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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA San Diego, California Saturday, February 4, 2012, 12:15 pm - 2:15 pm Co-Chair: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, 2011 meeting (Attachment 1) 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers a. LK04-02/GV01-01 Luger SM, Ringdén O, Zhang M-J, Pérez WS, Bishop MR, Bornhauser M, Bredeson CN, Cairo MS, Copelan EA, Gale RP, Giralt SA, Gulbas Z, Gupta V, Hale GA, Lazarus HM, Lewis VA, Lill MC, McCarthy PL, Weisdorf DJ, Pulsipher MA. Similar outcomes using myeloablative versus reduced intensity allogeneic transplant preparative regimens for Acute Myeloid Leukemia or Myelodysplasia. Bone Marrow Transplantation, b. LK04-03 Keating A, DaSilva G, Pérez WS, Gupta V, Cutler CS, Ballen KK, Cairo MS, Camitta BM, Champlin RE, Gajewski JL, Horan JT, Lazarus HM, Lill M, Marks DI, Nabhan C, Schiller GJ, Socie G, Szer J, Tallman MS, Weisdorf DJ. Autologous blood cell transplantation versus HLA-identical sibling transplantation for Acute Myeloid Leukemia in first complete remission. Submitted. c. LK06-01 Farag SS, Maharry K, Zhang MJ, Pérez WS, George SL, Mrózek K, Dipersio J, Bunjes DW, Marcucci G, Baer MR, Cairo MS, Copelan EA, Cutler CS, Isola LM, Lazarus HM, Litzow MR, Marks DI, Ringden O, Rizzieri DA, Soiffer RJ, 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. Biology of Blood & Marrow Transplantation, Epub ahead of print. 1

2 Not for publication or presentation d. LK07-01 Armand P, Kim HT, Zhang MJ, Pérez WS, Cin PD, Klumpp TR, Lazarus HM, Artz AS, Gupta V, Isola LM, Halter J, Rowe JM, Antin JH, Camitta BM, Cairo MS, Sierra J, Stiff PJ, Nabhan C, Jakubowski AA, Devine SM, Maziarz RT, Marks DI, Aljurf MD, Soiffer RJ, Weisdorf DJ. Classifying cytogenetics in patients with AML in complete remission undergoing allogeneic transplantation: a CIBMTR study. Biology of Blood and Marrow Transplantation, In Press. e. LK07-03b Warlick ED, McClune B, Pedersen TL, Awn KW, Antin JH, Cahn JY, DeLima M, Gupta V, Marks DI, Bunjes D, DiPersio JF, Devine S, Weisdorf DJ. Older adults with chronic myelogenous leukemia (CML), during the tyrosine kinase inhibitor (TKI) era, can be successfully treated with reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) using sibling or unrelated donors: a Center for International Blood and Marrow Transplant Research (CIBMTR) analysis. Presented at the American Society of Hematology in San Diego, California, December Manuscript in preparation. f. LK07-03b McClune B, Pedersen TL, Ahn KW, Warlick ED, Pidala J, Waller EK, Rizzo JD, Cairo MS, Woolfrey A, Artz A, Lazarus HM, Weisdorf DJ. Reduced intensity or non-ablative hematopoietic cell transplantation in older patients with non-hodgkin lymphoma (NHL): encouraging survival for patients 55 years. Presented at the American Society of Hematology in San Diego, California, December Manuscript in preparation. g. LK08-02 Koreth J, Pidala J, Perez WS, Deeg HJ, Garcia-Manero G, Malcovati L, Cazzola M, Park S, Itzykson R, Ades L, Fenaux P, Jädersten M, Hellstrom-Lindberg E, Gale RP, Beach CL, Greenberg PL, Tallman MS, DiPersio JF, Bunjes D, Weisdorf DJ, Cutler CS. A decision analysis of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation for older patients with de-novo myelodysplastic syndrome (MDS): early transplantation offers survival benefit in higher-risk MDS. Presented at the American Society of Hematology in San Diego, California, December 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) Supplemental Data Collection (n=453) c. LK04-01 Allo and auto HCT for APML in CR2 (M Rubinger /M Tallman) Supplemental Data Collection Complete (n=152/283); Data File Preparation d. LK07-02 Scoring System as predictor in AML after HCT Data File Preparation (J Sierra) e. LK07-03b Allo HCT in older patients with Lymphoma/CML Manuscript Preparation (B McClune/ E Warlick) f. LK08-01 Landmark analysis for updated relapse/lfs estimates Manuscript Preparation for patients (S Lee) g. LK08-02 RIC in allo HCT for older patient with denovo MDS - Manuscript in preparation decision analysis (J Koreth/C Cutler) h. LK08-04/IB08-05 LTA alleles in AML relapse (P Posch) Deferred i. LK09-02 Monosomal karyotype and chromosomal 7 abnormalities in allo HCT for AML/MDS (M Pasquini/ M Battiwala) Data File Preparation 2

3 Not for publication or presentation j. LK10-02 Pre-HCT consolidation therapy on outcomes of RIC allo for AML in CR1 (E Warlick/M Litzow) k. LK10-03 Ph+ ALL in adults comparing RIC/MA allo HCT (V Bachanova) l. LK11-01 Extramedulary disease and outcome in allo HCT for AML (S Goyal/ G Uy) (Attachment 4) m. LK11-02 Prognostic scoring system to predict relapse of ALL after allo HCT (R Salit/ M Bishop/ D Porter) (Attachment 5) Protocol Development Funded Supplemental Data Collection (NST/RIC=83; MA=160) Draft Protocol Received Draft Protocol Received 5. Future/ Proposed studies AML a. PROP A prognostic risk index for older patients with AML in CR1 undergoing allogeneic stem cell transplantation (Y-B Chen/S Devine) (Attachment 6) b. PROP Allogeneic stem cell transplantation for FLT3/ITD positive AML in CR1 (S Sengsayadeth/B Savani/M Jagasia) (Attachment 7) and PROP Impact of FLT3- internal tandem duplication (FLT3-ITD) mutation on outcomes of hematopoietic stem cell transplant for cytogenetically normal AML (A Deol) (Attachment 8) c. PROP Analysis of prognostic significance of persistent cytogenetic and molecular abnormalities at last evaluation prior to allogeneic hematopoietic stem cell transplantation in AML patients in first complete remission (B Oran/ D Weisdorf/ M de Lima) (Attachment 9) ALL d. PROP Chemotherapy versus allogeneic hematopoietic cell transplantation in philadelphia negative chromosome negative adult ALL (M Seftel) (Attachment 10) e. PROP Interaction between obesity and total body irradiation in allogeneic transplantation for acute leukemia (D Vogl) (Attachment 11) DROPPED e. PROP Outcomes of unrelated donor hematopoietic cell transplantation recipients enrolled in a multicenter clinical trial compared to standard of care (T Kroll/ M Pasquini/ C Bredeson) (overlaps with approved study HS11-01) g. PROP Examining differences in relapse management and response following T-cell replete versus T-cell depleted allogeneic stem cell transplantation in patients with AML or MDS (E Morawa/S Giralt) (not doable due to complexity of data required (multiple steps; evaluations and clinical decision points), cost of secondary data collection and difficulty for centers to provide the needed data) h. PROP Effect of post-remission chemotherapy before human leukocyte antigen identical sibling transplantation for AML in first complete remission (A Ghavamzadeh/ K Moghaddam) (overlaps with approved study LK10-02) i. PROP Impact of a structurally complex karyotype in outcome of stem cell transplantation for AML and MDS (C Dobbelstein/G Göhring/ A Ganser) (overlaps with approved study LK09-02) j. PROP Use of tyrosine kinase inhibitors after allogeneic hematopoietic stem cell transplantation for philadelphia chromosome positive ALL (M Litzow) (overlaps with approved study LK10-03) 6. Other business 3

4 Not for publication or presentation Attachment 1 MINUTES 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 The CIBMTR Acute Leukemia Working Committee was called to order at 2:45 pm on Sunday, February 20, 2011, by Dr. John DiPersio. The chairs, scientific director and statisticians were presented. Attendees were asked to have their name badges scanned for attendance purposes and to maintain the committee membership roster, and to fill out the Working Committee evaluations and voting sheets for proposals. The CIBMTR guidelines for voting on proposals were discussed. Previously accepted proposals where no work has been done were to be weighed against the new proposals in order to select the studies with highest impact. Because the Committee agenda was full, the meeting was limited to presentation and discussion of proposals. Attendees were asked to review the materials to assess the progress of ongoing studies and the committee s accomplishments for the past year. Each presentation was limited to 3-4 minutes (maximum 3-4 overheads) to allow for adequate time for discussion (5 minutes) of the previous proposals, the proposals not yet initiated, and the new proposals. The minutes of the February 2010 meeting were approved without modifications. 2. Accrual summary Due to the full agenda, the accrual summary of registration and research cases between 1995 and 2010 were not presented to the committee but were available as part of the Working Committee attachments: Registration only Research AML allogeneic ALL allogeneic AML autologous ALL autologous

5 Not for publication or presentation Attachment 1 3. Presentations, published or submitted papers Due to the full agenda, the 2010 presentations and published papers were not presented. Five papers were published, two submitted and one ASH presentation was 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. 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. In Press. 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. Submitted and Presented at the American Society of Hematology in Orlando, Florida, December Manuscript in preparation. 5

6 Not for publication or presentation Attachment 1 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 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: 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. b. 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. c. 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. d. 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. e. 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 6

7 Not for publication or presentation Attachment 1 at the 2010 American Society of Hematology meeting. A draft manuscript is in preparation and it is expected to be submitted by July f. 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. g. 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. h. 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. i. 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 j. 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. 7

8 Not for publication or presentation Attachment 1 k. LK08-04: LTA alleles in AML relapse (P Posch) This study is a collaboration with the Immunobiology Working Committee and is currently deferred. 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 Previous accepted studies but not initiated were presented and led by Dr. Devine: a. LK09-02: Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation for Acute Myeloid Leukemia and Myelodysplasia (M Pasquini/ M Battiwala): Dr. Pasquini presented this study. The originals proposals from Drs. Pasquini and Battiwala 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=1000), MK- (n=2124) and patients with normal cytogenetics (n=2499) and non-transplant MK+ SWOG data from Medeiros BC et al. published study in Blood 2010 (Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group experience) will be included. A draft protocol is available for review. b. 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): Dr. Weisdorf presented this study in Dr. Oran s absence. 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 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 and overall survival. There are 1377 HLA-identical 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 legacy forms ( 1997). A draft protocol is available for review. c. LK10-02: Effect of pre-transplant consolidation chemotherapy on outcomes of RIC Allogeneic transplant for adults with AML in CR1 (E Warlick): Dr. Warlick presented this study. 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. There are 146 patients who received no consolidation therapy, 72 who received standard-dose consolidation therapy and 209 high-dose consolidation therapy. A supplemental form is 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. It was also noted the limited data on consolidation therapy in the CIBMTR legacy forms ( 1997). A draft protocol is available for review. 8

9 Not for publication or presentation Attachment 1 5. Future/ Proposed studies Drs. Bunjes and DiPersio led this section. The proposals were the followings: 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 (Oran/Gupta/Loren) Dr. Gupta presented this proposal. The purpose of this proposal is (1) to define prognostic factors for leukemia free survival in AML patients age 55 who receive reduced intensity conditioning allogeneic hematopoietic stem cell transplantation in first or second remission and then develop prognostic scoring system if sample size allows; (2) to apply the scoring system model in validation cohort and assess its utility in predicting 3 year LFS after RIC HCT and (3) to analyze 3 year relapse incidence, transplantation related mortality incidences at day +100 and 2 years after HCT. There are 632 CR1 and 246 CR2 AML patients 55 years that underwent a nonmyeloablative transplant and reported to the CIBMTR between 1995 and b. PROP Outcomes of reduced-intensity allogeneic transplants for patients with relapsed/refractory acute myeloid leukemia (A Loren) Dr. Gupta presented this proposal in Dr. Loren s absence. The purpose of this proposal is (1) to estimate the 3-year overall survival of patients ages 18 years who underwent non-myeloablative or reduced-intensity allogeneic hematopoietic cell transplants with active AML (either relapsed/refractory or primary induction failure); (2) to evaluate the cumulative incidence of acute & chronic graft-vs-host disease, and of neutrophil and platelet engraftment in this population and (3) to identify prognostic features that may predict overall survival in patients with relapsed/refractory AML undergoing RIC/NST. There are 830 (PIF=401; relapse=429) AML patients 18 years of age that underwent a non-myeloablative/reduced-intensity transplant reported to the CIBMTR between 1998 and If approved, careful review of the data will be needed due to the unexpected high number of patients. c. PROP Stem cell transplantation for acute myeloid leukemia harboring MLL abnormalities (L Costa) Dr. Stuart presented this proposal in Dr. Costa s absence. The purpose of this proposal is (1) to describe the outcome of adult patients with MLL+ AML undergoing allogeneic HSCT. Adult patients with MLL+ AML are usually regarded as being at high risk of relapse and allogeneic transplantation is often indicated in CR1. Whether allogeneic transplantation can outcome the negative prognostic impact of MLL abnormalities remains to be demonstrated and (2) to describe factors associated with favorable outcome in MLL+ AML patients undergoing allogeneic HSCT. It is important to estimate the relative impact of several leukemia-related (e.g. de novo vs. therapy related, CR1 vs. other status), patient-related (e.g. age) and transplant-related (e.g. intensity of the conditioning regimen, time from diagnosis to transplantation) factors on outcome of patients with MLL+ AML undergoing HSCT. There are 240 AML patients 18 years of age who had 11q (n=134) or 11q23 (n=106) abnormality prior to HCT reported to the CIBMTR between 1995 and d. PROP Impact of extramedullary disease on the outcome of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia (S Goyal) Dr. Uy presented this proposal in Dr. Goyal s absence. The purpose of this proposal is (1) to describe the outcome of patients undergoing allohsct for AML with extramedullary involvement and (2) to assess patient, disease and transplant related factors which influence the outcome of allohsct in AML. There are 1044 AML patients 18 years of age with extramedullary disease prior to HCT reported to the CIBMTR between 1995 and

10 Not for publication or presentation Attachment 1 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) Dr. Marks presented this proposal. The purpose of this proposal is (1) to determine the outcome of myeloablative and reduced intensity sibling donor, unrelated donor and cord blood transplants for acute lymphoblastic leukaemia in CR1 that was initially refractory to induction therapy and (2) to examine the prognostic factors that determine outcome including the timing, degree of match, intensity of conditioning regimen, stem cell source, % blasts at day 28 etc. There are 882 CR1 ALL patients 16 years of age in with a time from diagnosis to CR1 between 42 and 181 days reported to the CIBMTR between 1995 and f. PROP Chemotherapy versus allogeneic hematopoietic cell transplantation in Philadelphia chromosome negative adult acute lymphoblastic leukemia (M Seftel) Dr. Seftel presented this proposal. The purpose of this proposal is (1) to compare overall survival (OS), disease-free survival (DFS), and treatment-related mortality (TRM) of young adults with Philadelphia chromosome negative (Ph-) Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) treated with either allogeneic hematopoietic cell transplantation (allohct) or with a pediatric style chemotherapy regimen and (2) to identify predictors of OS, DFS, and TRM in this population of adults with ALL. There are 484 Ph- ALL in CR1 patients between the ages of who underwent a myeloablative HCT and reported to the CIBMTR between 2002 and The chemotherapy group consists of 63 patients during the same time period. 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) Dr. Akpek presented this proposal. The purpose of this proposal is to compare relapse-free survival (RFS) and overall survival (OS) between patients with T-cell acute lymphoblastic leukemia (T- ALL) who underwent allogeneic hematopoietic stem cell transplantation at first complete remission (CR-1) and those who received HCT when they were beyond CR1. There are 231 adult patients in CR1 and 310 adult patients not in CR1 who underwent an allogeneic transplant for T-cell ALL between 1995 and 2008 reported to the CIBMTR. h. PROP Development of a Prognostic Scoring System to Predict Relapse of Acute Lymphocytic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation (R Salit) Dr. Salit presented this proposal. The purpose of this proposal is to develop a prognostic scoring system based on patient, disease, and transplant-specific factors that is predictive of relapse after allogeneic hematopoietic stem cell transplantation in patients with ALL and (2) to assess the association of the variables identified within this scoring system with transplantation outcomes and outcomes after relapse. There are 4165 ALL patients 18 years that underwent an allogeneic transplant and reported to the CIBMTR between 1995 and AML and ALL i. PROP Outcomes of HLA haploidentical related hematopoietic cell transplantation for acute leukemias (B Wirk) Dr. Wirk presented this proposal. The purpose of this proposal is to study the outcomes of HLA haploidentical related hematopoietic cell transplantation for acute leukemias. The primary endpoints will be treatment related mortality (TRM), progression free survival (PFS) and overall survival (OS). The secondary endpoints will be analysis of engraftment, relapse rate, acute and chronic graft versus host disease (GVHD) and to determine if there is a greater graft versus 10

11 Not for publication or presentation Attachment 1 leukemia effect with haploidentical HCT than matched related donor or matched unrelated donor HCT and whether this translates to a better overall survival HLA-identical sibling, 3500 matched unrelated and 530 haploidentical patients 18 years of age who underwent an allogeneic transplant for ALL or AML between 1995 and 2008 were reported to the CIBMTR. 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, scientific merit and the impact of the study on the field the following studies will move forward: 1. LK09-02: Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation for Acute Myeloid Leukemia and Myelodysplasia (M Pasquini/ M Battiwala) 2. LK10-02: Effect of pre-transplant consolidation chemotherapy on outcomes of RIC Allogeneic transplant for adults with AML in CR1 (E Warlick) 3. PROP Impact of extramedullary disease on the outcome of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia (S Goyal) 4. PROP Development of a Prognostic Scoring System to Predict Relapse of Acute Lymphocytic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation (R Salit) Dr. Weisdorf 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 4:35 pm. 11

12 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 2011 Characteristics of patients Registration only Research Number of patients Age at transplant, years Median (range) 41 (<1-93) 42 (<1-83) low thru ( 8) 1550 ( 9) 10 thru (10) 1817 (10) 20 thru (12) 2159 (12) 30 thru (17) 2547 (14) 40 thru (22) 3445 (20) 50 thru (19) 3656 (21) 60 thru (10) 2202 (13) 70 thru high 154 ( 1) 213 ( 1) Missing 18 (<1) 0 Sex Male (53) 9298 (53) Female 9734 (47) 8289 (47) Missing 54 (<1) 2 (<1) Donor Related (76) 6669 (38) Unrelated 5099 (24) (62) Graft type Bone marrow 7113 (34) 6140 (35) Peripheral blood (61) 9716 (55) Cord blood 619 ( 3) 1625 ( 9) Missing 446 ( 2) 108 ( 1) Year of transplant ( 7) 1624 ( 9) (10) 1446 ( 8) (12) 1419 ( 8) (13) 1768 (10) (14) 2092 (12) (14) 2518 (14) (12) 2896 (16) a 2494 (12) 3162 (18) 2011 a 1328 ( 6) 664 ( 4) a 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 allogeneic transplants for ALL reported to the CIBMTR between 1995 and 2011 Characteristics of patients Registration only Research Number of patients Age at transplant, years Median (range) 22 (<1-83) 21 (<1-72) low thru (20) 2419 (24) 10 thru (24) 2410 (24) 20 thru (20) 1791 (18) 30 thru (15) 1299 (13) 40 thru (12) 1107 (11) 50 thru ( 7) 712 ( 7) 60 thru ( 2) 203 ( 2) 70 thru high 9 (<1) 5 (<1) Missing 10 (<1) 2 (<1) Sex Male 7305 (61) 6093 (61) Female 4599 (39) 3850 (39) Missing 27 (<1) 5 (<1) Donor Related 8493 (71) 3374 (34) Unrelated 3438 (29) 6574 (66) Graft type Bone marrow 5542 (46) 4752 (48) Peripheral blood 5482 (46) 3679 (37) Cord blood 706 ( 6) 1460 (15) Missing 201 ( 2) 57 ( 1) Year of transplant ( 9) 1292 (13) (11) 1107 (11) (13) 1060 (11) (15) 1108 (11) (13) 1136 (11) (12) 1274 (13) (11) 1338 (13) a 1477 (12) 1327 (13) 2011 a 562 ( 5) 306 ( 3) 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 autologous transplants for AML reported to the CIBMTR between 1995 and 2011 Characteristics of patients Registration only Research Number of patients Age at transplant, years Median (range) 47 (<1-82) 43 (<1-74) low thru ( 4) 84 ( 7) 10 thru ( 6) 88 ( 7) 20 thru (11) 161 (14) 30 thru (16) 195 (16) 40 thru (22) 235 (20) 50 thru (27) 251 (21) 60 thru (12) 168 (14) 70 thru high 67 ( 1) 9 ( 1) Missing 1 (<1) 0 Sex Male 2365 (52) 603 (51) Female 2206 (48) 588 (49) Missing 17 (<1) 0 Graft type Bone marrow 538 (12) 183 (15) Peripheral blood 3705 (81) 944 (79) Missing 345 ( 7) 64 ( 5) Year of transplant (10) 308 (26) (13) 258 (22) (17) 129 (11) (16) 110 ( 9) (17) 73 ( 6) (12) 103 ( 9) ( 7) 147 (12) a 286 ( 6) 57 ( 5) 2011 a 56 ( 1) 6 ( 1) 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 ALL reported to the CIBMTR between 1995 and 2011 Characteristics of patients Registration only Research Number of patients 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 6 ( 1) 0 Sex Male 412 (58) 132 (65) Female 294 (42) 71 (35) Graft type Bone marrow 106 (15) 30 (15) Peripheral blood 466 (66) 155 (76) Missing 134 (19) 18 ( 9) Year of transplant (19) 75 (37) (15) 61 (30) (19) 20 (10) (18) 16 ( 8) (12) 5 ( 2) ( 9) 11 ( 5) ( 5) 13 ( 6) a 21 ( 3) 2 ( 1) 2011 a 1 (<1) 0 a Cases continue to be reported in this interval 15

16 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 is available for review and secondary data collection is underway. 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. 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. 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 manuscript for Lymphoma and CML are expected to be submitted after Tandem. 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 16

17 Not for publication or presentation Attachment 3 GVHD has developed, will be incorporated into the estimates. The analysis is underway. A draft manuscript is expected to be submitted by July 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. A draft manuscript is in preparation and it is expected to be submitted by July 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. The data file preparation is underway. 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. 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 is available for review and supplemental data collection is underway. Studies previously proposed, but not initiated LK11-01: Impact of extramedullary disease on the outcome of allogeneic HCT in AML ((S Goyal/ G Uy): The purpose of this proposal is (1) to describe the outcome of patients undergoing allohsct for AML with extramedullary involvement and (2) to assess patient, disease and transplant related factors which influence the outcome of allohsct in AML. There are 1044 AML patients 18 years of age with extramedullary disease prior to HCT reported to the CIBMTR between 1995 and A draft protocol is available for review. 17

18 Not for publication or presentation Attachment 3 LK11-02: Development of a prognostic scoring system to predict relapse of ALL after allogeneic HCT (R Salit/ M Bishop/ D Porter): The purpose of this proposal is to develop a prognostic scoring system based on patient, disease, and transplant-specific factors that is predictive of relapse after allogeneic hematopoietic stem cell transplantation in patients with ALL and (2) to assess the association of the variables identified within this scoring system with transplantation outcomes and outcomes after relapse. There are 4165 ALL patients 18 years that underwent an allogeneic transplant and reported to the CIBMTR between 1995 and 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 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 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. The study was discontinued due to assessment of lower scientific priority. Dr. Oran will be invited as a coauthor in the Working Committee s molecular studies. 18

19 Not for publication or presentation Attachment 4 CIBMTR LK11-01 IMPACT OF EXTRAMEDULLARY INVOLVEMENT ON THE OUTCOME OF ALLOGENEIC TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA DRAFT PROTOCOL Study Chairs: Sagun D. Goyal, MD Washington University School of Medicine 660 S. Euclid Ave., Campus Box 8007 St. Louis, MO Telephone: Fax: sgoyal@dom.wustl.edu Geoffrey L. Uy, MD Washington University School of Medicine 660 S. Euclid Ave., Campus Box 8007 St. Louis, MO Telephone: Fax: guy@dom.wustl.edu Study Statisticians: Waleska S. Pérez, MPH CIBMTR Statistical Center 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI USA Telephone: Fax: wperez@mcw.edu Mei-Jie Zhang, PhD CIBMTR 8701 W. Wisconsin Ave. Milwaukee, WI USA Telephone: Fax: meijie@mcw.edu Center - James Cancer Center 19

20 Not for publication or presentation Attachment 4 B316 Starling Loving Hall 320 W 10th Avenue Columbus, OH Telephone: Fax: steven.devine@osumc.edu John F. DiPersio, MD, PhD Division of Oncology Washington University School of Medicine Campus Box South Euclid Avenue St. Louis, MO Telephone: Fax: jdipersi@im.wustl.edu Donald Bunjes, MD University Hospital Ulm Prittwitzstraae 43 Ulm-Donau, Germany Telephone: Fax: donald.bunjes@uniklinik.ulm.de 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 20

21 Not for publication or presentation Attachment OBJECTIVES: 1.1 To compare the outcome of patients undergoing allohsct for AML with extramedullary involvement or myeloid sarcoma to those patients with AML without extramedullary involvement. 1.2 To determine the impact of the site of extramedullary involvement on the outcome of allohsct in AML. 1.3 To assess other patient-, disease- and transplant-related factors which influence the outcome of allohsct in AML with extramedullary involvement. 2.0 SCIENTIFIC JUSTIFICATION: Extramedullary (EM) disease presentation in AML is rare. Although the exact incidence is unknown, older retrospective series have estimated that it occurs in 3 8% of patients with (Reviewed in 1) AML. The impact of EM involvement in AML is controversial. A retrospective analysis of patients entered in Children's Cancer Group (CCG) trials demonstrated significantly worse EFS for patients with EM involvement of the skin but and improved EFS for EM involving other sites. (2) Byrd et al. showed significantly worse outcomes in patients with EM AML and t(8:21) and suggested that more intensive therapies are needed in these patients. (3) The CR rates (50% vs 92%) and overall survival (5.4 vs 59.5 months) were markedly worse in patients with t(8:21) and EM AML when compared to those patients with t(8:21) but without EM disease. While the use of allosct is attractive overcome the potential poor prognostic impact of AML EM involvement, data supporting this approach is limited. In a series of 18 patients with EM AML published by Spruce et al., (4) EM disease was associated with a significant increase in leukemia recurrence and decrease in survival post-allosct when compared to a cohort without EM involvement. More recently, an analysis of 51 patients with EM AML who underwent allosct in the SFGM-TC registry demonstrated a favorable 5-year OS and DFS at 47% and 36%, respectively. (5) Though a comparison cohort without EM disease was not examined in this study, results suggested first-line allohsct to be a beneficial therapeutic modality. This concept was supported by series presented by Avni et al. in which 19 patients with granulocytic sarcoma (GS) were compared to 235 patients with AML without GS. (6) No statistically significant differences in CR rates nor OS were seen, but transplantation (both autologous and allogeneic) was associated with prolonged survival in the GS and comparison AML cohorts. Because a prospective study to determine the benefit of allosct for EM AML is not feasible, the CIMBTR database will offer the largest and most comprehensive data to identify factors which influence the outcome of allohsct for EM AML. Isolated EM relapses are common following allosct in patients with AML indicating a relative lack of graft vs. leukemia effect in EM sites. (7,8) The use of reduced intensity conditioning regimens, T cell depleted grafts, or non-tbi based conditioning regimens may be associated with higher rates of EM relapse and similarly may reduce the effectiveness of allosct in AML with EM disease. (9-11) Preliminary data search has identified over 1000 patients with extramedullary AML that will be available for analysis. Assessment of outcomes by comparison to a cohort with similar baseline features, but without EM involvement, will also help delineate the magnitude of benefit that allosct provides in this setting. 21

22 Not for publication or presentation Attachment STUDY POPULATION: The study population will include all patients age undergoing allogeneic stem cell transplantation for either AML from , reported to the CIBMTR. 4.0 OUTCOMES: 4.1 Overall survival: time to death. Patients are censored at time of last follow-up 4.2 Disease-free survival: Time to treatment failure (death or relapse). 4.3 Relapse: Recurrence of disease. This event is summarized by the cumulative incidence estimate with TRM as the competing risk 4.4 Treatment-related mortality: time to death without evidence of leukemia recurrence. 5.0 VARIABLES TO BE ANALYZED: Disease-related: Granulocytic sarcoma vs AML with extramedullary disease Site of extramedullary disease: CNS, skin, liver/spleen, lymph node Timing of initial extramedullary disease presentation (at diagnosis vs. relapse) Morphologic sub-type (FAB, M4-M5 vs non M4-M5) WBC at diagnosis x 10 9 /L Previous history of myelodysplastic syndrome or myeloproliferative disorder (yes/no) Cytogenetic abnormalities (stratify into favorable, intermediate, vs poor-risk) Disease status at HCT: PIF vs. CR1 vs. CR2 vs. relapse Duration of first complete remission (for AML patients transplanted in CR2): <6 * vs vs. >12 months vs. unknown Site of relapse for patients transplanted in CR2 or relapse, (bone marrow, CNS, Testes, other) Treatment related: Time from diagnosis to transplant Time from extramedullary disease to transplant Local therapy (radiation, surgery, intrathecal therapy) for extramedullary disease Type of consolidation treatment (HiDAC vs no HiDAC) Number of consolidation treatments prior to transplant (0, 1 vs. >=2) Transplant related: Conditioning regimen: TBI vs. non-tbi; myeloablative vs non-ablative/reduced intensity, ATG: no vs. yes HLA-matching: HLA-identical sibling vs. well-matched unrelated vs. partiallymatched unrelated vs. mismatched unrelated Source of stem cells: BM vs. PBSC Donor-recipient CMV status: D-/R- * vs. D+/R- vs. recipient positive vs. unknown Year of transplant: GVHD prophylaxis: based on distribution Donor cell infusion (yes/no) Acute GVHD: none vs II-IV Chronic GVHD: (yes/no) Post-transplant therapy (intrathecal drugs, CNS irradiation or other) 22

23 Not for publication or presentation Attachment STUDY DESIGN: Patient-, disease- and treatment-related factors will be compared between the two conditioning regimen groups, using Chi-square test for categorical and Mann-Whitney test for continuous 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 included in Section 4.0 will be generated using cumulative incidence estimates. Patients with and without extramedullary involvement will be compared using proportional hazards regression models. The proportional hazards assumptions for all the variables will be examined by adding a time-dependent 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 the presence of extramedullary disease is the main interest of this study, the risk factor of type of transplant 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 extramedullary involvement and all significant covariates will be examined. Further adjustment will be applied when test indicates that interactions are significant. Adjusted probability of diseasefree survival and overall survival will be computed based on final Cox regression model, stratified by treatment groups, 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. 7.0 REFERENCES: 1. Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. Journal of Clinical Oncology 1995;13: Dusenbery KE, Howells WB, Arthur DC, et al. Extramedullary Leukemia in Children With Newly Diagnosed Acute Myeloid Leukemia: A Report From the Children's Cancer Group. Journal of Pediatric Hematology/Oncology 2003;25: Byrd JC, Weiss RB, Arthur DC, et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;22): Results from Cancer and Leukemia Group B Jounal of Clinical Oncology 1997;15(2): Spruce WE, Forman SJ, Krance RA, et al. Outcome of bone marrow transplantation in patients with extramedullary involvement of acute leukemia. Blut 1983;48: Chevallier P, Mohty M, Lioure B, et al. Allogeneic hematopoietic stem-cell transplantation for myeloid sarcoma: a retrospective study from the SFGM-TC. Journal of Clinical Oncology 2008;26(30): Avni BR, Rund D, Levin M, et al. Clinical implications of acute myeloid leukemia presenting as granulocytic sarcoma. ASH Annual Meeting Abstracts 2010;116: Kata D, Markiewicz M, Czerw T, Seweryn M, Kyrcz-Krzemien S. Incidence, Clinical Presentations and Management of Isolated Extramedullary Relapses After Allogeneic Hematopoietic Stem Cell Transplantation for Acute and Chronic Leukemias: An Updated Single-Center Analysis of 612 Patients. ASH Annual Meeting Abstracts 2010;116:

24 Not for publication or presentation Attachment 4 8. Harris AC, Mageneau J, Braun T, et al. Extramedullary Relapse In Acute Leukemia Following Allogeneic Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors And Outcomes. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2010;16:S177-S8. 9. Craddock C, Nagra S, Peniket A, et al. Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2010;95: Schmid C, Schleuning M, Schwerdtfeger R, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 2006;108: Lee KH, Lee JH, Choi SJ, et al. Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course. Bone Marrow Transplant 2003;32:

25 Not for publication or presentation Attachment 4 Table 1. Characteristics of patients 18 years of age with extramedullary disease who underwent an allogeneic transplant for AML between 1995 and 2008 reported to the CIBMTR Characteristics of patients N (%) Number of patients 1044 Number of centers 193 Age at transplant, years Median (range) 41 (18-76) ( 5) (22) (21) (24) (20) >=60 99 ( 9) Sex Male 580 (56) Female 462 (44) Missing 2 (<1) Karnofsky score <90% 405 (39) % 589 (56) Missing 50 ( 5) Type of AML denovo AML 889 (85) secondary AML 153 (15) Missing 2 (<1) WBC at diagnosis, x10 9 /L < (48) (24) > (14) Missing 152 (15) Extramedullary disease on CNS 322 (31) Cytogenetic test Abnormal 516 (49) Normal 380 (36) Missing 148 (14) Conditioning regimen Myeloablative 810 (78) Non-myeloablative 216 (21) TBD 18 ( 2) 25

26 Not for publication or presentation Attachment 4 Table 1. Continued. Characteristics of patients N (%) Disease status at HCT PIF 107 (10) 1st CR 278 (27) 2nd CR 282 (27) >CR2 40 ( 4) Relapse 333 (32) Missing 4 (<1) Type of donor HLA-id sibling 396 (38) Other relative 65 ( 6) URD well-matched 222 (21) URD partially matched 118 (11) URD mismatched 67 ( 6) URD matching to be classified 176 (17) D-R sex match M-M 339 (32) M-F 225 (22) F-M 213 (20) F-F 213 (20) Missing 54 ( 5) D-R CMV status +/+ 334 (32) +/- 100 (10) -/+ 265 (25) -/- 238 (23) Missing 107 (10) Graft type Bone marrow 408 (39) Peripheral blood 589 (56) Cord blood 47 ( 5) Year of HCT (14) (11) (13) (15) (18) (16) (13) 26

27 Not for publication or presentation Attachment 4 Table 1. Continued. Characteristics of patients N (%) GVHD prophylaxis T-cell depletion 80 ( 8) FK506+MTX+-other 219 (21) FK506+-other 109 (10) CsA+MTX+-other 451 (43) CsA+-other 157 (15) Other/Missing 28 ( 3) Median FU of survivors, months 61 (3-181) Twin transplants were excluded 27

28 Not for publication or presentation Attachment 5 CIBMTR LK11-02 DEVELOPMENT OF A PROGNOSTIC SCORING SYSTEM TO PREDICT THE RELAPSE OF ACUTE LYMPHOCYTIC LEUKEMIA AFTER ALLOGENEIC HSCT REVISED PROTOCOL Study Co-Chair: Study Co-Chair: Study Co-Chair: Study Statisticians: Rachel B. Salit, MD National Cancer Institute Experimental Transplantation and Immunology Branch 10 Center Drive, Building 10 Room Bethesda, MD Telephone: Fax: salitr@mail.nih.gov Michael R. Bishop, MD Medical College of Wisconsin Clinical Cancer Center 4th Floor - Room C West Wisconsin Avenue Milwaukee, WI Phone: Fax: mbishop@mcw.edu David L. Porter, MD Abramson Cancer Center, University of Pennsylvania Medical Center Philadelphia, Pennsylvania, 19104, USA Phone: Fax: david.porter@uphs.upenn.edu Waleska S. Pérez CIBMTR Statistical Center Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI USA Telephone: Fax: wperez@mcw.edu 28

29 Not for publication or presentation Attachment 5 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 Bunjes, MD University Hospital Ulm Prittwitzstraae 43 Ulm-Donau, GERMANY Telephone: Fax: donald.bunjes@uniklinik.ulm.de Steven Devine, MD The Ohio State University Comprehensive Cancer Center Columbus, OH, USA Telephone: Fax: steven.devine@osumc.edu John F. DiPersio, MD, PhD Division of Oncology Washington University School of Medicine Campus Box South Euclid Avenue St. Louis, MO Telephone: 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: Fax: weisd001@umn.edu 29

30 Not for publication or presentation Attachment OBJECTIVES: 1.1 To develop a prognostic scoring system based on patient, disease, and transplantspecific factors that is predictive of relapse after allogeneic hematopoietic stem cell transplantation in patients with Acute Lymphocytic Leukemia (ALL). 1.2 To assess the association of the variables identified within this scoring system with transplantation outcomes and outcomes after relapse. 2.0 SCIENTIFIC JUSTIFICATION: First-line regimens in adult ALL result in complete response (CR) in up to 90% and long-term survival rates from 30% to 50% (1-4). However, most adults with ALL will die from disease progression. The indication for allogeneic stem cell transplantation for most subtypes of acute lymphocytic leukemia in CR1 is controversial despite the fact that patients with primary refractory disease or in first recurrence achieve CR rates of only 30% to 50% with salvage therapy and cure rates of less than 5%. A recent single center analysis of 245 patients treated at MD Anderson Cancer Center proposed a set of prognostic factors including age, karyotype, hemoglobin level, white blood cell count, platelet count, percentage blasts, LDH and albumin levels as poor prognostic factors for response after induction failure or short first remission duration (5). Risk of relapse following allogeneic hematopoetic stem cell transplantation (HSCT) for ALL is substantial with a 20-40% relapse rate in CR1, 40%-60% in CR2, and 70% in patients with recurrent disease (6). However, there currently is no uniform definition of ALL relapse risk in transplant studies and identifying high-risk patients for early relapse remains the most promising approach to reduce relapse hazards (6). In our proposed study we intend to develop a prognostic scoring system to define which patients with ALL are at high risk for relapse or death after allogeneic HSCT. The proposed study is most appropriately performed on a large dataset as single center studies do not have sufficient patient numbers to adequately examine this issue with the necessary statistical power. Using data from multiple sites will also increase the degree to which the patients are representative of patients with ALL, and make the findings more generalizable. Strategies to prevent relapse after transplantation are needed in patients with ALL. If validated, a prognostic scoring system to predict relapse in this population would allow for identification of individuals who are most likely to benefit from investigational approaches designed to prevent relapse. 3.0 PATIENT ELIGIBILITY: Patients greater than 18 years of age with ALL with or without CNS involvement reported to the CIBMTR who received a myeloablative, nonmyeloablative or reduced intensity peripheral blood stem cell, bone marrow, or cord blood transplant while in complete remission or with relapsed disease from a matched related, unrelated or cord blood donor between 1995 and DATA REQUIREMENTS: The proposed study does not require the collection of supplemental data outside of the current data collection forms. The proposed study will incorporate data currently compiled in the LK , LK-08-03, LK10-03, LK-03-03, and R datasets. Additionally, the following data collection forms may be required to supplement outcome or variable data not included in the above dataset: Recipient Baseline Data (2000), Hematopoietic Stem Cell Transplant Infusion (2006), Acute Lymphocytic Leukemia Pre-HSCT Data (2011), 100 Day Post-HSCT Data (2100), Acute Lymphocytic Leukemia Post-HSCT Data (2111), Six Months to Two Years Post-HSCT Data (2200), Yearly Follow-Up for Greater than Two Years Post-HSCT 30

31 Not for publication or presentation Attachment 5 Data (2300), Pre-Transplant Essential Data (2400), Post-Transplant Essential Data (2450), Chimerism (2451), Selective Post-Transplant Essential Data (2455), Recipient Death Data (2900). 5.0 VARIABLES TO BE ANALYZED: Patient Specific: Patient age Patient gender Karnofsky performance status Disease Specific Prior Therapy: Disease status at transplant: CR versus not CR Patient karyotype Percentage Bone Marrow involvement at transplant Peripheral Blasts at transplant Cytopenias at time of transplant Elevated LDH at transplant CNS involvement Number of prior chemotherapy regimens received Transplant Specific: Primary refractory disease: Y or N Response to last therapy, duration of response Time from diagnosis to transplant Conditioning regimen CD34+ cell dose infused ATG given for any reason Alemtuzumab given for any reason CD3+ cell dose infused Donor-recipient gender match: M/M versus M/F versus F/M versus F/F Source of stem cells: bone marrow versus peripheral blood versus cord matched sibling vs unrelated donor vs cord blood Type of GVHD prophylaxis Donor-recipient HLA disparity Days to neutrophil recovery Days to lymphocyte recovery Recovery of normal Immunoglobulin levels Time to full donor chimerism Engraftment syndrome Donor cell infusion for any reason Time of donor cell infusion post-transplant Development of acute graft versus host disease, grade Development of chronic graft versus host disease Post-transplant tyrosine kinase inhibitor therapy This list is in addition to data related to the outcome needed to do the analyses: date of transplant, date of relapse following transplant, date of last follow-up, date of death, whether a death was due to treatment or not. 6.0 STUDY DESIGN: Initial analysis: Variables related to patient, disease, and transplant characteristics (Table 1) will be summarized using descriptive statistics. The primary analysis will be actuarial 31

32 Not for publication or presentation Attachment 5 (Kaplan-Meier) curve of time to progression or relapse (in which deaths due to treatment will be censored). Cumulative incidence curves for relapse competing with non-relapse mortality (NRM), and NRM, will also be calculated. Patient-related, disease-related, and transplantrelated variables found to be significant in univariate (log-rank) analyses will subsequently be evaluated in a Cox proportional hazards model. Secondary outcomes to be explored include the incidence of late relapse (>12 months after transplant), and NRM. Three patient cohorts will be evaluated for relapse and OS primary outcomes: a) Patients at transplant baseline prior to starting conditioning; b) Patients survivors at day 100 post transplant in which case the impact of post-transplant variables and acute GVHD will be included; c) Patients survivors at 12 months post-transplant in which case the impact of post-transplant variables and acute and chronic GVHD will be included. Relapse risk score development: Our primary objective will be to develop a risk score for relapse free survival, event free survival and OS in patients at transplant baseline using the above identified predictive variables. Each individual factor identified to be significantly associated with a given outcome in a univariate analysis and then found to be jointly prognostic in a Cox model will be included in the final risk score, which, for simplicity of implementation, will consist of the number of such factors that a patient possesses. 7.0 REFERENCES: 1. Flowers CR, Sinha R, Vose JM. Improving Outcomes for Patients with Diffuse Large B- cell Lymphoma. CA Cancer J Clin Nov-Dec;60(6): A predictive model for aggressive non-hodgkin lymphoma. The International Non- Hodgkin Lymphoma Prognostic FactorsProject. N Engl J Med. 1993;329: Oliansky DM, Czuczman M, Fisher RI, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of diffuse large B-cell lymphoma: update of the 2001 evidence-based review. Biol Blood Marrow Transplant. 4. Tomblyn M, Brunstein C, Burns LJ, et al. Similar and promising outcomes in lymphoma patients treated with myeloablative or nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14: Pavletic, S.Z., et al., NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biology of Blood and Marrow Transplantation, (7): p

33 Not for publication or presentation Attachment 5 Characteristics of patients 18 years of age that underwent an allogeneic transplant for ALL reported to the CIBMTR between 1995 and 2008 Characteristics of patients N (%) Number of patients 4165 Number of centers 302 Age at transplant Median (range) 33 (18-72) yrs 407 (10) yrs 1407 (34) yrs 1013 (24) yrs 789 (19) yrs 447 (11) >=60 yrs 102 ( 2) Sex Male 2521 (61) Female 1639 (39) Missing 5 (<1) Karnofsky score <90% 1280 (31) % 2695 (65) Missing 190 ( 5) WBC at diagnosis, x10 9 /L < (58) (15) > (10) Missing 718 (17) Cytogenetic test Abnormal 2091 (50) Normal 1099 (26) Missing 975 (23) Conditioning regimen Myeloablative 3702 (89) Non-myeloablative 423 (10) TBD 40 ( 1) Disease status at HCT PIF 239 ( 6) 1st CR 1873 (45) 2nd CR 1044 (25) >CR2 199 ( 5) Relapse 804 (19) Missing 6 (<1) 33

34 Not for publication or presentation Attachment 5 Continued. Characteristics of patients N (%) Type of donor HLA-id sibling 1458 (35) Twin 16 (<1) Other relative 184 ( 4) URD well-matched 950 (23) URD partially matched 585 (14) URD mismatched 346 ( 8) URD matching to be classified 626 (15) D-R sex match M-M 1530 (37) M-F 832 (20) F-M 892 (21) F-F 731 (18) Missing 180 ( 4) D-R CMV status +/ (31) +/- 494 (12) -/+ 937 (22) -/ (25) Missing 404 (10) Graft type Bone marrow 1997 (48) Peripheral blood 1975 (47) Cord blood 193 ( 5) Year of HCT (14) (12) (13) (15) (15) (19) (13) GVHD prophylaxis T-cell depletion 240 ( 6) FK506+MTX+-other 1041 (25) FK506+-other 321 ( 8) CsA+MTX+-other 1956 (47) CsA+-other 467 (11) Other 129 ( 3) Missing 11 (<1) Median FU of survivors, months 53 (3-180) 34

35 Not for publication or presentation Attachment 6 Study Proposal Study Title: A Prognostic Risk Index for Older Patients with AML in CR1 Undergoing Allogeneic Stem Cell Transplantation. Yi-Bin Chen, MD, Massachusetts General Hospital, Boston, MA Steve Devine, MD, The Ohio State University, Columbus, OH Specific Aims: This study will seek to validate the hematopoietic cell transplantation comorbidity index (HCT-CI) for older patients with AML in CR1 undergoing allogeneic stem cell transplantation (HSCT) as well as analyze if several other clinical factors are predictive for non-relapse mortality after RIC SCT. Patients will be stratified myeloablative (MAC) vs reduced intensity (RIC) given the historical difference in NRM between these two groups If the HCT-CI does not prove to be predictive of non-relapse mortality (NRM), then we will identify the chronic medical conditions and other clinical factors which are important for predicting NRM for older patients with AML in CR1 undergoing RIC SCT. The HCT-CI or a new prognostic index will then be hopefully integrated with clinical, cytogenetic, and molecular data into a scoring system to predict overall survival probabilities for older patients with AML in CR1 undergoing allogeneic SCT. Scientific Justification: The optimal consolidation therapy for older patients with acute myeloid leukemia (AML) in CR1 is unclear. Historical series have suggested that < 20% of older patients with AML in CR1 will achieve 3- year disease-free survival (DFS). 1 These poor outcomes have been attributed to several factors including 1) increased treatment-related mortality, 2) reduced dose intensity delivered, and 3) the inherent chemoresistance of AML in the elderly. In younger patients, allogeneic hematopoietic stem cell transplantation (HSCT) has been able to deliver higher rates of DFS when compared with standard chemotherapy consolidation or autologous stem cell transplantation (ASCT). 2, 3 Traditionally, older patients were not included in allogeneic HSCT trials given fears of excess transplant-related morbidity and mortality. However, with advent of reduced intensity conditioning (RIC) approaches and improvements in supportive care, allogeneic HSCT has become an increasingly popular option for older patients with AML. Indeed a large, multi-center cooperative group prospective phase II study (CALGB / CTN 0502) of RIC PBSCT for elderly patients with AML in CR1 is nearing completion of accrual and preliminary results are encouraging (Devine S, personal communication). Even with the promising results of RIC SCT for elderly AML patients, it is difficult to know what to recommend as the best consolidation therapy for an individual patient. Developing transplant-related prognostic scores which balance the risk of relapse with the risk of non-relapse mortality (NRM) would be valuable in helping patients and physicians make decisions. While the risk of relapse for an individual patient is most likely associated with the biology of the disease such as certain clinical, cytogenetic, and molecular factors, the risk of NRM is most likely related to the intensity of the conditioning regimen and individual patient characteristics and comorbidities. The HCT-CI (hematopoietic cell transplantation specific comorbidity index) was defined by Sorror et al. in 2005 and identified several comorbid conditions as predictive for TRM after HSCT in over 1000 patients who were treated at the Fred Hutchinson Cancer Research Center (FHCRC), however, the population used in the training and validation cohorts were heterogeneous in disease, age, intensity of conditioning regimen, and stem cell source. 4 Nevertheless, the HCT-CI has since been validated in many specific settings including patients with AML in CR1 undergoing SCT (mostly MAC), 5 undergoing RIC SCT for several diagnoses including 35

36 Not for publication or presentation Attachment 6 multiple myeloma and lymphoma, 6-8 at other institutions, 9 multiple myeloma undergoing autologous stem cell transplant (ASCT), 10 11, 12 and in pediatric patients, adolescents, and young adults undergoing HSCT. In this analysis, we hope to validate the HCT-CI for older patients with AML in CR1 undergoing allogeneic SCT and to identify other clinical factors, including specific donor and transplant characteristics, which are predictive of NRM to establish an accurate risk index for such patients. Eventually, we hope to incorporate either the HCT-CI or a new risk index with clinical, cytogenetic, and molecular data to develop an accurate model to predict overall outcomes for older patients with AML in CR1 considered for allogeneic SCT. Patient Eligibility Population: Patients age 50 or older with AML in CR1 (or CRi) who underwent allogeneic SCT from related or unrelated bone marrow or peripheral blood stem cells (PBSCs) or umbilical cord blood (UCB). Patients will be stratified by having undergone myeloablative vs reduced intensity conditioning regimens given the historical difference in NRM between such regimens. RIC regimens will be defined by the consensus definition as established by the ASBMT. 13 Patients will have achieved CR1 after no more than two cycles of accepted standard induction chemotherapy or after no more than four cycles of chemotherapy with a hypomethylating agent. Patients will have received at most 2 cycles of consolidation chemotherapy. Patients will have undergone HSCT no more than 6 months after achieving CR1. Data Requirements: Recipient clinical conditions / factors to analyze: Age: vs vs vs vs > 75 Performance status (KPS) Previous solid tumor Previous autologous stem cell transplant (ASCT) Cerebrovascular disease (occlusive or hemorrhagic stroke) Autoimmune / Rheumatologic disease Cardiovascular disease Atrial fibrillation Other arrhythmia LVEF < 50% Coronary artery disease (no myocardial infarction) Previous myocardial infarction (MI) Hypertension Peripheral vascular disease (PVD) Heart valve disease Psychiatric disease Endocrine disease Diabetes mellitus Thyroid disease Osteoporosis GI disease Peptic ulcer disease (PUD) Inflammatory bowel disease (UC or IBD) GERD Renal disease Requiring or previous renal replacement therapy Previous renal transplantation 36

37 Not for publication or presentation Attachment 6 Cr above institution s upper limit of normal Prior DVT or PE Liver disease Active HBV HCV LFT abnormalities AST or ALT 1.5x-3x vs > 3x ULN Serum total bilirubin 1.5x-3x vs > 3x ULN Pulmonary Asthma Restrictive lung disease COPD DLCO < 50% of predicted Smoking Active (within the past year) Past Infectious Disease Past fungal infection Donor characteristics RD vs URD vs UCB Female donor-male recipient vs other Any CMV pos vs both CMV neg (serostatus) PBSC vs BM HLA typing Transplant characteristics TBI vs no TBI In vivo TCD vs none Sample Requirements: N/A Study Design: All patients ages 50 and above with AML in CR1 who underwent SCT from the years 2008 through 2010 will be included as this is when data relevant to the HCT-CI have been collected. The HCT- CI assigns weight of 1, 2, or 3 to comorbidities according to their impact on NRM. The final evaluation of the number and seriousness of all comorbidities will be represented by a summation of scores with no upper limit. These factors are shown in the table below (adapted from Sorror et al): 4 37

38 Not for publication or presentation Attachment 6 First, the HCT-CI as defined above will be analyzed to see if it is predictive of NRM in the 2 cohorts of patients (MAC vs RIC). If the HCT-CI is found to be predictive of NRM, then the other variables collected, including donor and transplant characteristics, will be analyzed for their predictive value as described below. If, the HCT-CI is found to be not predictive of NRM, then all patients will be randomly divided into 2 cohorts with 2/3 assigned to a training set to develop scoring weights and 1/3 will make up the validation set. Weights will be derived from Cox proportional hazards modeling applied to the training set, with NRM over the first 2 years after HSCT as the primary outcome. Disease progression and relapse will be treated as competing risks. Adjusted hazard ratios (HRs) for NRM were calculated for each comorbid condition, controlling for the presence of all coexisting comorbidities. References : 1. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994;331(14): Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995;332(4): Cassileth PA, Lynch E, Hines JD, et al. Varying intensity of postremission therapy in acute myeloid leukemia. Blood 1992;79(8):