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Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA Orlando, FL Thursday, February 23rd, 2017, 12:15 – 2:15 pm

Co-Chair: Marcos de Lima, MD, University Hospitals Case Medical Center, Cleveland, OH; Telephone: 216-286-6869; E-mail: [email protected]

Co-Chair: H Jean Khoury, MD, Winship Cancer Institute of Emory University, Atlanta, GA; Telephone: 404-778-3932; E-mail: [email protected]

Co-Chair: Brenda Sandmaier, MD, Fred Hutchinson Cancer Research Center, Seattle, WA; Telephone: 206-667-4961; E-mail: [email protected]

Scientific Director: Daniel J. Weisdorf, MD, University of Minnesota Medical Center, Minneapolis, MN; Telephone: 612-624-3101; E-mail: [email protected]

Assistant Scientific Director: Wael Saber, MD, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0700; E-mail: [email protected]

Statistical Director: Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-8375; E-mail: [email protected]

Statistician: Hai-Lin Wang, MPH, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0647; E-mail: [email protected]

1. Introduction

a. Minutes and Overview Plan from February 2016 meeting (Attachment 1)

2. Accrual summary (Attachment 2)

3. Presentations, published or submitted papers

a. LK12-02 Deol A, Sengsayadeth S, Ahn HW, Wang HL, Aljurf M, Antin JH, Bornhauser M, Cahn JY,Camitta B, Chen YB, Cutler CS, Gale RP, Ganguly S, Hamadani M, Inamoto Y, Jagasia M, Kamble R,Koreth J, Lazarus HM, Liesveld J, Litzow MR, Marks DI, Nishihori T, Olsson RF, Reshef R, Rowe JM,Saad AA, Sabloff M, Schouten HC, Shea TC, Soiffer RJ, Uy GL, Waller EK, Wiernik PH, Wirk B,Woolfrey AE, Bunjes D, Devine S, de Lima M, Sandmaier BM, Weisdorf DJ, Khoury HJ, Saber W.(2016) Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acutemyeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR)analysis. Cancer, 2016 Oct; 122(19):3005-14.

b. LK13-01 Rosko AE, Wang HL, de Lima M, Sandmaier B, Khoury HJ, Artz A, Brammer J, Bredeson C,Farag S, Kharfan‐Dabaja M, Lazarus HM, Marks DI, Martino Bufarull R, McGuirk J, Mohty M,Nishihori T, Nivison‐Smith I, Rashidi A, Ringden O, Seftel M, Weisdorf D, Bachanova V, SaberW. (2016). Reduced intensity conditioned allograft yields favorable survival for older adults with B‐cell acute lymphoblastic leukemia. American Journal of Hematology, 2017 Jan; 92(1):42-49.

c. LK13-03 Munker R, Brazauskas R, Wang HL, de Lima M, Khoury HJ, Gale RP, Maziarz RT, SandmaierBM, Weisdorf D, Saber W. Allogeneic Hematopoietic Cell Transplantation for Patients with MixedPhenotype Acute Leukemia. Biology of Blood and Marrow Transplantation, 2016 Jun 30;22(6):1024-9.

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d. LK14-03 Ganzel C, Mathews V, Alimoghaddam K, Ghavamzadeh A, Kuk D, Devlin S, Wang HL, ZhangM‐J, Weisdorf D, Douer D, Rowe JM, Estev J, Nagler A, Mohty M, Tallman MS. AutologousTransplant remains the Preferred Therapy for Relapsed APL in CR2. Bone Marrow Transplantation,2016 Sep; 51(9):1180-3.

e. LK14-02 Michelis FV, Gupta V, Zhang MJ, Wang HL, Aljurf M, Bacher U, Beitinjaneh A, Chen YB,DeFilipp Z, Gale RP, Kebriaei P, Kharfan‐Dabaja M, Lazarus HM, Nishihori T, Olsson RF, Oran B,Rashidi A, Rizzieri DA, Tallman MS, de Lima M, Khoury HJ, Sandmaier BM, Weisdorf DJ, Saber W.Cytogenetic risk determines outcomes following allogeneic transplantation in older patients withacute myeloid leukemia in second complete remission: A CIBMTR cohort analysis. Cancer, 2016.

f. LK15-05 Ustun C, Giannotti F, Zhang MJ, Wang HL, Brunstein C, Labopin M, Rocha V, de Lima M,Baron F, Sandmaier BM, Eapen M, Gluckman E, Nagler A, Weisdorf DJ, Ruggeri A. Outcomes of UCBtransplantation are comparable in FLT3+ AML: results of CIBMTR, EuroCord and EBMTcollaboration. Leukemia, 2016.

g. SC15-05 Weisdorf D, Millard HR, Horowitz MM, Hyare P, Champlin R, Ho V, Mielcarek M, Rezvani A,Stockerl‐Goldstein K, Khoury HJ, De Lima M, Saber W, Sandmaier B, Zhang MJ, Eapen M. AllogeneicTransplantation for Advanced AML: The Value of Complete Remission. Cancer, 2017.

4. Studies in progress (Attachment 3)a. LK13-02 Prognostic significance of cytogenetic abnormalities in patients with Philadelphia ‐ negative

acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation incomplete remission (A Lazaryan/V Bachanova/D Weisdorf) Analysis

b. LK14-01 Effect of post‐remission consolidation chemotherapy prior to allogeneic transplantation foracute lymphocytic leukemia in first complete remission (N Bejanyan/A Lazaryan/D Weisdorf)Manuscript preparation

c. LK15-01 AlloHCT vs. other consolidation therapies per Alliance and SWOG protocols in older AML inCR1 (A Artz / C Ustun) Data file preparation

d. LK15-02 Impact of GVHD on outcome after allogeneic hematopoietic cell transplantation foracute lymphocytic leukemia (M Yeshurun/J Rowe/M Tallman/V Bachanova) Analysis

e. LK15-03 Comparison of outcomes of older adolescents and young adults with Philadelphia‐chromosome/BCR‐ABL1‐negative acute lymphoblastic leukemia receiving post‐remissionconsolidation chemotherapy with pediatric‐inspired chemotherapy on CALGB 10403 ormyeloablative allogeneic hematopoietic cell transplantation (M Wieduwilt/W Stock) Data filepreparation

f. LK15-04 Outcome of hematopoietic stem cell transplantation using total body irradiation‐basedversus chemotherapy‐based full intensity conditioning regimens for adults with acute lymphoblasticleukemia (P Kebriaei/I Aldoss/V Pullarkat/C Anasetti/D Marks) Manuscript preparation

g. LK16-01 Reduced Intensity Conditioning (RIC) regimens for Acute Myeloid Leukemia (AML): Acomparison of Busulfan (B) and Melphlan (M) based regimens from the CIBMTR database (ZartashGul/ Gulrayz Ahmed/ Muhammed Khan/ Gerhard Hilderbrandt/ Hassan Alkhateeb/ MoussabDamlaj/ Miranal Patnaik/ Rajneesh Nath/ Zheng Zhou/ Jan Cerny) Protocol development

h. LK16-02 DRI‐guided Choice of Conditioning Intensity for Allogeneic Hematopoietic CellTransplantation in Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes (NelliBejanyan/ Erica Warlick/ Claudio Brunstein/ Daniel Weisdorf) Protocol development

i. LK16-03 Allogeneic transplantation to treat therapy related acute myeloid leukemia andmyelodysplastic syndromes (Natalie Callander/ Leland Metheny/ Marcos De Lima / Aric Hall)Protocol development

j. LK16-04 Comparing outcomes between HLA‐haploidentical and matched sibling allogeneictransplants in patients with acute myeloid leukemia (Rizwan Romee/ Armin Rashidi/ MehdiHamadani/ Wael Saber) Protocol development

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k. LK17-01 Outcomes of acute myeloid leukemia patients who undergo allogeneic transplant stratifiedby depth of clinical response (Mary‐Elizabeth Percival / Brenda Sandmaier / Eli Estey) Protocolreceived

5. Future/proposed studiesa. PROP 1510-21/1611-08/1611-70 Impact of Maintenance Therapy after Allogeneic Hematopoietic

Cell Transplant (HCT) on Outcomes in Acute Myeloid Leukemia (AML) (Masumi Ueda, Tania Jain,Jeanne Palmer, Lisa Sproat, Amer Assal, Sergio Giralt, Marcos de Lima) (Attachment 4)

b. PROP 1611-33 Fludarabine/busulfan versus fludarabine/melphalan conditioning in patients withacute lymphoblastic leukemia (Yasuyuki Arai) (Attachment 5)

c. PROP 1611-49 Hypomethylating agents prior to allogeneic hematopoietic cell transplant in AML: aretrospective matched cohort analysis of disease free survival and overall survival (Zachary Crees,Geoffrey Uy, John DiPersio) (Attachment 6)

d. PROP 1611-64/1611-102/1611-152 The Influence of Donor Source, Cytogenetics, and MolecularMarkers on Outcomes after a Second Hematopoietic Cell Transplant for Patients with RelapsedLeukemia and MDS (Marcos de Lima, Leland Metheny, Kalyan Nadiminti, Margarida Silverman, EricHuselton, Mark Schroeder) (Attachment 7)

e. PROP 1611-95 Allogeneic Hematopoietic Transplant Outcomes in Adult Patients with MLL‐rearranged Acute Myeloid Leukemia (Martin Tallman, Kamal Menghrajani) (Attachment 8)

f. PROP 1611-100 Optimizing Allogeneic Hematopoietic Cell Transplant Outcomes in Acute MyeloidLeukemia Using Next Generation Sequencing (Betty Hamilton, Navneet Majhail, JaroslawMaciejewski, Aziz Nazha) (Attachment 9)

g. PROP 1611-111/1611-112 Sorafenib use with allogeneic stem cell transplant for FLT3 mutationpositive acute myeloid leukemia (Benjamin Tomlinson, Marcos de Lima, Yi‐Bin Chen)(Attachment 10)

h. PROP 1611-163 Impact of post‐transplant maintenance therapy with BCR‐ABL tyrosine kinaseinhibitors on outcomes of Philadelphia chromosome‐positive acute lymphoblastic leukemia (ZackDeFilipp, Yi‐Bin Chen) (Attachment 11)

Proposed studies; not accepted for consideration at this time a. PROP 1609-01 Impact of FLT3 mutation on post‐transplant outcomes of patients with AML who are

not in remission at the time of hematopoietic stem cell transplant (Divaya Bhutani, Abhinav Deol)b. PROP 1610-14 Clinical Outcomes of Patients with a History of Prior Autologous Transplant

Undergoing a Second Allogeneic Transplant for Therapy Related AML/MDSc. PROP 1611-27 Evaluation of allogeneic hematpoietic cell transplantation outcomes and prognostic

factors in acute megakaryoblastic leukemia: a CIBMTR analysisd. PROP 1611-39 Impact of time from diagnosis to hematopoietic cell transplantation on outcomes in

acute myeloid leukemia in first complete remissione. PROP 1611-58 Allogeneic transplant versus no allogeneic transplant in adult patients with MRD

negative Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in firstcomplete remission (CR1)

f. PROP 1611-66 Evaluating Primary Refractory Acute Myeloid Leukemia; the effects of DiseaseCharacteristics and Outcomes of Allogeneic Stem Cell Transplantation

g. PROP 1611-99 Comparing Autologous versus Allogeneic Stem Cell Transplantation for BlasticPlasmacytoid Dendritic Cell Neoplasm

h. PROP 1611-101 Outcomes of allo‐HCT of AML patients who achieved complete remission after twoor more cycles of induction chemotherapy versus patients with primary refractory AML undergoingallo‐HCT

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i. PROP 1611-114 Outcome of allogeneic hematopoietic stem cell transplantation for adolescent andyoung adults with relapsed Acute Lymphoblastic Leukemia following frontline therapy with anasparaginase‐containing regimen

j. PROP 1611-118 Comparison of melphalan‐based reduced intensity conditioning with myeloablativeconditioning for acute myeloid leukemia and myelodysplastic syndrome

k. PROP 1611-121 A Retrospective Study of Allogeneic Stem Cell Transplantation ComparingConditioning Chemotherapy Intensity of Regimen Containing Myeloablative Busulfan versusReduced Intensity Melphalan in Patients with Myelodysplastic Syndrome (MDS) or Acute MyeloidLeukemia (AML)

l. PROP 1611-125 Survival of patients with acute lymphoblastic leukemia (ALL) relapsing after firstallogeneic hematopoietic cell transplantation: Prognostic factors and impact of post‐relapsetherapies

m. PROP 1611-132 Predictive model for progression free survival in patients with acute myeloidleukemia receiving allogeneic stem cell transplantation

n. PROP 1611-135 Survival of patients with ALL relapsing after allogeneic transplantationo. PROP 1611-141 The role of haploidentical allogeneic HCT in FLT‐3 ITD positive acute myelogenous

leukemiap. PROP 1611-143 Comparison of outcomes of allogeneic hematopoietic cell transplantation (HCT) in

secondary acute myeloid leukemia (AML) with prior solid tumor history or antecedent hematologiccondition

q. PROP 1611-161 The impact of pretransplant diabetes on posttransplant outcomes in patients withacute myeloid leukemia

6. Other business

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Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA Honolulu, HI Saturday, February 20, 2016, 12:15 – 2:15 pm

Co-Chair: Marcos de Lima, MD, University Hospitals Case Medical Center, Cleveland, OH; Telephone: 216-286-6869; E-mail: [email protected]

Co-Chair: H Jean Khoury, MD, Winship Cancer Institute of Emory University, Atlanta, GA; Telephone : 404-778-3932; E-mail : [email protected]

Co-Chair: Brenda M. Sandmaier, MD, Fred Hutchinson Cancer Research Center, Seattle, WA; Telephone: 206-667-4961; E-mail: [email protected]

Scientific Director: Daniel J. Weisdorf, MD, University of Minnesota Medical Center, Minneapolis, MN; Telephone: 612-624-3101; E-mail: [email protected]

Assistant Scientific Director: Wael Saber, MD, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0700; E-mail: [email protected]

Statistical Director: Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-8375; E-mail: [email protected]

Statistician: Hai-Lin Wang, MPH, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0647; E-mail: [email protected]

1. Introduction The CIBMTR Acute Leukemia Working Committee was called to order at 12:15 pm on Friday, February

20th, 2016, by Dr. Brenda Sandmaier. The chairs, scientific director and statisticians were presented. Attendees were asked to have their name badges scanned for attendance purposes and to maintain committee membership, and to fill out the Working Committee evaluations and voting sheets for proposals. The meeting was limited to presentation and discussion of proposals. Dr. Sandmaier briefly introduced the committee’s accomplishments for the past year and progress of ongoing studies. Each proposal presentation was limited to 5 minutes to allow for adequate time for discussion (5 minutes). The minutes of the February 2015 meeting were approved without modifications.

2. Accrual summary Due to the full agenda, the accrual summary of registration and research cases between 1995 and 2015 were not presented to the committee but were available as part of the Working Committee attachments

3. Presentations, published or submitted papers Due to the full agenda, the 2015 presentations and published papers were mentioned, but not presented. Five papers were published, one submitted, and two ASH presentations were given during the past year.

a. LK09-02 Pasquini MC, Zhang MJ, Medeiros BC, Armand P, Hu ZH, Nishihori T, Aljurf MD, Akpek G, Cahn JY, Cairo MS, Cerny J, Copelan EA, Deol A, Freytes CO, Gale RP, Ganguly S, George B, Gupta V, Hale GA, Kamble RT, Klumpp TR, Lazarus HM, Luger SM, Liesveld JL, Litzow MR, Marks DI, Martino R, Norkin M, Olsson RF, Oran B, Pawarode A, Pulsipher MA, Ramanathan M, Reshef R, Saad AA, Saber W, Savani BN, Schouten HC, Ringdén O, Tallman MS, Uy GL, Wood WA Jr, Wirk B, Pérez WS,

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Batiwalla M, Weisdorf DJ. Hematopoietic cell transplantation outcomes in monosomal karyotype myeloid malignancies. Biol blood Marrow Transplant, 2015. [Epub ahead of print]

b. LK11-01 Goyal SD, Zhang MJ, Wang HL, Akpek G, Copelan EA, Freytes C, Gale RP, Hamadani M, Inamoto Y, Kamble RT, Lazarus HM, Marks DI, Nishihori T, Olsson RF, Reshef R, Ritchie DS, Saber W, Savani BN, Seber A, Shea TC, Tallman MS, Wirk B, Bunjes DW, Devine SM, de Lima M, Weisdorf DJ, Uy GL. Allogeneic hematopoietic cell transplant for acute myeloid leukemia: no impact of pre-transplant extramedullary disease on outcome. Bone Marrow Transplantation, 2015 Aug; 50(8):1057-62.

c. LK12-01 Seftel MD, Neuberg D, Zhang MJ, Wang HL, Ballen KK, Bergeron J, Couban S, Freytes CO, Hamadani M, Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Paulson K, Saber W, Sallan SE, Soiffer R, Tallman MS, Woolfrey AE, DeAngelo DJ, Weisdorf DJ. Pediatric-inspired Therapy compared to Allografting for Philadelphia Chromosome Negative Adult ALL in First Complete Remission. American Journal of Hematology, 2015. [Epub ahead of print]

d. LK13-03 Munker R, Brazauskas R, Wang HL, de Lima M, Khoury HJ, Gale RP, Maziarz RT, Sandmaier BM, Weisdorf DJ, Saber W. Allogeneic Hematopoietic Cell Transplantation for Patients with Mixed Phenotype Acute Leukemia. Biol blood Marrow Transplant, 2015.

e. LK14-03 Ganzel C, Mathews V, Alimoghaddam K, Ghavamzadeh A, Kuk D, Devlin S, Wang HL, Zhang M-J, Weisdorf D, Douer D, Rowe JM, Estev J, Nagler A, Mohty M, Tallman MS. Autologous Transplant remains the Preferred Therapy for Relapsed APL in CR2. Bone Marrow Transplantation, 2016

f. LK12-02 Deol A, Sengsayadeth S, Ahn HW, Wang HL, Aljurf M, Antin JH, Bornhauser M, Cahn JY, Camitta B, Chen YB, Cutler CS, Gale RP, Ganguly S, Hamadani M, Inamoto Y, Jagasia M, Kamble R, Koreth J, Lazarus HM, Liesveld J, Litzow MR, Marks DI, Nishihori T, Olsson RF, Reshef R, Rowe JM, Saad AA, Sabloff M, Schouten HC, Shea TC, Soiffer RJ, Uy GL, Waller EK, Wiernik PH, Wirk B, Woolfrey AE, Bunjes D, Devine S, de Lima M, Sandmaier BM, Weisdorf DJ, Khoury HJ, Saber W. FLT3 Mutation Does Not Significantly Impact Overall Survival after Allogeneic Hematopoietic Cell Transplant for AML: A CIBMTR Analysis. Submitted.

4. Studies in progress The progress of the ongoing studies during the past year was not presented in order to provide reasonable time to the new proposals for presentation and discussion. A summary of the progress was provided as an attachment to the committee members.

a. LK13-01 Evaluating outcomes of reduced intensity conditioning allogeneic SCT in older adult lymphoblastic leukemia patients reported to the CIBMTR: impact of age on transplant outcomes (A Rosko/M de Lima/M Mohty/V Bachanova) Manuscript preparation

b. LK13-02 Prognostic significance of cytogenetic abnormalities in patients with Philadelphia - negative acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission (A Lazaryan/V Bachanova/D Weisdorf) Protocol development

c. LK14-01 Effect of post-remission consolidation chemotherapy prior to allogeneic transplantation for acute lymphocytic leukemia in first complete remission (N Bejanyan/A Lazaryan/D Weisdorf) Protocol development

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d. LK14-02 Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first and second complete remission (F Michelis/V Gupta) Manuscript preparation

e. LK15-01 AlloHCT vs. other consolidation therapies per Alliance protocols in older AML in CR1 (A Artz / C Ustun) Analysis

f. LK15-02 Impact of GVHD on outcome after allogeneic hematopoietic cell transplantation for acute lymphocytic leukemia (M Yeshurun/J Rowe/M Tallman/V Bachanova) Protocol development

g. LK15-03 Comparison of outcomes of older adolescents and young adults with Philadelphia-chromosome/BCR-ABL1-negative acute lymphoblastic leukemia receiving post-remission consolidation chemotherapy with pediatric-inspired chemotherapy on CALGB 10403 or myeloablative allogeneic hematopoietic cell transplantation (M Wieduwilt/W Stock) Protocol development

h. LK15-04 Outcome of hematopoietic stem cell transplantation using total body irradiation-based versus chemotherapy-based full intensity conditioning regimens for adults with acute lymphoblastic leukemia (P Kebriaei/I Aldoss/V Pullarkat/C Anasetti/D Marks) Protocol development

i. LK15-05 Umbilical cord blood transplants for FLT3 positive acute myeloid leukemia (C Ustun/M Eapen/ D Weisdorf) Manuscript preparation

5. Introduction to TED (Transplant Essential Data) vs. CRF (Case Report Form) level database (W Saber)

Dr. Saber presented this topic before all proposals so committee members had a brief idea of 2 different level of databases. It greatly helped the discussion of following proposals because TED level data were presented for some proposals.

6. Future/proposed studies

Drs. Sandmaier, Khoury and de Lima led this session.

a. PROP 1511-17 Evaluation of Allogeneic Stem Cell Transplantation Outcomes and Prognostic Factors in T-Cell Acute Lymphoblastic Leukemia (J Brammer /P Kebriaei /C Hosing) Dr. Brammer presented this proposal. There are 591 cases receiving first allo-HCT for T-cell ALL between 2000 and 2014. There were comments about comparing T vs. B cell ALL and concerns regarding smaller number if restricted to more homogeneous subsets.

b. PROP 1511-36 Prognostic Impact of a modified European LeukemiaNet (ELN) classification for predicting outcomes in adults with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation (A Jimenez / K Komanduri /M de Lima) Dr. Jimenez presented this proposal. There are 1781 cases receiving first allo-HCT for AML in CR1 between 2007 and 2014. There were comments about the availability of molecular markers in the proposals risk group and analysis plan for de-novo vs. secondary AML.

c. PROP 1511-64 Comparison of Outcomes between Reduced Intensity and Myeloablative Conditioning for AML and MDS Patients with Complex Cytogenetics (S Ciurea / P Kongtim /A Nagler /B Savani /M de Lima / Labopin / Champlin) Dr. Ciurea presented the proposal. There are 312 AML cases and 144 MDS cases receiving first allo-HCT with complex cytogenetics between 2000 and 2014. There were comments about comparing this proposal with BMT-CTN 09-01 published paper and concerns about the impact of different RIC regimens.

d. PROP 1511-78 DRI-guided Choice of Conditioning Intensity for Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes (N Bejanyan / E Warlick /C Brunstein /D Weisdorf)

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Dr. Bejanyan presented this proposal. There are 3876 AML cases and 2254 MDS cases receiving first allo-HCT between 2009 and 2014. There were comments about the statistical validity of this proposal since conditioning intensity was considered in the original model built for DRI.

e. PROP 1511-15 Outcomes and Prognostic Factors after Allogeneic Transplant for Relapsed or Refractory AML in Patients ≥ 60 years and Older (A Artz /C Ustun) Dr. Artz presented this proposal. There are 601 cases over 60 years receiving first allo-HCT for AML with active disease between 2004 and 2014. There were comments about the heterogeneity of patients who received different therapies before going to HCT with active disease.

f. PROP 1511-38 Evaluating Primary Refractory Acute Myeloid Leukemia; the effects of Disease Characteristics and Outcomes of Allogeneic Stem Cell Transplantation (K Adekola /J Mehta /N Majhail) Dr. Adekola presented the proposal. There are 3496 cases receiving first allo-HCT for AML with active disease between 2000 and 2014. There were comments about the overlap with the CIBMTR published paper (Duval et al., JCO 2010) and alternative chemotherapy treatment instead of transplant.

g. PROP 1505-02/1511-11 Blastic Plasmacytoid Dendritic Cell Neoplasm undergoing Allogeneic stem cell transplantation: A CIBMTR analysis (UR Deotare / FV Michelis / JH Lipton / S Ganguly) Dr. Deotare presented the proposal. There are 99 cases in TED level receiving transplant for this rare disease since 2000. There were comments about a recently published paper from EBMT with same topic.

h. PROP 1510-01/1511-130 Allogeneic Transplantation to Treat Therapy Related AML and MDS (NS Callander / L Metheny / M de Lima / AC Hall) Dr. Metheny presented this proposal. There are 956 and 911 therapy linked AML and MDS cases, respectively, receiving first allo-HCT between 2000 and 2014. There were comments about the availability of dates when original malignancy was diagnosed and post-HCT maintenance therapy.

i. PROP 1511-35/1511-50/1511-126 Reduced Intensity Conditioning (RIC) regimens for Acute Myeloid Leukemia (AML): A comparison of Busulfan (B) and Melphlan (M) based regimens from the CIBMTR database (R Nath / Z Zhou / J Cerny / Z Gul / G Ahmed / MW Khan / GC Hilderbrandt / HB Alkhateeb / MB Damlaj / MM Patnaik) Dr. Nath presented the proposal. There are 1005 Busulfan based RIC conditioning cases and 919 Melphalan based RIC conditioning cases receiving first allo-HCT for AML between 2001 and 2014. There were comments about the details of regimen including Busulfan dose and different Melphalan based regimen package since toxicity is of proposal.

j. PROP 1511-05/1511-53 Comparing Outcomes between HLA-Haploidentical and Matched Sibling Allogeneic Transplants in Patients with AML (A Rashidi/R Romee/W Saber/ M Hamadani) Dr. Rashidi presented the proposal. There are 104 cases in CRF level receiving first haplo donor allo-HCT for AML between 2007 and 2013. There were comments about the CIBMTR published paper (Ciurea et al., Blood 2014) using TED level data and concerns regarding smaller homogeneous subsets.

k. PROP 1510-13 Haplo-Identical Vs Matched Unrelated Donor Transplantation for Acute Lymphocytic Leukemia (L Metheny / M de Lima) Dr. Metheny presented the proposal. There are 38 CRF level cases and 270 TED level cases receiving first haplo donor allo-HCT for ALL between 2007 and 2013. There were comments about small population size and suggestion to exclude cases with both peripheral and cord blood graft.

Dropped proposed studies Dropped proposed studies were not discussed during the meeting.

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a. PROP 1509-03 Assessing the significance of conditioning regimen intensity (myeloablative vs. reduced intensity/non-myeloablative) in non-T-cell depleted haploidentical donor transplantation for acute Leukemias (ALL/AML/MDS) when using post-transplant cyclophosphamide. Dropped due to feasibility - low numbers

b. PROP 1511-57 Reduced Intensity Conditioning Compared with Myeloablative Conditioning Using Haploidentical Donor Transplants in Patients with Myeloid Malignancies. Dropped due to feasibility - low numbers

c. PROP 1503-01 Evaluate the outcomes of patients with AML undergoing Allogeneic Stem Cell Transplantation after receiving Non-intensive therapies for remission induction. Dropped due to feasibility- insufficient follow up

d. PROP 1511-62 Can RIC HCT control disease relapse after lower intensity pre-HCT therapy (hypomethylating agents or low dose cytarabine) for elderly AML? Dropped due to feasibility- insufficient follow up

e. PROP 1510-21 Outcomes following maintenance azacitidine therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation. Dropped due to feasibility- insufficient follow up

f. PROP 1511-19 Do hypo-methylating agents following HLA/KIR mismatched transplantation improve clinical outcome in acute myeloid leukemia? Dropped due to feasibility- insufficient follow up

g. PROP 1511-21 Impact of maintenance therapy post allogeneic hematopoietic stem cell transplant on outcomes in acute myeloid leukemia and myelodysplastic syndromes. Dropped due to feasibility- insufficient follow up

h. PROP 1511-108 Outcomes in high risk AML patients utilizing maintenance with hypomethylating agents after allogeneic stem cell transplantation. Dropped due to feasibility- insufficient follow up

i. PROP 1511-02 A study of clinical outcomes among patients receiving calcineurin inhibitors vs. calcineurin inhibitors +methotrexate for acute graft versus host disease prophylaxis following matched sibling allogeneic bone marrow transplantation for acute lymphoblastic leukemia. Dropped due to feasibility - low numbers in subgroup

j. PROP 1511-86 The clinical outcome of rare cytogenetic abnormalities on post-transplant outcomes in patients with acute myeloid leukemia in complete remission. Dropped due to feasibility

k. PROP 1511-115 Does prophylactic cranial radiation improve relapse rate in patients with acute Leukemias who have allogeneic transplantation? Dropped due to feasibility

l. PROP 1511-127 Impact of pre-transplant chemotherapeutic regimen on outcome after allogeneic hematopoietic stem cell transplant (aHSCT) in adult Ph+ ALL. Dropped due to feasibility

7. Other business

After 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, current scientific merit and the impact of the study on the field, the following studies will move forward as the committee’s research portfolio for the upcoming year: PROP 1511-78 DRI-guided Choice of Conditioning Intensity for Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes (N Bejanyan / E Warlick /C Brunstein /D Weisdorf) PROP 1510-01/1511-130 Allogeneic Transplantation to Treat Therapy Related AML and MDS (NS Callander / L Metheny / M de Lima / AC Hall)

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PROP 1511-35/1511-50/1511-126 Reduced Intensity Conditioning (RIC) regimens for Acute Myeloid Leukemia (AML): A comparison of Busulfan (B) and Melphlan (M) based regimens from the CIBMTR database (R Nath / Z Zhou / J Cerny / Z Gul / G Ahmed / MW Khan / GC Hilderbrandt / HB Alkhateeb / MB Damlaj / MM Patnaik) PROP 1511-05/1511-53 Comparing Outcomes between HLA-Haploidentical and Matched Sibling Allogeneic Transplants in Patients with AML (A Rashidi/R Romee/W Saber/ M Hamadani)

a. LK13-01: Evaluating outcomes of reduced intensity conditioning allogeneic SCT in older adult lymphoblastic leukemia patients reported to the CIBMTR and EBMT. Manuscript is in revision and we plan to submit by June 2016.

b. LK13-02: Prognostic significance of cytogenetic abnormalities in patients with Philadelphia negative

acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission. Protocol development is underway and we plan to finish analysis by June 2016 and submit paper by June 2017.

c. LK14-01: Effect of post-remission consolidation chemotherapy prior to allogeneic transplantation

for acute lymphocytic leukemia in first complete remission: A Center for International Blood and Marrow Transplant Research Study. Data file preparation is underway and we plan to finish analysis by June 2016 and publish paper by June 2017.

d. LK14-02: Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell

transplantation for acute myeloid leukemia in first and second complete remission. Manuscript is underway and we plan to submit paper by June 2016.

e. LK15-01: Comparison of Allogeneic Hematopoietic Cell Transplantation with Other Consolidation Therapies Per Alliance Protocols in Older (≥60 years) AML Patients in First Complete Remission. Protocol development is underway and we plan to submit paper by June 2016.

f. LK15-02: Impact of GVHD on outcome after allogeneic hematopoietic cell transplantation for acute lymphocytic leukemia. Protocol development is under way and we plan to move to data file preparation by June 2016 and manuscript preparation by June 2017.

g. LK15-03: Comparison of outcomes of older adolescents and young adults with Philadelphia- chromosome/BCR-ABL1-negative acute lymphoblastic leukemia receiving post-remission consolidation chemotherapy with pediatric-inspired chemotherapy on CALGB 10403 or myeloablative allogeneic hematopoietic cell transplantation. Protocol development is under way and we plan to move to data file preparation by June 2016 and manuscript preparation by June 2017.

h. LK15-04: Comparison of total body irradiation (TBI)-based with intravenous (IV) busulfan (Bu) containing chemotherapy-only myeloablative transplant conditioning regimens in adult patients with acute lymphoblastic leukemia. Data file preparation is under way and we plan to finish analysis by June 2016 and submit paper by June 2017.

Working Committee Overview Plan for 2016 - 2017

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i. LK15-05: Umbilical cord blood transplantation outcomes in FLT3 mutation positive patients with Acute

Myelogenous Leukemia. Manuscript is underway and we plan to submit paper by June 2016.

j. LK16-01: DRI-guided choice of conditioning intensity for allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia and myelodysplastic syndromes. We anticipate developing the study protocol after July 2016 and move to data file preparation and analysis by June 2017.

k. LK16-02: Allogeneic transplantation to treat therapy related acute myeloid leukemia and myelodysplastic syndromes. We anticipate developing the study protocol after July 2016 and move to data file preparation and analysis by June 2017.

l. LK16-03: Reduced intensity conditioning regimens for acute myeloid leukemia: A comparison of busulfan and melphalan based regimens from the CIBMTR database. We anticipate developing the study protocol after July 2016 and finish analysis by June 2017.

m. LK16-04: Comparing outcomes between HLA-haploidentical and matched sibling allogeneic transplants in patients with acute myeloid leukemia. We anticipate developing the study protocol after July 2016 and move to data file preparation and analysis by June 2017.

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Daniel Weisdorf LK13-02: Prognostic significance of cytogenetic abnormalities in patients with Philadelphia-negative acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission LK15-01: Comparison of Allogeneic Hematopoietic Cell Transplantation with Other Consolidation Therapies Per Alliance Protocols in Older (≥60 years) AML Patients in First Complete Remission. LK15-03: Comparison of outcomes of older adolescents and young adults with Philadelphia-chromosome/BCR-ABL1-negative acute lymphoblastic leukemia receiving post-remission consolidation chemotherapy with pediatric-inspired chemotherapy on CALGB 10403 or myeloablative allogeneic hematopoietic cell transplantation.

Wael Saber LK13-01: Evaluating outcomes of reduced intensity conditioning allogeneic

SCT in older adult lymphoblastic leukemia patients reported to the CIBMTR and EBMT LK15-04: Comparison of total body irradiation (TBI)-based with intravenous (IV) busulfan (Bu) containing chemotherapy-only myeloablative transplant conditioning regimens in adult patients with acute lymphoblastic leukemia.

Marcos de Lima LK16-03: Allogeneic transplantation to treat therapy related acute myeloid

leukemia and myelodysplastic syndromes. LK16-04: Comparing outcomes between HLA-haploidentical and matched

sibling allogeneic transplants in patients with acute myeloid leukemia. Brenda Sandmaier LK15-02: Impact of GVHD on outcome after allogeneic hematopoietic cell

transplantation for acute lymphocytic leukemia. LK16-02: DRI-guided choice of conditioning intensity for allogeneic

hematopoietic cell transplantation in adults with acute myeloid leukemia and myelodysplastic syndromes.

LK16-01: Reduced intensity conditioning regimens for acute myeloid leukemia: A comparison of busulfan and melphalan based regimens from the CIBMTR database.

H Jean Khoury LK14-01: Effect of post-remission consolidation chemotherapy prior to

allogeneic transplantation for acute lymphocytic leukemia in first complete remission. LK14-02: Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first and second complete remission.

Oversight Assignments for Working Committee Leadership (March 2016)

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Accrual Summary for the Acute Leukemia Working Committee

Characteristics of recipients of first allogeneic transplants for AML and ALL reporteda to the CIBMTR between 1995 and 2016

Variable AML ALL Number of patients 19969 10328 Number of centers 395 374 Age in decades

Median (range) 43 (<1-83) 21 (<1-75) <10 1772 (9) 2500 (24) 10-19 1995 (10) 2494 (24) 20-29 2370 (12) 1832 (18) 30-39 2783 (14) 1359 (13) 40-49 3768 (19) 1159 (11) 50-59 4231 (21) 722 (7) 60-69 2693 (13) 255 (2) >=70 357 (2) 7 (<1) Gender Male 10553 (53) 6325 (61) Female 9415 (47) 4002 (39) Missing 1 (<1) 1 (<1) HCT-CI 0 3257 (16) 1551 (15) 1 989 (5) 357 (3) 2 808 (4) 255 (2) 3+ 2367 (12) 609 (6) N/A, earlier than 2007 12447 (62) 7533 (73) Missing 101 (<1) 23 (<1) Disease status prior to HCT Primary induction failure 2617 (13) 354 (3) CR1 9491 (48) 4232 (41) CR2 4237 (21) 3538 (34) >=CR3 388 (2) 904 (9) Relapse 3174 (16) 1291 (13) Missing 62 (<1) 9 (<1) Time from diagnosis to HCT

Median (range) 6 (<1-607) 11 (<1-499) <6 months 9489 (48) 2899 (28) 6 - 12 months 4845 (24) 2379 (23) >12 months 5616 (28) 5045 (49) Missing 19 (<1) 5 (<1)

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Variable AML ALL Conditioning regimen intensity Myeloablative 14706 (74) 9391 (91) RIC 3249 (16) 454 (4) NMA 1367 (7) 243 (2) TBD 474 (2) 158 (2) Missing 173 (<1) 82 (<1) Graft type Bone marrow 6721 (34) 4827 (47) Peripheral blood 10858 (54) 3681 (36) Umbilical cord blood 2385 (12) 1817 (18) Missing 5 (<1) 3 (<1) Type of donor HLA-identical sibling 6513 (33) 2978 (29) Identical twin 83 (<1) 57 (<1) Other relative 1255 (6) 664 (6) Unrelated 9684 (48) 4790 (46) Cord blood 2385 (12) 1817 (18) Missing 49 (<1) 22 (<1) Year of HCT 1995-1996 1711 (9) 1306 (13) 1997-1998 1516 (8) 1135 (11) 1999-2000 1466 (7) 1068 (10) 2001-2002 1827 (9) 1101 (11) 2003-2004 2169 (11) 1116 (11) 2005-2006 2606 (13) 1249 (12) 2007-2008 2451 (12) 1070 (10) 2009-2010 2144 (11) 638 (6) 2011-2012 901 (5) 429 (4) 2013-2014b 2140 (11) 807 (8) 2015-currentb 1038 (5) 409 (4) Median follow-up of survivors (range), months 73 (1-250) 77 (1-247) a Patients have available comprehensive research form and consented for research b Cases continue to be reported in this interval

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Accrual Summary for Acute Leukemia Working Committee

Characteristics of recipients of first autologous transplants for AML and ALL reporteda to the CIBMTR between 1995 and 2016

Variable AML ALL Number of patients 983 156 Number of centers 178 59 Age in decades

Median (range) 44 (<1-78) 30 (1-66) <10 61 (6) 16 (10) 10-19 68 (7) 25 (16) 20-29 121 (12) 38 (24) 30-39 166 (17) 19 (12) 40-49 187 (19) 28 (18) 50-59 217 (22) 23 (15) 60-69 155 (16) 7 (4) >=70 8 (<1) 0 Gender Male 500 (51) 98 (63) Female 483 (49) 58 (37) Disease status prior to HCT Primary induction failure 10 (1) 2 (1) CR1 636 (65) 99 (63) CR2 254 (26) 44 (28) >=CR3 14 (1) 6 (4) Relapse 66 (7) 5 (3) Missing 3 (<1) 0 Time from diagnosis to HCT

Median (range) 7 (0-182) 9 (2-153) <6 months 412 (42) 22 (14) 6 - 12 months 264 (27) 73 (47) >12 months 307 (31) 61 (39) Conditioning regimen intensity Myeloablative 793 (81) 148 (95) RIC 8 (<1) 2 (1) TBD 181 (18) 6 (4) Missing 1 (<1) 0 Graft type Bone marrow 171 (17) 25 (16) Peripheral blood 809 (82) 130 (83) Missing 3 (<1) 1 (<1)

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Variable AML ALL Year of HCT 1995-1996 266 (27) 55 (35) 1997-1998 221 (22) 45 (29) 1999-2000 107 (11) 16 (10) 2001-2002 89 (9) 12 (8) 2003-2004 65 (7) 5 (3) 2005-2006 86 (9) 9 (6) 2007-2008 103 (10) 10 (6) 2009-2010 20 (2) 1 (<1) 2011-2012 6 (<1) 0 2013-2014b 14 (1) 3 (2) 2015-currentb 6 (<1) 0 Median follow-up of survivors (range), months 98 (1-247) 145 (2-241) a Patients have available comprehensive research form and consented for research b Cases continue to be reported in this interval

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TO: Acute Leukemia Working Committee Members FROM: Daniel J. Weisdorf, MD; Scientific Director and Wael Saber, MD, MS; Assistant Scientific

Director for the Acute Leukemia Working Committee RE: Studies in Progress Summary LK13-02: Prognostic significance of cytogenetic abnormalities in patients with Philadelphia-negative ALL undergoing allogeneic Hematopoietic Stem Cell Transplantation in complete remission (A Lazaryan/ V Bachanova) The purpose of this study is: (1) To develop allo-HCT specific cytogenetic classification of Ph-negative ALL for prognostication of relapse and survival outcomes following allo-HCT. (2) To validate within the CIBMTR database the prognostic significance of existing cytogenetic classifications of Ph-negative ALL in the context of the allo-HCT. (3) To compare the performance of both CIBMTR-based and existing classifications of Ph-negative ALL treated with allo-HCT. Analysis is underway. LK14-01: Effect of post-remission consolidation chemotherapy prior to allogeneic transplantation for acute lymphocytic leukemia in first complete remission (N Bejanyan/ A Lazaryan/ D Weisdorf) The purpose of this study is: (1) To study relapse, TRM and survival outcomes of ALL patients in CR1 receiving 0 vs. 1 vs. ≥2 post-remission consolidation cycles prior to allo-HCT. (2) To study relapse, TRM and survival outcomes in subgroup of ALL patients with MRD positivity who receive 0 vs. 1 vs. ≥2 post-remission consolidation cycles prior to allo-HCT. Manuscript preparation is underway. LK15-01: Comparison of Allogeneic Hematopoietic Cell Transplantation (AlloHCT) with Other Consolidation Therapies Per Alliance and SWOG Protocols in Older (≥60 years) AML Patients in First Complete Remission (CR1) (A Artz / C Ustun) The purpose of this study is: (1) To compare DFS and TRM between alloHCT and non-alloHCT consolidations. (2) To find the frequency of acute and chronic graft-versus-host disease (GVHD) in the alloHCT cohort (3) To identify patient or disease characteristics (age, cytogenetic risk group, etc.) which preferentially benefit patients receiving alloHCT vs. non-alloHCT consolidation therapy. Data file preparation is underway. LK15-02: Impact of GVHD on outcome after allogeneic hematopoietic cell transplantation for acute lymphocytic leukemia (M Yeshurun/ J Rowe/ M Tallman/ V Bachanova) The purpose of this study is: (1) Identify any differential GVHD-associated GVL influences after alloHCT for ALL, using either myeloablative or reduced intensity conditioning regimens. (2) Study the impact of acute and chronic GVHD and its extent on relapse, NRM, DFS and OS rates after alloHCT for ALL. Analysis is underway.

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LK15-03: Comparison of outcomes of older adolescents and young adults with Philadelphia-chromosome/BCR-ABL1-negative acute lymphoblastic leukemia receiving post-remission consolidation chemotherapy with pediatric-inspired chemotherapy on CALGB 10403 or myeloablative allogeneic hematopoietic cell transplantation (M Wieduwilt/ W Stock) The purpose of this study is: (1) To compare overall survival, relapse-free survival, relapse, and non-relapse mortality between older adolescent and young adults aged 16-39 years with Ph/BCR-ABL1-negative acute lymphoblastic leukemia in first complete remission receiving consolidation therapy with pediatric-inspired chemotherapy on CALGB 10403 to myeloablative allogeneic hematopoietic cell transplantation. (2) To compare outcomes of CALGB 10403 to allogeneic HCT using fully matched related or unrelated donors in patients who attained CR1 in <8 weeks. (3) To compare outcomes of obese and non-obese ALL patients between cohorts (4) To compare CNS relapse rates in the two cohorts. (5) To determine patient and disease factors influencing outcomes of consolidation with pediatric-inspired chemotherapy versus allogeneic hematopoietic cell transplantation. Data file preparation is underway. LK15-04: Outcome of hematopoietic stem cell transplantation using total body irradiation-based versus chemotherapy-based full intensity conditioning regimens for adults with acute lymphoblastic leukemia (P Kebriaei/ I Aldoss/ V Pullarkat/ C Anasetti/ D Marks) The purpose of this study is: (1) To compare HCT outcomes [overall survival (OS), leukemia-free survival (LFS), relapse rate (RR) and non-relapse mortality (NRM)] between TBI- and non-TBI-, IV Bu-based myeloablative conditioning regimens in adults with ALL undergoing allogeneic HCT. (2) To evaluate the influence of the conditioning regimen (TBI versus IV Bu) on post HCT outcomes among ALL risk subgroups (standard versus high) classified based on age, initial WBC and cytogenetics at diagnosis in adults with ALL undergoing allogeneic HCT. This aim will also address the effect of remission status (CR1 versus CR2) on the outcomes after TBI based versus Bu-based conditioning. (3) To evaluate the impact on extramedullary relapse patterns, specifically central nervous system relapse, with the two different conditioning approaches. (4) To evaluate the regimen related toxicity profile, and to compare graft versus host disease, of the two different conditioning approaches. Manuscript preparation is underway. LK16-01: Reduced Intensity Conditioning (RIC) regimens for Acute Myeloid Leukemia (AML): A comparison of Busulfan (B) and Melphlan (M) based regimens from the CIBMTR database (Zartash Gul/ Gulrayz Ahmed/ Muhammed Khan/ Gerhard Hilderbrandt/ Hassan Alkhateeb/ Moussab Damlaj/ Miranal Patnaik/ Rajneesh Nath/ Zheng Zhou/ Jan Cerny). The purpose of this study is: (1) To compare the treatment related toxicity of M based and B based RIC regimens in terms of non-relapse mortality and incidence and severity of acute and chronic GVHD. (2) To compare hematologic recovery, engraftment kinetics, incidence of relapse, progression free survival and overall survival between the two regimens. Protocol development is underway.

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LK16-02: DRI-guided Choice of Conditioning Intensity for Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes (Nelli Bejanyan/ Erica Warlick/ Claudio Brunstein/ Daniel Weisdorf). The purpose of this study is: (1) To study the effect of conditioning intensity on overall survival (OS) of adult allograft recipients with AML and MDS based on DRI assignment. (2) To study neutrophil recovery, platelet recovery, acute and chronic GVHD, treatment-related mortality (TRM), malignancy relapse and leukemia-free survival (LFS). Protocol development is underway. LK16-03: Allogeneic transplantation to treat therapy related acute myeloid leukemia and myelodysplastic syndromes (Natalie Callander/ Leland Metheny/ Marcos De Lima / Aric Hall). The purpose of this study is: (1) To evaluate overall survival of adult allogeneic HCT patients with therapy related AML and MDS (t-AML and t-MDS). (2) To assess day-30 mortality, day-100 mortality, leukemia-free-survival (LFS), treatment- related mortality (TRM), non-relapse mortality (NRM), relapse rate (REL), acute and chronic GVHD (3) To evaluate overall survival of adult allogeneic HCT patients with t-AML/ t-MDS secondary to autologous transplant. (4) To assess the effect of preparative regimen intensity on outcomes. (5) To identify patient, disease and transplant related prognostic factors for outcome after allogeneic hematopoietic stem cell transplantation. Protocol development is underway. LK16-04: Comparing outcomes between HLA-haploidentical and matched sibling allogeneic transplants in patients with acute myeloid leukemia (Rizwan Romee/ Armin Rashidi/ Mehdi Hamadani/ Wael Saber). The purpose of this study is: (1) To compare post-transplantation outcomes in patients with AML undergoing T-replete matched sibling allo-HCT versus T-replete haploidentical related donor allo-HCT (with PT-CY) including: neutrophil and platelet recovery, acute and chronic GVHD, non-relapse mortality, relapse, Leukemia-free survival and overall survival. Protocol development is underway. LK17-01: Outcomes of acute myeloid leukemia patients who undergo allogeneic transplant stratified by depth of clinical response (Mary-Elizabeth Percival / Brenda Sandmaier / Eli Estey). The purpose of this study is: (1) To compare overall survival in AML patients undergoing HCT in CR1 who have CR vs. a response less than complete remission. (2) To evaluate event-free survival and treatment-related mortality in AML patients undergoing HCT in CR1 who have CR vs. a response less than complete remission. Draft protocol has been received.

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PROP 1510-21/PROP 1611-08/PROP 1611-70 Title: Impact of Maintenance Therapy after Allogeneic Hematopoietic Cell Transplant (HCT) on Outcomes in Acute Myeloid Leukemia (AML) Masumi Ueda, Fred Hutchinson Cancer Research Center, [email protected] Tania Jain, Mayo Clinic Cancer Center, Phoenix, [email protected] Jeanne Palmer, Mayo Clinic Cancer Center, Phoenix, [email protected] Lisa Sproat, Mayo Clinic Cancer Center, Phoenix, [email protected] Amer Assal, Columbia University Medical Center, [email protected] Sergio Giralt, Memorial Sloan Kettering Cancer Center, [email protected] Marcos de Lima, Seidman Cancer Center/Case Western Reserve University, [email protected] Hypothesis: Maintenance therapy after allogeneic HCT reduces relapse and improves survival in AML

Specific aims: Compare relapse rate, disease-free survival, and overall survival in patients who received maintenance therapy vs. control cohort who did not receive any maintenance therapy Secondary Aims:

• Compare rates of acute and chronic GVHD in patients receiving maintenance therapy vs. control cohort

• Identify factors associated with receipt of maintenance therapy after transplant Scientific justification: Disease relapse after allogeneic HCT for AML is the most common cause of treatment failure and is associated with poor outcomes. Interventions aimed at preventing disease relapse may be more successful than treatment of overt disease relapse. Several interventions to prevent AML relapse after HCT have been explored, including use of hypomethylating agents (1-7), FLT3 receptor tyrosine kinase inhibitors (TKIs) (8-10), histone deacetylase inhibitors (11) and donor cellular infusions (12-16). Hypomethylating agents are particularly interesting for its potential to enhance graft-versus leukemia effects and modulate graft-versus-host response (17-19). Small prospective studies have been performed to study the safety and efficacy of various FLT3 inhibitors and hypomethylating agents as a maintenance strategy; however many questions remain including identification of patients most likely to benefit, the ideal agent for use, duration, toxicities, and impact on immune reconstitution and graft-versus-host disease (GVHD) (20). Use of international registry data would allow for investigation of the benefit of maintenance strategies in a larger group of patients with longer follow-up and may provide evidence for further support of this approach in future larger prospective studies. We propose a retrospective cohort study with matched control to investigate the benefit of various maintenance therapies after allogeneic HCT in reducing relapse and improving survival. We also aim to characterize practice patterns and factors associated with initiation of maintenance therapy post-transplant.

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Patient eligibility criteria: Inclusion Criteria

• First allogeneic HCT for AML • Age ≥18 years • Year of HCT: 2013 through 2016

Exclusion Criteria • Death or relapse before Day 60 after HCT • Grade III or IV acute GVHD at or before Day 60 after HCT

Data requirements: Patient factors

• Age at transplant • Sex • Race • HCT-CI, Karnofsky performance status

Disease-related factors • Cytogenetics risk group • Molecular markers (FLT3 ITD/TKD, NPM1, CEBPA, c-KIT, etc) • De novo vs. secondary vs. therapy-related AML • Disease status prior to HCT (CR1, CR2, refractory) • Marrow blasts at diagnosis and transplant • Blood blasts at diagnosis and transplant • Measureable-residual disease at HCT (by flow and cytogenetics/molecular) • Extramedullary disease at diagnosis and transplant • Therapy prior to transplant and number of cycles

Transplant-related factors • Year of transplant • Time from diagnosis to transplant • Preparative regimen and intensity • Graft type (marrow, mobilized blood, cord) • Donor type (matched sibling, matched unrelated, partially-matched unrelated, cord, non-sibling

relative) • Donor/recipient sex match • CMV donor/recipient status • GVHD prophylaxis • ATG • Cell infusion dose

Post-HCT data • Type of maintenance therapy • Maintenance therapy Y or N at 3months, 6 months, and 1 year • Time to relapse • Nature of relapse (Marrow, extramedullary, CNS, MRD only) • Acute GVHD (time to diagnosis, grade) • Chronic GHVD (time to diagnosis, severity) • Infectious complications (CMV, EBV reactivation/disease, fungal infection) • Cause of death

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Study design: This retrospective cohort study will compare outcomes in AML patients who receive post-transplant maintenance therapy to a control cohort not receiving any maintenance therapy. The primary outcome will be disease relapse and death and secondary outcomes will be acute and chronic GVHD. Risk ratio and odds ratio will be determined to calculate relative risk of the primary and secondary endpoints. Disease free survival will be measured from the date of HCT to the date of death or relapse, whichever occurs first and censored at the date of last contact. Chi-squared or Fisher exact test will be used to determine association between categorical variables and outcomes. Variables associated with primary and secondary outcomes will be examined using multivariate analysis. Subgroup analysis according to category of maintenance therapy (hypomethylating agents, TKIs, donor cellular infusion) will be performed. Survival distribution will be estimated using Kaplan-Meier methods and difference between groups will be analyzed using log rank. The effect of various factors on time-to-event outcomes such as time from HCT to disease relapse, development of acute and chronic GHVD, and death will be analyzed by Cox model with time-dependent covariates after adjusting for the effects of other confounders. Control group: Assuming limitations of data available on post-HCT time to initiation of azacitidine, we will estimate that only subjects surviving 60 days from HCT, without evidence of relapse and without severe, grade III/IV acute GVHD would have been considered for maintenance therapies. We would also assume that most patients receiving maintenance start treatment within the first 50-100 days, and would only accrue controls that would be granted 2 months of survival after transplant. This will mitigate the survival bias in those who are well enough to receive maintenance therapies. References: 1. Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood. 2012;119(14):3361-9. 2. de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer. 2010;116(23):5420-31. 3. Antar A, Kharfan-Dabaja MA, Abou Ghaddara H, Mahfouz R, Bazarbachi A. Azacitidine Maintenance after Allogeneic Stem Cell Transplantation Is Feasible in Patients with Acute Myeloid Leukemia and Myelodysplasia. Blood. 2014;124(21):5884-. 4. Craddock C, Jilani N, Siddique S, Yap C, Khan J, Nagra S, et al. Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial. Biol Blood Marrow Transplant. 2016;22(2):385-90. 5. Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia. 2012;26(3):381-9. 6. Pusic I, Choi J, Fiala MA, Gao F, Holt M, Cashen AF, et al. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 2015;21(10):1761-9. 7. Oshikawa G, Kakihana K, Saito M, Aoki J, Najima Y, Kobayashi T, et al. Post-transplant maintenance therapy with azacitidine and gemtuzumab ozogamicin for high-risk acute myeloid leukaemia. Br J Haematol. 2015;169(5):756-9.

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8. Chen YB, Li S, Lane AA, Connolly C, Del Rio C, Valles B, et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20(12):2042-8. 9. Sandmaier BM, Khaled SK, Oran B, Gammon G, Trone D, Frankfurt O. Results of a Phase 1 Study of Quizartinib (AC220) As Maintenance Therapy in Subjects with Acute Myeloid Leukemia in Remission Following Allogeneic Hematopoietic Cell Transplantation. Blood. 2014;124(21):428-. 10. Brunner AM, Li S, Fathi AT, Wadleigh M, Ho VT, Collier K, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. 2016;175(3):496-504. 11. Bug G, Burchert A, Nicolaus K, Huenecke S, Duenzinger U, Wolf A, et al. Post-Transplant Maintenance With The Deacetylase Inhibitor Panobinostat In Patients With High-Risk AML Or MDS: Results Of The Phase I Part Of The Panobest Trial. Blood. 2013;122(21):3315-. 12. de Lima M, Bonamino M, Vasconcelos Z, Colares M, Diamond H, Zalcberg I, et al. Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease. Bone marrow transplantation. 2001;27(1):73-8. 13. Dey BR, McAfee S, Colby C, Sackstein R, Saidman S, Tarbell N, et al. Impact of prophylactic donor leukocyte infusions on mixed chimerism, graft-versus-host disease, and antitumor response in patients with advanced hematologic malignancies treated with nonmyeloablative conditioning and allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2003;9(5):320-9. 14. Kumar AJ, Hexner EO, Frey NV, Luger SM, Loren AW, Reshef R, et al. Pilot study of prophylactic ex vivo costimulated donor leukocyte infusion after reduced-intensity conditioned allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19(7):1094-101. 15. Huang XJ, Wang Y, Liu DH, Xu LP, Chen H, Chen YH, et al. Modified donor lymphocyte infusion (DLI) for the prophylaxis of leukemia relapse after hematopoietic stem cell transplantation in patients with advanced leukemia--feasibility and safety study. Journal of clinical immunology. 2008;28(4):390-7. 16. Schmid C, Labopin M, Veelken H, Schaap NPM, Schleuning M, Stadler M, et al. Efficacy, Safety and Long Term Results of Prophylactic and Preemptive Donor Lymphocyte Infusion after Allogeneic Stem Cell Transplantation for Acute Leukemia: A Registry-Based Evaluation on 343 Patients By the Acute Leukemia Working Party of EBMT. Blood. 2015;126(23):863-. 17. Choi J, Ritchey J, Prior JL, Holt M, Shannon WD, Deych E, et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood. 2010;116(1):129-39. 18. Schroeder MA, Choi J, Cooper ML, Schwab D, Willey S, Liu J, et al. A Phase I/II Trial of Intravenous Azacitidine for Acute Gvhd Prophylaxis in Patients Undergoing Matched Unrelated Stem Cell Transplantation: Phase I Results. Blood. 2015;126(23):1935-. 19. Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, Karbach J, Pfeifer D, Jager E, et al. The DNA demethylating agent 5-aza-2'-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk Res. 2010;34(7):899-905. 20. DeFilipp Z, Chen YB. Strategies and Challenges for Pharmacological Maintenance Therapies after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2016;22(12):2134-40.

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Baseline characteristics for adult patients undergoing first allo-HCT for AML between 2013-2016 with post-HCT maintenance information available

Post-HCT maintenance Variable No Yes Number of patients 2664 410 Number of centers 162 88 Patient age 18-29 245 (9) 48 (12) 30-39 281 (11) 38 (9) 40-49 408 (15) 59 (14) 50-59 674 (25) 111 (27) 60-69 860 (32) 133 (32) >=70 196 (7) 21 (5) Median (range) 56 (18-82) 56 (18-82) Gender Male 1399 (53) 242 (59) Female 1265 (47) 168 (41) Karnofsky score <90% 1045 (39) 183 (45) >=90% 1587 (60) 222 (54) Missing 32 (1) 5 (1) HCT-CI 0 675 (25) 107 (26) 1 391 (15) 67 (16) 2 369 (14) 55 (13) 3+ 1214 (46) 181 (44) Missing 15 (<1) 0 White blood count at diagnosis <= 30 1806 (68) 229 (56) 30 - 100 408 (15) 77 (19) > 100 199 (7) 53 (13) Missing 251 (9) 51 (12) Median (range) 7 (<1-1900) 15 (<1-408) Extramedullary disease at diagnosis No 2415 (91) 345 (84) Yes 85 (3) 28 (7) Missing 164 (6) 37 (9) Type of AML De-novo 2008 (75) 336 (82) Transformed from MDS/MPS 476 (18) 55 (13) Therapy linked 180 (7) 19 (5) Disease status prior to HCT Primary induction failure 329 (12) 58 (14) CR1 1633 (61) 248 (60) CR2 487 (18) 50 (12) >=CR3 25 (<1) 7 (2) Relapse 189 (7) 47 (11)

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Post-HCT maintenance Variable No Yes Missing 1 (<1) 0 Cytogenetic score Favorable 161 (6) 26 (6) Intermediate 1539 (58) 222 (54) Poor 653 (25) 113 (28) TBD 223 (8) 33 (8) NT 37 (1) 7 (2) Missing 51 (2) 9 (2) Conditioning regimen intensity Myeloablative 1304 (49) 220 (54) RIC 933 (35) 128 (31) NMA 351 (13) 43 (10) TBD 66 (2) 18 (4) Missing 10 (<1) 1 (<1) Donor type HLA-identical sibling 610 (23) 92 (22) Other relatives 446 (17) 63 (15) Well-matched unrelated 968 (36) 182 (44) Partially-matched unrelated 198 (7) 29 (7) Mis-matched unrelated 7 (<1) 0 Multi-donor 1 (<1) 0 Unrelated (matching unknown) 39 (1) 2 (<1) Cord blood 395 (15) 42 (10) Donor/recipient CMV serostatus +/+ 815 (31) 112 (27) +/- 232 (9) 38 (9) -/+ 692 (26) 119 (29) -/- 442 (17) 90 (22) CB/+ 285 (11) 34 (8) CB/- 106 (4) 8 (2) Missing 92 (3) 9 (2) Donor/recipient sex match M-M 799 (30) 153 (37) M-F 626 (23) 88 (21) F-M 405 (15) 68 (17) F-F 418 (16) 59 (14) CB-M 179 (7) 21 (5) CB-F 216 (8) 21 (5) Missing 21 (<1) 0 Graft type Bone marrow 342 (13) 52 (13) Peripheral blood 1926 (72) 315 (77) Umbilical cord blood 395 (15) 42 (10) PB + OTH (new: 2+90) 1 (<1) 1 (<1) GVHD prophylaxis No GVHD prophylaxis 34 (1) 7 (2)

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Post-HCT maintenance Variable No Yes Ex-vivo T-cell depletion 27 (1) 1 (<1) CD34 selection 64 (2) 23 (6) Post-CY + other(s) 292 (11) 49 (12) TAC + MMF +- other(s) (except post-CY) 458 (17) 55 (13) TAC + MTX +- other(s) (except MMF, post-CY) 1062 (40) 184 (45) TAC + other(s) (except MMF, MTX, post-CY) 142 (5) 16 (4) TAC alone 52 (2) 18 (4) CSA + MMF +- other(s) (except post-CY) 287 (11) 35 (9) CSA + MTX +- other(s) (except MMF, post-CY) 184 (7) 13 (3) CSA + other(s) (except MMF, MTX, post-CY) 9 (<1) 1 (<1) CSA alone 18 (<1) 2 (<1) Other(s) 33 (1) 6 (1) Missing 2 (<1) 0 ATG/Campath ATG + CAMPATH 1 (<1) 0 ATG alone 592 (22) 129 (31) CAMPATH alone 47 (2) 18 (4) No ATG or CAMPATH 2022 (76) 262 (64) Missing 2 (<1) 1 (<1) Year of HCT 2013 736 (28) 110 (27) 2014 905 (34) 139 (34) 2015 785 (29) 140 (34) 2016 238 (9) 21 (5) Median follow-up of survivors (range), months 13 (2-43) 14 (3-43)

Post-HCT maintenance therapy (n=410) Frequency Intrathecal 16 Intrathecal + Other 1 Other 19 Cytarabine 9 Cytarabine + Intrathecal 3 Cytarabine + Decitabine + Idarubicin + Intrathecal 1 Cytarabine + Idarubicin 2 Cytarabine + VP16 + Mitoxantrone 1 Clofarabine 1 Clofarabine + Cytarabine 3 Clofarabine + Cytarabine + Sorafenib 1 Decitabine 16 Decitabine + Intrathecal 1 Decitabine + Other 2 Decitabine + VP16 1 VP16 + Mitoxantrone 1 Sorafenib 75 Sorafenib + Other 5

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Post-HCT maintenance therapy (n=410) Frequency ATRA 1 ATRA + Arsenic + Gemtuzumab 1 Azacytidine 132 Azacytidine + Intrathecal 1 Azacytidine + Intrathecal + Other 1 Azacytidine + Other 1 Azacytidine + Cytarabine 1 Azacytidine + Cytarabine + Sorafenib 1 Azacytidine + Decitabine 5 Azacytidine + Idarubicin 1 Azacytidine + Sorafenib 16 Missing 91

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Proposal 1611-33 Title: Fludarabine/busulfan versus fludarabine/melphalan conditioning in patients with acute lymphoblastic leukemia Yasuyuki Arai, National Institutes of Health, [email protected] Hypothesis: Among reduced intensity conditioning (RIC) regimens, fludarabine/busulfan (Flu/Bu) regimen will show better prognosis compared to fludarabine/melphalan (Flu/Mel) regimen in adult patients undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia (ALL). Scientific impact: The RIC regimen which can suppress post-transplant relapse without increasing therapy-related mortality is awaited in patients with ALL especially with older age or various comorbidities. To decide which of the two major RIC regimens is superior will be beneficial to improve the overall survival in these patients. Specific aims: To compare the overall survival, relapse, and non-relapse mortality between the two widely used RIC regimens (Flu/Bu vs. Flu/Mel) in patients with ALL. Scientific justification: Flu/Bu and Flu/Mel are the two widely used RIC regimens in allogeneic hematopoietic stem cell transplantation. The first large scale comparison between these two regimens goes back to 2007, when Shimoni A, et al. showed that Flu/Mel is related to higher non-relapse mortality and lower incidence of relapse [1]. The recent study showed the same profile and no significant difference in overall survival [2]. These studies, however, mainly dealt with patients with acute myeloid leukemia, and analysis of ALL patients is not yet to be performed. As the number of allogeneic transplantation for ALL increases, more patients with older age or various comorbidities are undergoing transplantation; thus, the selection of safer and more effective RIC regimen is all the more important, and the evidence comparing these two major RIC regimens (Flu/Bu vs. Flu/Mel) is awaited. This newly proposed study will focus on this comparison using the large database from CIBMTR, and it can propose important clues to establish the best RIC regimen for patients with ALL. Patient eligibility population: Adult patients (18 years or older at transplantation) who underwent first reduced-intensity allogeneic stem cell transplantation (including Flu/Bu or Flu/Mel) for ALL from any donor source in the year 2000 or after.

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Data requirements: The following data is necessary from each data collection form: Recipient Baseline Data (2000; Rev 1.0) Recipient Demographics (#5Gender, #8Date of Birth), Primary Disease for HSCT (#9primary disease, ALL subtype), Clinical Status of Recipient Prior to the Preparative Regimen (#20ABO, #21KS, #61coexisting disease), Pre-HSCT Preparative Regimen (#184-371), and HSCT history (#372) Acute Lymphocytic Leukemia Pre-HSCT Data (2011; Rev 1.0) All recipient data HSCT Infusion (2006; Rev 1.0) HSCT type, Product type, Pre-Collection Therapy (#1), and Product Processing/Manipulation (#44-91) Confirmation of HLA Typing (2005; Rev 2.0) Tested person (#1), and HLA Typing by DNA Technology (#5-9) 100 Days Post-HSCT Data (2100; Rev 2.0) Vital Status (#1Date, #5Subsequent HSCT), Acute GVHD (#198-227therapy, #228-346GVHD report), and Subsequent HSCT (#566) Acute Lymphoblastic Leukemia Post-HSCT Data (2111; Rev 1.0) All data included Six Months to Two Years Post-HSCT Data (2200; Rev 2.0) Vital Status (#1Date, #2Subsequent HSCT), Acute GVHD (#169-216GVHD report), Chronic GVHD (#217-288GVHD report), and Subsequent HSCT (#507) Yearly Follow-Up for Greater Than Two Years Post-HSCT Data (2300; Rev 2.0) Vital Status (#2Date, #3Subsequent HSCT), Acute GVHD (#11-58GVHD report), Chronic GVHD (#59-130GVHD report), and Subsequent HSCT (#216) Selective Post-Transplant Essential Data (2455; Rev 2.0) Survival (#44-56) Recipient Death Data (2900; Rev 1.0) #1-4 Study design: Flu/Bu will be compared with Flu/Mel regimen in terms of prognosis (overall survival and therapy-related mortality) and the incidence of relapse, graft-versus-host disease, and other complications. Overall survival will be calculated with the Kaplan-Meier method and compared using log-rank tests for each covariant related to pre-transplant patient characteristics. Multivariate analysis will be performed with the Cox proportional hazards model. Therapy-related mortality will be analyzed considering relapse as a competing risk. The Fine-Gray proportional hazards model will be used in multivariate analyses. Each comparison will also be evaluated in the subgroup analyses; thus, the appropriate RIC regimen will be suggested in each subgroup of patient.

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References: 1. Shimoni A, Hardan I, Shem-Tov N, et al. Comparison between two fludarabine-based reduced- intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan. Leukemia. 2007;21:2109-16. 2. Baron F, Labopin M, Peniket A, et al. Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer. 2015;121:1048-55.

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Baseline characteristics for adult patient undergoing first allo-HCT for ALL

with reduced intensity conditioning between 2000-2015 Variable Flu+Bu Flu+Mel Other Number of patients 124 201 52 Number of centers 52 57 30 Patient age 18-29 21 (17) 26 (13) 11 (21) 30-39 8 (6) 25 (12) 4 (8) 40-49 16 (13) 41 (20) 8 (15) 50-59 38 (31) 50 (25) 12 (23) 60-69 41 (33) 57 (28) 17 (33) >=70 0 2 (<1) 0 Median (range) 57 (19-70) 53 (19-72) 51 (19-68) Gender Male 67 (54) 111 (55) 29 (56) Female 57 (46) 90 (45) 23 (44) Karnofsky score <90% 63 (51) 83 (41) 21 (40) >=90% 61 (49) 113 (56) 30 (58) Missing 0 5 (2) 1 (2) HCT-CI 0 19 (15) 37 (18) 14 (27) 1 9 (7) 23 (11) 7 (13) 2 8 (6) 21 (10) 1 (2) 3+ 34 (27) 45 (22) 9 (17) N/A, earlier than 2007 53 (43) 74 (37) 21 (40) Missing 1 (<1) 1 (<1) 0 Ph+ No 67 (54) 114 (57) 34 (65) Yes 51 (41) 79 (39) 17 (33) Missing 6 (5) 8 (4) 1 (2) FAB classification T-cell 9 (7) 26 (13) 10 (19) B-cell 106 (85) 165 (82) 41 (79) Unspecified 9 (7) 10 (5) 1 (2) WBC at dx by lineage T,<=100 7 (6) 16 (8) 8 (15) T,>100 0 2 (<1) 1 (2) T, missing 2 (2) 8 (4) 1 (2) B,<=30 73 (59) 92 (46) 25 (48) B,>30 29 (23) 44 (22) 10 (19) B, missing 4 (3) 29 (14) 6 (12) Missing lineage,<=30 7 (6) 7 (3) 0 Missing lineage,30-100 0 0 1 (2) Missing 2 (2) 3 (1) 0 Median (range) 11 (<1-685) 11 (<1-248) 11 (<1-310)

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Variable Flu+Bu Flu+Mel Other Disease status prior to HCT Primary induction failure 5 (4) 11 (5) 2 (4) CR1 82 (66) 113 (56) 29 (56) CR2 23 (19) 46 (23) 15 (29) >=CR3 4 (3) 13 (6) 4 (8) Relapse 10 (8) 18 (9) 2 (4) Cytogenetic score Normal 25 (20) 47 (23) 13 (25) Poor 58 (47) 93 (46) 19 (37) Other 7 (6) 8 (4) 6 (12) TBD 19 (15) 32 (16) 7 (13) NT 4 (3) 7 (3) 1 (2) Missing 11 (9) 14 (7) 6 (12) Donor type HLA-identical sibling 33 (27) 47 (23) 17 (33) Other relatives 11 (9) 13 (6) 3 (6) Well-matched unrelated 59 (48) 84 (42) 13 (25) Partially-matched unrelated 17 (14) 17 (8) 6 (12) Mis-matched unrelated 0 2 (<1) 4 (8) Unrelated (matching unknown) 2 (2) 2 (<1) 1 (2) Cord blood 2 (2) 36 (18) 8 (15) Donor/recipient CMV serostatus +/+ 42 (34) 61 (30) 12 (23) +/- 15 (12) 19 (9) 6 (12) -/+ 24 (19) 48 (24) 15 (29) -/- 34 (27) 28 (14) 8 (15) CB/+ 2 (2) 28 (14) 6 (12) CB/- 0 8 (4) 2 (4) Missing 7 (6) 9 (4) 3 (6) Donor/recipient sex match M-M 47 (38) 71 (35) 11 (21) M-F 34 (27) 44 (22) 11 (21) F-M 19 (15) 22 (11) 10 (19) F-F 20 (16) 28 (14) 10 (19) CB-M 0 18 (9) 7 (13) CB-F 2 (2) 18 (9) 1 (2) Missing 2 (2) 0 2 (4) Graft type Bone marrow 12 (10) 33 (16) 12 (23) Peripheral blood 110 (89) 132 (66) 32 (62) Umbilical cord blood 2 (2) 36 (18) 8 (15) GVHD prophylaxis No GVHD prophylaxis 4 (3) 9 (4) 0 Ex-vivo T-cell depletion 0 6 (3) 1 (2) CD34 selection 1 (<1) 13 (6) 1 (2) Post-CY + other(s) 3 (2) 10 (5) 1 (2) TAC + MMF +- other(s) (except post-CY) 17 (14) 35 (17) 8 (15)

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Variable Flu+Bu Flu+Mel Other TAC + MTX +- other(s) (except MMF, post-CY) 34 (27) 52 (26) 14 (27) TAC + other(s) (except MMF, MTX, post-CY) 3 (2) 24 (12) 3 (6) TAC alone 4 (3) 14 (7) 5 (10) CSA + MMF +- other(s) (except post-CY) 19 (15) 14 (7) 9 (17) CSA + MTX +- other(s) (except MMF, post-CY) 19 (15) 15 (7) 10 (19) CSA + other(s) (except MMF, MTX, post-CY) 2 (2) 3 (1) 0 CSA alone 16 (13) 4 (2) 0 Other(s) 2 (2) 2 (<1) 0 ATG/Campath ATG alone 62 (50) 71 (35) 8 (15) CAMPATH alone 1 (<1) 12 (6) 2 (4) No ATG or CAMPATH 61 (49) 117 (58) 42 (81) Missing 0 1 (<1) 0 Year of HCT 2000-2005 37 (30) 39 (19) 20 (38) 2006-2010 30 (24) 67 (33) 12 (23) 2011-2015 57 (46) 95 (47) 20 (38) Median follow-up of survivors (range), months 24 (3-191) 34 (3-145) 60 (6-170)

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Proposal 1611-49

Title: Hypomethylating Agents prior to Allogeneic Hematopoietic Cell Transplant in AML: A Retrospective Matched Cohort Analysis of Disease Free Survival and Overall Survival Zachary D. Crees, MD, Washington University in Saint Louis, School of Medicine, Department of Medicine, [email protected] Geoffrey L. Uy, MD, Washington University in Saint Louis, School of Medicine, Department of Medicine, Division of Oncology, [email protected] John F. DiPersio, MD, PhD, Washington University in Saint Louis, School of Medicine, Department of Medicine, Division of Oncology, [email protected] Hypothesis: Hypomethylating agents (HMAs), such as decitabine and azacitidine, are commonly used for older adults with AML1,2,3,4,5. HMAs are relatively well-tolerated and demonstrate promising disease activity2,3,4. The effectiveness of HMAs as induction chemotherapy prior to allogeneic hematopoietic cell transplant (allo-HCT) is not known. Recently, data from Welch et al suggest that HMAs are associated with high rates of anti-tumor response in AML harboring mutations in TP53 (NEJM, in press)6. However, it is not known whether these improved response rates prior to allo-HCT translate into improved long-term outcomes. We hypothesize that HMAs prior to allo-HCT may be associated with similar post-transplant disease free survival (DFS) and overall survival (OS) compared to traditional anthracycline/cytarabine (AC) based induction regimens. Additionally, we hypothesize that specific AML subsets, such as complex/high risk cytogenetics and monosomal karyotypes (MKs), may be associated with improved outcomes post-transplant following induction with HMAs compared to traditional AC based induction regimens. Scientific impact: Allo-HCT can achieve rates of 40-60% long-term DFS and improved OS in patients with AML7. However, patient disease status at the time of transplant and the disease cytogenetic/molecular profile are both significant predictors of risk of recurrence, long-term DFS and OS7. Patients with advanced disease, complex/high risk cytogenetics and MKs often do not achieve a complete remission (CR) prior to allo-HCT, with high rates of relapse post-allo-HCT7,8,9. Still others cannot tolerate myeloablative (MA) conditioning regimens due to poor performance status and age, opting for reduced intensity non-myeloablative (RIC/NMA) regimens. In such cases, rates of disease relapse post-transplant have been observed to be as high as 70 percent with a median survival of 3-4 months if untreated9,10,11,12. Treatment options following post-transplant relapse, including donor lymphocyte infusions, second allo-HCT and investigational systemic therapies are limited in efficacy7. Therefore, optimizing disease control prior to allo-HCT is a major need. Recent data suggest HMA treatment prior to allo-HCT is associated with lower toxicity than MA regimens and may induce higher rates of CR compared to standard RIC/NMA regimens in patients with complex/high risk cytogenetic profiles5,6. However, the impact of induction HMAs on post-transplant DFS and OS is not known. Therefore, evaluating the impact of pre-allo-HCT HMAs on long-term outcomes in AML patients with sub-analysis of those with complex/high risk cytogenetics and MKs may generate data to support prospective evaluation of HMAs as pre-allo-HCT treatment regimens in high risk AML populations with a potential impact on DFS and OS. The large CIBMTR Registry provides a valuable source of data to adequately evaluate these outcomes.

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mailto:[email protected]




Specific aims: • To evaluate post-allo-HCT DFS and OS in patients with AML who received initial therapy with an

HMA against similar patients receiving traditional induction chemotherapy prior to allo-HCT. • To perform a pre-specified multivariate sub-analysis, comparing those with MKs, complex/high risk

cytogenetics and specifically monosomy -17 (as a surrogate for TP53 mutation/deletion) to their low/intermediate risk counterparts in order to evaluate whether specific cytogenetic abnormalities correlate with responsiveness to HMAs and improved outcomes.

Scientific justification: Allo-HCT for AML is a potentially curative treatment, however a significant number of patients experience disease relapse following HCT. Relapse is more frequent in those with high-risk disease and those who cannot tolerate MA regimens. Alternative regimens, including HMA containing regimens, are of growing interest. Azacitidine and decitabine are both cytidine nuceloside analogues that are thought to function primarily as HMAs via depletion of DNA methyltransferase-113. Hypomethylation ultimately induces expression of pro-apoptotic and pro-differentiation genes while also as causing direct DNA damage13,14. Remarkably, studies further elucidating their mechanism of action (MOA) have described azacitidine and decitabine regulating >1500 genes, with each influencing ~65-75% unique genes comparatively13. HMAs in pre-allo-HCT regimens for AML may be particularly effective, given that one possible MOA they exert is through upregulation of epigenetically silenced tumor-associated antigens (TAAs) via hypomethylation of CpG islands, which may have the ability to stimulate specific T cell responses14. Clinical results with HMAs have reported CR rates of approximately 40% to 47% in older AML patients4,5. Additionally, improved CR rates with HMAs have been reported in patients with high risk AML, as defined as those with complex cytogenetic abnormalities or -7 karyotypes4,5,6. Interestingly, these CR rates are comparable with those achieved after intensive chemotherapy in older AML patients and appear to be superior to traditional CR rates in those with high risk/complex cytogenetic disease4,5. In particular, those with -17 or TP53 mutations may be a sub-population of individuals who benefit from HMAs. TP53 is a tumor suppressor gene that plays an integral role in transcriptional regulation6,7. TP53 mutations occur in ~8% of all cases of AML. However, the frequency of TP53 mutations is enriched in patients with complex/high risk cytogenetics to ~55-75% of all cases7. One effect of HMAs is the regulation of key late differentiation factors CEBPε and p27/CDKN1B, which induced cellular differentiation and cell-cycle exit in AML TP53 mutant/null cytarabine-resistant AML cells15. This effect resulted in significantly extended survival with reduced toxicity in xenograft AML TP53 null/mutant murine models15. In clinical practice, Welch et al have reported that TP53 mutations predict response to pre-allo-HCT HMAs, with excellent CR rates6. Nevertheless, despite this growing body of evidence supporting the use of HMAs it is unclear whether HMAs improve long-term outcomes post-allo-HCT. Therefore, evaluating whether pre-allo-HCT HMA induction therapy is associated with increased DFS and OS remains a clinically important yet unanswered scientific question. Patient e ligibility p opulation: Our analysis will include:

• Patients with AML (any stage) receiving 1st Allo-HCT in 1st remission during dates ranging • from the first year HMA use was reported to the CIBMTR database until present. • Patients of age 18 years or older • Patients receiving allo-HCT from matched related or matched unrelated donors using bone

marrow (BM) or peripheral blood (PB). Additionally, we will define the following groups and request data regarding:

• Favorable, Intermediate, and Adverse Risk Profiles as defined by the 2012 CIBMTR Cytogenetics Grouping Schema for pre-allo-HCT AML16:

o Favorable: Normal, inv(16) or t(16:16), t(8:21), 11q23 abnormality o Intermediate: all other abnormalities

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o Adverse: complex (≥4 cytogenetic abnormalities) • Monosomal Karyotypes (MKs) will be defined as a single autosomal monosomy associated with

any other structural abnormality (i.e. clonal deletion, addition, inversion or translocation) • Those with -17, -17q and 17p abnormality will also be analyzed as discrete cytogenetic groups

(independent of favorable/intermediate vs adverse risk categorization) Data requirements:

• We will request data from Form 2010 R3.0: Acute Myelogenous Leukemia (AML) Pre-HCT Data and Form 2110 R3.0: Acute Myelogenous Leukemia (AML) Post-HCT.

• Specific data requested from Form 2010 R3.0 will include: age, sex, coexisting medical conditions, performance status (KPS and/or ECOG), Date of Diagnosis, MDS or therapy related vs primary AML, prior non-AML therapies received, WBC count, peripheral and marrow blasts, presence and location of extramedullary disease, cytogenetic and molecular findings, pre-HCT therapies with dates/cycles, best response to therapy and dates, disease status prior to and following conditioning with dates.

• Specific data requested from Form 2110 R3.0 will include: type of HCT, donor type (related vs unrelated, matched vs haplo), product type (bone marrow vs peripheral blood), immune- suppressive regimen, presence and severity of GVHD, date of disease relapse, date of death.

Study design: This will be a retrospective, observational study using Kaplan-Meier time-to-event analysis to assess differences in DFS and OS between patients with AML treated with HMAs vs traditional regimens. We will perform a sub-analysis assessing DFS and OS for those with complex karyotypes, high risk cytogenetics and monosomal karyotypes treated with HMAs vs traditional regimens. We will also perform a multivariate sub-analysis to assess if any of the various chromosomal abnormalities correlate with responsiveness to HMAs compared to traditional regimens. Outcomes:

• Overall survival: Time to death from any cause. Events will be summarized by a survival curve. Cases will be analyzed at the time of last follow-up.

• Disease-free survival: Time to death or relapse. Events will be summarized by a Kaplan- Meier curve. Cases will be analyzed at the time of last follow-up.

• Treatment-related mortality: Death in continuous remission of primary disease. Events will be summarized by the cumulative incidence estimate with relapse as a competing risk.

• Relapse: Development of clinical (hematologic) relapse as defined by the CIBMTR. The event will be summarized by the cumulative incidence estimate and patients analyzed at last follow-up. Death in remission is a competing risk.

• Acute and chronic GVHD: Occurrence of grade II, III, and/or IV skin, GI or liver abnormalities fulfilling the Consensus Criteria of acute GVHD, and limited and extensive chronic GVHD analyzed as cumulative incidence with death without GVHD as a competing risk.

Variables to be described:

• Patient-related: age, sex, performance status and comorbidity index • Disease-related: stage, primary vs secondary AML, WBC count, cytogenetic profile/risk • Transplant-related: conditioning regimen, donor type, GHVD treatment

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Variables to be analyzed: • Age at transplant: 18+, stratified by decade • Gender: male vs female • Karnofsky performance status transplant: <90% vs ≥90% • Co-morbidity index: 0 vs 1-2 vs ≥3 • Cytogenetics: as previously defined above (MK, Adverse, Intermediate and Favorable risk) • Conditioning regimen: MAC w/ TBI vs MAC w/o TBI vs RIC/NMA vs HMA • Graft type: BM vs PB • Donor type: HLA identical sibling vs. well-matched unrelated donor • GVHD prophylaxis: Tacrolimus based vs Cyclosporine based regimens J. Year of HCT: 2000-2003 vs

2004-2007 vs 2008-2011 vs 2012-2014 References: 1. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562-69. 2. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30:2670-77. 3. Lübbert M, Bertz H, Müller MJ, Finke J. When azanucleoside treatment can be curative: nonintensive bridging strategy before allografting in older patients with myelodysplastic syndrome/acute myeloid leukemia. J Clin Oncol. 2013;31:822-23. 4. Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a10-day schedule of decitabine. Proc Natl Acad Sci USA. 2010;107: 7473-78. 5 Ritchie EK, Feldman EJ, Christos PJ, et al. Decitabine in patients with newly diagnosed and relapsed acute myeloid leukemia. Leuk Lymphoma. 2013;54:2003-7. Welch JS, et al. TP53 mutations predict clinical responses to decitabine in AML and MDS patients. NEJM 2016, [in press]. 5. Dohner H, et al. Acute Myeloid Leukemia. N Engl J Med 2015;373:1136-52. Pasquini MS, et al. Hematopoietic cell transplantation outcomes in monosomal karyotype myeloid malignancies. Biol Blood Marrow Transplant 2016;22:248-57. 6. Marmont AM, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991;78:2120-30 Wagner JE, et al. Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits. J Clin Oncol 1992;10:779-89. 5. Sullivan KM, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989;73:1720-28. 6. Frassoni F, et al. Relapse after allogeneic bone marrow transplantation for acute leukaemia: a survey by the E.B.M.T. of 117 cases. Br J Haematol 1988;70(3):317. Hollenbach PW, et al. A Comparison of Azacitidine and Decitabine Activities in Acute Myeloid Leukemia Cell Lines. PLoS ONE 2010;5(2):e9001. 7. Goodyear O, Agathanggelou A, Novitzky-Basso I, et al. Induction of a CD8. T cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116:1908-18. 8. Peng Ng K, et al. p53 independent epigenetic-differentiation treatment in xenotransplant models of acute myeloid leukemia. Leukemia 2011;25(11):1739-50. 9. Armand P, et al. Classifying Cytogenetics in Patients with AML in Complete Remission Undergoing Allogeneic Transplantation: A CIBMTR Study. Biol Blood Marrow Transplant. 2012;18(2):280–88.

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Baseline characteristics for adult patients undergoing first BM/PB graft allo-HCT for AML in CR1 between 2013-2015

Hypomethylating agents Variable No Yes Number of patients 1328 160 Number of centers 143 60 Patient age 18-29 125 (9) 7 (4) 30-39 132 (10) 7 (4) 40-49 193 (15) 10 (6) 50-59 364 (27) 36 (23) 60-69 430 (32) 80 (50) >=70 84 (6) 20 (13) Median (range) 56 (18-78) 63 (18-76) Gender Male 715 (54) 91 (57) Female 613 (46) 69 (43) Karnofsky score <90% 484 (36) 73 (46) >=90% 834 (63) 87 (54) Missing 10 (<1) 0 HCT-CI 0 362 (27) 28 (18) 1 205 (15) 24 (15) 2 189 (14) 32 (20) 3+ 562 (42) 76 (48) Missing 10 (<1) 0 White blood count at diagnosis <= 30 897 (68) 121 (76) 30 - 100 228 (17) 23 (14) > 100 100 (8) 4 (3) Missing 103 (8) 12 (8) Median (range) 7 (<1-1230) 4 (<1-203) Cytogenetic score Favorable 48 (4) 1 (<1) Intermediate 779 (59) 89 (56) Poor 348 (26) 56 (35) TBD 107 (8) 14 (9) NT 17 (1) 0 Missing 29 (2) 0 Decitabine received No 1328 56 (35) Yes 0 104 (65) Azacytidine received No 1328 103 (64) Yes 0 57 (36) Conditioning regimen intensity Myeloablative 672 (51) 57 (36)

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Hypomethylating agents Variable No Yes RIC 494 (37) 77 (48) NMA 134 (10) 24 (15) TBD 23 (2) 2 (1) Missing 5 (<1) 0 Donor type HLA-identical sibling 391 (29) 31 (19) Other relatives 215 (16) 28 (18) Well-matched unrelated 587 (44) 90 (56) Partially-matched unrelated 116 (9) 11 (7) Mis-matched unrelated 4 (<1) 0 Multi-donor 1 (<1) 0 Unrelated (matching unknown) 14 (1) 0 Donor/recipient CMV serostatus +/+ 458 (34) 26 (16) +/- 126 (9) 20 (13) -/+ 397 (30) 64 (40) -/- 300 (23) 44 (28) Missing 47 (4) 6 (4) Donor/recipient sex match M-M 485 (37) 62 (39) M-F 352 (27) 50 (31) F-M 225 (17) 29 (18) F-F 259 (20) 19 (12) Missing 7 (<1) 0 Graft type Bone marrow 195 (15) 25 (16) Peripheral blood 1133 (85) 135 (84) GVHD prophylaxis No GVHD prophylaxis 14 (1) 0 Ex-vivo T-cell depletion 12 (<1) 0 CD34 selection 27 (2) 1 (<1) Post-CY + other(s) 144 (11) 22 (14) TAC + MMF +- other(s) (except post-CY) 173 (13) 28 (18) TAC + MTX +- other(s) (except MMF, post-CY) 661 (50) 82 (51) TAC + other(s) (except MMF, MTX, post-CY) 68 (5) 11 (7) TAC alone 28 (2) 1 (<1) CSA + MMF +- other(s) (except post-CY) 69 (5) 9 (6) CSA + MTX +- other(s) (except MMF, post-CY) 111 (8) 3 (2) CSA + other(s) (except MMF, MTX, post-CY) 5 (<1) 1 (<1) CSA alone 7 (<1) 1 (<1) Other(s) 8 (<1) 1 (<1) Missing 1 (<1) 0 ATG/Campath ATG alone 314 (24) 26 (16) CAMPATH alone 27 (2) 6 (4) No ATG or CAMPATH 987 (74) 128 (80) Year of HCT

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Hypomethylating agents Variable No Yes 2013 400 (30) 22 (14) 2014 476 (36) 75 (47) 2015 452 (34) 63 (39) Median follow-up of survivors (range), months 13 (3-43) 13 (3-36)

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Proposal 1611-102/1611-152 Title: The Influence of Donor Source, Cytogenetics, and Molecular Markers on Outcomes after a Second Hematopoietic Cell Transplant for Patients with Relapsed Leukemia and MDS Marcos de Lima, MD, University Hospitals Case Medical Center Cleveland Ohio, [email protected] Leland Metheny, MD, University Hospitals Case Medical Center Cleveland Ohio, [email protected] Kalyan Nadiminti, University of Iowa, [email protected] Margarida Magalhaes-Silverman, MD, University of Iowa, [email protected] Eric Huselton, MD, Washington University School of Medicine, [email protected] Mark Schroeder, MD, Washington University School of Medicine, [email protected] Hypothesis: Second donor selection as well as cytogenetic and molecular abnormalities will affect survival after second transplant in recipients with relapsed Leukemias post allogeneic transplant. Specific aims: Primary Objective:

• To evaluate the influence of second donor type on overall survival after a second transplant. Secondary objectives:

• To evaluate the influence of cytogenetics and molecular markers on overall survival in this patient group.

• To assess the effects of other patient, disease, and transplant characteristics on OS, EFS, DFS/relapse rate, TRM, aGVHD, and cGvHD.

Scientific impact: Currently there is no standard treatment for patients with leukemia and MDS who relapse after allogeneic hematopoietic cell transplantation. While intensive chemotherapy and donor lymphocyte infusion (DLI) may be able to salvage a small minority of these patients, a second transplant is usually the only potentially curable option, yet this is performed in very few patients (6% of patients that relapse post-transplant in one case series). A prior CIBMTR study of AML patients that relapsed after allogeneic transplant found that patients who underwent a second allogeneic transplant had a one year overall survival after disease relapse of 49.1%, compared to 32.6% for patients who only received a DLI and 23% for the total patient population.(1) While patient selection certainly influences these outcomes, this data suggests a second transplant is the most effective treatment strategy for AML that relapses post-transplant. The influence of second transplant characteristics and relevant patient risk factors that often guide patient selection were not explored and leave clinicians with little guidance regarding patient selection and transplant decisions. The impact of donor source, conditioning intensity, cytogenetic and molecular markers, age, disease-risk index, and other key clinical information likely impacts overall survival after second transplant. Also, given the increased use of alternative donor sources in recent years, re-examining this data could help determine whether haploidentical donors are better than matched unrelated donors and could change clinical practice. With better information regarding overall survival after a second allogeneic transplant and the impact of donor selection along with other patient, disease, and transplant factors on survival, it will be easier to select patients for this potentially curative treatment. Perhaps more importantly, this

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data may help identify patients who will likely have a poor outcome with a second transplant and should pursue clinical trials with novel treatment strategies or other treatment options. Scientific justification: Allogeneic hematopoietic cell transplantation (HCT) can produce long term disease free survival in 40-60 percent of patients with hematologic malignancies; however, disease relapse remains the major cause of transplant failure and treatment options are limited for these patients that relapse post-transplant.(2) While donor lymphocyte infusion (DLI) can produce long lasting remissions in post-transplant relapses for CML, it has been far less effective in non-CML hematologic malignancies. DLI is also associated with significant morbidity, with rates of acute graft versus host disease (GvHD) as high as 66%.(3) A second HCT can be performed for post-transplant relapse, but at the cost of significant mortality. Early mortality rates have been reported as high as 55% and relapse-free survival after second transplant is as low as 7% at one year.(4) Variables such as younger age, remission status at the time of second transplant, and longer time between first transplant and relapse correlate with better outcomes.(5) However, these risk factors are not clear-cut and other retrospective analyses suggest that transplant for non-malignant disease, a HLA-matched sibling donor, and reduced intensity conditioning were variables that impacted clinical outcomes.(6) Poor risk cytogenetics and molecular markers such as FLT3-ITD+ are known to have a negative impact on the disease free survival with double the relapse rate after a first allogenic transplant.(7, 8) However, they have not been well studied in the second transplant setting. Most of the disease relapses occur with the recurrence of the de novo chromosomal alterations and mutations indicating persistence of the disease clones. Often, new chromosomal abnormalities and/or mutations may also be noted at the time of relapse. Cytogenetic and molecular data may supplement traditional risk factors and more fully inform the clinician of the outcomes after a second transplant. Eapen et al with the CIBMTR reported 279 patients who received a second HCT for disease relapse. They found that disease relapse more than 6 months after the first HCT and age less than 20 years were associated with better overall survival. The 1 year and 5-year overall survival (OS) was 41% and 28%.(9) However, no data on cytogenetics or molecular markers was reported. Shaw et al reported the outcomes of 71 patients who received reduced intensity conditioning for their second HCT for relapsed disease. They found better overall survival to be associated with relapse more than 11 months after the first transplant, chronic GvHD, and aGVHD in patients who relapsed before 11 months. There was no association with age, bone marrow source, donor type, or conditioning intensity. One and 2-year OS were 42% and 27% with a significantly worse 2-year OS of 18-22% in patients with leukemia and MDS.(10) Bosi et al report a case series that suggests remission status at time of second HCT, use of TBI for conditioning, and presence of acute GvHD with the first transplant are associated with overall survival.(11) Other series did not find these associations.(4, 10, 12-14) Data on patient outcomes after a second HCT is limited, with most of these data collected more than 20 years ago. 127 patients at Washington University in St. Louis underwent a second HCT after the year 2000 with a 1-year overall survival of 34.9%. There was no association between OS after a second transplant with age, active disease, or length of disease free survival after the first transplant. The donor type did not affect overall survival but myeloablative regimens and using the same donor were associated with better overall survival. (Unpublished data)

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Given the advances in HCT, including improved treatments for GvHD, the use of alternative donors and post-transplant cyclophosphamide, more recent use of risk-directed therapy based on cytogenetics, molecular markers, and minimal residual disease monitoring, new studies are necessary to characterize outcomes after second HCT. This data is crucial to help inform patients and clinicians to make treatment decisions and choose the most effective transplant strategies. Patient eligibility population:

• All patients who receive a second allogeneic transplant for relapsed disease after a first allogeneic transplant for AML, MDS, CML, ALL, and CLL.

• Received second transplant between 2000-2016 • Age > 18 at time of second transplant

Data requirements: Data Collection forms needed:

1. 2000: Baseline data 2. 2006: HSCT Infusion 3. 2010 AML pre-HSCT 4. 2011 ALL pre-HSCT 5. 2012 CML pre-HSCT 6. 2013 CLL pre-HSCT 7. 2014 MDS pre-HSCT 8. 2100 D100 Post-HSCT 9. 2110 AML post-HSCT 10. 2111 ALL post-HSCT 11. 2112 CML post-HSCT 12. 2113 CLL post-HSCT 13. 2114 MDS post-HSCT 14. 2200: 6mo – 1 yr Post-HSCT 15. 2300: Yearly follow up 16. 2400: Pre-HSCT data 17. 2450: Post-HSCT data 18. 2451: Chimerism data 19. 2455: Post-HSCT data 20. 2530: Post-transplant relapse data 21. 2900: Death data

Data required: • Patient characteristics: age at transplants, gender, ethnicity, blood type, CMV status,

performance status. • Disease characteristics: disease type, cytogenetics and molecular markers (pre-allo1, relapse

post-allo1, pre-allo2), disease risk index, ELN risk group, HCT CI score, WBC count/blast % at allo2.

• Transplant characteristics: number of transplants, prior transplant types, dates of transplants, conditioning regimens, donor source/match type, stem cell source, donor blood type, donor CMV status, conditioning intensities, presence of donor specific antibodies, disease status at transplant (active, MRD+, remission), graft composition, GvHD prophylaxis.

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• Outcomes: overall survival, disease free survival, treatment related mortality, relapse, aGVHD, aGVHD organ, aGVHD stage, cGvHD, cGvHD stage, ANC recovery, platelet recovery, chimerism, graft failure, CMV reactivation, cause of death.

Sample requirements (if study will use biologic samples from the NMDP Research Sample Repository): N/A Study Design (Scientific Plan): The primary outcome of this study is overall survival after second HCT. Secondary outcomes would include disease free survival (DFS), treatment related mortality (TRM), time to engraftment, rates of acute and chronic GvHD, and the impact of cytogenetics, molecular markers, and other patient, disease, and transplant characteristics on these outcomes. This data would be obtained from the CIBMTR database. Event-time distributions will be measured from the date of the second HCT. Data Analysis: Baseline demographics and disease characteristics will be summarized using counts and frequencies (for categorical variables) or means and standard deviations (for continuous ones). The distribution of OS will be estimated using Kaplan-Meier product limit method. Univariate and multivariate Cox proportional hazard models will be used to evaluate the association between OS and baseline demographic/clinical characteristics. The proportional hazards assumption will be assessed using Schoenfeld residual plots and counting-process Cox models will be built to deal with the time-dependent variable if needed. Hazard ratios (HRs) and their 95% CIs will be estimated. The overall performance of the resultant Cox models will be assessed using Harrell’s C-index with bootstrapped 95% CIs. The model calibration will also be performed using graphs of individual observed and predicted 1-year survival probabilities, and to assess whether the slope of the observed probabilities on predicted event probabilities was equal to 1. Similar analyses will be performed for the other time-to-event endpoints (DFS, TRM, and relapse). TRM will be assess using Gray’s sub-distribution method to account for the presence of competing risks for death due to other causes. Similarly, in the analysis of relapse, non-relapse mortality (NRM) will be treated as competing risk events. Univariate and multivariate logistic regression will be used to assess the rates of acute and chronic GvHD, while ordinary least-square linear regression models will be used for the analysis of time to engraftment.

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Power justification: A preliminary search of CIBMTR data (see attached) of AML patients who received a second transplant for relapsed disease between 2008-2015 yielded 287 patients. By expanding inclusion criteria to include all Leukemias and MDS and expanding the search range from 2000-2016, we expect that a cohort of ~500 patients will be eligible for our study. A 1-year overall survival of 49.1% was obtained in patients receiving 2nd HCT based on a prior CIBMTR study. (1) A power analysis was performed for the association between covariates and OS. Due to lack of follow-up information, the power was assessed using Chi-square test and assuming a 1-yr OS of 50% in the whole cohort. Figure below shows the minimal detectable difference of OS in a given risk factor. For a risk factor with prevalence of 10% (N=50 versus 450), for example, we can detect a minimum of 20% difference with 80% power at 2-sided alpha=0.05. For a risk factor with prevalence of 50% (N=250 versus 250), we can detect a minimal of 12% difference in 1-yr OS. We expect that more power will be achieved because OS will be assessed as a time-to-event data in the actual data analysis and this allows us to use information more efficiently (i.e., not only the rate of death, but also the timing of death). Data source: N/A References: 1. Bejanyan N, Weisdorf DJ, Logan BR, Wang HL, Devine SM, de Lima M, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant. 2015;21(3):454-9. 2. Dazzi F, Fozza C. Disease relapse after haematopoietic stem cell transplantation: risk factors and treatment. Best Pract Res Clin Haematol. 2007;20(2):311-27. 3. Miller JS, Weisdorf DJ, Burns LJ, Slungaard A, Wagner JE, Verneris MR, et al. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood. 2007;110(7):2761-3. 4. Mrsic M, Horowitz MM, Atkinson K, Biggs JC, Champlin RE, Ehninger G, et al. Second HLA-identical sibling transplants for leukemia recurrence. Bone Marrow Transplant. 1992;9(4):269-75. 5. Arfons LM, Tomblyn M, Rocha V, Lazarus HM. Second hematopoietic stem cell transplantation in myeloid malignancies. Curr Opin Hematol. 2009;16(2):112-23. 6. Kedmi M, Resnick IB, Dray L, Aker M, Samuel S, Gesundheit B, et al. A retrospective review of the outcome after second or subsequent allogeneic transplantation. Biol Blood Marrow Transplant. 2009;15(4):483-9.

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7. Fang M, Storer B, Estey E, Othus M, Zhang L, Sandmaier BM, et al. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. Blood. 2011;118(6):1490-4. 8. Brunet S, Labopin M, Esteve J, Cornelissen J, Socie G, Iori AP, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30(7):735-41. 9. Eapen M, Giralt SA, Horowitz MM, Klein JP, Wagner JE, Zhang MJ, et al. Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant. 2004;34(8):721-7. 10. Shaw BE, Mufti GJ, Mackinnon S, Cavenagh JD, Pearce RM, Towlson KE, et al. Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant. 2008;42(12):783-9. 11. Bosi A, Laszlo D, Labopin M, Reffeirs J, Michallet M, Gluckman E, et al. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol. 2001;19(16):3675-84. 12. Pollyea DA, Artz AS, Stock W, Daugherty C, Godley L, Odenike OM, et al. Outcomes of patients with AML and MDS who relapse or progress after reduced intensity allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2007;40(11):1027-32. 13. Michallet M, Tanguy ML, Socie G, Thiebaut A, Belhabri A, Milpied N, et al. Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemia for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Societe Francaise de Greffe de moelle (SFGM). Br J Haematol. 2000;108(2):400-7. 14. Baron F, Storb R, Storer BE, Maris MB, Niederwieser D, Shizuru JA, et al. Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopoietic cell transplantation. J Clin Oncol. 2006;24(25):4150-7.

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Baseline characteristics for adult patients undergoing second allo-HCT for persistent/relapsed AML/ALL/CML/CLL/MDS between 2000-2015

Variable 1st HCT 2nd HCT Number of patients 850 850 Number of centers 166 166 Patient age <10 1 (<1) 0 10-17 33 (4) 0 18-29 187 (22) 188 (22) 30-39 154 (18) 145 (17) 40-49 207 (24) 202 (24) 50-59 170 (20) 188 (22) 60-69 89 (10) 110 (13) >=70 9 (1) 17 (2) Median (range) 43 (5-74) 45 (18-75) Gender Male 481 (57) 481 (57) Female 369 (43) 369 (43) Karnofsky score <90% 239 (28) 413 (49) >=90% 538 (63) 370 (44) Missing 73 (9) 67 (8) HCT-CI 0 158 (19) 143 (17) 1 48 (6) 20 (2) 2 40 (5) 27 (3) 3+ 70 (8) 76 (9) N/A, earlier than 2007 529 (62) 398 (47) Missing 5 (<1) 186 (22) Primary disease code AML 507 (60) 538 (63) ALL 137 (16) 137 (16) CLL 27 (3) 26 (3) CML 93 (11) 93 (11) MDS 86 (10) 56 (7) White blood count at diagnosis <= 30 388 (46) 399 (47) 30 - 100 130 (15) 136 (16) > 100 89 (10) 95 (11) Missing 243 (29) 220 (26) Median (range) 13 (<1-800) 13 (<1-800) Disease status prior to HCT AML/ALL PIF 90 (11) 31 (4) AML/ALL CR1 308 (36) 16 (2) AML/ALL CR2 134 (16) 176 (21) AML/ALL >=CR3 9 (1) 108 (13) AML/ALL relapse 92 (11) 342 (40)

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Variable 1st HCT 2nd HCT MDS early 19 (2) 17 (2) MDS advanced 50 (6) 32 (4) CML early 72 (8) 31 (4) CML intermediate 17 (2) 31 (4) CML advanced 9 (1) 16 (2) CLL CR 2 (<1) 1 (<1) CLL PR 2 (<1) 3 (<1) CLL stable 3 (<1) 1 (<1) CLL Progressive 3 (<1) 6 (<1) CLL untreated 0 1 (<1) Missing 40 (5) 38 (4) Conditioning regimen intensity Myeloablative 509 (60) 247 (29) RIC 169 (20) 232 (27) NMA 67 (8) 81 (10) TBD 25 (3) 171 (20) Missing 80 (9) 119 (14) Donor type HLA-identical sibling 326 (38) 290 (34) Twin 15 (2) 3 (<1) Other relatives 73 (9) 71 (8) Well-matched unrelated 244 (29) 219 (26) Partially-matched unrelated 80 (9) 73 (9) Mis-matched unrelated 23 (3) 21 (2) Unrelated (matching unknown) 10 (1) 97 (11) Cord blood 72 (8) 75 (9) Missing 7 (<1) 1 (<1) Donor/recipient CMV serostatus +/+ 259 (30) 229 (27) +/- 78 (9) 73 (9) -/+ 183 (22) 182 (21) -/- 193 (23) 149 (18) CB/+ 42 (5) 49 (6) CB/- 24 (3) 25 (3) Missing 71 (8) 143 (17) Donor/recipient sex match M-M 270 (32) 243 (29) M-F 187 (22) 176 (21) F-M 117 (14) 128 (15) F-F 121 (14) 116 (14) CB-M 41 (5) 45 (5) CB-F 31 (4) 30 (4) Missing 83 (10) 112 (13) Graft type Bone marrow 244 (29) 96 (11) Peripheral blood 527 (62) 673 (79) Umbilical cord blood 72 (8) 75 (9)

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Variable 1st HCT 2nd HCT Other, specify 0 5 (<1) PB + OTH (new: 2+90) 0 1 (<1) Missing 7 (<1) 0 GVHD prophylaxis No GVHD prophylaxis 17 (2) 153 (18) Ex-vivo T-cell depletion 30 (4) 16 (2) CD34 selection 24 (3) 29 (3) Post-CY + other(s) 7 (<1) 26 (3) TAC + MMF +- other(s) (except post-CY) 71 (8) 109 (13) TAC + MTX +- other(s) (except MMF, post-CY) 251 (30) 178 (21) TAC + other(s) (except MMF, MTX, post-CY) 25 (3) 43 (5) TAC alone 26 (3) 35 (4) CSA + MMF +- other(s) (except post-CY) 76 (9) 72 (8) CSA + MTX +- other(s) (except MMF, post-CY) 188 (22) 87 (10) CSA + other(s) (except MMF, MTX, post-CY) 18 (2) 29 (3) CSA alone 29 (3) 37 (4) Other(s) 10 (1) 30 (4) Missing 78 (9) 6 (<1) ATG/Campath ATG + CAMPATH 0 1 (<1) ATG alone 229 (27) 157 (18) CAMPATH alone 25 (3) 25 (3) No ATG or CAMPATH 506 (60) 650 (76) Missing 90 (11) 17 (2) Year of HCT 1985 1 (<1) 0 1989 2 (<1) 0 1990 1 (<1) 0 1991 3 (<1) 0 1992 2 (<1) 0 1993 4 (<1) 0 1994 4 (<1) 0 1995 4 (<1) 0 1996 4 (<1) 0 1997 11 (1) 0 1998 25 (3) 0 1999 58 (7) 0 2000 57 (7) 74 (9) 2001 50 (6) 54 (6) 2002 51 (6) 63 (7) 2003 36 (4) 47 (6) 2004 42 (5) 34 (4) 2005 51 (6) 41 (5) 2006 59 (7) 35 (4) 2007 64 (8) 50 (6) 2008 76 (9) 55 (6) 2009 75 (9) 83 (10)

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Variable 1st HCT 2nd HCT 2010 48 (6) 76 (9) 2011 25 (3) 64 (8) 2012 20 (2) 38 (4) 2013 43 (5) 29 (3) 2014 29 (3) 52 (6) 2015 5 (<1) 55 (6) Median follow-up of survivors (range), months 106 (10-306) 64 (3-191)

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Proposal 1611-95 Title: Allogeneic Hematopoietic Transplant Outcomes in Adult Patients with MLL-rearranged Acute Myeloid Leukemia Martin S. Tallman, MD, Memorial Sloan Kettering Cancer Center, [email protected] Kamal Menghrajani, MD, Memorial Sloan Kettering Cancer Center, [email protected] Hypothesis: Adult patients with MLL-rearranged acute myeloid leukemia who undergo allogeneic bone marrow transplant at CR1 or beyond have a higher likelihood of relapse and a higher rate of mortality than those with AML that presents with other cytogenetic or molecular abnormalities that would place them in the intermediate or adverse risk disease categories. Specific aims:

• Retrospectively evaluate the overall survival, leukemia-free survival, relapse incidence, and non-relapse mortality of adult AML patients with MLL-rearranged acute myeloid leukemia who underwent an allogeneic bone marrow transplant at or beyond CR1

• Evaluate whether or not the type of MLL rearrangement (e.g.11q- or any balanced 11q23 abnormality) allows for stratification of the above outcomes

• Understand how outcomes differ for patients who undergo allogeneic transplant for MLL-rearranged leukemia as compared to AML with other intermediate- or adverse-risk features

Scientific impact:

• While similar questions have been studied using other resources (e.g. the Acute Leukemia Working Party data gathered between 2000 and 20101), these questions remain outstanding in terms of more patients treated more recently and those registered with CIBMTR, one of the world’s largest observational databases of clinical information

• The results of these data could help develop a better understanding of whether alternative treatment / conditioning options should be considered for patients with MLL-rearranged acute myeloid Leukemias

Scientific justification: Structural abnormalities involving chromosome 11, band q23, are some of the most common cytogenetic abnormalities consistently seen in hematopoietic malignancies, including AML. MLL rearrangements include acquired deletions, duplications, inversions and reciprocal translocations at 11q23.2 Another type of MLL rearrangement is the partial tandem duplication (MLL–PTD), which occurs as a result of an internal tandem duplication of select exons.3 Leukemias bearing translocations involving the MLL gene on chromosome 11q23 possess unique clinical and biological characteristics. MLL rearrangements are found in about 5-10% of adult AML, and are seen more commonly in therapy-related Leukemias (AML more frequently than ALL) that develop in patients previously treated with topoisomerase II inhibitors.4-6 More than 50 different translocation fusion partners for 11q23 have been identified; however, a subset account for most cases. The five most frequent MLL rearrangements, accounting for approximately 80% of all MLL-translocation-bearing Leukemias, are: t (4;11) (q21; q23) or MLL–AF4; t (9;11) (p22; q23) or MLL–AF9; t (11;19) (q23; p13.3) or MLL–ENL; t (10;11) (p12; q23) or MLL–AF10; and t (6;11) (q27; q23) or MLL–AF6.4, 6, 7 Regardless of their association with other high-risk factors at presentation, 11q23 rearrangements are strongly

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predictive of poor clinical outcomes.8 Patients with MLL-rearranged Leukemias are more likely to present with hyperleukocytosis, extramedullary leukemic involvement, shorter remission durations, and a higher frequency of relapse, although there is noted variability based on the type of 11q rearrangement involved.8 While the poorer prognosis of MLL-rearranged AML has been well established, outcomes after allogeneic hematopoietic stem cell transplantation are less well understood. Recent data have suggested that post-transplant outcomes in this group may be especially poor. A study by Muto et al., published in 2015, retrospectively analyzed eight patients with MLL-rearranged leukemia who received an alloHSCT at CR1 or beyond. Of the three patients who received a transplant during relapse or CR2, all three died due to AML progression after alloHSCT. Of the remaining five patients who underwent transplantation during CR1, four (50% of the initial cohort) remained alive at five years9. Another study published in 2015 by Pigneux et al. retrospectively evaluated 159 adult patients with MLL-rearranged leukemia who had undergone alloHSCT between 2000 and 2010 from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) registry. They found that overall survival at two years was 56 + 4% among these patients, with a relapse incidence of 31 + 3%. Upon further analysis of the subtypes of MLL-rearrangements, they suggested that t (11;19), in addition to t (9;11), portends a more favorable post-transplant prognosis w/ a two-year OS of 64 + 6% and 73 + 10% respectively, whereas patients with t (10;11) and t (6;11) tended to have a much lower two-year overall survival of 40 + 13% and 24 + 11%, respectively1. While these data are compelling, further study would help establish whether these patterns hold in a broader pool of patients, such as those registered with CIBMTR, and whether or not other translocation partners for 11q may be of significance in terms of post-transplant prognosis. Additionally, having a better understanding of whether or not alloHSCT should be considered as soon as a patient achieves CR1 may help drive changes in the approach the treatment of these patients.

Patient eligibility population: Patient eligibility criteria would include patient age of 18 years or older and 70 years or younger. The disease under study would be AML with an MLL rearrangement. We would also include data from patients with other types of high-risk AML (-5/-5q, -7/-7q, abnl 3q / inv (3), abnl 20q / 21q, del (9q), t (6;9), abn 17p, FLT3 ITD, FLT3 D835 point mut, complex karyotype with 3 or more abnormalities, therapy-related AML; where available - GATA2 / MECOM (EVI1) / TP53 / SRSF2 / BRAF mut) to form a comparator group. The disease stage would be CR1 or beyond. The year of transplant would be from 2007 to present, as data from the AML 2010 form includes assessment for 11q- and any balanced 11q23 abnormality. Graft and donor types would include cord blood, matched related, matched unrelated, and single HLA-locus mismatched donors. Prior treatments received would include hypomethylating agents, anthracyclines, antimetabolite agents (e.g. cytarabine, fludarabine), g-csf, etoposide, and / or investigational agents. Any transplant regimen may be used. Data requirements: If supplemental data is required, please review data collection forms at: http://www.cibmtr.org/DataManagement/DataCollectionForms/Pages/index.aspx Data collection forms needed: AML 2010, both retired and current.

- No other supplemental data need be collected - No other group’s data will be used in combination with CIBMTR data

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http://www.cibmtr.org/DataManagement/DataCollectionForms/Pages/index.aspx


Variables to be analyzed include: - Age - Time from diagnosis to transplant - Remission status at time of transplant - If progressed, time to progression after previous CR - Year of transplant - Secondary AML - Antecedent disease leading to secondary AML (MDS, breast cancer, lymphoma, etc.) - Sex of patient / donor - CMV in patient / donor - Type of donor - Source of stem cells - AML treatment regimen(s) - Conditioning regimen - T-cell depletion - Engraftment - Acute GVHD - Chronic GVHD - Type of 11q abnormality - Full cytogenetics from prior to transplant - Molecular testing results from prior to transplant

Desired outcome variables include: - overall survival - leukemia-free survival - relapse incidence - non-relapse mortality -

Sample requirements: If the study requires biologic samples from the NMDP Repository, the proposal should also include: 1) A detailed description of the proposed testing methodology; 2) A summary of the investigator’s previous experience with the proposed assay systems; 3) A Biosketch or brief curriculum vitae documenting experience in the laboratory methods proposed.

• Samples required would include DNA from pre-transplant bone marrow biopsy material on which cytogenetic analysis could be run. The reason for this is that several 11q rearrangements have been discovered and some are thought to portend a better prognosis than others (e.g. t (9;11)). The AML 2010 forms in use since 2007 included an assessment of 11q- or 11q23 abnormalities, but did not go into specifics regarding the exact abnormality found. Our ability to collect this information by performing cytogenetics on these samples would give us more robust information regarding how these changes may be associated with our outcomes of interest.

o The type of sample needed would be DNA, serum, cell lines or viable peripheral blood mononuclear cells, depending on what is available

o We would ask for 3-5mL of whole blood or at least 5 micrograms of extracted DNA w/ a concentration of 50 nanograms per microliter

• Cytogenetics would be performed by the MSKCC core laboratory, which performs cytogenetic analysis on all in-house bone marrow biopsy samples. Dr. Tallman has had extensive experience with clinical research utilizing this data.

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Study design: Specific aim 1: Retrospectively evaluate the overall survival, leukemia-free survival, relapse incidence, and non-relapse mortality of adult AML patients with MLL-rearranged acute myeloid leukemia who underwent an allogeneic bone marrow transplant at or beyond CR1 Study design: The primary endpoints will be overall survival (OS; time from alloHSCT to death from any cause), leukemia-free survival (LFS; survival w/ no evidence of relapse or progression), relapse incidence (> 5% blasts in the bone marrow and / or a myeloid sarcoma), and non-relapse mortality (death without evidence of relapse or progression). A database of the variables outlined above (in the data requirements section) will be constructed. The primary endpoints will be assessed for each patient and patient data will then be aggregated. Specific aim 2: Evaluate whether or not the type of MLL rearrangement (e.g.11q- or any balanced 11q23 abnormality) allows for stratification of the above outcomes. Study design: If a sufficient number of samples can be accessed from the CIBMTR Sample Repository, cytogenetic analysis will be performed on them in house. Cytogenetic analysis will be performed by the MSKCC cytogenetics core, part of the department of pathology. If the sample size is large enough, patients will be stratified by the type of MLL rearrangement they have to see if conclusions about the primary endpoints can be made based on the cytogenetic data. Specific aim 3: Understand how outcomes differ for patients who undergo allogeneic transplant for MLL-rearranged leukemia as compared to AML with other high-risk features. Study design: Some information regarding how other high-risk features may affect transplant outcomes is available in the literature (e.g. for 5q- / 7q- syndromes). Using the CIBMTR database, we hope to review outcomes in patients with non-MLL-R AML with high-risk cytogenetic features (-5/-5q, -7/-7q, abnl 3q / inv (3), abnl 20q / 21q, del (9q), t (6;9), abn 17p, complex karyotype with 3 or more abnormalities), therapy-related AML, and high-risk mutations (FLT3 ITD, FLT3 D835 point mut, TP53, and, if possible, GATA2 / MECOM (EVI1) / SRSF2 / BRAF mut) to serve as a comparator group. The data derived from our analysis would be used to compare how the outcomes in MLL-rearranged leukemia may differ from outcomes seen in other high-risk types of AML, and may help generate hypotheses on how to better treat this aggressive form of leukemia. Planned statistical methodology is as follows, but it will likely change based on further discussion with MSKCC and CIBMTR statisticians: Variables that will be considered for their potential prognostic value on outcome include recipient (age, gender, MLL-r subtype, other cytogenetic abnormalities, induction regimen / regimens used), donor (type, gender, human leukocyte antigen compatibility) and transplantation characteristics (year of transplantation, disease stage at transplantation (CR1 vs CR2), conditioning regimen intensity (MAC/RIC), use of in vivo T-cell depletion and stem-cell source). Relapse incidence and non-relapse mortality will be estimated using cumulative incidence functions (CIFs) in a competing-risks setting as death and relapse compete with one another. Leukemia-free and overall survival probabilities will be calculated using the Kaplan–Meier estimates. Univariate analysis using Gray’s test will be used for cumulative incidence functions and univariate analysis using the log-rank test will be used for leukemia-free and overall survival. All factors found to influence outcomes in univariate analysis with a p-value of 0.20 will be included into a Cox proportional hazard model or Fine–Gray model for competing events. All tests will be two sided. The type-1 error rate is to be fixed at 0.05 for determination of the factors associated with time to event outcomes. Statistical analyses will be performed with SPSS 19 (SPSS Inc./IBM, Armonk, NY, USA) and R 2.13.2 (R Development Core Team, Vienna, Austria) software packages.

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Non-CIBMTR data source: If applicable, please provide: 1) A description of external data source to which the CIBMTR data will be linked; 2) The rationale for why the linkage is required, i.e., neither database contains all the data required to answer the study question; 3) A list of the data elements available in both data sources that will be used to link the CIBMTR record with the external record; 4) The methodology used to link the datasets. This study will only use data from the CIBMTR Research Database and the CIBMTR Sample Repository. References: 1. Pigneux, A. et al. Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement (MLL-r AML). Leukemia 29, 2375-81 (2015). 2. Munoz, L. et al. Acute myeloid leukemia with MLL rearrangements: clinicobiological features, prognostic impact and value of flow cytometry in the detection of residual leukemic cells. Leukemia 17, 76-82 (2003). 3. Schichman, S.A. et al. ALL-1 tandem duplication in acute myeloid leukemia with a normal karyotype involves homologous recombination between Alu elements. Cancer Res 54, 4277-80 (1994). 4. Krivtsov, A.V. & Armstrong, S.A. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7, 823-33 (2007). 5. Super, H.J. et al. Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II. Blood 82, 3705-11 (1993). 6. Huret, J.L., Dessen, P. & Bernheim, A. An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Leukemia 15, 987-9 (2001). 7. Meyer, C. et al. The MLL recombinome of acute leukemias. Leukemia 20, 777-84 (2006). 8. Dimartino, J.F. & Cleary, M.L. Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. Br J Haematol 106, 614-26 (1999). 9. Muto, T. et al. Efficacy of myeloablative allogeneic hematopoietic stem cell transplantation in adult patients with MLL-ELL-positive acute myeloid leukemia. Int J Hematol 102, 86-92 (2015).

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Baseline characteristics for adult patients undergoing first allo-HCT for high risk AML in CR1 or beyond between 2008-2015

Variable MLL Other high risk Number of patients 443 2191 Number of centers 109 167 Patient age 18-29 77 (17) 255 (12) 30-39 74 (17) 234 (11) 40-49 86 (19) 420 (19) 50-59 129 (29) 687 (31) 60-69 77 (17) 595 (27) Median (range) 48 (18-70) 53 (18-70) Gender Male 196 (44) 1091 (50) Female 247 (56) 1100 (50) Karnofsky score <90% 161 (36) 790 (36) >=90% 274 (62) 1360 (62) Missing 8 (2) 41 (2) HCT-CI 0 170 (38) 781 (36) 1 69 (16) 242 (11) 2 47 (11) 256 (12) 3+ 152 (34) 890 (41) Missing 5 (1) 22 (1) White blood count at diagnosis <= 30 283 (64) 1343 (61) 30 - 100 74 (17) 435 (20) > 100 41 (9) 224 (10) Missing 45 (10) 189 (9) Median (range) 9 (<1-432) 10 (<1-1000) Type of AML De-novo 333 (75) 1582 (72) Transformed from MDS/MPS 42 (9) 330 (15) Therapy linked 68 (15) 279 (13) Disease status prior to HCT CR1 336 (76) 1641 (75) CR2 62 (14) 287 (13) >=CR3 5 (1) 19 (<1) Relapse 40 (9) 244 (11) Cytogenetic score Favorable 0 73 (3) Intermediate 264 (60) 784 (36) Poor 179 (40) 1169 (53) TBD 0 131 (6) NT 0 19 (<1) Missing 0 15 (<1)

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Variable MLL Other high risk Del(11q)/11q- at dx or tx No 355 (80) 1484 (68) Yes 76 (17) 0 Missing 12 (3) 707 (32) (11q23) abnormality at dx or tx No 52 (12) 1487 (68) Yes 391 (88) 0 Missing 0 704 (32) Conditioning regimen intensity Myeloablative 295 (67) 1318 (60) RIC 89 (20) 556 (25) NMA 46 (10) 273 (12) TBD 12 (3) 39 (2) Missing 1 (<1) 5 (<1) Donor type HLA-identical sibling 111 (25) 565 (26) Other relatives 42 (9) 198 (9) Well-matched unrelated 157 (35) 782 (36) Partially-matched unrelated 54 (12) 200 (9) Mis-matched unrelated 2 (<1) 12 (<1) Unrelated (matching unknown) 0 9 (<1) Cord blood 77 (17) 425 (19) Donor/recipient CMV serostatus +/+ 129 (29) 552 (25) +/- 35 (8) 178 (8) -/+ 112 (25) 580 (26) -/- 84 (19) 430 (20) CB/+ 57 (13) 306 (14) CB/- 18 (4) 116 (5) Missing 8 (2) 29 (1) Donor/recipient sex match M-M 115 (26) 580 (26) M-F 117 (26) 522 (24) F-M 53 (12) 310 (14) F-F 81 (18) 351 (16) CB-M 28 (6) 198 (9) CB-F 49 (11) 227 (10) Missing 0 3 (<1) Graft type Bone marrow 61 (14) 274 (13) Peripheral blood 304 (69) 1492 (68) Umbilical cord blood 77 (17) 425 (19) PB + OTH (new: 2+90) 1 (<1) 0 GVHD prophylaxis No GVHD prophylaxis 7 (2) 31 (1) Ex-vivo T-cell depletion 2 (<1) 20 (<1) CD34 selection 10 (2) 50 (2)

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Variable MLL Other high risk Post-CY + other(s) 32 (7) 126 (6) TAC + MMF +- other(s) (except post-CY) 103 (23) 360 (16) TAC + MTX +- other(s) (except MMF, post-CY) 179 (40) 950 (43) TAC + other(s) (except MMF, MTX, post-CY) 21 (5) 126 (6) TAC alone 10 (2) 50 (2) CSA + MMF +- other(s) (except post-CY) 52 (12) 301 (14) CSA + MTX +- other(s) (except MMF, post-CY) 16 (4) 119 (5) CSA + other(s) (except MMF, MTX, post-CY) 2 (<1) 13 (<1) CSA alone 6 (1) 21 (<1) Other(s) 3 (<1) 22 (1) Missing 0 2 (<1) ATG/Campath ATG alone 109 (25) 572 (26) CAMPATH alone 9 (2) 37 (2) No ATG or CAMPATH 325 (73) 1580 (72) Missing 0 2 (<1) Year of HCT 2008 71 (16) 325 (15) 2009 75 (17) 303 (14) 2010 70 (16) 270 (12) 2011 25 (6) 145 (7) 2012 23 (5) 139 (6) 2013 61 (14) 278 (13) 2014 76 (17) 390 (18) 2015 42 (9) 341 (16) Median follow-up of survivors (range), months 48 (3-97) 36 (3-98)

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Proposal 1611-100 Title: Optimizing Allogeneic Hematopoietic Cell Transplant Outcomes in Acute Myeloid Leukemia Using Next Generation Sequencing Betty Ky Hamilton MD, Cleveland Clinic, [email protected] Navneet Majhail MD, Cleveland Clinic, [email protected] Jaroslaw Maciejewski MD PhD, Cleveland Clinic, [email protected] Aziz Nazha MD, Cleveland Clinic, [email protected] Hypothesis: We hypothesize that next generation sequencing (NGS) based mutational diagnostics may help better select and manage patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT) to identify patients at high risk of disease relapse post-transplant. Specific aims: We propose a pilot study to investigate the impact of pre-HCT mutation burden and minimal residual disease in AML on post-transplant relapse and survival. The primary aim of this study is to apply a multi-mutational deep NGS panel to identify pre-transplantation molecular mutations and their association with the risk of relapse and overall survival in patients with AML who subsequently undergo allogeneic HCT. The study will be done in two phases:

• Pilot phase: A pilot cohort of AML patients with (1) known active disease (N=50), (2) in CR with unknown mutation status (N=50). This step is to assess the feasibility of using our proposed NGS platform to identify molecular mutations, and define in the cohort of patients who are in morphologic CR at the time of transplantation (and may not have circulating blasts) the presence of molecular residual disease.

• Validation phase: If the feasibility of performing NGS in patients with AML in CR is confirmed, conducting an analysis in a larger cohort of patients to determine the association of pre-transplant mutational profile and survival and relapse after allogeneic HCT.

Scientific justification: Allogeneic HCT is a potentially curative therapy for patients with AML, and is typically reserved for patients with the most aggressive and least favorable prognoses. Leukemic relapse, however, remains the most common cause of treatment failure, and it is no longer clear that HCT benefits all patients with high risk disease. Although cytogenetic risk classifications in AML help predict survival and disease progression1-3, more recently discovered genetic changes on the molecular level have been identified as prognostically relevant4-7. New molecular technologies such as NGS are furthering our understanding of the genetic complexity of myeloid malignancies such as AML and myelodysplastic syndromes (MDS), with the hope of further elucidating the pathophysiology and mechanisms to treatment response and progression, such as with allogeneic HCT. We hypothesize that the risk of relapse may be better defined with the use of leukemia-specific molecular markers as targets for detection of minimal residual disease. Although the influence of common mutations such as NPM1 and FLT3 in AML and HCT outcomes have been described7, 8, there is limited data on the influence of the remaining complex genomic landscape of AML. Over the last decade, the discovery of many genetic mutations and pathways, such as in the RNA-splicing machinery (SF3B1, SRSF1, ZRSR2, U2AF1); epigenetic regulation (ASXL1, TET2, EZH2, DNMT3A, IDH1/2); transcriptional regulation (RUNX1, BCOR, ETV6); and signal transduction pathways (CBL, NRAS, JAK2); has provided further insights into disease pathogenesis and phenotype. There have been a wealth

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of studies demonstrating the prognostic significance of these genetic lesions individually or in combination with each other in AML and MDS4, 9; however only a handful of reports have evaluated the significance of these mutations in the context of allogeneic transplant5, 10, 11 Luskin et al. recently reported on the risk of relapse following allogeneic HCT and the association of 26 commonly mutated genes in AML12. The authors reported that mutations in TP53 (N=9), WT1 (N=8), and FLT3-ITD (N=32) were associated with an increased risk of relapse after allogeneic HCT. In the context of MDS, Bejar et al. previously reported that mutations in TP53 (N=18), DNMT3A (N=16), and TET2 (N=11) were associated with poor survival after allogeneic HCT5. There have been subsequent reports that both confirm and refute these findings, with variable results regarding the significance of these and other mutations10, 11. Given the diversity of genes evaluated, conclusions have thus far been limited by the small number of patients harboring individual mutations. Significantly larger scale prospective collaborative efforts are needed to confirm these reports, and the CIBMTR database provides a rich platform to study this pre-transplant. The presence of MRD can provide prognostic information in the context of AML,13-16 and patients with MRD prior to HCT are more likely to relapse compared to those without17-20. In the context of systemic molecular profiling, however, the routine assessment of MRD has not been readily adopted given its complex molecular heterogeneity17, 21-23. With increasing understanding it has become evident that each leukemic population has a clonal landscape and mutational hierarchy, which has been hypothesized to arise in a temporal fashion, with some present in a founding clone, and others arising in subclones. These may then subsequently evolve over time and come under the effect of selective pressures from systemic therapies such as chemotherapy. Pre-transplant assessment of MRD, may thus give the most accurate assessment of disease status prior to allogeneic HCT. In collaboration with Dr. Maciejewski’s laboratory, we have previously established the necessary clinical and laboratory infrastructure to evaluate molecular architecture in allogeneic transplant recipients. Dr. Maciejewski’s laboratory has generated a 60 gene multiplexed diagnostic NGS panel, targeting the top 60 most commonly mutated exons as previously determined by whole exome sequencing. The panel has been applied to date to over 1000 patients with myeloid neoplasms24. We thus propose to use this panel in a cohort of transplant recipients within the CIMBTR to evaluate the incidence and prognostic significance of molecular minimal residual disease on post-transplant relapse and survival. Patient eligibility population: Adult and pediatric patients Patients with AML in first complete remission who received a first allogeneic HCT from 2008-2015 Myeloablative, reduced-intensity, and non-myeloablative regimens will be included Peripheral blood and bone marrow stem cell grafts All donor sources will be included Available research sample with stored DNA As noted in objectives above, the pilot phase will include a cohort of patients with active disease, and in CR with and without FLT3/NPM1 mutations. Data requirements: Data to be analyzed will be from data collected in the CIBMTR forms. Matched, pre-transplant research samples form the Research Sample Repository will also be used. Patient, disease, and transplant variables include: Patient characteristics:

• Age at transplant • Gender

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• Race • Karnofsky performance score at transplant • Comorbidity index

Disease characteristics: • Cytogenetics • FLT3 ITD mutation status • NPM1 mutation status • Disease risk/status at transplant

Transplant characteristics: • Preparative regimen • Donor relationship • Donor age • Donor-recipient gender match • Donor-recipient CMV status • Donor cell dose- bone marrow versus peripheral blood

Outcomes: • Relapse • Transplant-related mortality • Relapse-free survival • Overall survival • Cause of Death

Study design: This is a retrospective study describing the incidence and characteristics of minimal residual disease by molecular analysis in a cohort of patients with AML prior to allogeneic HCT. Given that many patients with AML do not have circulating/active disease at time of transplant, we will first plan to evaluate a pilot cohort of AML patients with (1) known active disease (N=50), (2) in morphologic CR with unknown molecular status (N=50), at the time of HCT to assess feasibility of using our proposed NGS platform, especially in the cohort of patients in morphologic CR at time of transplantation. In prior analyses at our institution, 65% of patients with AML had at least one mutation present using our NGS 60 gene platform; thus feasibility of performing NGS in patients with AML will be defined as being able to detect mutations in at least 60% of the cohort with active disease at time of HCT.We will thus then define the ability to detect MRD in patients who are in morphologic CR. If feasibility is confirmed, we will conduct an analysis in a larger cohort of patient to determine the association of pre-transplant mutational profile and survival and relapse after allogeneic HCT. The impact of minimal residual disease of somatic molecular mutations on relapse, relapse-free and overall survival will be analyzed. Cox proportional hazards models to include other patient, disease, and transplant characteristics will be used in this analysis. Kaplan-Meier curves will be generated to present survival differences for cases with mutations versus those without mutations. Log-rank test will be used to quantify differences between pairs of such survival curves. The significance of Cox model parameters of mutations will be tested using univariate models. Those with significant coefficients will be included in multivariate models including main effects and interactions; using stepwise regression to pare down the model. Associations between mutations will be quantified using Chi-squared and Fisher exact tests, and where associations exist, variant allelic frequency will be used to inform clone dominance. Variant allelic frequency will be compared and assessed for relapse and survival outcomes. References:

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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 1998; 92(7): 2322-33. 2. 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 2002; 100(13): 4325-36. 3. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of pre-remission and post-remission therapy in adult acute myeloid leukemia: A Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96(13): 4075-83. 4. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364(26): 2496-506. 5. Bejar R, Stevenson KE, Caughey B, Lindsley RC, Mar BG, Stojanov P et al. Somatic Mutations Predict Poor Outcome in Patients with Myelodysplastic Syndrome After Hematopoietic Stem-Cell Transplantation. J Clin Oncol 2014 Sep 1; 32(25):2691-8. 6. Marcucci G, Haferlach T, Dohner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011; 29(5): 475-86. 7. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358(18): 1909-18. 8. Schmid C, Labopin M, Socie G, Daguindau E, Volin L, Huynh A et al. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood 2015; 126(17): 2062-9. 9. Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood 2016; 127(1): 29-41. 10. Hamilton BK, Majhail NS, Hirsch CM, Przychodzen B, Rybicki LA, De Lima M et al. Prognostic Impact of Molecular Mutations in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) on Allogeneic Hematopoietic Cell Transplant (HCT) Outcomes: Adverse Impact of TET2 Mutations. Blood 2015; 126(23). 11. Yoshizato T, Shiozawa Y, Yoshida K, Atsuta Y, Ito C, Kataoka K et al. Impact of Somatic Mutations on Outcome in Patients with MDS after Stem-Cell Transplantation. Blood 2015; 126(23). 12. Luskin MR, Carroll M, Lieberman D, Morrissette JJ, Zhao J, Crisalli L et al. Clinical Utility of Next-Generation Sequencing for Oncogenic Mutations in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant 2016 Nov;22(11):1961-1967. 13. Shayegi N, Kramer M, Bornhauser M, Schaich M, Schetelig J, Platzbecker U et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood 2013; 122(1): 83-92. 14. Kronke J, Schlenk RF, Jensen KO, Tschurtz F, Corbacioglu A, Gaidzik VI et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol 2011; 29(19): 2709-16. 15. Schnittger S, Kern W, Tschulik C, Weiss T, Dicker F, Falini B et al. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood 2009; 114(11): 2220-31. 16. Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A et al. Assessment of Minimal Residual Disease in Standard-Risk AML. N Engl J Med 2016; 374(5): 422-33. 17. Grunwald MR, Tseng LH, Lin MT, Pratz KW, Eshleman JR, Levis MJ et al. Improved FLT3 internal tandem duplication PCR assay predicts outcome after allogeneic transplant for acute myeloid leukemia. Biol Blood Marrow Transplant 2014; 20(12): 1989-95.

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18. Oran B, Jorgensen JL, Marin D, Wang S, Ahmed S, Alousi AM et al. Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia. Haematologica 2016. 19. Araki D, Wood BL, Othus M, Radich JP, Halpern AB, Zhou Y et al. Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission? J Clin Oncol 2016; 34(4): 329-36. 20. Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood 2013; 122(10): 1813-21. 21. Goswami M, McGowan KS, Lu K, Jain N, Candia J, Hensel NF et al. A multigene array for measurable residual disease detection in AML patients undergoing SCT. Bone Marrow Transplant 2015; 50(5): 642-51. 22. Karas M, Steinerova K, Lysak D, Hrabetova M, Jungova A, Sramek J et al. Pre-transplant Quantitative Determination of NPM1 Mutation Significantly Predicts Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Normal Karyotype AML in Complete Remission. Anticancer research 2016; 36(10): 5487-5498. 23. Kayser S, Benner A, Thiede C, Martens U, Huber J, Stadtherr P et al. Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia. Blood cancer journal 2016; 6(7): e449. 24. Makishima H, LaFramboise T, Przychodzen BP, Yoshida K, Ruffalo M, Gomez-Segui I et al. Clinical "MUTATOME" Of Myelodysplastic Syndrome; Comparison to Primary Acute Myelogenous Leukemia. Blood 2013; 122(21).

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Number of samples available for patients undergoing first BM/PB graft allo-HCT for AML between 2008-2015 in proposed study groups

Sample available Study group Recipient+Donor Recipient Donor Total Active disease 496 114 30 640 CR with FLT3/NPM1 negative pre-HCT 34 10 0 44 CR with FLT3/NMP1 positive pre-HCT 8 0 4 12 CR with other scenario (mostly mol. markers unknown)

1549 319 134 2002

Total 2087 443 168 2698 Note: 1) FLT3 and NPM1 status showing in above table are based on CIBMTR forms reported 2) Most of the samples are taken at time of prior to HCT.

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Proposal 1611-111/1611-112 Title: Sorafenib use with allogeneic stem cell transplant for FLT3 mutation positive acute myeloid leukemia Benjamin Kent Nagy Tomlinson, MD, University Hospitals Seidman Cancer Center, [email protected] Yi-Bin Albert Chen, MD, Massachusetts General Hospital, [email protected] Marcos de Lima, MD, University Hospitals Seidman Cancer Center, [email protected] Hypothesis: Sorafenib as part of therapy before or after allogeneic stem cell transplant improves risk of relapse for patients with FLT3 mutation positive acute myeloid leukemia. Specific aims: Primary Objectives:

• Compare leukemia free survival of allogeneic hematopoietic stem cell transplant (HSCT) recipients with a diagnosis of acute myeloid leukemia (AML) with FLT3-ITD mutation who did or did not receive sorafenib as part of therapy from 2010-2016.

Secondary Objective: • Evaluate treatment outcomes including overall survival, treatment related mortality, and rates

of graft versus host disease (GVHD in alloHSCT recipients with a diagnosis of acute myeloid leukemia (AML) that is positive for FLT3-ITD mutation who received sorafenib as part of therapy from 2010-2016.

• Compare treatment outcomes including overall survival, leukemia free survival, non-relapse mortality, and rates of graft versus host disease in in allogeneic stem cell transplant recipients with a diagnosis of acute myeloid leukemia (AML) that is positive for FLT3-ITD mutation for patients who were treated with sorafenib only before alloHSCT, and patients any sorafenib treatment after alloHSCT.

• Identify potential risk factors for adverse outcomes including treatment related mortality and graft versus host disease in patients who were treated with sorafenib only before alloHSCT, and patients any sorafenib treatment after alloHSCT.

Scientific justification: FLT3-ITD mutations have been identified as high risk features for patients with acute myeloid leukemia (AML).1 The disease often presents with a high disease burden and leukocytosis, and complete remissions (CR) with standard therapy are often relatively short, with relapses often being rapidly fatal.2 Allogeneic hematopoietic stem cell transplant (alloHSCT) is commonly pursued as post-remission therapy for eligible patients with FLT3-ITD mutated on the basis of data suggesting a strong graft versus leukemia(GVL) effect and overall survival(OS) benefit.3 Several small molecule tyrosine kinase inhibitors that target FLT3 have shown promising clinical efficacy both as single agents and in combination chemotherapy. One such compound, midostaurin, was the first agent in decades to demonstrate a clear OS benefit in combination with standard induction therapy.4 Though promising, a majority of these compounds remain in clinical trials and do not have FDA approval for broad use. The exception is the medication sorafenib, which is FDA approved to several solid tumors, has been used off label for AML and has demonstrated efficacy in FLT3-ITD mutated AML. In the relapsed/refractory setting, there are case series and reports with sorafenib monotherapy achieving CR rates as high as 23%, sometimes successfully bridging otherwise poor

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prognosis patients to alloHSCT.5 Additionally, combination therapies of sorafenib with standard chemotherapies have reported promising results. Ravendi et al reported a phase I/II study of sorafenib combined with standard induction for patients under 60. The CR rate was more than double for patients with FLT3 mutations compared to wild type.6 Improved OS compared to historical controls was reported for 83 FLT3-ITD mutated patients in the Alliance C11001 trial.7,8 Combinations with lower intensity therapy also suggest efficacy in the older FLT3-ITD mutated patient population. A phase II study of sorafenib combined with azacitidine in elderly patients with AML, sorafenib induced CR in 23% of patients.9 Even with the potential for FLT3 inhibitors such as sorafenib, many patients with FLT3-ITD mutated AML proceed to alloHSCT. Registry studies suggest that alloSCT in FLT3-ITD mutated AML results in outcomes closer to FLT3 wildtype AML, though relapse rates of FLT3-ITD mutated AML are consistently higher.10,11 Given the consistently reported higher rates of relapse after alloHSCT, sorafenib maintenance after alloHSCT has been proposed as a strategy to improve outcomes.12 Clinical activity and reasonable safety of sorafenib for relapsed FLT3-ITD AML after alloHSCT was first suggested in several case reports.12,13 Additional early literature on sorafenib maintenance were small case series that universally reported more durable remissions than anticipated by historical norms. Skin graft versus host disease (GVHD) reports was reported to be common in these reports, and some authors suggested that sorafenib may facilitate a graft versus leukemia effect in patients with chronic GVH.14-16 In a pediatric population, Tarlock and associates reported on 6 patients under 18 with FLT3-ITD mutated AML treated with sorafenib maintenance, and suggested that sorafenib was most effected at clearance of minimal residual disease, when detected before or after transplant.17 The most robust data to date evaluating the use of sorafenib as a maintenance therapy after alloHSCT come from Dr. Chen and colleagues in a Phase I study of sorafenib that identified a maximum tolerated dose of 400mg twice daily following alloHSCT from a variety of donor sources. Sorafenib was started between 45 and 120 days following alloHSCT. 22 patients were evaluated and followed after alloHSCT and had favorable one year outcomes of OS of 95% with a progression free survival of 85%. Reversible skin rashes were observed, but felt inconsistent with GVHD and no severe acute GVHD appeared to be observed after starting sorafenib, calling into question earlier reports of higher GVHD of the skin.18 The same group has presented retrospective data of 80 AML patients with FLT3-ITD mutations who did or did not receive oral sorafenib maintenance therapy at a single institution, and found a significant 2-year OS benefit of 83% vs 58%, with no differences in non-relapse mortality.19 The available evidence suggests that sorafenib may improve outcomes for FLT3-ITD mutated AML either as part of pre-transplant therapy or as a maintenance therapy and warrants additional evaluation. The currently available evidence is limited to retrospective studies, and one or few institutions. Despite this limited evidence, use of sorafenib has been sufficiently widespread that CIBMTR includes sorafenib in their data collection forms. Thus, we propose using the CIBMTR database to compare the outcomes of FLT3-ITD mutated AML patients who underwent alloHSCT that were treated with sorafenib at any point in their treatment course to those who did not. Additionally, we propose to compare outcomes for those treated with sorafenib only before alloHSCT and those treated any time after alloHSCT to evaluate potential impacts of timing of sorafenib treatment. This study could provide data for comparative endpoints for future studies. Patient eligibility population: Inclusion criteria

• AlloHSCT recipient’s primary diagnosis of acute myeloid leukemia with a documented FLT3-ITD mutation undergoing first alloHSCT from 2013-2016.

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Exclusion criteria • Prior alloHSCT (prior autologous stem cell transplant for consolidation permitted.) • Core Binding Factor AML with FLT3-ITD mutation • Acute promyelocytic leukemia • Exposure to FLT3 inhibitor other than sorafenib before or after alloHSCT. • Sorafenib given only for relapsed disease after alloHSCT. • Alternative therapy given for maintenance of remission following alloHSCT, including azacitidine,

decitabine, thioguanine, cytarabine. Intrathecal maintenance therapy will be permitted.

Data requirements: Patient data

• Age • Gender • Race

AML information • Date of AML diagnosis • Additional baseline laboratory/Cytogenetic/molecular risk group (Intermediate vs unfavorable

for FLT3-ITD AML) • Disease status at time of HSCT • Therapy received prior to transplant (induction, low intensity treatment) • Documentation of sorafenib use during treatment (none, before alloHSCT only, after alloHSCT

only, both before and after alloHSCT) Allogeneic HSCT related data

• Date of allogeneic HSCT • Preparative regimen and preparative regimen intensity • Donor source • Stem cell source (bone marrow, mobilized peripheral blood, versus UCB) • Engraftment dates (neutrophils, platelets) • GVHD prophylaxis • GVHD occurrences and grade • Disease Status at Day 100 • Date of relapse (if applicable) • Date of death or last known contact • Cause of death (treatment vs disease vs unrelated)

Study design: This will be a retrospective review of all patients meeting inclusion and exclusion criteria. Patient and disease characteristics will be collected from the CIBMTR registry for patients receiving HSCT from 2013 through 2016. Groups’ characteristics will be compared with Chi-square or Wilcoxon statistics for categorical and continuous variables respectively. Overall survival and leukemia free survival will be evaluated with Kaplan-Meier methods. Acute and chronic GVHD, treatment related mortality and AML relapse will be calculated using cumulative incidence curves. Potential patient, disease, and treatment related prognostic factors will be evaluated with multivariate analysis with Cox proportional hazards regression to study association between treatment groups and outcomes.

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References: 1. Wagner K, Damm F, Thol F, et al. FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype. Haematologica. 2011;96(5):681-686. 2. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? ASH Education Program Book. 2013;2013(1):220-226. 3. Schlenk RF, Döhner K, Krauter J, et al. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia. New England Journal of Medicine. 2008;358(18):1909-1918. 4. Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015;126(23):6-6. 5. Metzelder SK, Schroeder T, Finck A, et al. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia. 2012;26(11):2353-2359. 6. Ravandi F, Cortes JE, Jones D, et al. Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia. Journal of Clinical Oncology. 2010;28(11):1856-1862. 7. Serve H, Krug U, Wagner R, et al. Sorafenib in Combination With Intensive Chemotherapy in Elderly Patients With Acute Myeloid Leukemia: Results From a Randomized, Placebo-Controlled Trial. Journal of Clinical Oncology. 2013;31(25):3110-3118. 8. Uy GL, Mandrekar S, Laumann K, et al. Addition of Sorafenib to Chemotherapy Improves the Overall Survival of Older Adults with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) (Alliance C11001). Blood. 2015;126(23):319. 9. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT3 internal tandem duplication mutation. Blood. 2013;121(23):4655. 10. Deol A, Sengsayadeth S, Ahn KW, et al. Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis. Cancer. 2016. 11. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 Internal Tandem Duplication on the Outcome of Related and Unrelated Hematopoietic Transplantation for Adult Acute Myeloid Leukemia in First Remission: A Retrospective Analysis. Journal of Clinical Oncology. 2012;30(7):735-741. 12. Metzelder S, Wang Y, Wollmer E, et al. Compassionate use of sorafenib in FLT3-ITD–positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood. 2009;113(26):6567. 13. Kruger WH, Hirt C, Kiefer T, Neumann T, Busemann C, Dolken G. Molecular remission of FLT3-ITD+ positive AML relapse after allo-SCT by acute GVHD in addition to sorafenib. Bone Marrow Transplant. 2012;47(1):137-138. 14. Antar A, Kharfan-Dabaja MA, Mahfouz R, Bazarbachi A. Sorafenib Maintenance Appears Safe and Improves Clinical Outcomes in FLT3-ITD Acute Myeloid Leukemia After Allogeneic Hematopoietic Cell Transplantation. Clinical lymphoma, myeloma & leukemia. 2015;15(5):298-302. 15. Winkler J, Rech D, Kallert S, et al. Sorafenib induces sustained molecular remission in FLT3-ITD positive AML with relapse after second allogeneic stem cell transplantation without exacerbation of acute GVHD: a case report. Leukemia research. 2010;34(10):e270-e272.

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16. Tschan-Plessl A, Halter JP, Heim D, Medinger M, Passweg JR, Gerull S. Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation. Annals of hematology. 2015;94(11):1899-1905. 17. Tarlock K, Chang B, Cooper T, et al. Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia. Pediatric blood & cancer. Jun 2015;62(6):1048-1054. 18. Chen YB, Li S, Lane AA, et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014;20(12):2042-2048. 19. Brunner AM, Li S, Fathi AT, et al. Hematopoietic Cell Transplantation with or without Sorafenib Maintenance for Patients with FLT3-ITD Acute Myeloid Leukemia in CR1. Blood. 2015;126(23):864-864.

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Baseline characteristics for adult patients undergoing first allo-HCT for FLT3 ITD mutated AML

between 2013-2016

Variable N (%) Number of patients 436 Number of centers 108 Patient age 18-29 40 (9) 30-39 52 (12) 40-49 80 (18) 50-59 120 (28) 60-69 118 (27) >=70 26 (6) Median (range) 55 (18-76) Gender Male 206 (47) Female 230 (53) Karnofsky score <90% 182 (42) >=90% 245 (56) Missing 9 (2) HCT-CI 0 103 (24) 1 69 (16) 2 64 (15) 3+ 200 (46) White blood count at diagnosis <= 30 206 (47) 30 - 100 130 (30) > 100 79 (18) Missing 21 (5) Median (range) 31 (<1-416) Disease status prior to HCT Primary induction failure 45 (10) CR1 320 (73) CR2 34 (8) >=CR3 3 (<1) Relapse 34 (8) Cytogenetic score Favorable 8 (2) Intermediate 336 (77) Poor 40 (9) TBD 46 (11) NT 3 (<1) Missing 3 (<1) FLT3 ITD mutation DX Negative 5 (1)

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Variable N (%) Positive 417 (96) Missing 14 (3) FLT3-ITD molec markers PR Negative 178 (41) Positive 51 (12) Not done 11 (3) Missing 196 (45) Sorafenib given prior to HCT No 372 (85) Yes 64 (15) Sorafenib given post HCT No 368 (84) Yes 63 (15)

Missing 5 (1) Sorafenib given pre/post HCT

No/missing 4 (1) No/no 324 (74) No/yes 44 (10) Yes/missing 1 (<1) Yes/no 44 (10) Yes/yes 19 (4)

Conditioning regimen intensity Myeloablative 232 (53) RIC 140 (32) NMA 46 (11) TBD 17 (4) Missing 1 (<1) Donor type HLA-identical sibling 106 (24) Other relatives 74 (17) Well-matched unrelated 150 (34) Partially-matched unrelated 35 (8) Mis-matched unrelated 2 (<1) Unrelated (matching unknown) 7 (2) Cord blood 62 (14) Donor/recipient CMV serostatus +/+ 119 (27) +/- 43 (10) -/+ 104 (24) -/- 94 (22) CB/+ 55 (13) CB/- 7 (2) Missing 14 (3) Donor/recipient sex match M-M 107 (25) M-F 126 (29) F-M 70 (16)

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Variable N (%) F-F 67 (15) CB-M 27 (6) CB-F 35 (8) Missing 4 (<1) Graft type Bone marrow 56 (13) Peripheral blood 317 (73) Umbilical cord blood 62 (14) PB + OTH (new: 2+90) 1 (<1) GVHD prophylaxis No GVHD prophylaxis 5 (1) Ex-vivo T-cell depletion 6 (1) CD34 selection 10 (2) Post-CY + other(s) 42 (10) TAC + MMF +- other(s) (except post-CY) 71 (16) TAC + MTX +- other(s) (except MMF, post-CY) 184 (42) TAC + other(s) (except MMF, MTX, post-CY) 22 (5) TAC alone 9 (2) CSA + MMF +- other(s) (except post-CY) 46 (11) CSA + MTX +- other(s) (except MMF, post-CY) 22 (5) CSA + other(s) (except MMF, MTX, post-CY) 4 (<1) CSA alone 7 (2) Other(s) 7 (2) Missing 1 (<1) ATG/Campath ATG alone 108 (25) CAMPATH alone 10 (2) No ATG or CAMPATH 317 (73) Missing 1 (<1) Year of HCT 2013 52 (12) 2014 172 (39) 2015 163 (37) 2016 49 (11) Median follow-up of survivors (range), months 12 (3-36) Note: Excluded core binding factor AML ( inv(16), t(16;16)) Excluded cases with Sorafenib given for post-HCT relapse

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1

Proposal 1611-163 Title: Impact of post-transplant maintenance therapy with BCR-ABL tyrosine kinase inhibitors on outcomes of Philadelphia chromosome-positive acute lymphoblastic leukemia Zack DeFilipp, MD. Massachusetts General Hospital Cancer Center, [email protected] Yi-Bin Chen, MD. Massachusetts General Hospital Cancer Center, [email protected] Hypothesis: We hypothesize that maintenance TKI following allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) will result in lower rates of relapse and improved disease-free survival (DFS). We hypothesize that the use of a TKI-based maintenance strategy will result in improved overall survival (OS) when compared to those without maintenance therapy who first initiate TKIs and/or chemotherapy as salvage strategy at relapse. Specific aims:

• The primary aim is to describe DFS (at 1- and 3-years post-transplant) of patients with Ph+ ALL undergoing allogeneic HCT in CR1 who received maintenance TKI therapy and compare to controls (no maintenance therapy).

• The secondary aim is to compare the OS (at 1- and 3-years post-transplant) between the same two groups (maintenance versus no maintenance).

• Additional aims to be evaluated: o To describe the general practice of maintenance TKI administered post-transplant o To describe the management of post-transplant relapses o To compare the incidence of acute and chronic GVHD in patients receiving maintenance

TKI versus control (no maintenance) Scientific justification: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), a subgroup comprising 20-30% of adult ALL, is considered a high-risk cytogenetic category and is associated with poor prognosis when treated with chemotherapy alone [1]. Thus, a traditional approach has been to recommend allogeneic hematopoietic cell transplantation (HCT) for adults in first complete remission (CR1). The introduction of tyrosine kinase inhibitors (TKIs) into induction and post-remission therapy has changed the therapeutic landscape for Ph+ ALL. In an analysis of the Ph+ arm in the UKLLXII/ECOG2993 study, the addition of imatinib improved complete remission rates and outcomes (4-year OS; imatinib-cohort 38%, pre-imatinib cohort 22%, p=0.003), although the OS benefit likely derives, at least in part, by facilitating allogeneic HCT [2]. Even with the incorporation of TKIs into current therapeutic approaches, disease relapse remains the major source of failure for such patients receiving allogeneic HCT. In a CIBMTR analysis of patients with Ph+ ALL receiving allogeneic HCT in CR1, the 3-year relapse rate was 49% for those receiving reduced-intensity conditioning (RIC) and 28% for those receiving myeloablative conditioning (MAC) [3]. On multivariate analysis, the absence of pre-HCT TKI (HR 1.88, p=0.018), RIC (HR=1.891, p=0.054), and pre-HCT MRD positivity (HR 1.6, p=0.070) were all associated with an increase relapse risk. Maintenance therapy, defined as therapy initiated and continued while the patient remains in CR, is a promising approach to reduce the rate of relapse following allogeneic HCT. Initial studies found maintenance imatinib to be safe and feasible when given after HCT. In one trial, imatinib was

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2

administered to 22 patients with Ph+ leukemia from the time of engraftment to one year after HCT, with 77% maintaining major molecular remission (MMR) and only 9% experiencing hematologic relapse [4]. Given that allogeneic HCT is increasingly performed in patients who fail first-line TKI and beyond, data on the safety and efficacy of later generation TKIs administered post-transplant is of great interest [5-8]. With variable responses to pre-HCT TKIs and the availability of multiple agents, individualized approaches to maintenance are being implemented [9]. Given that a randomized trial comparing maintenance TKI vs. no maintenance TKI is likely not feasible, an analysis of registry data is an important approach to attempt to evaluate the impact of post-transplant TKIs. Two registry studies have previously tried to evaluate the effect of post-transplant maintenance, but have been admittedly underpowered. In a prior CIBMTR analysis of allogeneic HCT for Ph+ ALL patients treated between 2000-2009, there were only 43 patients who received maintenance and no benefit to this practice was observed [3]. In an EBMT analysis of allogeneic HCT for Ph+ ALL performed between 2000-2010, only 60 received maintenance therapy afterwards, but there was an associated benefit with the use of maintenance TKI LFS HR 0.44 (p=0.002) and OS HR 0.42 (p=0.004)[10]. We propose to use the CIBMTR database to look at a more modern data set in which more transplants utilizing post-HCT maintenance therapy are captured in order to better evaluate the benefits of this approach. Patient eligibility population: All adult patients with Ph+ ALL who underwent first allogeneic HSCT between 2007 and 2014. Data requirements: Patient Specific (CIBMTR Form 2000) Age at transplant (date of birth) Gender Race Pre-transplant Disease Specific (CIBMTR Form 2011) Date of diagnosis CNS disease Additional cytogenetic abnormalities to t (9;22) Pre-HCT treatments Pre-HCT TKIs Response to previous therapies Disease status at transplant Specify remission as transplant (cytogenetic and/or molecular remission) Transplant Specific (CIBMTR Forms 2005 & 2006) Transplant date Conditioning regimen (myeloablative, reduced intensity/non-myeloablative) Donor-recipient HLA match Graft Source

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3

Post-transplant Disease Specific (CIBMTR Form 2111) Maintenance TKI therapy Maintenance or consolidation therapy (non-TKI) Disease assessment at time of best response to HSCT Disease relapse and/or progression post-HSCT Treatment for persistent, relapsed or progressive disease post-HSCT Outcome Measures (CIBMTR Forms 2100, 2200, & 2300) The incidence of acute and chronic GVHD Graft failure (primary and secondary) Incidence of disease relapse Time to disease relapse Death Sample requirements: No samples are required for this proposal. Study design (Scientific Plan): This is a proposal for a registry-based retrospective study using the CIBMTR database. Statistical analyses will be performed according to the recommendations of the CIBMTR statisticians. Descriptive statistics table of patients including demographics, disease-related factors, transplant-related factors will be prepared. Median and range will be listed for continuous variables. The total number of patients and the percentage of each subgroup will be calculated for categorical variables. Probability of progression-free survival and overall survival will be calculated using the Kaplan Meier estimator, with the variance estimated by the Greenwood’s formula. Probabilities of TRM and relapse will be generated using cumulative incidence estimates to accommodate the competing risk event. Multivariate analysis will be performed using proportional hazards models. These analyses will fit models to determine which risk factors may be related to a given outcome. References: 1. Moorman, A.V., C.J. Harrison, G.A. Buck, S.M. Richards, L.M. Secker-Walker, M. Martineau, et al., Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood, 2007. 109(8): p. 3189-97. 2. Fielding, A.K., J.M. Rowe, G. Buck, L. Foroni, G. Gerrard, M.R. Litzow, et al., UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood, 2014. 123(6): p. 843-50. 3. Bachanova, V., D.I. Marks, M.J. Zhang, H. Wang, M. de Lima, M.D. Aljurf, et al., Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia, 2014. 28(3): p. 658-65. 4. Carpenter, P.A., D.S. Snyder, M.E. Flowers, J.E. Sanders, T.A. Gooley, P.J. Martin, et al., Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood, 2007. 109(7): p. 2791-3. 5. Caocci, G., A. Vacca, A. Ledda, F. Murgia, E. Piras, M. Greco, et al., Prophylactic and preemptive therapy with dasatinib after hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Biol Blood Marrow Transplant, 2012. 18(4): p. 652-4.

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4

6. Teng, C.L., J.T. Yu, H.C. Chen, and W.L. Hwang, Maintenance therapy with dasatinib after allogeneic hematopoietic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann Hematol, 2013. 92(8): p. 1137-9. 7. Shimoni, A., Y. Volchek, M. Koren-Michowitz, N. Varda-Bloom, R. Somech, N. Shem-Tov, et al., Phase 1/2 study of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer, 2015. 121(6): p. 863-71. 8. Carpenter, P.A., L. Johnston, H.F. Fernandez, J.P. Radich, M.J. Mauro, M.E. Flowers, et al., A Multicenter Phase I/II Study of Relapse Prophylaxis with Nilotinib after Hematopoietic Cell Transplantation (HCT) for High-Risk Philadelphia Chromosome-Positive (Ph+) Leukemias. Biol Blood Marrow Transplant, 2015. 21(2): p. S274-S276. 9. DeFilipp, Z., A.A. Langston, Z. Chen, C. Zhang, M.L. Arellano, F. El-Rassi, et al., Does post-transplant maintenance therapy with tyrosine kinase inhibitors improve outcomes of high-risk Philadelphia chromosome-positive leukemia? Clin Lymphoma Myeloma Leuk, 2016. 10. Brissot, E., M. Labopin, M.M. Beckers, G. Socie, A. Rambaldi, L. Volin, et al., Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia. Haematologica, 2015. 100(3): p. 392-9.

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5

Baseline characteristics for adult patients undergoing first allo-HCT for Ph+ ALL between 2008-2015

post-HCT TKI as maintenance Variable Yes No Number of patients 383 282 Number of centers 102 85 Patient age 18-29 81 (21) 31 (11) 30-39 78 (20) 55 (20) 40-49 108 (28) 77 (27) 50-59 82 (21) 65 (23) 60-69 33 (9) 52 (18) >=70 1 (<1) 2 (<1) Median (range) 42 (18-70) 47 (18-73) Gender Male 209 (55) 154 (55) Female 174 (45) 128 (45) Karnofsky score <90% 145 (38) 100 (35) >=90% 235 (61) 182 (65) Missing 3 (<1) 0 HCT-CI 0 166 (43) 112 (40) 1 50 (13) 45 (16) 2 45 (12) 38 (13) 3+ 121 (32) 86 (30) Missing 1 (<1) 1 (<1) White blood count at diagnosis <= 30 182 (48) 148 (52) 30 - 100 65 (17) 49 (17) > 100 38 (10) 36 (13) Missing 98 (26) 49 (17) Median (range) 17 (<1-560) 16 (<1-548) Disease status prior to HCT Primary induction failure 15 (4) 10 (4) CR1 294 (77) 253 (90) CR2 49 (13) 17 (6) >=CR3 8 (2) 1 (<1) Relapse 17 (4) 1 (<1) Cytogenetic score Normal 16 (4) 2 (<1)

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6

post-HCT TKI as maintenance Variable Yes No Poor 355 (93) 275 (98) Other 3 (<1) 1 (<1) TBD 7 (2) 0 NT 0 2 (<1) Missing 2 (<1) 2 (<1) Conditioning regimen intensity Myeloablative 308 (80) 189 (67) RIC 42 (11) 41 (15) NMA 30 (8) 41 (15) TBD 3 (<1) 9 (3) Missing 0 2 (<1) Donor type HLA-identical sibling 99 (26) 90 (32) Other relatives 34 (9) 32 (11) Well-matched unrelated 117 (31) 89 (32) Partially-matched unrelated 27 (7) 26 (9) Mis-matched unrelated 3 (<1) 0 Unrelated (matching unknown) 2 (<1) 0 Cord blood 101 (26) 45 (16) Donor/recipient CMV serostatus +/+ 111 (29) 92 (33) +/- 35 (9) 25 (9) -/+ 75 (20) 59 (21) -/- 54 (14) 55 (20) CB/+ 64 (17) 30 (11) CB/- 36 (9) 14 (5) Missing 8 (2) 7 (2) Donor/recipient sex match M-M 99 (26) 87 (31) M-F 82 (21) 61 (22) F-M 54 (14) 39 (14) F-F 46 (12) 48 (17) CB-M 56 (15) 26 (9) CB-F 45 (12) 19 (7) Missing 1 (<1) 2 (<1) Graft type Bone marrow 58 (15) 34 (12) Peripheral blood 224 (58) 203 (72) Umbilical cord blood 101 (26) 45 (16)

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7

post-HCT TKI as maintenance Variable Yes No GVHD prophylaxis No GVHD prophylaxis 10 (3) 4 (1) Ex-vivo T-cell depletion 2 (<1) 1 (<1) CD34 selection 4 (1) 1 (<1) Post-CY + other(s) 22 (6) 20 (7) TAC + MMF +- other(s) (except post-CY) 65 (17) 48 (17) TAC + MTX +- other(s) (except MMF, post-CY) 140 (37) 114 (40) TAC + other(s) (except MMF, MTX, post-CY) 26 (7) 25 (9) TAC alone 8 (2) 11 (4) CSA + MMF +- other(s) (except post-CY) 64 (17) 36 (13) CSA + MTX +- other(s) (except MMF, post-CY) 38 (10) 19 (7) CSA + other(s) (except MMF, MTX, post-CY) 1 (<1) 1 (<1) CSA alone 1 (<1) 0 Other(s) 1 (<1) 2 (<1) Missing 1 (<1) 0 ATG/Campath ATG alone 74 (19) 47 (17) CAMPATH alone 5 (1) 6 (2) No ATG or CAMPATH 303 (79) 229 (81) Missing 1 (<1) 0 Post-HCT TKI as maintenance

No 0 383 Dasatinib 108 (38) Dasatinib + Imatinib 41 (15) Dasatinib + Nilotinib 12 (4) Imatinib 98 (35) Imatinib + Nilotinib 4 (1) Nilotinib 19 (7)

Year of HCT 2008 78 (20) 39 (14) 2009 51 (13) 25 (9) 2010 29 (8) 22 (8) 2011 39 (10) 17 (6) 2012 24 (6) 18 (6) 2013 42 (11) 42 (15) 2014 53 (14) 69 (24) 2015 67 (17) 50 (18) Median follow-up of survivors (range), months 38 (3-101) 26 (3-99)

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