CD3 cell dose, X 10 6 /kg: BM, above median vs. below median; PBSC above median vs. below median - Year of transplant - GVHD prophylaxis: CSA+/-other (not MTX) vs. CSA+MTX+/-other vs. FK506+/-other vs. T-cell depletion - Planned growth factors post transplant (GCSF/GMCSF) (yes/no) Post-transplant: - Acute GVHD: none vs II-IV - Chronic GVHD: (yes/no) - Donor cell infusion (yes/no) - Immune manipulation post transplant such as IL-2, IFN (yes/no) 6.0 STUDY DESIGN: Patient-, disease-, and transplant-related variables for patients receiving MSD and alternative donor transplants will be compared using chi-square statistic for categorical variables and the Kruskal-Wallis test for continuous variables. Univariate probabilities of LFS and survival will be calculated using the Kaplan-Meier estimator; the log-rank test will be used for univariate comparisons. Probabilities of hematopietic recovery, acute and chronic GVHD, treatment-related mortality and leukemia relapse will be calculated using cumulative incidence curves to accommodate competing risks. Assessment of potential risk factors for outcomes of interest will be evaluated in multivariate analyses using Cox proportional hazards regression. Variables considered in multivariable analysis are listed in Section 5. A backward stepwise model selection approach will be used to identify all significant risk factors. Each step of model building contained the main effect for donor type. Factors which were significant at a 5% level will be kept in the final model. The potential interactions between main effect and all significant risk factors will be tested. The proportionality assumption will be tested by adding a time-dependent covariate for each factor. When test indicated differential effects over time (non-proportional hazards), models will be constructed breaking the posttransplant course into two time periods, using the maximized partial likelihood method to find the most appropriate breakpoint. The proportionality assumptions were further tested. After the above modeling of time varying effects, the final multivariate model will be built. Adjusted probabilities of leukemia free survival (LFS) and overall survival will be generated from the final Cox models stratified on treatment of donor type and weighted by the pooled sample proportion value for each prognostic factor. These adjusted probabilities estimate likelihood of outcomes in populations with similar prognostic factors. 114

115 Not for publication or presentation Attachment REFERENCES: 1. Dastugue N, Payen C, Lafage-Pochitaloff M, Bernard P, Leroux D, Huguet-Rigal F, Stoppa AM, Marit G, Molina L, Michallet M, et al. Prognostic significance of karyotype in de novo adult acute myeloid leukemia. The BGMT group. Leukemia. 1995;9: Mrozek K, Heinonen K, de la Chapelle A, Bloomfield CD. Clinical significance of cytogenetics in acute myeloid leukemia. Semin Oncol. 1997;24: Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood. 1998;92: Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik MV, Steuber CP, Weinstein HJ, Carroll AJ. Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-pog Blood. 1999;94: Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96: Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, Koduru PR, Moore JO, Stone RM, Mayer RJ, Feldman EJ, Davey FR, Schiffer CA, Larson RA, Bloomfield CD. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100: Chalandon Y, Barnett MJ, Horsman DE, Conneally EA, Nantel SH, Nevill TJ, Nitta J, Shepherd JD, Sutherland HJ, Toze CL, Hogge DE. Influence of cytogenetic abnormalities on outcome after allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant. 2002;8: Ferrant A, Doyen C, Delannoy A, Straetmans N, Martiat P, Mineur P, Bosly A, Van den Berghe H, Michaux JL. Karyotype in acute myeloblastic leukemia: prognostic significance in a prospective study assessing bone marrow transplantation in first remission. Bone Marrow Transplant. 1995;15: Gale RP, Horowitz MM, Weiner RS, Ash RC, Atkinson K, Babu R, Dicke KA, Klein JP, Lowenberg B, Reiffers J, et al. Impact of cytogenetic abnormalities on outcome of bone marrow transplants in acute myelogenous leukemia in first remission. Bone Marrow Transplant. 1995;16: Ferrant A, Labopin M, Frassoni F, Prentice HG, Cahn JY, Blaise D, Reiffers J, Visani G, Sanz MA, Boogaerts MA, Lowenberg B, Gorin NC. Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in 115

116 Not for publication or presentation Attachment 9 first remission: a European Group for Blood and Marrow Transplantation study. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood. 1997;90: Suciu S, Mandelli F, de Witte T, Zittoun R, Gallo E, Labar B, De Rosa G, Belhabri A, Giustolisi R, Delarue R, Liso V, Mirto S, Leone G, Bourhis JH, Fioritoni G, Jehn U, Amadori S, Fazi P, Hagemeijer A, Willemze R. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood. 2003;102: Tallman M, Dewald G, Lazarus H, Gandham S, Nelson G, Logan B, Rowe J, Litzow M, Keating A, Mehta J, Wetzler M, Warren T, Weisdorf D. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for adults with AML. Blood. 2004;104:237a(abstract 830) 13. Gupta V, Yi QL, Brandwein J, Minden MD, Schuh AC, Wells RA, Chun K, Kamel- Reid S, Tsang R, Daly A, Kiss T, Lipton JH, Messner HA. The role of allogeneic bone marrow transplantation in adult patients below the age of 55 years with acute lymphoblastic leukemia in first complete remission: a donor vs no donor comparison. Bone Marrow Transplant. 2004;33: Kiehl MG, Kraut L, Schwerdtfeger R, Hertenstein B, Remberger M, Kroeger N, Stelljes M, Bornhaeuser M, Martin H, Scheid C, Ganser A, Zander AR, Kienast J, Ehninger G, Hoelzer D, Diehl V, Fauser AA, Ringden O. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission. J Clin Oncol. 2004;22:

117 Not for publication or presentation Attachment 9 Table 1. Characteristics of patients who underwent allogeneic stem cell transplantation for acute myelogenous leukemia with adverse-risk karyotype in first remission between 1995 and 2006, reported to the CIBMTR. Characteristics of patients: All patients, N (%) HLA-id, N (%) Unrelated, N (%) Number of patients Number of centers Age, median (range), years 40 (<1-79) 39 (<1-74) 42 (<1-79) Age at transplant, years <10 y 63 ( 8) 26 ( 9) 37 ( 8) y 77 (10) 40 (13) 37 ( 8) y 109 (14) 39 (13) 70 (15) y 121 (16) 50 (16) 71 (15) y 171 (22) 70 (23) 101 (22) y 152 (20) 57 (19) 95 (20) 60 y 78 (10) 22 ( 7) 56 (12) Male sex 435 (57) 174 (58) 261 (56) FAB subtype M0 35 ( 5) 14 (5) 21 ( 4) M1 123 (16) 47 (15) 76 (16) M2 163 (21) 69 (23) 94 (20) M3 3 (<1) 3 ( 1) 69 (15) M4 118 (15) 49 (16) 46 (10) M5 95 (12) 49 (16) 22 ( 5) M6 31 ( 4) 9 ( 3) 16 ( 3) M7 25 ( 3) 9 ( 3) 76 (16) Unclassified 93 (12) 23 ( 8) 70 (15) Other AML/transformed from MDS 25 ( 3) 21 ( 7) 4 ( 1) Karnofsky score prior to HCT, <90% 170 (23) 66 (22) 322 (75) Missing WBC at diagnosis, x10 9 /L median, range 5.7(<1-3110) 8.2 (<1-3110) 5 (<1-354) < 50 x10 9 /L 611 (85) 229 (80) 382 (88) > 50 x10 9 /L 110 (15) 59 (20) 51 (12) Missing Extramedullary disease 56 ( 7) 28 (9) 28 (6) CNS disease prior to transplant Yes 24 ( 3) 15 ( 5) 9 ( 2) No 747 (97) 289 (95) 458 (98) Prior myelodysplasia 137 (18) 44 (14) 93 (20) Missing Time from diagnosis to transplant Median (range), months 5(1-125) 4( 1-40) 5 (1-125) 117

118 Not for publication or presentation Attachment 9 3 months 74 (10) 41 (13) 33 ( 7) 3-6 months 468 (61) 200 (66) 268 (57) 6-9 months 160 (21) 41 (13) 119 (25) >9 months 69 ( 9) 22 ( 7) 47 (10) Table 1. Continued. Characteristics of patients: All patients, N (%) HLA-id, N (%) Unrelated, N (%) -5/5q- 166 (22) 55(18) 111 (24) -7/7q- 151 (20) 81 (27) 70 (15) -20/20q- 12 ( 2) 8 ( 3) 4 ( 1) ( 5) 28 ( 9) 10 ( 2) ( 2) 13 ( 4) 6 ( 1) Abnormal 3q 24 ( 3) 17 ( 6) 7 ( 2) Abnormal 11q 50 ( 6) 45 (15) 5 ( 1) Abnormal 16q 16 ( 2) 2 ( 1) 14 ( 3) t (1;7) 3 (<1) 22 ( 7) 1 (<1) t (6;9) 29 ( 4) 4 ( 1) 7 ( 2) t (8; 21) 11 ( 1) 4 ( 1) 7 ( 2) t (9;22) 26 ( 3) 19 ( 6) 7 ( 2) t (15;17) 5 (<1) 2 ( 1) 3 (<1) Other (specify) 598 (78) 194 (64) 404 (86) Fungal infection anytime prior to HCT 124 (16) 40 (13) 84 (18) Missing Conditioning regimen Myeloablative 594 (77) 249 (82) 345 (74) Non-myeloablative 177 (23) 55 (18) 122 (26) Type of donor HLA-identical sibling 304 (39) 304 (100) 0 URD well matched 246 (32) (53) URD partially matched 96 (12) 0 96 (21) URD mismatched 35 ( 5) 0 35 (7) URD (matching TBD) 90 (12) 0 90 (19) Graft type Bone marrow 346 (45) 125 (41) 221 (47) Peripheral blood 425 (55) 179 (59) 246 (53) Year of transplant (11) 54 (18) 27 ( 6) (10) 46 (15) 34 ( 7) (10) 43 (14) 35 ( 7) (17) 50 (16) 83 (18) (25) 60 (20) 136 (29) (26) 51 (17) 152 (33) GVHD prophylaxis FK506+MTX ± other 187 (24) 36 (12) 151 (32) FK506 ± other 72 ( 9) 13 ( 4) 59 (13) 118

119 Not for publication or presentation Attachment 9 MTX+CSA ± other 323 (42) 169 (56) 154 (33) CSA ± other 93 (12) 48 (16) 45 (10) T-cell depletion 77 (10) 26 ( 9) 51 (11) Other 12 ( 2) 8 ( 3) 4 ( 1) None/missing (need to contact centers) 7 ( 1) 4 ( 1) 3 ( 1) Median (range) follow-up of survivors, months 42 (1-135) 57 (1-131) 35 (1-135) 119

120 Not for publication or presentation Attachment 9 Table 1. Continued. Abbreviations: FK506 = tacrolimus; CSA = cyclosporine; MTX = methotrexate. Data has not been Cap-modeled; *overall complete index follow-up: 78% Breakdown of followup: <1 year 71 ( 9) 2 years 62 ( 8) 3 years 45 ( 6) 4 years 35 ( 4) 5 years 27 ( 4) >5 years 86 (11) Dead 445 (58) Applied selection criteria: # excluded N Inclusion: First allo HCT for AML in CR1, Exclusion: Twin transplants Exclusion: Unknown cytogenetics abnormality prior to tx Exclusion: Normal cytogenetics abnormality prior to tx Inclusion: Patients with adverse-risk karyotype* Exclusion: Cord blood tx Exclusion: Other related tx Exclusion: Conditioning intensity missing *The adverse-risk karyotype is defined as previously described by the study of SWOG/ECOG. 5 According to this study unfavourable or adverse-risk karyotypes in AML are: del(5q)/-5, - 7/del(7q), abn 3q,9q,11q,20q, 21q,17p,t(6;9),t(9;22) and complex karyotype ( 3 unrelated abn). Patients with other, specify field in the AML disease-insert form were reviewed by PI and are included. Patients with other, specify field in the AML disease-insert form were reviewed by PI and are included. 120

121 Not for publication or presentation Attachment 10 CIBMTR LK07-02 CIBMTR SCORING SYSTEM TO PREDICT THE OUTCOME AFTER ALLOGENEIC TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA PROTOCOL SENT TO WORKING COMMITTEE Study Chair: Study Statistician: Working Committee Chairs: Jorge Sierra, MD Professor of Medicine Director, Clinical Hematology and BMT Program Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona Barcelona, Spain, Telephone: (34) Fax: (34) jsierra@santpau.es Waleska S. Pérez, MPH CIBMTR Statistical Center 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI USA Telephone: Fax: wperez@mcw.edu Martin Tallman, MD Professor of Medicine Division of Heamatology-Oncology Department of Medicine, Northwestern Memorial Hospital Northwestern University 676 North St. Clair Street, Suite 850 Chicago, IL Telephone: Fax: m-tallman@northwestern.edu 121

122 Not for publication or presentation Attachment 10 Working Committee Chairs: Jorge Sierra, MD Professor of Medicine Director, Clinical Hematology and BMT Program Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona Barcelona, Spain, Telephone: (34) Fax: (34) jsierra@santpau.es John F. DiPersio, MD, PhD Division of Oncology Washington University School of Medicine Campus Box South Euclid Avenue St. Louis, MO Phone: Fax: jdipersi@im.wustl.edu Scientific Director: Daniel J. Weisdorf, MD Division of Hematology University of Minnesota 420 Delaware Street, SE, Box 480, UMHC Minneapolis, MN USA Telephone: (612) Fax: (612) weisd001@maroon.tc.umn.edu 122

123 Not for publication or presentation Attachment OBJECTIVES: Primary: 1.1 To identify the factors that will impact leukemia-free survival after allogeneic hematopoietic transplantation following myeloablative conditioning as treatment for primary AML. Based on the factors identified, a scoring system predicting the outcome will be generated. Secondary: 1.2 To analyze engraftment, GVHD, and causes of death. 1.3 To identify prognostic factors for relapse, non-relapse mortality and survival. 2.0 SCIENTIFIC JUSTIFICATION: Hematopoietic transplantation from HLA-compatible donors is increasingly been used as treatment for acute myeloid leukemia. 1 This procedure associates to decreased leukemia recurrence as compared to chemotherapy or autografting. 2-5 Allogeneic transplantation leads to significant morbidity and mortality which counterbalances the positive impact of this treatment on relapse rate. 6 Different studies have analyzed predictive factors for procedure-related mortality, leukemia re-growth and survival in transplant recipients for AML. 7 Young age at transplant and early disease-stage are universally recognized as positive characteristics. In contrast, old age, advanced disease-stage, CMV positive serostatus in the recipient and transplantation from alternative donors have been associated to increased mortality and decreased survival. In chronic myeloid leukemia, the European Blood and Marrow Transplant Group was able to precisely indicate what parameters had a major impact on transplantation outcome. 8 Based on the characteristics identified, the EBMT established a simple scoring system separating 5 groups with significantly different probabilities of survival and transplant related mortality. A similar scoring system has not been generated for AML. The results of this type of study would be of help to anticipate the prognosis in particular patients with AML. This is particularly relevant nowadays, since different type of donors and stem cell sources are available. Also, because the improved knowledge of biologic factors predicting a relatively good outcome in certain subsets of chemotherapy treated AML patients makes particularly important to predict the risks and prognosis after hematopoietic transplantation Recently, a hematopoietic transplantation comorbidity index (CI) has been developed. 15,16 This index provides useful information which has to be taken into account in prediction studies. For this reason, in the present study, comorbidities will be analyzed to be included as modified CI, with the available data provided in the core insert form. 3.0 STUDY POPULATION: The study population will include all patients between years of age undergoing HLA-identical or unrelated donor myeloablative transplant for primary AML from

124 Not for publication or presentation Attachment 10 to 2005, reported to the CIBMTR. Patients with unknown cytogenetics will be excluded. Potential numbers of subjects are given in Table OUTCOMES: Univariate analysis: - Hematopoietic recovery: The achievement of an absolute neutrophil count of 500 neutrophils/mm³ sustained for three consecutive days. The event will be summarized by the cumulative incidence estimate with death, relapse and second transplant as competing risks. Univariate and multivariate analysis: - Acute GVHD: Occurrence of grade II, III and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD. - Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the diagnostic criteria of chronic GVHD. - Treatment-related mortality: time to death without evidence of leukaemia recurrence. - Relapse: time to onset of leukaemia recurrence. Event will be summarized by the cumulative incidence estimate with treatment related mortality as a competing risk. - Disease free survival: time to treatment failure (death or relapse). Patients are censored at time of last follow-up. - Overall survival: time to death. Patients are censored at time of last follow-up. 5.0 VARIABLES TO BE ANALYZED: Patient related: - Age at transplant: <30 yrs vs yrs vs yrs - Gender: female vs. male - Karnofsky performance score: <90% vs. 90% - Comorbidities Disease-related: - FAB subtype - WBC: <25 vs vs vs. >100x10 9 /L - Cytogenetics: good vs. intermediate/no abnormalities vs. poor - Disease status at transplantation: CR1 vs. CR2 vs. >CR2 vs. relapse/pif - Number of cycles to achieve CR: 1 vs. 2 vs. >2 - Duration of CR1 (for CR2): <6m vs. 6-12m vs. >12m Transplant related: - Conditioning regimen: CyTBI±others vs. BuCy±others vs. others - Time from diagnosis to transplant: <3 m vs. 3-6m vs. >6 m 124

125 Not for publication or presentation Attachment 10 - Type of donor: HLA-id sibling vs. matched unrelated vs. partially matched unrelated vs. mismatched unrelated - Source of stem cells: BM vs. PBSC - Donor age: 18-30y vs y vs. >46 y - Donor-recipient gender match: F-M vs. M-F vs. M-M vs. F-F - Donor parity: parous female vs. non-parous female vs. male - Donor-recipient CMV serostatus: -/- vs. -/+ vs. +/- vs. +/+ - Year of transplant: vs vs vs Cell dose: <2x10 6 /kg vs. 2-4x10 6 /kg vs. 4-8x10 6 /kg vs. >8x10 6 /kg; separately for BM and PBSC - GVHD prophylaxis: T-cell depletion vs. CSP or FK plus MTX vs. MMF plus others vs. others 6.0 STUDY DESIGN: Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. Probabilities of survival and disease-free survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood s formula. Values for other endpoints will be generated using cumulative incidence estimates. Multivariate analyses will be performed using proportional hazards models separately for HLA-identical sibling transplant and related donors. These analyses will fit models to determine which risk factors (Sec 5.0) may be related to a given outcome. All variables will first be examined to assure that they comply with the proportional hazards assumption. Factors found to have non-proportional hazards will be adjusted for in subsequent analyses. A stepwise model building approach will then be used to develop models for GVHD, relapse, treatment-related mortality, disease-free survival and overall survival. A Cox regression model of overall survival will also be built but only using patient and disease related risk factors. Based on the regression coefficients of this final model, groups of patients who have the best, intermediate and worst survival outcomes will be identified. This risk factor score analysis will be done separately for HLAidentical sibling transplant and related donors. 7.0 REFERENCES: 1. Gratwohl A. Baldomero H, Frauendorfer K, Urbano-Ispizua A; Joint Accreditation Committee, International Society for Cellular Therapy; European Group for Blood and Marrow Transplantation. EBMT activity survey 2004 and changes in disease indication over the past 15 years. Bone Marrow Transplant. 2006; 12: Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 1995; 332:

126 Not for publication or presentation Attachment Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339: Burnett AK, Wheatley K, Goldstone AH, et al. Medical Research Council Adult and Paediatric Working Parties. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol 2002; 118: Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: Copelan E. Hematopoietic stem cell transplantation. N Engl J Med 2006; 354: Cornelissen JJ, Lowenberg B. Role of allogeneic stem cell transplantation in current treatment of acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2005; Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukemia before allogeneic blood or marrow transplantation. Lancet 1998; 352: Rowe JM, Liesveld JL. Treatment and prognostic factors in acute myeloid leukaemia. Baillière s Clinical Haematology 1996; 9: Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 2003; 3: Barragan E, Cervera J, Bolufer P, et al. Prognostic implications of Wilms' tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica. 2004;89: Munoz L, Nomdedeu JF, Villamor N, et al. Acute myeloid leukemia with MLL rearrangements: clinicobiological features, prognostic impact and value of flow cytometry in the detection of residual leukemic cells. Leukemia. 2003; 17: Valk PJ, Verhaak RG, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004; 350: Bullinger L, Dohner K, Bair E, Frohling S, Schlenk RF, Tibshirani R, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 2004; 350: Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: Sorror ML, Sandmaier BM, Storer BE, et al. Comorbidity and disease status-based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 2007; 25:

127 Not for publication or presentation Attachment 10 Table 1. Characteristics of patients years of age who underwent myeloablative allo HCT for primary acute myelogenous leukemia reported to the CIBMTR between 1995 and Characteristics of patients: HLA-identical N (%) Unrelated N (%) Number of patients Number of centers Age, median (range), years 39 (18-60) 3 (18-60) Age at transplant, years <30 y 420 (25) 455 (29) y 467 (28) 412 (26) y 537 (33) 473 (30) y 233 (14) 248 (15) Male sex 875 (33) 836 (53) Karnofsky score prior to transplant <90% 459 (28) 471 (32) Missing Co-existing disease a 562 (34) 590 (37) Missing 4 5 Type of co-existing disease Hemorrhage 29 ( 5) 31 ( 5) Other malignancy 16 ( 3) 32 ( 5) Autoimmune 31 ( 6) 17 ( 3) Cardiovascular 156 (28) 180 (31) Chromosomal 3 ( 1) 3 ( 1) CNS/Psychiatric 82 (15) 55 ( 9) Endocrine 68 (12) 102 (17) Gastrointestinal 109 (19) 82 (14) Genitourinary 69 (12) 49 ( 8) Hematologic 26 ( 5) 24 ( 4) Liver 67 (12) 23 ( 4) Pulmonary 120 (21) 120 (20) Other 214 (38) 251 (43) FAB classification M1 251 (15) 267 (17) M2 457 (27) 385 (24) M3 145 ( 9) 60 ( 4) M4 344 (21) 359 (23) M5 215 (13) 178 (11) M6 41 ( 2) 47 ( 3) M7 9 ( 1) 24 ( 2) Unclassified AML 100 ( 6) 132 ( 8) Other AML 95 ( 6) 136 ( 8) 127

128 Not for publication or presentation Attachment 10 Table 1. Continued. HLA-identical N (%) Unrelated N (%) Characteristics of patients: WBC at diagnosis, x10 9 /L < (63) 817 (59) (13) 188 (13) ( 8) 128 ( 9) ( 5) 81 ( 6) > (11) 179 (13) Missing Disease status prior transplant 1 st complete remission 956 (58) 470 (30) 2 nd complete remission 286 (17) 523 (33) Relapse/ Primary induction failure 415 (25) 595 (37) Number of cycles to achieve CR1 (not for PIF patients) (75) 237 (68) (22) 92 (26) >2 47 ( 3) 22 ( 6) Missing b Duration of CR1 (for CR2) <6 months 52 (22) 98 (21) 6-12 months 65 (28) 179 (38) >12 months 117 (50) 196 (41) Missing Cytogenetics No abnormalities 779 (47) 563 (35) Good prognosis 200 (12) 220 (14) Intermediate prognosis 509 (31) 694 (44) Poor prognosis 169 (10) 111 ( 7) Conditioning regimen CY+TBI± others 612 (37) 957 (60) BU+CY± others 827 (50) 427 (27) Others 218 (13) 204 (13) Time from diagnosis to transplant <3 months 177 (11) 24 ( 1) 3-6 months 832 (50) 469 (30) >6 months 648 (39) 1095 (69) Type of donor HLA-identical sibling 1657 (100) 0 URD well matched (38) URD partially matched (24) URD mismatched (10) URD (matching to be determined) (28) 128

129 Not for publication or presentation Attachment 10 Table 1. Continued. HLA-identical N (%) Unrelated N (%) Characteristics of patients: Donor age, years <30 y 444 (27) 462 (30) y 469 (29) 601 (39) y 450 (27) 377 (25) y 223 (14) 95 ( 6) 60 y 53 ( 3) 2 (<1) Missing Donor-recipient sex match M-M 481 (29) 566 (36) M-F 384 (23) 439 (28) F-M 392 (24) 267 (17) F-F 396 (24) 310 (19) Missing 4 6 Donor parity Parous female 380 (26) 278 (20) Non-parous female 199 (14) 94 ( 7) Male 865 (60) 1005 (73) Missing Donor-recipient CMV serostatus +/+ 781 (49) 389 (25) +/- 179 (11) 208 (13) -/+ 281 (18) 501 (33) -/- 357 (22) 443 (29) Missing Graft type Bone marrow 736 (44) 1048 (66) Peripheral blood ± bone marrow 921 (56) 540 (34) Year of transplant (13) 76 ( 5) (14) 103 ( 6) (11) 91 ( 6) ( 9) 112 ( 7) ( 8) 111 ( 7) ( 7) 141 ( 9) ( 8) 148 ( 9) ( 7) 158 (10) ( 6) 182 (11) ( 9) 216 (14) ( 8) 250 (16) 129

130 Not for publication or presentation Attachment 10 Table 1. Continued. HLA-identical N (%) Unrelated N (%) Characteristics of patients: GVHD prophylaxis FK506+MTX ± other 131 ( 8) 512 (32) FK506 ± other 55 ( 3) 96 ( 6) MTX+CSA ± other 1143 (69) 744 (47) CSA ± other 169 (10) 39 ( 3) T-cell depletion 145 ( 9) 179 (11) Other c 8 ( 1) 5 (<1) None (need to contact centers) 6 (<1) 13 ( 1) Median (range) follow-up of survivors, months 63 (3-152) 48 (1-151) Abbreviations: FK506 = tacrolimus; MTX = methotrexate; CsA = cyslosporine. a Crosstab of co-existing *karnofsky score: KPS Co-existing disease <90% 90% Missing No Yes Missing b Not collected on NMDP forms c Other GVHD prophylaxis were: CY (n=2); MTX (n=4); MTX+corticosteroids (n=1); MMF+ corticosteroids (n=1); MTX+MMF (n=2); not specified (n=3). Completeness index follow-up: 74% Breakdown of follow-up: <1 year 146 ( 5) 2 years 159 ( 5) 3 years 190 ( 6) 4 years 179 ( 6) 5 years 148 ( 5) >5 years 572 (18) Dead 1851 (57) Applied selection criteria: # excluded N First allo HCT for AML, after CAP model 9249 Exclusion: therapy-related leukemia Exclusion: prior MDS or pre-leukemia Exclusion: transformed from MDS (per registration) and pre-lk= Age years Donor=HLA-id; other related, URD Myeloablative conditioning regimen Graft type=bm or PBSC Exclusion: unknown cytogenetics Exclusion: disease status missing Exclusion: GVHD prophylaxis missing Exclusion: Other related donor (per statistical meeting)

131 Not for publication or presentation Attachment 11 TO: FROM: Writing Committee for CIBMTR Study #LK07-03 Brian McClune, Sergio Giralt, Tanya Pedersen, Gisela Tunes da Silva, and Dan Weisdorf DATE: January 30, 2009 RE: Final analysis for CIBMTR Study #LK07-03: Outcome of Allogeneic HSCT in Older Patients with AML, MDS, CML and NHL Enclosed is a description of the patient population and results of univariate and multivariate analyses of acute and chronic GVHD, neutrophil recovery, treatment-related mortality (TRM), relapse, leukemia-free survival (LFS), and overall survival for patients 40 years of age who received a nonmyeloablative allogeneic HSCT for AML in first complete remission or MDS, reported to the CIBMTR between 1995 and The primary objective of the study is to compare the above outcomes of older patients to younger patients. Acute and chronic GVHD, TRM, LFS, and relapse outcomes for patients with CML and NHL are in the process of being cleaned and reviewed and are not presented here. It was decided to proceed with the analysis in the AML and MDS cohorts at this time since this is the focus of the ASBMT Governmental Affairs committee and NMDP representatives for consideration of a position paper summarizing the outcomes in order to aid patients in obtaining 3rd party coverage for allografting in this age group. Tables 1a-1d shows the patient, disease, and transplant characteristics of the patients included in the study. These characteristics were compared across age groups using the chi-square statistic for categorical and the Kruskal-Wallis test fro continuous variables. Tables 2a-2h shows the univariate analyses of the outcomes of interest. Probability of leukemiafree survival and overall survival was calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood s formula. Values for other outcomes were calculated using cumulative incidence curves to accommodate competing risks. Table 3 gives the causes of death for the AML/MDS patient population by disease. Table 4 lists all variables considered in the multivariate analysis. Tables 5-11b give the results of the multivariate analysis for the AML/MDS cohort. 131

132 Not for publication or presentation Attachment 11 Acute and chronic GVHD, neutrophil recovery outcomes were analyzed via a Cox model. Also, all the variables listed on Table 4 were tested, as well as interactions between the main effect and the other covariates. Only the variables that reached the 5% level of significance were kept in the final model. The proportional hazards assumption was examined by appropriate residuals and tests. For the time to ANC recovery, the proportional hazards assumption did not hold for graft groups, so a stratified model was fitted with graft groups as the strata. For this model, the main effect age is significant, and older people have higher engraftment. Conditioning regimen intensity is also significant, with those receiving a nonmyeloablative preparative regimen having lower engraftment. For time to acute and chronic GVHD, age is not significant. For chronic GVHD, none of the variables are significant and for acute GVHD only HLA match categories attains the 5% level of significance. For overall survival, LFS, TRM and relapse, the analysis was done using the pseudo values technique. This approach allows one to fit different models for each time point of interest and one of the advantages of this technique is that the assumption of proportional hazards is not needed. For each outcome two different time points were considered: one year and two years. For overall survival and LFS, the pseudo values were computed based on the Kaplan-Meier estimator of the survival distribution. For TRM and relapse, the pseudo value analysis was conducted based on cumulative incidence functions, since death and relapse are competing risks. All variables listed in Table 4 were tested in all models. Only the variables that were significant at a 5% level were kept in the final model. Also, all interactions of main effect with other covariates were tested. The results show that the main effect of age is not significant for survival, treatment mortality, relapse, and leukemia free survival. Disease and its status have an important influence on all four outcomes considered at one year, and for TRM and relapse at two years. Please review this summary critically and send your comments by December 29, 2008 to: Brian McClune, MD; University of Minnesota; MMC 480, 420 Delaware Street S.E.; Minneapolis, MN 55445; Telephone: (612) ; bmcclune@umn.edu With a copy to: Tanya L. Pedersen; Fax: (612) ; tpederse@nmdp.org You should note that any member of a Writing Committee who does not make a substantive contribution to the design, analysis, interpretation or manuscript would be expected to withdraw as a co-author or, alternatively, the lead author could remove names of non-contributors. If we do not hear from you by December 29,2008 we may assume you no longer wish to participate in the study. The rules of the CIBMTR require inclusion of the following statement: "The enclosed raw data are confidential. If used publicly, the following statement must be included: The data presented here were obtained from the Statistical Center of the International Bone Marrow Transplant Registry. The analysis has not been reviewed or approved by the Advisory Committee of the CIBMTR. The data may not be published without prior approval of the Advisory Committee." If the data are used in an oral presentation, please send us the name, place and dates of the meeting where the data are presented, and the title of your presentation. 132

133 Not for publication or presentation Attachment 11 CIBMTR LK07-03 ASSESSMENT OF ALLOGENEIC HCT IN OLDER PATIENTS WITH AML, MDS, NHL, AND CML Study Chairs: Brian McClune, MD Assistant Professor Division of Hematology, Oncology and Transplantation Department of Medicine University of Minnesota MMC 480, 420 Delaware Street S.E. Minneapolis, MN Telephone: (612) Sergio Giralt, MD MD Anderson Cancer Center 1515 Holcombe Blvd., Box 423 Houston, TX Telephone: Fax: Study Statistician: Tanya L. Pedersen CIBMTR 3001 Broadway Street NE, Suite 110 Minneapolis, MN USA Telephone: Fax:

134 Not for publication or presentation Attachment 11 Working Committee Chairs: Armand Keating, MD Chief of Medical Services Head of the Dept. of Medical Hematology/ Oncology Princess Margaret Hospital 610 University Avenue, Suite Toronto, Ontario, CANADA M5G 2M9 Telephone: Fax: Martin Tallman, MD Professor of Medicine Division of Hematology-Oncology Department of Medicine, Northwestern Memorial Hospital Northwestern University 676 North St. Clair Street, Suite 850 Chicago, IL Telephone: Fax: Jorge Sierra, MD Professor of Medicine Director, Clinical Hematology and BMT Program Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona Barcelona, SPAIN, Telephone: (34) Fax: (34) jsierra@hsp.santpau.es Scientific Director: Daniel J. Weisdorf, MD Division of Hematology University of Minnesota 420 Delaware Street, SE, Box 480, UMHC Minneapolis, MN USA Telephone: Fax: weisd001@maroon.tc.umn.edu 134

135 Not for publication or presentation Attachment OBJECTIVES: 1.1 To compare the clinical outcomes of older adults with myelodysplastic syndrome (MDS), de novo acute myeloid leukemia (AML), and AML evolving from preceding MDS after allogeneic hematopoietic cell transplantation (HCT) to younger adults as to the following: - Hematopoietic recovery (neutrophil engraftment); - Acute GVHD; - Chronic GVHD; - Treatment-related mortality; - Relapse; - Disease-free survival; - Overall survival. 1.2 To compare the clinical outcomes of older adults with CML, and higher risk (diffuse) NHL vs. lower risk (follicular) NHL after allogeneic hematopoietic cell transplantation (HCT) to younger adults as to the following: Hematopoietic recovery (neutrophil engraftment); Acute GVHD; Chronic GVHD; Treatment-related mortality; Relapse/Progression; Disease-free survival; Overall survival. Impact of age will be addressed by evaluating engraftment, GVHD, and overall survival across all diseases. 2.0 SCIENTIFIC JUSTIFICATION: Application of allogeneic HCT can be curative for a variety of malignant and nonmalignant blood and marrow disorders. Increasing frequency of high risk disease phenotypes such as adverse cytogenetic characteristics and higher rates of peri-transplant mortality have limited application of HCT to older patients who are compromising an increasingly larger number of patients seen. These same patients may be ineligible for HCT due to traditional age eligibility criteria and not for other medical reasons. Only few reports are available which provide sufficient detail in both clinical and disease-related factors which may bias the results of HCT in older patients. These limited data have compromised clinical decision-making and confounded assurance to third party payors including Centers for Medicare and Medicaid Services (CMS) that proposed transplant therapy has satisfactory safety and efficacy to be appropriate for older beneficiaries. Currently, CMS will only cover transplant services for AML. 135

136 Not for publication or presentation Attachment 11 In this analysis we propose to examine post-hct outcomes in older (including over 65 years) vs. younger patients undergoing allografting in order to evaluate patient, disease and treatment factors which modify transplant outcomes. Because delay in time to HCT may compromise outcomes, the assessment of HCT outcomes for MDS; AML evolving from preceding MDS and de novo AML will be compared in these age cohorts as well. Since similar funding restrictions and difficult decision-making can confound choices of therapy including allo-transplantation for patients with NHL, a similar age-based comparison will be determined for NHL patients comparing higher risk (diffuse NHL) vs. lower risk (follicular NHL) but excluding mantle, immunoblastic and lymphoblastic NHL. 3.0 STUDY POPULATION: The study population will include patients reported to the CIBMTR aged 40 years or older who received a nonmyeloablative allogeneic HCT from either an HLA-identical sibling or unrelated donor reported to the CIBMTR from 1995 to 2005 for one of the following indications: MDS, AML in CR1 with or without preceding MDS, follicular NHL in any stage/remission, diffuse NHL in any stage/remission, and CML. Patients with prior autologous transplant will be included. Patients with mantle, lymphoblastic, or immunoblastic NHL will be excluded. Cord blood transplants will be excluded. 4.0 OUTCOMES: 4.1. Hematopoietic recovery: The primary measure of hematopoietic recovery will be: Time to absolute neutrophil count of 500 neutrophils/mm³ sustained for three consecutive days Acute graft-versus-host disease: Occurrence of grade II, III and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD Chronic graft-versus-host disease: Occurrence of symptoms in any organ system fulfilling the criteria of chronic GVHD Treatment-related mortality (TRM): any death in the first 28 days post-transplant or any death after day 28 in continuous remission are events Relapse (AML/MDS/CML): disease recurrence or persistent disease for patients not in CR at transplant. Those who survive without recurrence or persistent disease are censored at the date of last contact. 136

137 Not for publication or presentation Attachment Relapse/Progression (NHL): progressive disease or recurrence of disease are events. Those who survive without recurrence or progressive disease are censored at the date of last contact Disease-free survival (AML/MDS/CML): survival without death or relapse. Those who survive without recurrence or persistent disease are censored at the date of last contact Disease-free survival (NHL): survival without death, persistent disease, recurrence or progression. Those who survive without recurrence or progressive disease are censored at the date of last contact Overall survival: time to death from any cause. Surviving patients are censored at time of last contact. 5.0 VARIABLES TO BE ANALYZED: Main effect: - Age: vs vs vs. 65+ Patient related: - Gender: male vs. female - Karnofsky performance status: <80% vs. 80% Disease related: - Disease and status at time of transplant: AML: CR1 with prior MDS vs. CR1 without prior MDS; MDS/CML: early vs. intermediate vs. advanced; NHL: follicular vs. diffuse; resistant vs. CR1 vs. CR2+ vs. REL1 vs. REL2+ vs. unknown/untested sensitivity - Time from diagnosis to transplant: <1 year vs. 1 year Transplant related: - Donor age: continuous variable - Donor-recipient CMV status: -/- vs. -/+ vs. +/- vs. +/+ - Donor-recipient HLA match: HLA matched sibling vs. well-matched unrelated donor (no known mismatch at HLA- A, B, C, DRB1) vs. partially matched (single locus mismatch at HLA- A, B, C, DRB1) vs. mismatched (2 or more mismatches at HLA- A, B, C, DRB1) - Stem cell source: bone marrow vs. peripheral blood - GVHD prophylaxis: CsA or FK +MTX ± other vs. ex vivo T cell depletion vs. other - Post-transplant therapy prior to post transplant relapse: AML: planned DLI: yes vs. no; NHL: rituximab: yes vs. no - Donor-recipient gender match: M-M vs. M-F vs. F-M vs. F-F - Donor relationship: HLA-identical sibling vs. unrelated 137

138 Not for publication or presentation Attachment STUDY DESIGN: Patient-, disease-, and transplant-related factors will be compared between groups using the Chi-square test for categorical variables and the Kruskal-Wallis test for continuous variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Univariate probabilities of disease-free, and overall survival will be calculated using the Kaplan-Meier estimator with the variance estimated by Greenwood s formula. Probabilities of acute and chronic GVHD, TRM and relapse/progression will be calculated using cumulative incidence curves to accommodate competing risks. Ninetyfive percent confidence intervals for all probabilities and p-values of pairwise comparisons will be derived from pointwise estimates and calculated using standard techniques. The age groups will be compared using proportional hazards regression models. The proportional hazards assumptions for all the variables will be examined by adding a timedependent covariate. Time dependent covariates with piecewise constant of regression coefficients will be used to model time-varying effect when the proportionality assumption does not hold. The optimal time cut point will be determined by the maximum likelihood method. The proportionality assumption will be further examined for the piecewise constant regression coefficient Cox model. A stepwise forward method will be used to build the regression model for the outcomes of treatment-related mortality, relapse, disease-free survival and overall survival. The risk factors listed in section 5.0 will be considered in the model building procedure. Since recipient age is the main interest of this study, the risk factor of age will be included in all steps of model building procedure. The risk factors with significant level of p < 0.05 will be included in the model. The potential interaction between main effect of age and all significant covariates will be examined. Further adjustment will be applied when test indicates that interactions are significant. Adjusted probability of disease-free survival and overall survival will be computed based on final Cox regression model, stratified by age, and weighted by the pooled sample proportion value for all significant risk factors. These adjusted probabilities estimate likelihood of outcomes in populations with similar prognostic factors. SAS programs will be used in all the analyses. 7.0 REFERENCES: 1. Shapira M, Tsirigotis P, Resnick I.B. et al. Allogeneic hematopoietic stem cell transplantation in the elderly. Epub. Crit Rev Oncol/Hematol, Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on the outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children s Leukemia Working Parties. Blood 92: , Shipp M, Harrington D, Anderson J. The International non-hodgkin s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-hodgkin s Lymphoma. NEJM 329:987-94,

139 Not for publication or presentation Attachment de Lima M, Giralt S. Allogeneic transplantation for the elderly patient with acute myelogenous leukemia or myelodysplastic syndrome. Semin. Hematol 43: , Wong R, Giralt S, Martin T, et al. Reduced intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood 102:3052-9, Golberg S, Klumpp T, Magdalinski A, et al. Value of the pre-transplant evaluation in predicting toxic 100-day mortality among blood stem cell and bone marrow recipients. J Clin Oncol 16: , Shahjahan M, Alamo J, de Lima M, et al. Effect of comorbidities on allogeneic hematopoietic stem cell transplant outcomes in AML/MDS patients in first complete remission. Biol Blood Marrow Transpl 10(suppl 2):12-3, US Dept of Human Services. CMS Medicare Coverage Database. Publication Number 100-3, Manual Section Number , Version Deeg H, Shulman H, Anderson J, et al. Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients years of age. Blood 95: , Bertz H, Potthoff K, Finke J. Allogeneic stem cell transplantation from related and unrelated donor in older patients with myeloid leukemia. J Clin Oncol, 21:1480-4, Shimoni A, Kroger N, Zabelina T, et al. Hematopoietic stem cell transplantation from unrelated donors in elderly patients (age >55 years) with hematologic malignancies: older age is no longer a contraindication when using a reduced intensity conditioning. Leukemia 19:7-12, van Biesen K, Sobocinski K, Rowlings P, et al. Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92:1832-6, Khoury I, Champlin R. Nonmyeloablative stem cell transplantation for lymphoma. Semin Oncol 31:22-6,

140 Not for publication or presentation Attachment 11 Table 1a. Characteristics of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML in first complete remission reported to the CIBMTR, P-value Characteristics of patients N (%) N (%) N (%) N (%) Number of patients Number of centers Age, median (range), years 49 (40-54) 58 (55-59) 62 (60-64) 67 (65-79) <0.001 Male sex 97 (48) 90 (60) 77 (58) 34 (54) Missing 1 ( 0) 0 (.) 1 ( 1) 0 (.) Karnofsky score prior transplant 80% 169 (84) 126 (85) 116 (88) 53 (84) Missing 11 ( 5) 13 ( 9) 8 ( 6) 7 (11) Prior autologous transplant 5 ( 2) 4 ( 3) 2 ( 2) 0 (.) AML transformation <0.001 from prior MDS/MPD 35 (17) 43 (29) 51 (38) 25 (40) from other prior disease 1 (<1) 0 (.) 0 (.) 0 (.) De novo AML 162 (81) 96 (64) 71 (54) 34 (54) Missing 3 ( 1) 10 ( 7) 10 ( 8) 4 ( 6) Cytogenetic classification Normal a 71 (35) 63 (42) 52 (39) 30 (78) Good a 8 ( 4) 0 (.) 3 ( 2) 0 (.) Intermediate a 63 (31) 50 (34) 38 (29) 16 (25) High 33 (16) 19 (13) 26 (20) 10 (16) Missing 26 (13) 17 (11) 13 (10) 7 (11) Interval from diagnosis to transplant, 5 (1-24) 5 (2-22) 6 (2-125) 5 (1-27) median (range), months Donor HLA-identical sibling 110 (55) 60 (40) 53 (40) 32 (51) Unrelated 91 (45) 89 (60) 79 (60) 31 (49) Donor age, median (range), years 43 (19-65) 43 (19-72) 45 (19-74) 54 (21-78) <0.001 Missing 1 ( 1) 1 ( 2) Donor-recipient sex match M-M 59 (29) 62 (42) 46 (35) 20 (32) M-F 57 (28) 34 (23) 30 (23) 19 (30) F-M 38 (19) 28 (19) 31 (23) 14 (22) F-F 44 (22) 25 (17) 23 (17) 10 (16) Missing 3 ( 1) 0 (.) 2 ( 2) 0 (.) Donor-recipient CMV match /- 40 (20) 24 (16) 32 (24) 14 (22) -/+ 62 (31) 46 (31) 40 (30) 25 (40) +/+ 75 (37) 57 (38) 47 (36) 21 (33) +/- 20 (10) 17 (11) 11 ( 8) 2 ( 3) Missing 4 ( 2) 5 ( 3) 2 ( 2) 1 ( 2) Graft type <0.001 Bone marrow 43 (21) 18 (12) 13 (10) 2 ( 3) Peripheral blood 158 (79) 131 (88) 119 (90) 61 (97) 140

141 Not for publication or presentation Attachment 11 Table 1a Continued P-value Characteristics of patients N (%) N (%) N (%) N (%) Unrelated donor-recipient HLA Match Well-matched 63 (69) 55 (62) 49 (62) 23 (74) Partially matched 16 (18) 22 (25) 23 (29) 5 (16) Mismatched 9 (10) 10 (11) 4 ( 5) 1 ( 3) Missing 3 ( 3) 2 ( 2) 3 ( 4) 2 ( 6) Year of transplant (42) 46 (31) 38 (29) 14 (22) (58) 103 (69) 94 (71) 49 (78) Conditioning regimen <0.001 Cy+TBI±other 20 (10) 3 ( 2) 0 (.) 0 (.) TBI±other 34 (17) 44 (30) 37 (28) 23 (37) Bu+Cy±other 36 (18) 10 ( 7) 4 ( 3) 0 (.) Cy±other 20 (10) 15 (10) 22 (17) 11 (17) Flu±other 81 (40) 68 (46) 60 (45) 26 (41) Other 10 ( 5) 9 ( 7) 9 ( 7) 3 ( 5) Conditioning intensity <0.001 Reduced intensity 150 (75) 97 (65) 77 (58) 30 (48) Nonmyeloablative 51 (25) 52 (35) 55 (42) 33 (52) GVHD prophylaxis CsA±other 68 (34) 30 (20) 21 (16) 6 (10) CsA+MTX±other 63 (31) 61 (41) 59 (45) 34 (54) FK506±other 34 (17) 28 (19) 28 (21) 13 (21) FK506+MTX±other 27 (13) 28 (19) 24 (18) 9 (14) T-cell depletion 2 ( 1) 0 (.) 0 (.) 0 (.) Other 3 ( 1) 1 ( 1) 0 (.) 1 ( 2) None 4 ( 2) 0 (.) 0 (.) 0 (.) Missing 0 (.) 1 ( 1) 0 (.) 0 (.) DLI given to prevent relapse b Yes 2 ( 2) 4 ( 6) No 130 (98) 59 (94) Median follow-up of survivors, months 37 (2-110) 25 (1-87) 36 (3-96) 29 (3-59) Abbreviations: Cy=cyclophosphomide, TBI=total body irradiation, Bu=busulfan, Flu=fludarabine, CsA=cyclosporine, MTX=methotrexate a These groups will be combined in the multivariate analysis. b DLIs were identified from the AML insert (q. 119) and AML follow-up insert (q. 1) Was treatment given posttransplant to prevent recurrence of AML since date of last report? DLI would be captured in the Other, specify field. This was crosstabbed with the Subsequent DCI section. Cross-tab of Year of transplant and graft type: Yeartx BM PB (50) 1 (50) (100) 0 (.) (100) 0 (.) (38) 5 (63) (18) 9 (82) (13) 28 (88) (12) 43 (88) (14) 66 (86) (13) 72 (87) (12) 112 (88) (13) 133 (87) 141

142 Not for publication or presentation Attachment 11 Table 1b. Characteristics of patients aged 40 years receiving nonmyeloablative allogeneic HCT for diffuse or follicular NHL reported to the CIBMTR, Characteristics of patients N (%) N (%) N (%) N (%) Number of patients Number of centers Male sex 192 (59) 61 (56) 40 (66) 9 (69) Karnofsky score prior transplant 80% 275 (84) 87 (81) 52 (85) 11 (85) Missing 18 ( 6) 5 ( 5) 3 ( 5) 0 (.) Prior autologous transplant 64 (20) 26 (24) 13 (21) 2 (15) NHL Histology and status at transplant Follicular 227 (70) 60 (56) 33 (54) 6 (46) 1 st Complete Remission 12 ( 5) 4 ( 6) 1 ( 3) 0 (.) 2 nd Complete Remission 39 (17) 12 (20) 8 (24) 1 (17) Resistant disease 59 (26) 12 (20) 8 (24) 3 (50) 1 st Partial Remission 23 (10) 8 (13) 3 ( 9) 0 (.) 2 nd Partial Remission 54 (24) 18 (30) 11 (33) 1 (17) Unknown or untested sensitivity 21 ( 9) 3 ( 5) 0 (.) 1 (17) Missing 19 ( 8) 3 ( 5) 2 ( 6) 0 (.) Diffuse 99 (30) 48 (44) 28 (46) 7 (54) 1 st Complete Remission 4 ( 4) 3 ( 6) 1 ( 4) 0 (.) 2 nd Complete Remission 14 (14) 12 (25) 5 (18) 1 (14) Resistant disease 22 (22) 11 (22) 8 (29) 2 (29) 1 st Partial Remission 9 ( 9) 6 (13) 1 ( 4) 0 (.) 2 nd Partial Remission 22 (22) 13 (27) 11 (39) 4 (57) Unknown or untested sensitivity 10 (10) 3 ( 6) 1 ( 4) 0 (.) Missing 18 (18) 0 (.) 1 ( 4) 0 (.) Interval from diagnosis to transplant, median 37 (5-309) 40 (6-312) 41 (9-196) 69 (14-172) (range), months Missing 1 (<1) 0 (.) 0 (.) 0 (.) Donor HLA-identical sibling 165 (51) 43 (40) 28 (46) 5 (38) Unrelated 161 (49) 65 (60) 33 (54) 8 (62) Donor age, median (range), years 43 (20-66) 41 (20-72) 45 (22-73) 49 (25-65) Missing 4 ( 1) 0 (.) 1 ( 2) 0 (.) Donor-recipient sex match M-M 124 (38) 39 (36) 27 (44) 6 (46) M-F 79 (24) 22 (20) 11 (18) 1 ( 8) F-M 68 (21) 22 (20) 13 (21) 3 (23) F-F 55 (17) 25 (23) 10 (16) 3 (23) Donor-recipient CMV match -/- 102 (31) 28 (26) 17 (28) 2 (15) -/+ 87 (27) 32 (30) 17 (28) 4 (31) +/+ 93 (29) 34 (31) 18 (30) 5 (38) +/- 29 ( 9) 13 (12) 9 (15) 2 (15) Missing 15 ( 5) 1 ( 1) 0 (.) 0 (.) 142

143 Not for publication or presentation Attachment 11 Table 1b. Continued Characteristics of patients N (%) N (%) N (%) N (%) Graft type Bone marrow 84 (26) 28 (26) 2 ( 3) 3 (23) Peripheral blood 242 (74) 80 (74) 59 (97) 10 (77) Unrelated donor-recipient HLA Match a Well-matched 84 (59) 37 (65) 23 (72) 6 (75) Partially matched 49 (35) 16 (28) 7 (22) 2 (25) Mismatched 9 ( 6) 4 ( 7) 2 ( 6) 0 (.) Year of transplant (26) 10 ( 9) 4 ( 7) 4 (31) (74) 98 (91) 57 (93) 9 (69) GVHD prophylaxis CsA±other 61 (19) 17 (16) 7 (11) 2 (15) CsA+MTX±other 120 (37) 33 (31) 20 (33) 1 ( 8) FK506±other 90 (28) 30 (28) 21 (34) 6 (46) FK506+MTX±other 42 (13) 27 (25) 11 (18) 4 (31) T-cell depletion 5 ( 2) 1 ( 1) 0 (.) 0 (.) Other 3 ( 1) 0 (.) 1 ( 2) 0 (.) None 4 ( 1) 0 (.) 1 ( 2) 0 (.) Missing 1 (<1) 0 (.) 0 (.) 0 (.) Median follow-up of survivors, months 42 (3-120) 33 (3-77) 38 (3-64) 36 (14-96) Abbreviations: CsA=cyclosporine, MTX=methotrexate NMDP cases only 143

144 Not for publication or presentation Attachment 11 Table 1c. Characteristics of patients aged 40 years receiving nonmyeloablative allogeneic HCT for MDS reported to the CIBMTR, P-value Characteristics of patients N (%) N (%) N (%) N (%) Number of patients Number of centers Age, median (range) years 50 (40- < ) 57 (55-59) 62 (60-64) 67 (65-78) Male sex 119 (57) 108 (74) 83 (66) 39 (71) Karnofsky score prior transplant 80% 170 (82) 118 (81) 102 (81) 42 (76) Missing 12 ( 6) 11 ( 8) 9 ( 7) 3 ( 5) Prior autologous transplant 23 (11) 15 (10) 8 ( 6) 7 (13) Disease status at transplant Early 93 (45) 53 (36) 47 (37) 26 (47) Advanced 115 (55) 93 (64) 79 (63) 29 (53) Cytogenetic classification Normal 64 (31) 45 (31) 41 (33) 18 (33) Good 0 (.) 0 (.) 0 (.) 1 ( 2) Intermediate 55 (26) 30 (21) 32 (25) 17 (31) High 55 ( 26) 42 (29) 35 (28) 10 (18) Missing 34 (16) 29 (20) 18 (14) 9 (16) Interval from diagnosis to transplant, median 8 (1-302) 9 (1-132) 10 (2-153) 9 (1-120) (range), months Missing 0 (.) 0 (.) 1 ( 1) 0 (.) Donor HLA-identical sibling 90 (43) 56 (38) 53 (42) 15 (27) Unrelated 118 (57) 90 (62) 73 (58) 40 (73) Donor age, median (range), years 41 (20-41 (21-71) 47 (19-75) 36 (20-75) ) Missing 3( 1) 3 ( 2) 1( 1) 1 ( 1) Donor-recipient sex match M-M 75 (36) 68 (47) 55 (44) 24 (44) M-F 49 (24) 22 (15) 30 (24) 11 (20) F-M 44 (21) 40 (27) 27 (21) 15 (27) F-F 40 (19) 16 (11) 13 (10) 5 ( 9) Missing 0 (.) 0 (.) 1 ( 1) 0 (.) Donor-recipient CMV match /- 51 (25) 45 (31) 36 (29) 8 (15) -/+ 51 (25) 31 (21) 30 (24) 14 (25) +/+ 78 (38) 45 (31) 48 (38) 26 (47) +/- 22 (11) 18 (12) 7 ( 6) 4 ( 7) Missing 6 ( 3) 7 ( 5) 5 ( 4) 3 ( 5) Graft type Bone marrow 52 (25) 33 (23) 15 (12) 8 (15) Peripheral blood 156 (75) 113 (77) 111 (88) 47 (85) Unrelated donor-recipient HLA Match Well-matched 55 (47) 51 (57) 46 (63) 27 (68) Partially matched 33 (28) 27 (30) 18 (25) 9 (23) 144

145 Not for publication or presentation Attachment P-value Characteristics of patients N (%) N (%) N (%) N (%) Mismatched 14 (12) 11 (12) 3 ( 4) 3 ( 8) Missing 16 (14) 1 ( 1) 6 ( 8) 1 ( 3) Table 1c. Continued P-value Characteristics of patients N (%) N (%) N (%) N (%) Year of transplant (50) 62 (42) 52 (41) 16 (29) (50) 84 (58) 74 (59) 39 (71) Conditioning regimen Cy+TBI±other 8 ( 4) 2 ( 1) 1 ( 1) 0 (.) TBI±other 29 (14) 44 (30) 31 (25) 17 (31) Bu+Cy±other 29 (14) 14 (10) 8 ( 6) 1 ( 2) Cy±other 22 (11) 15 (10) 6 ( 5) 6 (11) Flu±other 113 (54) 66 (45) 70 (56) 30 (55) Other 7 ( 3) 5 ( 3) 10 ( 8) 1 ( 2) Conditioning intensity Reduced intensity 163 (78) 99 (68) 87 (69) 36 (65) Nonmyeloablative 45 (22) 47 (32) 39 (31) 19 (35) GVHD prophylaxis CsA±other 66 (32) 28 (19) 27 (21) 7 (13) CsA+MTX±other 76 (37) 64 (44) 56 (44) 22 (40) FK506±other 24 (12) 21 (14) 15 (12) 13 (24) FK506+MTX±other 40 (19) 28 (19) 24 (19) 13 (24) T-cell depletion 0 (.) 2 ( 1) 0 (.) 0 (.) Other 2 ( 1) 2 ( 1) 3 ( 2) 0 (.) None 0 (.) 1 ( 1) 1 ( 1) 0 (.) Median follow-up of survivors, months 36 (2-86) 40 (3-86) 35 (3-68) 36 (3-85) Abbreviations: Cy=cyclophosphomide, TBI=total body irradiation, Bu=busulfan, Flu=fludarabine, CsA=cyclosporine, MTX=methotrexate a These groups will be combined in the multivariate analysis. Cross-tab of Year of transplant and graft type: Yeartx BM PB (100) 0 (.) (.) 3 (100) (71) 2 (29) (29) 5 (71) (50) 7 (50) (17) 52 (83) (26) 49 (73) (21) 55 (79) (20) 75 (80) (18) 83 (82) (10) 96 (90) 145

146 Not for publication or presentation Attachment 11 Table 1d. Characteristics of patients aged 40 years receiving nonmyeloablative allogeneic HCT for CML reported to the CIBMTR, Characteristics of patients N (%) N (%) N (%) N (%) Number of patients Number of centers Male sex 130 (53) 41 (58) 20 (48) 13 (65) Missing 1 (<1) 1 ( 1) 0 (.) 0 (.) Karnofsky score prior transplant 80% 224 (91) 62 (87) 36 (86) 18 (90) Missing 9 ( 4) 6 ( 8) 2 ( 5) 0 (.) Prior autologous transplant 4 ( 2) 5 ( 7) 1 ( 2) 0 (.) Disease status at transplant Early 163 (66) 33 (46) 15 (36) 5 (25) Intermediate 69 (28) 30 (42) 23 (55) 11 (55) Advanced 9 ( 4) 5 ( 7) 3 ( 7) 4 (20) Missing 5 ( 2) 3 ( 4) 1 ( 2) 0 (.) Interval from diagnosis to transplant, median 17 (2-161) 20 (3-154) 35 (3-220) 29 (3-133) (range), months Missing 1 (<1) 0 (.) 0 (.) 0 (.) Donor HLA-identical sibling 129 (52) 34 (48) 23 (55) 11 (55) Unrelated 117 (48) 37 (52) 19 (45) 9 (45) Donor age, median (range), years 43 (20-65) 47 (20-71) 54 (21-80) 59 (23-73) Missing 9 ( 4) 3 ( 4) 0 (.) 1 ( 5) Donor-recipient sex match M-M 74 (30) 30 (42) 12 (29) 10 (50) M-F 68 (28) 13 (18) 8 (19) 4 (20) F-M 56 (23) 11 (15) 8 (19) 3 (15) F-F 47 (19) 16 (23) 14 (33) 3 (15) Missing 1 (<1) 1 ( 1) 0 (.) 0 (.) Donor-recipient CMV match -/- 49 (20) 21 (30) 10 (24) 4 (20) -/+ 49 (20) 18 (25) 8 (19) 2 (10) +/+ 107 (43) 21 (30) 20 (48) 12 (60) +/- 35 (14) 7 (10) 3 ( 7) 1 ( 5) Missing 6 ( 2) 4 ( 6) 1 ( 2) 1 ( 5) Graft type Bone marrow 93 (38) 22 (31) 7 (17) 2 (10) Peripheral blood 153 (62) 49 (69) 35 (83) 18 (90) Unrelated donor-recipient HLA Match a Well-matched 43 (55) 14 (61) 10 (67) 4 (57) Partially matched 28 (36) 9 (39) 5 (33) 0 (.) Mismatched 7 ( 9) 0 (.) 0 (.) 3 (43) Year of transplant (38) 21 (30) 10 (24) 4 (20) (62) 50 (70) 32 (76) 16 (80) 146

147 Not for publication or presentation Attachment 11 Table 1d. Continued Characteristics of patients N (%) N (%) N (%) N (%) GVHD prophylaxis CsA±other 93 (38) 21 (30) 13 (31) 2 (10) CsA+MTX±other 77 (31) 27 (38) 24 (57) 12 (60) FK506±other 43 (17) 15 (21) 2 ( 5) 6 (30) FK506+MTX±other 18 ( 7) 5 ( 7) 2 ( 5) 0 (.) T-cell depletion 5 ( 2) 1 ( 1) 0 (.) 0 (.) Other 3 ( 1) 0 (.) 1 ( 2) 0 (.) None 6 ( 2) 1 ( 1) 0 (.) 0 (.) Missing 1 (<1) 1 ( 1) 0 (.) 0 (.) Median follow-up of survivors, months 44 (2-139) 38 (3-118) 48 (12-64) 51 (12-69) Abbreviations: CsA=cyclosporine, MTX=methotrexate NMDP cases only 147

148 Not for publication or presentation Attachment 11 Table 2a. Univariate probabilities of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML in first complete remission reported to the CIBMTR, Outcome Event N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Overall Survival days 84 (78-88)% 92 (87-96)% 83 (76-89)% 89 (80-95)% 1 year 57 (50-64)% 60 (52-68)% 51 (42-60)% 51 (39-64)% 2 years 44 (37-52)% 50 (41-59)% 34 (25-43)% 36 (24-49)% 3 years 42 (35-49)% 47 (38-56)% 30 (22-39)% 36 (24-49)% Neutrophil Engraftment days 89 (84-93)% 92 (87-96)% 92 (87-96)% 97 (91-100)% 60 days 93 (89-96)% 96 (92-99)% 95 (90-98)% 98 (94-100)% Transplant-related days 11 (7-16)% 6 (3-10)% 13 (8-20)% 10 (4-18)% 1 year 21 (15-27)% 18 (12-25)% 24 (17-33)% 30 (19-42)% Acute GVHD days 33 (26-39)% 35 (27-43)% 35 (27-43)% 33 (22-45)% Chronic GVHD year 37 (30-44)% 47 (38-56)% 39 (31-48)% 47 (34-60)% 2 years 41 (34-48)% 49 (40-58)% 43 (34-52)% 53 (40-65)% Relapse year 29 (22-35)% 33 (26-41)% 31 (23-40)% 22 (12-33)% 2 years 33 (26-40)% 34 (27-42)% 37 (29-47)% 33 (21-46)% 3 years 34 (27-41)% 34 (27-42)% 39 (30-49)% 33 (21-46)% Leukemia-free survival year 51 (43-58)% 49 (41-57)% 44 (35-53)% 48 (36-61)% 2 years 42 (35-49)% 43 (35-52)% 31 (22-40)% 34 (22-47)% 3 years 40 (32-47)% 40 (32-49)% 27 (19-37)% 34 (22-47)%

149 Not for publication or presentation Attachment 11 Table 2b. Univariate probabilities of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML in first complete remission with prior MDS/MPS reported to the CIBMTR, Outcome Event N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Overall Survival years 32 (17-49)% 42 (27-57)% 28 (16-43)% 43 (24-63)% 3 years 32 (17-49)% 38 (23-54)% 28 (16-43)% 43 (24-63)% Leukemia-free survival years 35 (20-52)% 43 (28-58)% 31 (18-46)% 39 (20-59)% 3 years 35 (20-52)% 38 (24-55)% 31 (18-46)% 39 (20-59)% Table 2c. Univariate probabilities of patients aged 40 years receiving nonmyeloablative allogeneic HCT for de novo AML in first complete remission reported to the CIBMTR, Outcome Event N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Overall Survival years 47 (38-55)% 50 (39-61)% 36 (24-49)% 29 (14-47)% 3 years 43 (35-52)% 47 (35-59)% 31 (20-44)% 29 (14-47)% Leukemia-free survival years 43 (35-51)% 41 (30-52)% 31 (19-44)% 27 (12-46)% 3 years 40 (32-49)% 38 (27-50)% 25 (13-38)% 27 (12-46)%

150 Not for publication or presentation Attachment 11 Table 2d. Univariate probabilities of patients aged 40 years receiving nonmyeloablative allogeneic HCT for diffuse or follicular NHL reported to the CIBMTR, Outcome Event N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Overall Survival days 77 (72-81)% 72 (63-80)% 74 (62-84)% 77 (51-95)% 1 year 59 (53-64)% 53 (43-62)% 51 (38-63)% 62 (35-85)% 2 years 52 (46-57)% 39 (30-49)% 49 (36-61)% 53 (26-79)% Neutrophil Engraftment days 83 (78-87)% 75 (65-84)% 81 (68-91)% 84 (59-98)% 60 days 83 (79-88)% 77 (68-86)% 81 (68-91)% 84 (59-98)%

151 Not for publication or presentation Attachment 11 Table 2e. Univariate probabilities of patients aged 40 years receiving nonmyeloablative allogeneic HCT for MDS reported to the CIBMTR, Outcome Event N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Overall Survival days 77 (71-82)% 76 (69-83)% 82 (75-88)% 76 (64-87)% 1 year 50 (44-57)% 46 (38-54)% 53 (44-62)% 48 (35-61)% 2 years 42 (35-49)% 35 (27-43)% 45 (36-54)% 38 (25-51)% 3 years 40 (33-47)% 29 (22-38)% 30 (21-40)% 29 (17-43)% Neutrophil Engraftment days 83 (77-88)% 80 (73-86)% 88 (82-93)% 87 (77-95)% 60 days 86 (80-90)% 85 (78-90)% 90 (84-94)% 87 (77-95)% Transplant-related days 17 (12-22)% 17 (12-24)% 13 (8-20)% 19 (10-30)% 1 year 29 (23-36)% 32 (25-40)% 32 (24-40)% 35 (22-48)% Acute GVHD days 33 (26-39)% 36 (28-44)% 31 (23-40)% 34 (22-47)% Chronic GVHD year 35 (28-42)% 36 (28-45)% 35 (26-44)% 34 (22-47)% 2 years 37 (30-44)% 38 (30-47)% 40 (31-49)% 45 (31-59)% Relapse year 27 (21-33)% 27 (20-35)% 25 (18-33)% 23 (13-36)% 2 years 28 (22-34)% 29 (22-37)% 29 (21-38)% 25 (14-38)% 3 years 29 (23-36)% 29 (22-37)% 31 (23-40)% 31 (19-45)% Leukemia-free survival year 44 (37-51)% 40 (32-49)% 43 (34-52)% 42 (29-56)% 2 years 39 (32-46)% 32 (24-40)% 35 (27-45)% 36 (23-49)% 3 years 36 (29-44)% 27 (20-35)% 29 (21-39)% 23 (12-38)%

152 Not for publication or presentation Attachment 11 Table 2f. Univariate probabilities of patients aged 40 years receiving nonmyeloablative allogeneic HCT for early MDS reported to the CIBMTR, Outcome Event N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Overall Survival years 47 (37-58)% 42 (29-56)% 41 (27-57)% 53 (34-72)% 3 years 47 (37-58)% 36 (23-50)% 30 (16-46)% 41 (21-62)% Leukemia-free survival years 46 (36-57)% 39 (26-53)% 35 (22-50)% 53 (34-72)% 3 years 45 (34-56)% 33 (20-48)% 28 (15-44)% 41 (21-62)% Table 2g. Univariate probabilities of patients aged 40 years receiving nonmyeloablative allogeneic HCT for advanced MDS reported to the CIBMTR, Outcome Event N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Overall Survival years 37 (28-46)% 30 (21-41)% 47 (36-59)% 23 (9-41)% 3 years 34 (25-44)% 25 (16-35)% 31 (19-44)% 18 (6-36)% Leukemia-free survival years 33 (24-42)% 27 (18-38)% 36 (25-47)% 17 (5-35)% 3 years 30 (21-39)% 23 (14-34)% 31 (20-43)% 6 (0-20)%

153 Not for publication or presentation Attachment 11 Table 2h. Univariate probabilities of patients aged 40 years receiving nonmyeloablative allogeneic HCT for CML reported to the CIBMTR, Outcome Event N Prob (95%CI) N Prob (95%CI) N Prob (95% CI) N Prob (95%CI) P-value Overall Survival days 84 (79-88)% 87 (79-94)% 86 (74-95)% 60 (38-80)% 1 year 66 (60-72)% 67 (55-77)% 62 (47-76)% 40 (20-62)% 2 years 57 (51-64)% 54 (42-66)% 45 (30-60)% 40 (20-62)% Neutrophil Engraftment days 92 (88-96)% 90 (81-96)% 88 (76-96)% 95 (78-100)% 60 days 96 (94-98)% 93 (86-98)% 95 (87-100)% 95 (78-100)%

154 Not for publication or presentation Attachment 11 Table 3. Causes of death of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML in first complete remission of MDS reported to the CIBMTR, AML MDS N (%) N (%) Number of deaths Causes of death Primary disease 123 (39) 90 (26) New malignancy 3 ( 1) 7 ( 2) GVHD 36 (12) 54 (16) IPN 21 ( 7) 10 ( 3) Infection 56 (18) 80 (23) Organ failure 41 (13) 51 (15) Hemorrhage 9 ( 3) 16 ( 5) Vascular 4 ( 1) 0 (.) Prior malignancy 3 ( 1) 0 (.) Graft rejection/failure 0 (.) 16 ( 5) Other 3 ( 1) 1 ( <1) Unknown 14 ( 4) 16 ( 5) 154

155 Not for publication or presentation Attachment 11 Table 4. Variables tested in mulitivariate models. Main effect a : Age: b vs vs vs. 65+ Patient related: Gender: male vs. female Karnofsky performance status: <80% vs. 80% vs. unknown Disease related: Disease and status at time of transplant: AML: CR1 with prior MDS vs. CR1 without prior MDS/MPD; MDS: early vs. intermediate vs. advanced Time from diagnosis to transplant: <1 year vs. 1 year Cytogenetic risk classification: good/intermediate risk/normal b vs. high risk vs. missing Transplant related: Donor age: continuous variable Donor-recipient CMV status: -/- vs. -/+ vs. +/- vs. +/+ Donor-recipient HLA match: HLA matched sibling b vs. well-matched unrelated donor (no known mismatch at HLA- A, B, C, DRB1) vs. partially matched (single locus mismatch at HLA- A, B, C, DRB1) vs. mismatched (2 or more mismatches at HLA- A, B, C, DRB1) Stem cell source: bone marrow vs. peripheral blood GVHD prophylaxis: CsA or FK +MTX ± vs. other/unknown Donor-recipient gender match: M-M vs. M-F vs. F-M vs. F-F Conditioning regimen intensity: reduced intensity vs. nonmyeloablative a Included in all models b Reference group for analysis 155

156 Not for publication or presentation Attachment 11 Table 5. Multivariate analysis of neutrophil recovery a of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: b P overall = c ( ) ( ) ( ) Other significant covariates: Conditioning regimen intensity Reduced intensity b P overall = 0.02 Nonmyeloablative ( ) a Stratified by graft type. b Reference group. c Chi-square test with 3 d.f. Table 6. Multivariate analysis of acute GVHD of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall = b ( ) ( ) ( ) 0.61 Other significant covariates: Donor-recipient HLA match HLA-identical sibling a P overall < c Well-matched ( ) < Partially matched ( ) < Mismatched ( ) 0.08 Unknown ( ) 0.72 a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 4 d.f. Table 7. Multivariate analysis of chronic GVHD of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall =0.174 b ( ) ( ) ( ) 0.04 a Reference group. b Chi-square test with 3 d.f. 156

157 Not for publication or presentation Attachment 11 Table 8a. Multivariate analysis of overall 1 year of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall =0.811 b ( ) ( ) ( ) 0.72 Other significant covariates: Disease status AML, w/ prior MDS a P overall = d AML, w/o prior MDS ( ) <0.01 AML, unknown ( ) 0.02 MDS, early ( ) MDS, advanced ( ) 0.56 Karnofsky score < a P overall = c ( ) <0.001 Unknown ( ) <0.001 Sex Male a Female ( ) P overall = Donor-recipient HLA match HLA-identical sibling a P overall < d Well-matched ( ) Partially matched ( ) < Mismatched ( ) < Cytogenetic risk group Good/intermediate/normal a P overall < c High ( ) < Unknown ( ) 0.65 Donor age (continuous) Donor age 1.01 ( ) 0.02 a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 2 d.f. d Chi-square test with 4 d.f. 157

158 Not for publication or presentation Attachment 11 Table 8b. Multivariate analysis of overall 2 years of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall =0.571 b ( ) ( ) ( ) 0.21 Other significant covariates: Karnofsky score < a P overall =0.006 c ( ) Unknown ( ) Donor-recipient HLA match HLA-identical sibling a P overall = d Well-matched ( ) 0.09 Partially matched ( ) 0.24 Mismatched ( ) Unknown ( ) 0.64 Cytogenetic risk group Good/intermediate/normal a P overall < c High ( ) < Unknown ( ) 0.99 a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 2 d.f. d Chi-square test with 4 d.f. 158

159 Not for publication or presentation Attachment 11 Table 9a.. Multivariate analysis of leukemia-free 1 years of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall = b ( ) ( ) ( ) 0.88 Other significant covariates: Disease status AML, w/ prior MDS a P overall = d AML, w/o prior MDS ( ) 0.32 AML, unknown ( ) 0.25 MDS, early ( ) 0.03 MDS, advanced ( ) 0.32 Karnofsky score < a P overall = c ( ) <0.01 Unknown ( ) 0.02 Donor-recipient HLA match HLA-identical sibling a P overall = d Well-matched ( ) 0.02 Partially matched ( ) Mismatched ( ) Unknown ( ) 0.16 Donor age (continuous) Donor age 1.01 ( ) 0.03 Cytogenetic risk group Good/intermediate/normal a P overall < c High ( ) < Unknown ( ) 0.64 a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 2 d.f. d Chi-square test with 4 d.f. 159

160 Not for publication or presentation Attachment 11 Table 9b. Multivariate analysis of leukemia-free 2 years of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall = b ( ) ( ) ( ) 0.54 Other significant covariates: Donor-recipient HLA match HLA-identical sibling a P overall = d Well-matched ( ) Partially matched ( ) 0.03 Mismatched ( ) Unknown ( ) 0.24 Cytogenetic risk group Good/intermediate/normal a P overall < c High ( ) < Unknown ( ) 0.59 Donor age (continuous) Donor age 1.01 ( ) 0.02 a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 2 d.f. d Chi-square test with 4 d.f. 160

161 Not for publication or presentation Attachment 11 Table 10a. Multivariate analysis of treatment-related 1 year of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall = b ( ) ( ) ( ) 0.22 Other significant covariates: Disease status AML, w/ prior MDS a P overall = c AML, w/o prior MDS ( ) 0.06 AML, unknown ( ) 0.20 MDS, early ( ) 0.80 MDS, advanced ( ) 0.40 Donor-recipient HLA match HLA-identical sibling a P overall < c Well-matched ( ) 0.04 Partially matched ( ) < Mismatched ( ) < Unknown ( ) Donor age (continuous) Donor age 1.02 ( ) 0.01 a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 4 d.f. 161

162 Not for publication or presentation Attachment 11 Table 10b. Multivariate analysis of treatment-related 2 years of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall = b ( ) ( ) ( ) 0.43 Other significant covariates: Donor-recipient HLA match HLA-identical sibling a P overall < c Well-matched ( ) Partially matched ( ) < Mismatched ( ) < Unknown ( ) 0.01 Donor age (continuous) Donor age 1.01 ( ) 0.03 a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 4 d.f. 162

163 Not for publication or presentation Attachment 11 Table 11a. Multivariate analysis of 1 year of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall = b ( ) ( ) ( ) 0.36 Other significant covariates: Disease status AML, w/ prior MDS a P overall = d AML, w/o prior MDS ( ) 0.15 AML, unknown ( ) 0.31 MDS, early ( ) 0.11 MDS, advanced ( ) 0.34 Graft type Bone marrow a Peripheral blood ( ) 0.02 Cytogenetic risk group Good/intermediate/normal a P overall < c High ( ) < Unknown ( ) 0.56 Conditioning regimen intensity Reduced intensity b P overall < 0.01 Nonmyeloablative ( ) a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 2 d.f. d Chi-square test with 4 d.f 163

164 Not for publication or presentation Attachment 11 Table 11b.Multivariate analysis of 2 years of patients aged 40 years receiving nonmyeloablative allogeneic HCT for AML and MDS. Variables N RR (95% CI) P-value Age group: a P overall = b ( ) ( ) ( ) 0.71 Other significant covariates: Disease status AML, w/ prior MDS a P overall = d AML, w/o prior MDS ( ) 0.11 AML, unknown ( ) 0.28 MDS, early ( ) 0.10 MDS, advanced ( ) 0.54 Cytogenetic risk group Good/intermediate/normal a P overall < c High ( ) < Unknown ( ) 0.46 Conditioning intensity Reduced intensity a P overall = c Nonmyeloablative ( ) a Reference group. b Chi-square test with 3 d.f. c Chi-square test with 2 d.f. d Chi-square test with 4 d.f 164

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