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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA Honolulu, Hawaii Sunday, February 20, 2011, 2:45 pm - 4:45 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: Donald Bunjes, MD, University Hospital Ulm, Ulm, Germany Phone: ; Fax: ; donald.bunjes@uniklinik.ulm.de Steven Devine, MD, Ohio State Medical Center - James Cancer Center Phone: ; Fax: ; steven.devine@osumc.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 Minutes of February, 2010 meeting (Attachment 1) 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers a. LK02-02 Litzow M, Tarima S, Pérez WS, Bolwell BJ, Cairo MS, Camitta BM, Cutler CS, de Lima M, DiPersio JF, Gale RP, Keating A, Lazarus HM, Luger S, Marks DI, Maziarz RT, McCarthy PL, Pasquini M, Phillips GL, Rizzo JD, Sierra J, Tallman MS, Weisdorf DJ. Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood. 115: , b. LK03-03 Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, Kamble R, Copelan E, de Lima M, Gupta V, Keating A, Lazarus HM, Litzow MR, Marks DI, Maziarz RT, Rizzieri DA, Schiller G, Schultz KR, Tallman MS, Weisdorf D. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. Journal of Clinical Oncology 28: , c. LK04-02/GV01-01 Luger SM, Ringdén O, Zhang M-J, Pérez WS, Ballen KK, Bishop MR, Bornhauser M, Bredeson CN, Bujan WA, Cairo MS, Copelan EA, Gale RP, Giralt SA, Goldstein SC, Gulbas Z, Gupta V, Hale GA, Herzig RH, Ilhan O, Isola LM, Lazarus HM, Lewis VA, Liesveld JL, Lill MC, McCarthy PL, Milone GA, Rizzieri DA, Russell JA, Sabloff M, Santarone S, Schiller G, Soiffer RJ, Waller EK, Weiner RS, Wiernik PH, Weisdorf DJ, Pulsipher MA. Similar outcomes using myeloablative versus reduced intensity allogeneic transplant preparative regimens for AML or MDS. Submitted-Revised. 1

2 Not for publication or presentation d. LK05-01 Gupta V, Tallman MS, He W, Logan BR, Copelan E, Gale RP, Khoury HJ, Klumpp T, Koreth J, Lazarus HM, Marks DI, Martino R, Rizzieri DA, Rowe JM, Sabloff M, Waller EK, DiPersio JF, Bunjes DW, Weisdorf DJ. Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis. Blood Sep 16;116(11): Epub 2010 Jun 10. e. LK06-01 Farag SS, Maharry K, Zhang M-J, Pérez WS, George SL, Mrózek K, DiPersio J, Bunjes DW, Marcucci G, Baer MR, Cairo M, Copelan E, Cutler C, Isola L, Lazarus HM, Litzow MR, Marks DI, Ringdén O, Rizzieri DA, Soiffer R, Larson RA, Tallman MS, Bloomfield CD, Weisdorf DJ. Comparison of reduced-intensity allogeneic hematopoietic cell transplantation with chemotherapy in patients aged years with acute myeloid leukemia in first remission: A Center for International Blood and Marrow Transplant Research and Cancer and Leukemia Group B study. Submitted. f. LK07-01 Armand P, Pérez WS, Zhang M-J, Kim HT, Dal Cin P, Klump TR, Waller EK, Litzow MR, Liesveld J, Lazarus HM, Artz A, Gupta V, Savani BN, McCarthy P, Cahn J-Y, Schouten HC, Finke J, Ball E, Aljurf M, Cutler C, Rowe JM, Antin JH, Isola L, Bartolomeo PD, Camitta B, Miller A, Cairo MS, Stockerl-Goldstein K, Sierra J, Lynn Savoie M, Halter J, Stiff P, Nabhan C, Jakubowski A, Bunjes D, Petersdorf EW, Devine S, Maziarz RT, Bornhauser M, Lewis V, Marks D, Bredeson CN, Soiffer RJ, Weisdorf DJ. Cytogenetics Abnormalities Predict the Outcome of Allogeneic Transplantation in AML: A CIBMTR Study. Presented at the American Society of Hematology in Orlando, Florida, December Manuscript in preparation. g. LK07-03a McClune BL, Weisdorf DJ, Pedersen TL, Tunes de Silva G, Tallman MS, Sierra J, DiPersio J, Keating A, Gale RP, George B, Gupta V, Isola L, Jagasia M, Lazarus H, Marks D, Marks D, Maziarz R, Miller A, Waller EK, Bredeson C, Giralt S. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission and myelodysplastic syndrome. Journal of Clinical Oncology 28: , h. LK08-03 Marks DI, Wang T, Pérez WS, Antin JH, Copelan E, Gale RP, George B, Gupta V, Halter J, Khoury HJ, Klumpp TR, Lazarus HM, Lewis VA, McCarthy P, Rizzieri DA, Sabloff M, Szer J, Tallman MS, Weisdorf D. The outcome of full-intensity versus reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood 116: , Studies in progress (Attachment 3) a. R02-05 URD after failed autologous transplant (J Foran) Manuscript Preparation b. R02-09 DLI after relapse (A Loren) Data Collection (n=453) c. LK04-01 Allo and auto HCT for APML in CR2 (M Rubinger /M Tallman) d. LK04-03 PBSC autologous vs. HLA-id allogeneic for AML (A Keating) e. LK07-01 Cytogenetic risk groups in AML/MDS (P Armand/ R Soiffer) f. LK07-02 Scoring System as predictor in AML after HCT (J Sierra) Supplemental Data Collection Complete (n=152/283); Data File Preparation Manuscript Preparation Manuscript Preparation Data File Preparation 2

3 Not for publication or presentation g. LK07-03b Allo HCT in older patients with NHL and CML (E Data File Preparation Warlick/ B McClune) h. LK08-01 Landmark analysis for updated relapse/lfs estimates Data File Preparation for patients (S Lee) i. LK08-02 RIC in allo HCT for older patient with denovo MDS - Analysis decision analysis (J Koreth/C Cutler) j. LK08-04/IB08-05 LTA alleles in AML relapse (P Posch) Deferred k. LK09-01 CNS therapy in allo HCT (N Esiashvili) Discontinued l. LK09-02 Monosomal karyotype and chromosomal 7 Protocol Development abnormalities in allo HCT for AML/MDS (M Pasquini/ M Battiwala) (Attachment 4) m. LK10-01 Allo HCT for AML with intermediate risk karyotype Protocol Development in CR1 using MSD/alternative donors (B Oran) (Attachment 5) n. LK10-02 Pre-HCT consolidation therapy on outcomes of RIC Protocol Development allo for AML in CR1 (E Warlick/M Litzow) (Attachment 6) o. LK10-03 Ph+ ALL in adults comparing RIC/MA allo HCT (V Bachanova) Funded Supplemental Data Collection (NST/RIC=83; MA=160) 5. Future/ Proposed studies AML a. PROP / / Prognostic scoring system for predicting leukemia free survival in AML patients age 55 after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (B Oran/Gupta/Loren) (Attachment 7) b. PROP Outcomes of reduced-intensity allogeneic transplants for patients with relapsed/refractory acute myeloid leukemia (A Loren) (Attachment 8) c. PROP Stem cell transplantation for acute myeloid leukemia harboring MLL abnormalities (L Costa) (Attachment 9) d. PROP Impact of extramedullary disease on the outcome of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia (S Goyal) (Attachment 10) ALL e. PROP The outcome of sibling, unrelated donor and cord blood transplantation for acute lymphoblastic leukemia in first complete remission that was initially refractory to induction chemotherapy (D Marks) (Attachment 11) f. PROP Chemotherapy versus allogeneic hematopoietic cell transplantation in philadelphia negative chromosome negative adult acute lymphoblastic leukemia (M Seftel) (Attachment 12) g. PROP Comparison of outcomes of allogeneic hematopoietic stem cell transplantation in patients with T-cell acute lymphoblastic leukemia in first complete remission and beyond (G Akpek) (Attachment 13) h. PROP Development of a Prognostic Scoring System to Predict Relapse of Acute Lymphocytic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation (R Salit) (Attachment 14) AML and ALL i. PROP Outcomes of HLA haploidentical related hematopoietic cell transplantation for acute leukemias (B Wirk) (Attachment 15) 3

4 Not for publication or presentation DEFERRED j. PROP Predictive factors for outcome of allogeneic hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia in first relapse (P Kebriaei) (Attachment 16; Deferred due to requirement of secondary data collection) k. PROP Outcomes of second reduced intensity/nonmyeloablative allogeneic stem cell transplant for acute leukemia relapse after a first reduced intensity/nonmyeloablative allogeneic stem cell transplant (B Wirk) (Attachment 17; Deferred due to low number of reported cases; MA-=35; NMA/RIC=27) l. PROP Minimal residual disease and 100-day mortality post allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia (N Saba) (Attachment 18; Deferred due to requirement of secondary data collection) m. PROP Influence of persistent karyotypic abnormalities on post-transplant outcomes in patients with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation in first complete hematologic remission (M Norkin) (Attachment 19; Deferred due to requirement of secondary data collection and incomplete data detail) 6. Other business 4

5 Not for publication or presentation Attachment 1 MINUTES CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA Orlando, Florida Saturday, February 25, 2010, 12:15 pm - 2:15 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: 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 Donald Bunjes, MD, University Hospital Ulm, Ulm, Germany Phone: ; Fax: ; donald.bunjes@uniklinik.ulm.de 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 The CIBMTR Working Committee for Acute Leukemia was called to order at 12:20 pm on Thursday February 25, 2010 by Dr. Martin Tallman. The chairs, scientific director and statisticians were presented. The newly appointed chair, Dr. Steven Devine, was introduced. Attendees were asked to sign the attendance sheet in order to maintain the committee membership, fill out the Working Committee evaluations as well as the WC voting sheets for proposals. The CIBMTR guidelines for voting on proposals were discussed. As the Committee had a full agenda, it was suggested to limit each presentation to 4 minutes (maximum 3-4 overheads) so that there would be adequate time for discussion (6 minutes) for the previous proposals; not initiated and for the new proposals. The minutes of the previous meeting from February 2009 were approved without modifications. 2. Accrual summary Due to the full agenda, the accrual summary of registration and research cases between 1995 and 2009 were briefly presented to the committee: Registration only Research AML allogeneic ALL allogeneic AML autologous ALL autologous Details of the characteristics were not presented to the committee but were available as part of the Working Committee attachments. 5

6 Not for publication or presentation Attachment 1 3. Presentations, published or submitted papers Due to the full agenda, the 2009 presentations and published papers were not presented. One paper was published, one paper in press, four submitted and four ASH presentations were given during the past year. These include: a. LK02-02 Litzow M, Tarima S, Pérez WS, Bolwell BJ, Cairo MS, Camitta BM, Cutler CS, de Lima M, DiPersio JF, Gale RP, Keating A, Lazarus HM, Luger S, Marks DI, Maziarz RT, McCarthy PL, Pasquini M, Phillips GL, Rizzo JD, Sierra J, Tallman MS, Weisdorf DJ. Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood. Prepublished online Dec 23, 2009; doi: /blood b. LK03-03 Duval M, Klein JP, He W, Cahn J-Y, Cairo M, Camitta BM, Campbell R, Copelan EA, de Lima M, Gupta G, Keating A, Lazarus HM, Litzow M, Marks DI, Maziarz R, Rizzieri D, Schiller G, Schultz K, Tallman MS, Weisdorf DJ. Hematopoietic stem cell transplantation in acute leukemia in relapse or primary induction failure: pre-transplant variables define subgroups with different outcomes. Submitted. c. LK04-02/GV01-01 Luger SM, Ringdén O, Zhang M-J, Pérez WS, Ballen KK, Bishop MR, Bornhauser M, Bredeson CN, Bujan WA, Cairo MS, Copelan EA, Gale RP, Giralt SA, Goldstein SC, Gulbas Z, Gupta V, Hale GA, Herzig RH, Ilhan O, Isola LM, Lazarus HM, Lewis VA, Liesveld JL, Lill MC, McCarthy PL, Milone GA, Rizzieri DA, Russell JA, Sabloff M, Santarone S, Schiller G, Soiffer RJ, Waller EK, Weiner RS, Wiernik PH, Weisdorf DJ, Pulsipher MA. Similar outcomes using myeloablative versus reduced intensity allogeneic transplant preparative regimens for AML or MDS. Submitted. d. LK05-01 Gupta V, Tallman MS, He W, Logan BR, Copelan E, Gale RP, Khoury HJ, Klumpp T, Koreth J, Lazarus HM, Marks DI, Martino R, Rizzieri DA, Rowe JM, Sabloff M, Waller E, DiPersio JF, Bunjes DW, Weisdorf DJ. Comparable Survival after well-matched unrelated or matched sibling donor transplantation in acute myeloid leukemia with unfavorable risk cytogenetics in first remission - A report from the Center for International Blood and Marrow Transplant Research. Submitted. e. LK07-03a McClune BL, Weisdorf DJ, Pedersen TL,Tunes-de-Silva G, Tallman MS, Sierra J, DiPersio J, Keating A, Gale RP, George B, Gupta V, Hahn T, Isola L, Jagasia M, Lazarus H, Marks D, Maziarz R, Waller EK, Bredeson C, Giralt S. Effect of age on outcome of reducedintensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission and myelodysplastic syndrome. JCO. Mar : doi: / JCO f. LK08-03 Marks DI, Wang T, Pérez WS, Marks DI, Wang T, Pérez WS, Antin J, Copelan E, Gale RP, George B, Gupta V, Halter J, Khoury J, Klumpp TR, Lazarus HM, Lewis VA, McCarthy P, Rizzieri DA, Sabloff M, Szer J, Tallman MS, Weisdorf DJ. The outcome of full intensity versus reduced intensity conditioning matched sibling or unrelated donor (URD) transplantation in adults with philadelphia chromosome negative acute lymphoblastic leukaemia (Ph- ALL) in first and second complete remission (CR1 and CR2). Submitted. g. LK03-03 Duval M He W, Klein JP, Tallman MS, DiPersio JF, Bunjes DW and Daniel J. Weisdorf. Allogeneic Hematopoietic Cell Transplantation Can Cure Some Patients with Acute Leukemia in Relapse or Primary Induction Failure: A CIBMTR Study. Presented at the American Society of Hematology in New Orleans, Louisiana, December

7 Not for publication or presentation Attachment 1 h. LK05-01 Gupta V, Tallman MS, He W, Logan BR, DiPersio JF, Bunjes D and Daniel Weisdorf on behalf of the Acute Leukemia Working Committee, Center for International Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, USA. Comparable Disease-free and Overall Survival After Well-Matched Unrelated Donor and Matched Sibling Donor Transplantation in Acute Myeloid Leukemia With Adverse Risk Karyotype in First Complete Remission - A Report From the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research. Presented at the American Society of Hematology in New Orleans, Louisiana, December i. LK06-01 Farag SS, Maharry K, Perez WS, Zhang M-J, DiPersio J, Bunjes D, Marcucci G, Baer MR, Larson RA, Tallman MS, Bloomfield CD and Weisdorf D on behalf of the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplantation Research (CIBMTR) and the Leukemia Committee of Cancer and Leukemia Group B (CALGB). Reduced-intensity allogeneic hematopoietic stem cell transplantation improves leukemia-free survival compared to chemotherapy alone in patients aged 60 years and older with acute myeloid leukemia: a comparative study of the Center for International Blood and Marrow Transplantation Research and Cancer and Leukemia Group B. Presented at the American Society of Hematology in New Orleans, Louisiana, December j. LK08-03 Marks DI, Wang T, Peréz WS, Bunjes DW, DiPersio JF, Tallman MS and Daniel J. Weisdorf on behalf of the Acute Leukemia Working Committee, CIBMTR, Milwaukee, WI, USA. Comparison of outcomes for non-myeloablative (NMA) and myeloablative (MA) conditioning for adults with acute lymphoblastic leukaemia (ALL) in first and second complete remission (CR): A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis. Presented at the American Society of Hematology in New Orleans, Louisiana, December Studies in progress Dr. Bunjes led this section. The studies which made progress during the past year were not presented due to the enormous activity of the committee and the limited allocated time of the meeting. A summary of the progress was provided as an attachment to the committee members. These were: a. 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. A draft manuscript is underway and it is expected to be submitted by July b. 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. Secondary data collection is required and is underway (n=670). The protocol is available for review. c. 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 was completed (n=152/283) and the data file preparation is underway. 7

8 Not for publication or presentation Attachment 1 d. LK04-03: PBSC autologous vs. matched sibling allografts for AML (A Keating): This comparative analysis will assess the utility of allogeneic and peripheral blood 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 by July e. LK06-01: AlloHCT vs chemo for AML-CR1 elderly (S Farag): This study compares the outcomes of TRM, relapse, LFS and overall survival among patients who underwent allogeneic HCT in first CR vs. conventional chemotherapy in AML patients 60 years of age. The analysis was presented at the 2009 American Society of Hematology meeting in New Orleans, Louisiana. A draft manuscript is underway and it is expected to be submitted after Tandem. f. 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 was completed and cytogenetics reports were reviewed by the principal investigator (n=957/1268). The data file preparation is underway. g. 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 data file preparation is underway. h. LK07-03b: Allo HCT in older patients with NHL and CML (E Warlick/ 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. The manuscript for the AML and MDS population will be published in JCO and the data file preparation for the Lymphoma and CML population is underway. i. 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 data file preparation is underway. j. LK08-02: RIC in allohct for older patient with denovo MDS - decision analysis (J Koreth). The purpose of this study is to use decision analysis and the best available databases to determine the optimal role and timing of RIC allohct for de-novo MDS patients 60 years. The dataset will include data from four patients cohorts: (1) natural history cohort from the IMRAW group at Stanford University and the Pavia group at the University of Pavia medical School in Italy; (2) erythropoiesis agent therapy cohort from the Groupe Francophone des Myelodysplasies (GFM); (3) hypomethylating agent therapy cohort from the AZA-001 Phase III Study of the International Vidaza High-Risk MDS Survival Study Group (IVHMSS) and those receiving decitabine therapy on research studies at M.D. Anderson Cancer Center and (4) transplantation cohort from the CIBMTR, EBMT, DFCI and FHCRC. A protocol is available 8

9 Not for publication or presentation Attachment 1 for review and the data file preparation is underway. k. LK08-04/ IB08-05: 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. The samples are being tested which will provide a basis for the protocol. The concern is that the results of the typing may not be helpful enough to move forward with the study. Previous accepted studies but not initiated were presented and led by Dr. Bunjes. l. LK09-01: CNS Therapy in Allo HCT (N Esiashvili). Dr. Haight presented this study. The purpose of this study is to assess the role of cranial radiotherapy boost and post hematopoietic progenitor cell transplant intrathecal chemotherapy for controlling CNS site in patients with ALL. Patients will be divided in four cohorts: (1) patients who were not treated with CRT boost and did not received post-intrathecal therapy (n=2334); (2) patients not treated with CRT boost but received post-intrathecal therapy (n=387); (3) patients treated with CRT boost but did not received a post-intrathecal therapy (n=453) and (4) patients treated with CRT boost and received a post-intrathecal therapy (n=66). Outcomes to be studies are patterns of post-transplant relapse (CNS vs. non-cns sites), relapse-free survival and overall survival. A draft protocol was available for review and it was recommended to include the type of irradiation received (cranial vs. spinal). m. LK09-02: Monosomal Karyotype and chromosomal 7 abnormalities in allo HCT for AML/MDS (M Pasquini/ M Battiwala). Dr. Pasquini presented this study. The original proposals from Drs. Battiwala and Pasquini were combined into one study. The purpose of this study is to identify the impact of high risk cytogenetic subsets: specifically chromosome 7 abnormalities (either monosomy7 or del(7q)) and monosomal karyotype in outcomes for AML and MDS after allogeneic HCT and to evaluate the impact of conditioning intensity in the outcome of patients with AML and monosomal karyotype. The study includes three cohorts: MK- (n=2124), MK+ (n=1000) and patients with normal cytogenetics (n=2499). Chromosomal 7 abnormalities will be added as a covariate in the multivariate model to test its impact. A draft protocol was available for review. It was recommended to include in the protocol the description of therapyrelated AML cases. n. LK09-03: AML with core binding factor/cytogenetic abnormalities when allo HCT after relapse (L Akard). Dr. Akard presented this study. The original purpose of this study was to compare the outcomes of patients with core binding factor t(8,21) or inv(16) cytogenetic abnormalities treated with allogeneic or autologous transplants after relapse. Due to the small sample size in the autologous group (n=20), the study now proposes to compare the outcome of patients with relapsed (CR2 or 1 st relapse) CBF AML who have had allogeneic transplants with AML compared to AML with normal cytogenetics. The study includes three cohorts: normal cytogenetics (n=2350), abnormality t(8;21) (n=236) and inv(16) abnormality (n=136). It was recommended to include molecular markers but this information is not collected in the CIBMTR forms for the study period ( ). A draft protocol was available for review. 9

10 Not for publication or presentation Attachment 1 5. Future/ Proposed studies Drs. Bunjes and DiPersio led this section. The proposals are the followings: a. PROP Effect of cytogenetic response on the outcome of allogeneic hematopoietic stem cell transplantation in adult patients with AML (C Ustun) The purpose of this proposal is to evaluate the effect of cytogenetics at the time of transplantation on the outcome of allogeneic hematopoietic cell transplantation in adult patients with acute myelogenous leukemia at first complete remission or second complete remission between 1990 and The proposal was not presented due to our current limitations of cytogenetics reports available at diagnosis and at transplant and cytogenetics response information. b. PROP Outcomes of second reduced intensity/nonmyeloablative allogeneic stem cell transplant for acute leukemia relapse after a first reduced intensity/nonmyeloablative allogeneic stem cell transplant (B Wirk) The purpose of this proposal is to analyze the response rate, engraftment kinetics, incidence of acute and chronic graft-versus-host disease, treatment related mortality, progression free survival, relapse rate and overall survival after second reduced intensity conditioned/ non myeloablative allogeneic hematopoietic stem cell transplant for acute myelogenous leukemia or acute lymphocytic leukemia relapse after a first RIC/NMAB HCT. The proposal was not presented due to the low numbers of reported cases (myeloablative (n=29); non-myeloablative (n=36)). The study may be addressed in the future if more cases are reported. c. PROP Anti-leukemia effect and outcome of second transplantation for ALL and AML with identical versus different donors (K Schultz) The purpose of this proposal is to compare the relapse rate and development of acute and chronic GVHD between patients receiving a second transplantation from the same versus a different donor for ALL and AML. The proposal was not presented due to the low numbers of reported cases (different donor (n=97); same donor (n=274)). The study may be addressed in the future if more cases are reported and integrated with an earlier deferred proposal from several years ago. d. PROP Comparison of outcomes of allogeneic hematopoietic stem cell transplantation in AML with intermediate risk karyotype in first complete remission using matched sibling donor and alternative donors (B Oran) Dr. Oran presented this proposal. The purpose of this proposal is to compare the outcomes of allogeneic HCT for AML patients with intermediate risk karyotype in CR1 with matched sibling and alternative donors. The end points of the proposal are leukemia free survival, hematopoietic recovery, relapse, treatment related mortality and overall survival. There are 1377 HLAidentical sibling and 1302 unrelated donor 18 years of age reported to the CIBMTR between 1995 and It was noted the lack of molecular markers not collected in the CIBMTR forms for the study period. e. PROP Impact of pre-transplant consolidation chemotherapy on outcomes for patients undergoing reduced-intensity conditioning hematopoietic stem cell transplantation for AML in first complete remission (S McCormack) and PROP Effect of pre-transplant consolidation chemotherapy on outcomes of reduced intensity conditioning allogeneic transplantation for AML in first complete remission (M Litzow) Dr. Warlick presented this as a combined proposal. Both of these proposals look at the outcomes of adults with AML in first remission who have received no consolidation, standard-dose cytarabine consolidation, or high-dose cytarabine consolidation followed by reduced intensity conditioning related or unrelated donor allogeneic stem cell transplantation. Outcomes of relapse 10

11 Not for publication or presentation Attachment 1 rates, transplant-related mortality, disease-free and overall survival will be assessed. There are 146 patients who received no consolidation therapy, 72 who received standard-dose consolidation therapy and 209 high-dose consolidation therapy. Four-hundred seventy-seven cases have missing information on consolidation therapy (98% URD) reported to the CIBMTR during the proposed time period ( ). If approved, a supplemental form will be needed to capture the type of consolidation therapy for the unrelated donor cases since this information was not captured on the former NMDP research forms. f. PROP Prognostic scoring system for predicting relapse incidence and non relapse mortality in AML patients after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (B Oran) Dr. Oran presented this proposal. The purpose of this proposal is (1) to develop a prognostic model for predicting cumulative incidence of relapse in AML patients who receive reduced intensity conditioning allogeneic hematopoietic stem cell transplantation in first or second remission; (2) to develop a prognostic model for predicting non-relapse mortality in AML patients who receive RIC allogeneic HCT in CR1 and CR2 and (3) to apply this model in validation cohort and assess its utility in predicting relapse-free survival after HCT. There are 1331 patients reported to the CIBMTR between 1995 and 2007 (917 in CR1 and 414 in CR2). It was suggested to develop a simpler score based on survival. g. PROP Assessment of trends in allogeneic transplantation for MDS over the last decade (E Warlick) and PROP Impact of stem cell transplantation for MDS and development of predictive model including type of transplant, donor type and use of novel therapies (P Mehta) Dr Warlick presented this as a combined proposal. Both of these proposals look at the outcomes and trends of transplantation of myelodysplastic syndrome from with respect to conditioning intensity, donor type (sibling, MUD, cord), cell source (bone marrow or peripheral blood), disease status at transplant and the impact of novel agents. The purpose o f this proposal is to develop a predictive model for MDS patients undergoing HCT based on specific variables such as diagnostic cytogenetics, disease burden at transplant, transfusion dependence, exposure to chemotherapy vs. novel agents prior to transplant, donor type, conditioning intensity that may help predict who will benefit most from HCT. There are 531 patients between , 579 between and 757 between reported to the CIBMTR. It was suggested to look at the number of patients who received azacytidine or decitabine although this would require secondary data collection. h. PROP Influence of peritransplantation tyrosine kinase inhibitors on philadelphia positive ALL outcomes: An analysis of CIBMTR data (R Kamble) Dr. Giralt presented this proposal on behalf of Dr. Kamble s absence. The purpose of this proposal is to determine the pattern of pre and post allogeneic stem cell transplant tyrosine kinase inhibitors (TKIs) use in patients with Philadelphia positive acute lymphoblastic leukemia and to determine the impact of TKIs use on transplant outcomes in Ph + ALL. If approved, a supplemental form will be needed to capture the information on TKI since this information was not captured in the former CIBMTR forms (before 2009). It was recommended to delay the study for few years in order to capture TKI patient s information which is now available on the current CIBMTR forms. i. PROP The outcome of adults with philadelphia positive ALL comparing reduced intensity conditioning and myeloablative conditioning allogeneic stem cell transplantation (V Bachanova) Dr. Weisdorf presented this proposal in Dr. Bachanova s absence. The purpose of this proposal is to compare outcomes of adults with Ph + ALL who received reduced intensity versus 11

12 Not for publication or presentation Attachment 1 myeloablative conditioning followed by sibling or matched unrelated donor HCT and to examine the prognostic significance of patient, disease and transplant related characteristics on transplant outcomes. There are 549 patients who received myeloablative conditioning and 83 nonmyeloablative/reduced-intensity conditioning between reported to the CIBMTR. Due to the importance of tyrosine kinase inhibitor use and response in this group, it was noted that secondary data collection would be required for this study. 6. Other business After the previous accepted studies but not initiated and the new proposals were presented, each participant in the meeting had the opportunity to rate each proposal using paper ballots. Based on the voting results, the following studies will move forward: 1. LK09-02 Monosomal Karyotype and chromo 7 abnormalities in allo HCT for AML/MDS (M Pasquini/ M Battiwala) 2. PROP Outcomes of allotx in AML with intermediate risk karyotype in CR1 using matched sibling donor and alternative donors (B Oran) 3. PROP Pre-HCT consolidation chemotherapy in RIC HCT for AML in CR1 and PROP Pre-HCT consolidation chemotherapy on outcomes of RIC allotx for AML in CR1 (E Warlick/M Litzow) 4. PROP The outcome of adults with Ph+ ALL comparing RIC and MA conditioning allotx (V Bachanova) Dr. Weisdorf, on behalf of the Working Committee, thanked Dr. Tallman for his contributions to the Working Committee in the past four years. He also expressed gratitude to the Committee members for their active role and valuable support to the Committee and lastly, a special thanks to Waleska Pérez for her hard work. Without additional comments, the meeting was adjourned at 2:20 pm. 12

13 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 2010 Characteristics of patients Registration Research Number of patients Number of centers Age at transplant, years Median (range) 41 (<1-83) 41 (<1-83) low thru ( 8) 1434 ( 9) 10 thru (10) 1684 (11) 20 thru (12) 1954 (13) 30 thru (17) 2290 (15) 40 thru (22) 3099 (20) 50 thru (19) 3190 (21) 60 thru (11) 1589 (10) 70 thru high 200 ( 1) 131 ( 1) Missing 18 (<1) 1 (<1) Sex Male (53) 8132 (53) Female 9740 (47) 7236 (47) Missing 56 (<1) 4 (<1) Donor Related (71) 6523 (42) Unrelated 5966 (29) 8849 (58) Graft type Bone marrow 7111 (34) 5734 (37) Peripheral blood (61) 8241 (54) Cord blood 675 ( 3) 1370 ( 9) Missing 412 ( 2) 27 (<1) Year of transplant ( 7) 1625 (11) (10) 1445 ( 9) (12) 1418 ( 9) (13) 1772 (12) (14) 2090 (14) (14) 2500 (16) a 2917 (14) 2470 (16) a 3396 (16) 2052 (13) a Cases continue to be reported in this interval 13

14 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 2010 Characteristics of patients Registration Research Number of patients Number of centers Age at transplant, years Median (range) 22 (<1-83) 20 (<1-72) low thru (20) 2212 (25) 10 thru (24) 2218 (25) 20 thru (20) 1529 (18) 30 thru (14) 1131 (13) 40 thru (12) 943 (11) 50 thru ( 7) 551 ( 6) 60 thru ( 2) 133 ( 2) 70 thru high 7 (<1) 3 (<1) Missing 10 (<1) 2 (<1) Sex Male 7377 (61) 5352 (61) Female 4612 (38) 3365 (39) Missing 28 (<1) 5 (<1) Donor Related 8048 (67) 3303 (38) Unrelated 3969 (33) 5419 (62) Graft type Bone marrow 5568 (46) 4422 (51) Peripheral blood 5524 (46) 3011 (35) Cord blood 735 ( 6) 1269 (15) Missing 190 ( 2) 20 (<1) Year of transplant ( 9) 1293 (15) (11) 1109 (13) (13) 1058 (12) (14) 1111 (13) (13) 1132 (13) (12) 1261 (14) a 1495 (12) 1133 (13) a 1887 (16) 625 ( 7) a Cases continue to be reported in this interval 14

15 Not for publication or presentation Attachment 2 Accrual Summary for Acute Leukemia Working Committee Characteristics of recipients of autologous transplants for AML reported to the CIBMTR between 1995 and 2010 Characteristics of patients Registration Research Number of patients Number of centers Age at transplant, years Median (range) 47 (<1-82) 43 (<1-74) low thru ( 4) 84 ( 7) 10 thru ( 6) 87 ( 8) 20 thru (11) 153 (13) 30 thru (16) 188 (16) 40 thru (22) 225 (20) 50 thru (27) 238 (21) 60 thru (12) 166 (14) 70 thru high 66 ( 1) 9 ( 1) Missing 1 (<1) 0 Sex Male 2327 (51) 587 (51) Female 2180 (48) 563 (49) Missing 17 (<1) 0 Graft type Bone marrow 534 (12) 184 (16) Peripheral blood 3647 (81) 903 (79) Missing 343( 8) 63 ( 5) Year of transplant (10) 308 (27) (13) 258 (22) (17) 129 (11) (17) 110 (10) (17) 75 ( 7) (12) 101 ( 9) a 330 ( 7) 136 (12) a 276 ( 6) 33 ( 3) a Cases continue to be reported in this interval 15

16 Not for publication or presentation Attachment 2 Accrual Summary for Acute Leukemia Working Committee Characteristics of recipients of autologous transplants for ALL reported to the CIBMTR between 1995 and 2010 Characteristics of patients Registration Research Number of patients Number of centers Age at transplant, years Median (range) 30 (<1-73) 26 (1-66) low thru 9 59 ( 8) 27 (13) 10 thru (16) 41 (20) 20 thru (25) 48 (24) 30 thru (20) 19 ( 9) 40 thru (13) 38 (19) 50 thru (13) 22 (11) 60 thru ( 4) 8 ( 4) 70 thru high 5 ( 1) 0 Sex Male 412 (59) 132 (65) Female 289 (41) 71 (35) Graft type Bone marrow 106 (15) 30 (15) Peripheral blood 461 (66) 155 (76) Missing 134 (19) 18 ( 9) Year of transplant (19) 75 (37) (15) 61 (30) (19) 20 (10) (18) 16 ( 8) (13) 5 ( 2) ( 9) 11 ( 5) a 32 ( 5) 13 ( 6) a 17 ( 2) 2 ( 1) a Cases continue to be reported in this interval 16

17 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 Studies in progress R02-05: Unrelated donor stem cell transplantation in AML and all patients who failed an autologous transplant (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. A draft manuscript is in preparation and it is expected to be submitted after Tandem. R02-09: Evaluation of donor leukocyte infusions to treat relapsed hematologic malignancies after related and unrelated donor myeloablative allogeneic hematopoietic stem cell transplantation (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. Secondary data collection is required and is underway. The protocol and the secondary data collection instrument are available for review. LK04-01: Comparison of autologous and allogeneic hematopoietic stem cell transplantation for patients with acute promyelocytic leukemia (APL)in second complete remission (M Rubinger/M Tallman): This project analyzes outcome of APL in second CR including details of molecular remission prior to transplant. Secondary data collection was completed and the data file preparation is underway. LK04-03: Comparison of autologous blood cell and HLA-identical sibling transplants for acute myeloid leukemia in first complete remission (A Keating): This comparative analysis will assess the utility of allogeneic and peripheral blood autografts in AML CR1. The analysis was presented at the 2008 American Society of Hematology meeting in San Francisco, California. A draft manuscript is in preparation and it is expected to be submitted after Tandem. LK07-01: Cytogenetic risk groups for patients with AML or MDS undergoing allogeneic transplantation (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 was completed and cytogenetics reports were reviewed by the principal investigator. The analysis was completed in August 2010 and presented at the 2010 American Society of Hematology meeting. A draft manuscript is in preparation and it is expected to be submitted by July LK07-02: CIBMTR scoring system to predict the outcome after allogeneic transplantation for acute myeloid leukemia (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 data file preparation is underway. 17

18 Not for publication or presentation Attachment 3 LK07-03b: Assessment of allogeneic HCT in older patients with Non-Hodgkin Lymphoma and Chronic Myelogenous Leukemia (E Warlick/ 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. The manuscript for the AML and MDS population was published in JCO and the data file preparation for the Lymphoma and CML population is underway. LK08-01: Using landmark analysis to provide updated relapse and leukemia-free or overall survival estimates to patients (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 data file preparation is underway. LK08-02: A decision analysis of reduced intensity conditioning allogeneic stem cell transplantation for older patients with de-novo myelodysplastic syndrome (J Koreth): The purpose of this study is to use decision analysis and the best available databases to determine the optimal role and timing of RIC allohct for de-novo MDS patients 60 years. The dataset includes data from four patients cohorts: (1) natural history cohort from the IMRAW group at Stanford University and the Pavia group at the University of Pavia medical School in Italy; (2) erythropoiesis agent therapy cohort from the Groupe Francophone des Myelodysplasies (GFM); (3) hypomethylating agent therapy cohort from the AZA-001 Phase III Study of the International Vidaza High-Risk MDS Survival Study Group (IVHMSS) and those receiving decitabine therapy on research studies at M.D. Anderson Cancer Center and (4) transplantation cohort from the CIBMTR, EBMT, DFCI and FHCRC. The analysis is underway. A draft manuscript is expected to be submitted by July LK10-03: The outcome of adults with Philadelphia positive acute lymphoblastic leukemia comparing reduced intensity conditioning and Myeloablative Conditioning allogeneic Stem Cell Transplantation (V Bachanova): The purpose of this study is to (1) to compare outcomes of adults with Ph + ALL who received reduced intensity versus myeloablative conditioning followed by sibling or matched unrelated donor HCT; (2) to examine the effect of pre-transplant treatment with tyrosine kinase inhibitors (TKI) on transplant outcomes using RIC and MA conditioning and (3) to examine the prognostic significance of patient, disease and transplant related characteristics on transplant outcomes. Supplemental data collection regarding TKI use is required and funds are available for this purpose. The protocol and the secondary data collection instrument are available for review. Studies previously proposed, but not initiated LK09-02: Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation for Acute Myeloid Leukemia and Myelodysplasia (M Pasquini/ M Battiwala): The purpose of this study is to identify the impact of high risk cytogenetic subsets: specifically chromosome 7 abnormalities (either monosomy7 or del(7q)) and monosomal karyotype in outcomes for AML and MDS after allogeneic HCT and to evaluate the impact of conditioning intensity in the outcome of patients with AML and monosomal karyotype. A draft protocol is available for review. LK10-01: Comparison of outcomes of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia with intermediate risk karyotype in first complete remission using matched sibling donor and alternative donors (B Oran): The purpose of this study is to compare the outcomes of allogeneic HCT for AML patients with intermediate risk karyotype in CR1 with matched sibling and 18

19 Not for publication or presentation Attachment 3 alternative donors. The primary end point of the study to be compared is leukemia free survival. Other endpoints of interest are: hematopoietic recovery, relapse, treatment related mortality (TRM) and overall survival. A draft protocol is available for review. LK10-02: Effect of pre-transplant consolidation chemotherapy on outcomes of RIC Allogeneic transplant for adults with AML in CR1 (E Warlick): The purpose of this study is to (1) compare the outcomes of adults with AML in first remission who have received no consolidation, standard-dose cytarabine consolidation, or high-dose cytarabine consolidation followed by reduced intensity conditioning related or unrelated donor allogeneic stem cell transplantation (HCT) and (2) to determine if there is an exposure threshold (number of cycles of consolidation) that impacts post-transplant outcomes. A draft protocol is available for review. Studies previously deferred, for discussion during this forum LK08-04/ IB08-05: Evaluation of lymphotoxin alpha (LTA) alleles in relation to relapse in AML and CML (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 July Studies previously discontinued LK09-01: The role of CNS Therapy for outcome of patients undergoing allogeneic hematopoietic progenitor cell transplantation (N Esiashvili): The purpose of this study is to assess the role of cranial radiotherapy boost and post hematopoietic progenitor cell transplant intrathecal chemotherapy for controlling CNS site in patients with ALL. Patients will be divided in four cohorts: (1) patients who were not treated with CRT boost and did not received post-intrathecal therapy; (2) patients not treated with CRT boost but received post-intrathecal therapy; (3) patients treated with CRT boost but did not received a post-intrathecal therapy and (4) patients treated with CRT boost and received a post-intrathecal therapy. The study was discontinued due to completeness of available data and assessment of lower scientific priority. 19

20 Not for publication or presentation Attachment 4 CIBMTR LK09-02 IMPACT OF MONOSOMAL KARYOTYPE IN THE OUTCOME OF HEMATOPOIETIC CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA AND MYELODYSPLASIA DRAFT PROTOCOL Study Co-Chairs: (Alphabetical order) Marcelo C. Pasquini, MD, MS Medical College of Wisconsin 9200 W Wisconsin Ave, CCC5500 Milwaukee, WI Tel: Fax: mpasquin@mcw.edu Minoo Battiwalla, MD, MS National Institutes of Health 10 Center Drive, Building 10 CRC, Room Bethesda, MD Telephone: Fax: minoo.battiwalla@nih.gov Philip L. McCarthy, MD Roswell Park Cancer Institute Elm and Carlton Streets Buffalo, NY Telephone: Fax: Philip.mccarthy@roswellpark.org Study Statisticians: Waleska S. Pérez, MPH CIBMTR Statistical Center Medical College of Wisconsin 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI USA Telephone: Fax: wperez@mcw.edu 20

21 Not for publication or presentation Attachment 4 Study Statisticians: Working Committee Chairs: Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: meijie@mcw.edu Donald W. Bunjes, MD Universitatsklinikum Ulm Albert-Einstein-Allee 23 Ulm D GERMANY Phone: Fax: donald.bunjes@uniklinik-ulm.de Steven M. Devine, MD James Cancer Center Ohio State Medical Center 320 W 10th Avenue A346 Columbus, OH Phone: Fax: steven.devine@osumc.edu John F. DiPersio, MD, PhD Siteman Cancer Center Barnes Jewish Hospital 660 South Euclid Avenue St. Louis, MO Telephone: Fax: jdipersi@dom.wustl.edu Scientific Director: Daniel Weisdorf, MD University of Minnesota Medical Center 915 Delaware Road, Minneapolis, MN Telephone: Fax: weisd001@umn.edu 21

22 Not for publication or presentation Attachment SPECIFIC AIMS: 1.1 To compare overall survival, relapse, treatment-related mortality and disease-free survival of patients with AML and MDS with and without monosomal karyotype after allogeneic HCT. 1.2 To evaluate the impact of conditioning intensity in the outcome of patients with AML/MDS and monosomal kayotype. 1.3 To identify the impact of isolated chromosome 7 abnormalities (either monosomy 7 or del(7q)) on post transplant outcome comparing to monosomal karyotype with normal 7 and to normal karyotype. 1.4 To evaluate the impact of planned post transplant growth factor administration (G-CSF and/or GM-CSF) on post transplant outcomes in high risk AML/MDS. 2.0 SCIENTIFIC JUSTIFICATION: The presence of several chromosomal abnormalities in leukemia cells, termed complex cytogenetics is associated with unfavorable outcome. The definition of complex cytogenetics varies from at least 3 to at least 5 cytogenetic abnormalities on a single clone(1, 2). Breems et al teased out this group of patients with poor risk disease and identified that the presence autosomal monosomies is associated with poor outcome(3). This classification has a tighter association with outcome comparing to other non-random cytogenetic changes under poor risk category and predicts a subset of patients with dismal outcome. The monosomal karyotype (MK) is defined as the presence of at least two autosomal monosomies or one autosomal monosomy associated with any other structure abnormality (MK+). Hematopoietic cell transplantation (HCT) is the treatment option for patients with cytogeneticdefined poor risk AML in first complete remission (CR), which may lead to 5 year survival in the range of 30 to 40% comparing to <10% with non transplant approaches(1, 4, 5). However, this data are from patients younger than 60 years receiving allogeneic transplantation with myeloablative conditioning. Reduced intensity conditioning is now the most common conditioning regimen used in allogeneic HCT for AML in patients older than 50 years (CIBMTR data). The reduction of conditioning intensity reduces early transplant mortality allowing patients not otherwise candidates to receive an allogeneic HCT. However, when comparing with myeloablative approaches this benefit is offset by increase in relapse rates(6). Additionally, a retrospective analysis done by the EBMT demonstrated that poor risk cytogenetics at diagnosis is associated with higher relapse and shorter leukemia-free survival in patients with AML in CR1 receiving RIC comparing to myeloablative conditioning regimens(7). The number of cytogenetic abnormalities in AML increases with age, including unfavorable risk and monosomal karyotype (MK)(3). MK+ AML was demonstrated to increase the risk of relapse after transplantation(8). This poor risk feature might also be seen with MDS, where complex cytogenetics are associated with worse outcome. For both AML and MDS, abnormalities in chromosome 7 are associated with worse prognosis (1, 9, 10). Long term survivors are observed with allogeneic HCT [OS 30-40%](11). One limitation is that survival data on chromosome 7 abnormalities have come from pooled analyses with other high-risk cytogenetic abnormalities and it is unclear how isolate 7 abnormalities impact transplant outcomes. 22

23 Not for publication or presentation Attachment 4 Monosomy 7 is observed in children with congenital neutropenia after long term exposure to G- CSF (12, 13). Sloand et al have investigated the impact of pharmacological doses of G-CSF on monosomy 7 cells.(14) G-CSF receptor expression is increased on CD34 cells from monosomy 7 clones arising in bone marrow failure states; the up-regulated G-CSF receptor (isoform IV) conferring a survival advantage for the clone. The mechanism is associated with acquisition of resistance to apoptosis by up-regulation of the Akt pathway.(15, 16) EBMT and Japanese data have shown that patients with aplastic anemia receiving G-CSF have demonstrated inferior outcomes. Clonal evolution with chromosome 7 abnormalities are a recurrent late complication in patients with SAA.(17) It is unclear whether clonal evolution is a feature of the underlying bone marrow failure state or induced by G-CSF. In the largest analysis of the impact of G-CSF in severe aplastic anemia (SAA) conducted by the EBMT, Socie et al described 840 patients who received first-line immunosuppressive therapy with (43%) or without (57%) G-CSF. Patients who received G-CSF had a higher incidence of MDS/AML (10.9%) than those who did or did not receive G- CSF (5.8%). (18). GCSF or GM CSF is used in some transplant centers routinely to hasten neutrophil recovery after allogeneic transplantation. This study will (1) analyze the impact of MK in patients with AML and MDS undergoing allogeneic transplantation; (2) assess whether utilization of reduced intensity conditioning is associated with worse outcomes in patients with this newly defined high risk disease; and (3) whether the impact on prognosis is different depending on the presence of monosomy 7. Furthermore, this study of patients with high risk AML/MDS will analyze whether the practice of planned growth factor utilization is associated with worse outcomes. 3.0 PATIENT ELIGIBILITY: Patients with AML and MDS in first or second CR who received a first allogeneic transplantation from 1998 to 2007 will be eligible for this study. Patients with AML M3, APL or presence of t(15;17); core binding factor leukemia [t(8;21) or inv(16)] will be excluded. Additionally recipients of umbilical cord blood, syngeneic transplants or ex vivo T-cell depleted grafts will be excluded from the analysis. 4.0 VARIABLES TO BE DESCRIBED: Patient related: Patient age: continuous Patient gender Performance score: < 80 vs 80 Disease specific variables: Cytogenetics at diagnosis: MK+, MK-, normal karyotype, isolated chromosome 7 abnormalities. Disease status at transplantation WBC at diagnosis IPSS at diagnosis (MDS only) Transplant related variable: Conditioning regimens intensity Conditioning regimen Year of transplant Type of donor 23

24 Not for publication or presentation Attachment 4 Donor-recipient match Graft sources GVHD prophylaxis D/R CMV status Donor Age Growth factor administration starting in the first 7 days after transplant 5.0 VARIABLES TO BE ANALYZED: Main effect: MK+ vs MK- vs Normal Cytogenetics For specific aim 1.3, cytogenetic abnormalities at transplantation will be added to multivariate models as a covariate with three groups: MK+ with normal 7, isolated chromosome 7 abnormalities and normal karyotype. Patient related: Age: continuous Karnofsky performance score at transplant: < 80 vs Disease related: Disease: AML vs MDS Disease status at transplant: CR1 vs. CR2 Cytogenetics : MK+ with normal 7, isolated chromosome 7 abnormalities and normal karyotype (specific aim 1.4) Transplant related: Year of transplant: continuous Donor/recipient CMV status: -/- vs. others Conditioning regimen intensity: myeloablative vs. reduced intensity vs. nonmyeloablative (according to the CIBMTR working definition) Graft sources: PB vs. BM Growth factor administration starting in the first 7 days after transplant: yes vs no. 6.0 OUTCOMES: Overall survival: time to death from any cause. Treatment-related mortality (TRM): Death in the first 28 days post-transplant or death in continuous remission. Relapse of AML/MDS is the competing risk. Relapse: Relapse post transplant is the event for this outcome. Death in remission is the competing risk. Disease-free survival: Disease relapse and death are events for this outcome. 7.0 DATA COLLECTION AND DEFINITION: This study will use data collected from CIBMTR research centers. Cytogenetic analysis to define MK is already collected in the AML specific form. Further clarification of cytogenetic abnormalities will be requested to centers if necessary. Monosomal karyotype (MK+): presence of at least two monosomies or one monosomy plus other chromosomal structure abnormalities. 24

25 Not for publication or presentation Attachment 4 Negative monosomal karyotype (MK-): presence of multiple cytogenetic abnormalities ( 3) but not fulfilling the criteria for MK+. Abnormalities in chromosome 7 (Abn7): presence of monosomy 7 (-7) or deletion of part of chromosome 7 (del(7q)). 8.0 STUDY DESIGN AND ANALYSIS: This is a retrospective cohort analysis to evaluate the effect of a novel AML cytogenetic classification on transplantation outcome. The analysis will be stratified according to donor type given the potential different outcomes after sibling and unrelated donor transplants. For all objectives, descriptive tables will be generated summarizing all variables selected above. Continuous variables will be described as median and ranges and categorical variables will be reported as absolute numbers and percent of total patients. Univariate comparisons will be done using Wilcoxon test for continuous variables and Chi-square test for categorical variables. Kaplan- Meier product-limit estimator will be used to estimate the median and range of follow up time. Overall and leukemia free survival will be calculated using the Kaplan Meier estimator, with variance estimated by Greenwood s formula. Leukemia relapse, acute and chronic GVHD and treatment related mortality will be calculated and plotted using cumulative incidence function. Comparison of survival curves will be done using the log-rank test. Multivariate analyses will be performed using proportional hazards models for each outcome specified in Section 6.0. Covariates will be tested in a stepwise approach. For objectives 1.1 and 1.2, Cox proportional hazard models will be built using cytogenetic classification as the main effect. For objective 1.3, cytogenetics will be classified in three subgroups and will be tested along with other covariates listed in Section 5.0 for each outcome model. 9.0 REFERENCES: 1. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. 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 Oct 1;92(7): Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, 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 Dec 15;96(13): Breems DA, Van Putten WLJ, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KBJ, Mellink CHM, et al. Monosomal Karyotype in Acute Myeloid Leukemia: A Better Indicator of Poor Prognosis Than a Complex Karyotype. J Clin Oncol October 10, 2008;26(29): Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. 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 December 15, 2002;100(13):

26 Not for publication or presentation Attachment 4 5. Tallman MS, Dewald GW, Gandham S, Logan BR, Keating A, Lazarus HM, et al. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Blood July 1, 2007;110(1): Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ, et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005;19(12): Mohty M, Labopin M, Milpied N-J, Cornelissen JJ, Blaise D, Petersen E, et al. Impact of Cytogenetics Risk on Outcome after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-sct) from An HLA Identical Sibling for Patients with Acute Myeloid Leukemia (AML) in First Complete Remission (CR1). ASH Annual Meeting Abstracts November 16, 2008;112(11): Oran B, Dolan M, Ma L, Brunstein C, Warlick E, Weisdorf DJ. Monosomal Karyotype Provides Better Prognostic Prediction After Allogeneic Stem Cell Transplantation in AML Patients. ASH Annual Meeting Abstracts November 20, 2009;114(22): Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. 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 Dec 15;100(13): Gale RP, Horowitz MM, Weiner RS, Ash RC, Atkinson K, Babu R, et al. Impact of cytogenetic abnormalities on outcome of bone marrow transplants in acute myelogenous leukemia in first remission. Bone Marrow Transplant Aug;16(2): Tallman MS, Dewald GW, Gandham S, Logan BR, Keating A, Lazarus HM, et al. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Blood Jul 1;110(1): Germeshausen M, Schulze H, Kratz C, Wilkens L, Repp R, Shannon K, et al. An acquired G- CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia. Leukemia Apr;19(4): Kojima S, Ohara A, Tsuchida M, Kudoh T, Hanada R, Okimoto Y, et al. Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood Aug 1;100(3): Sloand EM, Yong AS, Ramkissoon S, Solomou E, Bruno TC, Kim S, et al. Granulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells bearing the isoform IV receptor. Proc Natl Acad Sci U S A Sep 26;103(39): Aarts LH, Roovers O, Ward AC, Touw IP. Receptor activation and 2 distinct COOH-terminal motifs control G-CSF receptor distribution and internalization kinetics. Blood Jan 15;103(2):

27 Not for publication or presentation Attachment Hunter MG, Avalos BR. Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival. Blood Mar 15;95(6): Ohara A, Kojima S, Hamajima N, Tsuchida M, Imashuku S, Ohta S, et al. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood Aug 1;90(3): Socie G, Mary JY, Schrezenmeier H, Marsh J, Bacigalupo A, Locasciulli A, et al. Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT). Blood Apr 1;109(7):

28 Not for publication or presentation Attachment 4 Table 1. Characteristics of patients who underwent a bone marrow and/or peripheral blood allogeneic transplant for AML (in CR1 or CR2) or MDS reported to the CIBMTR between 1998 and 2007, by monosomal karyotype Characteristics of patients: MK- MK+ Normal Number of patients Number of centers Age at transplant, years 39 (<1-75) 50 (1-79) 46 (1-78) Age at transplant <10 yrs 185 ( 9) 59 ( 6) 123 ( 5) yrs 263 (12) 56 ( 6) 223 ( 9) yrs 315 (15) 65 ( 7) 286 (11) yrs 336 (16) 103 (10) 337 (13) yrs 401 (19) 220 (22) 557 (22) yrs 432 (20) 317 (32) 640 (26) >=60 yrs 192 ( 9) 180 (18) 333 (13) Sex Male 1122 (53) 576 (58) 1388 (56) Female 994 (47) 423 (42) 1107 (44) Missing 8 (<1) 1 (<1) 4 (<1) Karnofsky score <90% 473 (22) 304 (30) 601 (24) >=90% 1534 (72) 614 (61) 1759 (70) Missing 117 ( 6) 82 ( 8) 139 ( 6) Disease AML 1557 (73) 492 (49) 1773 (71) MDS 567 (27) 508 (51) 726 (29) Cytogenetics AML Intermediate-normal (100) Intermediate-other 1466 (94) 177 (36) 0 Poor 91 ( 6) 315 (64) 0 MDS Good 0 66 (13) 0 Intermediate-other 554 (98) 83 (16) 0 Intermediate-normal (100) Poor 13 ( 2) 359 (71) 0 Abnormality -7/7q- No 2124 (100) 507 (51) 2499 Yes (49) 0 28

29 Not for publication or presentation Attachment 4 Table 1. Continued. Characteristics of patients: MK- MK+ Normal Conditioning regimen Myeloablative 1534 (72) 595 (60) 1672 (67) Non-myeloablative 551 (26) 393 (39) 757 (30) TBD 39 ( 2) 12 ( 1) 70 ( 3) Disease status at HCT AML 1st CR 1149 (54) 420 (42) 1221 (49) AML 2nd CR 408 (19) 72 ( 7) 557 (22) MDS early 212 (10) 222 (22) 275 (11) MDS advance 355 (17) 286 (29) 446 (18) Type of donor HLA-identical sibling 805 (38) 305 (31) 1067 (43) Other relative 80 ( 4) 20 ( 2) 92 ( 4) URD well matched 714 (34) 410 (41) 761 (30) URD partially matched 317 (15) 173 (17) 337 (13) URD mismatched 101 ( 5) 44 ( 4) 103 ( 4) URD matching unknown 57 ( 3) 30 ( 3) 76 ( 3) URD matching TBD 50 ( 2) 18 ( 2) 63 ( 3) D-R sex match M-M 699 (33) 398 (40) 890 (36) M-F 581 (27) 238 (24) 626 (25) F-M 421 (20) 178 (18) 495 (20) F-F 412 (19) 185 (19) 477 (19) Missing 11 ( 1) 1 (<1) 11 (<1) D-R CMV status +/+ 766 (36) 291 (29) 916 (37) +/- 228 (11) 115 (12) 265 (11) -/+ 551 (26) 307 (31) 629 (25) -/- 525 (25) 258 (26) 617 (25) Missing 54 ( 3) 29 ( 3) 72 ( 3) Graft type Bone marrow 869 (41) 337 (34) 931 (37) Peripheral blood 1255 (59) 663 (66) 1568 (63) Year of HCT ( 6) 43 ( 4) 164 ( 7) (14) 103 (10) 344 (14) (18) 174 (17) 438 (18) (23) 259 (26) 540 (22) (29) 315 (32) 772 (31) (10) 106 (11) 241 (10) 29

30 Not for publication or presentation Attachment 4 Table 1. Continued. Characteristics of patients: MK- MK+ Normal GVHD prophylaxis FK506+MTX+-other 554 (26) 298 (30) 573 (23) FK506+-other 192 ( 9) 105 (11) 224 ( 9) CsA+MTX+-other 964 (45) 386 (39) 1210 (48) CsA+-other 296 (14) 174 (17) 363 (15) Other 28 ( 1) 14 ( 1) 29 ( 1) None 14 ( 1) 6 ( 1) 26 ( 1) Missing 76 ( 4) 17 ( 2) 74 ( 3) Planned GM or GCSF No 1056 (50) 514 (51) 1336 (53) Yes 765 (36) 341 (34) 824 (33) Missing 303 (14) 145 (15) 339 (14) Median FU of survivors (range), months 42 (3-133) 42 (3-132) 40(3-135) * The other, specify field in the AML disease-insert form was reviewed to capture additional MK+ patients. The other, specify field in the AML disease-insert form will be further review to capture additional patients with abnormalities in chromosome 7 * Exclusions: AML M3 patients Twin transplants Cord blood transplants T-cell depletion Presence of t(15;17) Core binding factor leukemia [t(8;21) or inv(16)] Unknown cytogenetic information Disease status MK- MK+ Normal AML PIF 356 (12) 174 (13) 315 ( 9) AML 1st CR 1149 (38) 420 (32) 1221 (36) AML 2nd CR 408 (14) 72 ( 6) 557 (17) AML >CR2 25 ( 1) 3 (<1) 42 ( 1) AML Relapse 449 (15) 95 ( 7) 474 (14) 30

31 Not for publication or presentation Attachment 5 CIBMTR LK10-01 COMPARISON OF OUTCOMES OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN ACUTE MYELOID LEUKEMIA (AML) WITH INTERMEDIATE RISK KARYOTYPE IN FIRST COMPLETE REMISSION (CR1) USING MATCHED SIBLING DONOR (MSD) AND ALTERNATIVE DONORS DRAFT PROTOCOL Study Co-Chairs: Betul Oran, MD, MS University of Minnesota Medical Center 420 Delaware Street SE Minneapolis, MN oranx002@umn.edu Daniel Weisdorf, MD University of Minnesota Medical Center 420 Delaware Street SE Minneapolis, MN Telephone: Fax: weisd001@umn.edu Study Statisticians: Waleska S. Perez, MPH CIBMTR Statistical Center 9200 W. Wisconsin Avenue CLCC, Suite C5500 Milwaukee, WI Telephone: Fax: wperez@mcw.edu Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: meijie@mcw.edu 31

32 Not for publication or presentation Attachment 5 Working Committee Chairs: Donald W. Bunjes, MD Universitatsklinikum Ulm Albert-Einstein-Allee 23 Ulm D GERMANY Phone: Fax: donald.bunjes@uniklinik-ulm.de Steven M. Devine, MD James Cancer Center Ohio State Medical Center 320 W 10th Avenue A346 Columbus, OH Phone: Fax: steven.devine@osumc.edu John F. DiPersio, MD, PhD Siteman Cancer Center Barnes Jewish Hospital 660 South Euclid Avenue St. Louis, MO Telephone: Fax: jdipersi@dom.wustl.edu Scientific Director: Daniel Weisdorf, MD University of Minnesota Medical Center 915 Delaware Road Minneapolis, MN Telephone: Fax: weisd001@umn.edu 32

33 Not for publication or presentation Attachment SPECIFIC AIMS: 1.1 To compare the outcomes of allogeneic HSCT for AML patients with intermediate risk karyotype in CR1 with matched sibling and alternative donors. The primary end point of the study to be compared is leukemia free survival (LFS). 1.2 Other endpoints of interest are: Hematopoietic recovery, relapse, treatment related mortality (TRM), overall survival (OS) and causes of death. 2.0 SCIENTIFIC JUSTIFICATION: Allogeneic HSCT has been established as an effective treatment modality to reduce the risk of relapse in patients with AML in CR1 [1]. However the risk group with most benefit from allogeneic HSCT remains to be a subject of debate. Since controlled trials have shown improved outcomes of patients younger than 60 with high risk karyotype after an HLA-identical sibling HSCT[2] and in patients older than 60 with reduced intensity conditioning (RIC)[3-4], current consensus for AML treatment reflected in treatment guidelines of National Comprehensive Cancer Network recommends allogeneic HSCT for younger patients with poor risk karyotype and for patients older than 60 only in the context of a clinical trial. The consensus has not stated a preferred post-remission therapy for patients with intermediate risk karyotyope although it acknowledges that transplant based options afforded a lesser risk of relapse and somewhat higher disease free survival. A recent meta-analysis reviewed all prospectively designed clinical trials of allogeneic HSCT vs. consolidation chemotherapy, autologus HSCT or both for AML in CR1 and younger than 60, based on the availability of a HLA-MSD in patients [5]. This review showed significant relapse free and OS benefit with allogeneic HSCT in intermediate risk AML who had a MSD. These findings suggest that all AML patients with intermediate risk karyotype should be considered for allogeneic HSCT from a MSD provided they are fit for such an intervention. It still remains unclear whether older patients might get a similar benefit. However, in the presence of poor outcomes with consolidation therapies including conventional chemotherapy and improved outcomes with RIC, allogeneic HSCT is an option to be considered for elderly patients with intermediate risk karyotype. However, widespread use of allogeneic HSCT is limited by donor availability, because only onethird of patients have HLA-identical sibling donors[6]. The chance of finding a sibling donor for older patients is even lower. Therefore stem cell grafts from alternative sources such as unrelated blood or marrow and cord blood is important. There are more than 10 million donors worldwide on various national and international registries. There is a high probability (65 70%) of finding an HLA-A, HLA-B and HLA-DR matched donor for Caucasian patients. The chances of finding a match for HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ (so-called 10/10 match), however, are relatively lower (35 40%). Unrelated umbilical cord blood (UCB) has also been investigated as an alternative source for hematopoietic stem cells. Rapid availability of a unit of cord blood may be of particular benefit in high-risk patients with acute leukemia. We have previously reported that in patients older than 55, TRM and survival following allogeneic HCT after RIC using either MSD or mismatched UCB was comparable [7]. Our results were also comparable to other reports of RIC HSCT using either a MSD or matched volunteer adult unrelated donor in older patients supporting the use of HLA 33

34 Not for publication or presentation Attachment 5 mismatched UCB as an alternative graft source for older patients who need a transplant but do not have an MSD. We believe that alternative donor sources will be important issues in intermediate risk CR1 AML patients considering that most patients with a disease of median age of will not have a HLA MSD available. Therefore our aim is to investigate disease outcomes using alternative donor sources, unrelated donor and cord, in AML CR1 patients with intermediate risk features. 3.0 PATIENT ELIGIBILITY POPULATION: The study will include all AML patients age 18 or older undergoing first allogeneic HSCT between 1995 and 2007 and meeting with following criteria: AML in first complete remission. Intermediate risk karyotype according to SWOG/ECOG [8] including patients characterized by +8, Y, +6, del(12p), or normal karyotype. Stem cells from one of the following donors (syngeneic transplants will be excluded) MSD Unrelated donors UCB 4.0 VARIABLES TO BE ANALYZED: Patient related variables: Age at transplantation (continuous) Gender: Female vs. male Karnofsky performance score: < 80% vs. 80% Disease related variables: Malignant (or non malignant disease) prior to diagnosis of AML treated with chemotherapy or radiotherapy (yes/no) Previous history of myelodysplastic syndrome or myeloproliferative disorder (yes/no) Single, specific cytogenetic abnormalities including +8, Y, +6, del(12p) and normal karyotype. Molecular markers including NPM1 and FLT3-ITD for normal karytotype patients. WBC count at diagnosis X 10 9 /L Presence of extramedullary disease prior to allogeneic HSCT (CNS vs. testes/soft tissue depositions vs. other) Time to CR from diagnosis Number of chemotherapy cycles to achieve CR (1 vs. >1) Time to allogeneic HSCT from achieving CR1 Number of consolidation treatments prior to transplantation (0 vs. 1, 2 vs.>2) and if 1 Cytarabine (yes; >2 g/m 2 or 2 g/m 2 vs. no) and Gemtuzumab (yes/no) Transplant related variables: Donor type: HLA matched sibling vs. HLA matched unrelated donor (matched for HLA A, B, C, DRB1) vs. partially matched unrelated donor (single locus mismatches at HLA A, B, C, DRB1) vs. mismatched unrelated donor (2 or more mismatches at HLA A, B, C, DRB1) vs. UCB. Conditioning regimen: TBI vs. non-tbi; myeloablative vs. non-myeloablative/reduced intensity 34

35 Not for publication or presentation Attachment 5 Source of stem cells: Bone marrow (BM) vs. peripheral blood stem cell (PBSC) vs. UCB CD34+ cell dose Nucleated cell dose Donor-recipient CMV serostatus: -/- vs. -/+ vs. +/- vs. +/+ GVHD prophylaxis: CSA or FK plus MTX vs. MMF+others vs. ex vivo T cell depletion vs. others Alemtuzumab (yes/no) and ATG (yes/no) Year of transplant: vs Post transplant related variables: Acute GVHD: grade 0-I vs. grade II-IV Chronic GVHD: (yes/no) Donor cell infusion (yes/no) 5.0 STUDY END POINTS AND DEFINITIONS: Hematopoietic recovery: Time to neutrophils (ANC) > 0.5x10 9 /L (first of 3 consecutive days) and time to platelets 20x10 9 /L (first of 3 consecutive days and no platelet transfusion for 7 days prior). Acute GVHD: Occurrence of grade II-IV GVHD will be analyzed based on Cluckberg s staging of skin, gastrointestinal tract and liver disease. Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the criteria of chronic GVHD and classified as limited or extensive. Relapse: Leukemia recurrence either in bone marrow or extramedullary. This event will be summarized by cumulative incidence estimate with TRM as the competing risk. LFS: Survival without disease progression or relapse; patients alive without disease progression or relapse will be censored at the time of last follow-up. TRM: Time to death without evidence of disease relapse. This event will be summarized as cumulative incidence estimate with relapse as competing risk. OS: Time to death, patients censored at last follow-up. 6.0 DATA COLLECTION: All requested data other than molecular data is available from existing data collection forms. 7.0 STUDY DESIGN: This is a retrospective cohort analysis to evaluate the effect of donor source on disease outcomes of AML patients in CR1 after allogeneic HSCT. Patient-, disease-, and transplant-related variables will be compared between MSD and alternative donors using the Chi-square test for categorical variables and the Kruskal-Wallis test for continuous variables. The Kaplan-Meier estimates will be used to analyze the median and range of follow-up time. Univariate probabilities of leukemia-free and overall survival will be calculated using the Kaplan- Meier estimate. Probabilities of hematopietic recovery, acute and chronic GVHD, relapse and TRM will be calculated using cumulative incidence curves to accommodate competing risks. Potential risk factors for outcomes of interest will be evaluated in multivariate analyses using Cox proportional hazards regression. A backward stepwise model selection approach will be used to 35

36 Not for publication or presentation Attachment 5 build the regression model for the outcomes of relapse, LFS, TRM and OS. Since donor type is the main interest of the study, the risk factor of donor type 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 the main effect of donor type and all significant variables will be analyzed. Further adjustments will be applied when test indicates that interactions are significant. Adjusted probability of disease-free survival and overall survival will be computed bases on final Cox regression model, stratified by donor type, 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. 8.0 REFERENCES: 1. Lowenberg, B., J.R. Downing, and A. Burnett, Acute myeloid leukemia. N Engl J Med, (14): p Suciu, S., et al., 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, (4): p Herr, A.L., et al., HLA-identical sibling allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning compared to autologous peripheral blood stem cell transplantation for elderly patients with de novo acute myeloid leukemia. Leukemia, (1): p Estey, E., et al., Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HHSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood, (4): p Koreth, J., et al., Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA, (22): p Beatty, P.G., et al., Probability of finding HLA-mismatched related or unrelated marrow or cord blood donors. Hum Immunol, (8): p Majhail, N.S., et al., Reduced-intensity allogeneic transplant in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor. Biol Blood Marrow Transplant, (3): p Slovak, M.L., 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, (13): p

37 Not for publication or presentation Attachment 5 Table 1. Characteristics of patients 18 years of age with intermediate or normal cytogenetics who underwent an allogeneic transplant for AML in CR1 reported to the CIBMTR between 1995 and 2007, by type of donor Characteristics of patients: HLA-identical URD Number of patients Number of centers Age, median (range), years 42 (18-73) 46 (18-75) Age at transplant, years yrs 48 ( 3) 42 ( 3) yrs 247 (18) 233 (18) yrs 306 (22) 215 (17) yrs 389 (28) 306 (24) yrs 292 (21) 333 (26) >=60 yrs 95 ( 7) 173 (13) Sex Male 712 (52) 659 (51) Female 663 (48) 640 (49) Missing 2 (<1) 3 (<1) Karnofsky score <90% 298 (22) 298 (23) >=90% 1049 (76) 920 (71) Missing 30 ( 2) 84 ( 6) Cytogenetics Normal 842 (61) 556 (43) Intermediate 535 (39) 746 (57) Conditioning regimen Myeloablative 1099 (80) 861 (66) Non-myeloablative 260 (19) 412 (32) TBD 18 ( 1) 29 ( 2) Type of donor HLA-id sibling 1377 (100) 0 URD well-matched (56) URD partially matched (25) URD mismatched (10) URD matching unknown 0 61 ( 5) URD matching TBD 0 50 ( 4) D-R sex match M-M 388 (28) 454 (35) M-F 357 (26) 389 (30) F-M 324 (24) 200 (15) F-F 302 (22) 247 (19) Missing 6 (<1) 12 ( 1) 37

38 Not for publication or presentation Attachment 5 Table 1. Continued. Variable HLA-identical URD D-R CMV status +/+ 658 (48) 325 (25) +/- 135 (10) 144 (11) -/+ 225 (16) 426 (33) -/- 316 (23) 334 (26) Missing 43 ( 3) 73 ( 6) Graft type Bone marrow 493 (36) 502 (39) Peripheral blood 884 (64) 744 (57) Cord blood 0 56 ( 4) Year of HCT (19) 51 ( 4) (15) 67 ( 5) (12) 95 ( 7) (14) 174 (13) (16) 253 (19) (20) 453 (35) ( 4) 209 (16) GVHD prophylaxis None 15 ( 1) 13 ( 1) T-cell depletion 111 ( 8) 88 ( 7) FK506+MTX+-other 154 (11) 398 (31) FK506+-other 49 ( 4) 180 (14) CsA+MTX+-other 856 (62) 385 (30) CsA+-other 182 (13) 148 (11) Other 9 ( 1) 7 ( 1) Missing 1 (<1) 83 ( 6) Median FU of survivors (range), months 57 (3-172) 36 (3-168) 38

39 Not for publication or presentation Attachment 6 CIBMTR LK10-02 EFFECT OF PRE-TRANSPLANT CONSOLIDATION CHEMOTHERAPY ON OUTCOMES OF RIC ALLOGENEIC TRANSPLANT FOR ADULTS WITH AML IN CR1 DRAFT PROTOCOL Study Co-Chairs: Erica Warlick, MD Assistant Professor Division of Hematology, Oncology and Transplantation University of Minnesota MMC 480, 420 Delaware Street S.E. Minneapolis, MN Telephone: ewarlick@umn.edu Steven McCormack, MD Fellow Division of Hematology, Oncology and Transplantation University of Minnesota MMC 480, 420 Delaware Street S.E. Minneapolis, MN Mark Litzow, MD Associate Professor Mayo Clinic 200 First St. SW Rochester, MN Telephone: litzow.mark@mayo.edu Study Statisticians: Waleska Perez, MPH Assistant Statistical Director Center for International Blood and Marrow Transplant Research Medical College of Wisconsin 9200 West Wisconsin Avenue, Suite C5500 Milwaukee, WI Phone: Fax: wperez@mcw.edu 39