A G E N D A ACUTE LEUKEMIA Co 293 9868; 614 293 6690;€¦ · Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA Grapevine, TX Saturday, March

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA Grapevine, TX Saturday, March 1, 2014, 2:45 pm ‐ 4:45 pm

Co‐Chair: Donald Bunjes, MD, University Hospital Ulm, Ulm, Germany Telephone: 49‐731‐500‐45532; Fax: 49‐731‐500‐45655;

E‐mail: [email protected] Co‐Chair: Steven Devine, MD, Ohio State Medical Center ‐ James Cancer Center Telephone: 614‐293‐9868; Fax: 614‐293‐6690; E‐mail: [email protected] Co‐Chair: Marcos de Lima, MD, Case Western Reserve University – University Hospitals

Case Medical Center; Telephone: 216‐286‐6869; Fax: 216‐201‐5451; E‐mail: [email protected]

Statisticians: Hai‐Lin Wang, MPH, CIBMTR Statistical Center Telephone: 414‐805‐0647; Fax: 414‐805‐0714; E‐mail: [email protected] Mei‐Jie Zhang, PhD, CIBMTR Statistical Center Telephone: 414‐456‐8375; Fax: 414‐456‐6530; E‐mail: [email protected]

Scientific Director: Daniel Weisdorf, MD, University of Minnesota Telephone: 612‐624‐3101; Fax: 612‐625‐6919; E‐mail: [email protected] Wael Saber, MD, MS, CIBMTR Statistical Center Telephone: 414‐805‐0677; Fax: 414‐805‐0714; E‐mail: [email protected] 1. Introduction

a. 2013 Tandem minutes for approval (Attachment 1) b. Newly appointed chair: Brenda Sandmaier, MD; Fred Hutchinson Cancer Research Center;

E‐mail: [email protected]

2. Accrual summary (Attachment 2)

3. Presentations, published or submitted papers a. LK08‐02 Koreth J, Pidala J, Perez WS, Deeg HJ, Garcia‐Manero G, Malcovati L, Cazzola M, Park

S, Itzykson R, Ades L, Fenaux P, Jadersten M, Hellstrom‐Lindberg E, Gale RP, Beach CL, Lee SJ, Horowitz MM, Greenberg PL, Tallman MS, DiPersio JF, Bunjes D, Weisdorf DJ, Cutler C. Role of reduced‐intensity conditioning allogeneic hematopoietic stem‐cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J Clin Oncol. 2013; 31(21):2662‐70.

b. LK02‐05 Foran JM, Pavletic SZ, Logan BR, Agovi‐Johnson MA, Perez WS, Bolwell BJ, Bornhauser M, Bredeson CN, Cairo MS, Camitta BM, Copelan EA, Dehn J, Gale RP, George B, Gupta V, Hale GA, Lazarus HM, Litzow MR, Maharaj D, Marks DI, Martino R, Maziarz RT, Rowe JM, Rowlings PA, Savani BN, Savoie ML, Szer J, Waller EK, Wiernik PH, Weisdorf DJ. Unrelated Donor Allogeneic Transplantation After Failure of Autologous Transplantation for Acute Myeloid Leukemia: A Study from the CIBMTR. Biol Blood Marrow Transplant. 2013; 19(7):1102‐8.

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c. LK08‐01 Lee SJ, Storer B, Wang H, Lazarus HM, Waller EK, Isola LM, Klumpp TR, Umejiego JB, Savani BN, Loren AW, Cairo MS, Camitta BM, Cutler CS, George B, Khoury HJ, Marks DI, Rizzieri DA, Copelan EA, Gupta V, Liesveld JL, Litzow MR, Miller AM, Schouten HC, Gale RP, Cahn JY, Weisdorf DJ. Providing Personalized Prognostic Information For Adult Leukemia Survivors. Biol Blood Marrow Transplant. 2013; 19(11):1600‐7.

d. LK10‐03 Bachanova V, Marks DI, Zhang MJ, Wang H, de Lima M, Aljurf MD, Arellano M, Artz AS, Bacher U, Cahn JY, Chen YB, Copelan EA, Drobyski WR, Gale RP, Greer JP, Gupta V, Hale GA, Kebriaei P, Lazarus HM, Lewis ID, Lewis VA, Liesveld JL, Litzow MR, Loren AW, Miller AM, Norkin M, Oran B, Pidala J, Rowe JM, Savani BN, Saber W, Vij R, Waller EK, Wiernik PH, Weisdorf DJ. 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 2013, Epub ahead of print.

e. LK10‐02 Warlick ED, Paulson K, Brazauskas R, Zhong X, Miller AM, Camitta BM, George B, Savani BN, Ustun C, Marks DI, Waller EK, Baron F, Freytes CO, Socie G, Akpek G, Schouten HC, Lazarus HM, Horwitz EM, Koreth J, Cahn JY, Bornhauser M, Seftel M, Cairo MS, Laughlin MJ, Sabloff M, Ringdén O, Gale RP, Kamble RT, Vij R, Gergis U, Mathews V, Saber W, Chen YB, Liesveld JL, Cutler CS, Ghobadi A, Uy GL, Eapen M, Weisdorf DJ, Litzow MR. Effect of Postremission Therapy before Reduced‐Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia in First Complete Remission. Biol Blood Marrow Transplant 2013, Epub ahead of print.

f. LK04‐01 Holter‐Chakrabarty JL, Rubinger M, Le‐Rademacher J, Wang HL, Grigg A, Selby GB, Szer J, Rowe JM, Weisdorf DJ, Tallman MS. Autologous is Superior to Allogeneic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukemia in Second Complete Remission. Submitted.

g. LK07‐03c McClune BL, Ahn KW, Wang HL, Antin JH, Artz AS, Cahn JY, Deol A, Freytes CO, Hamadani M, Holmberg LA, Jagasia MH, Jakubowski AA, Kharfan‐Dabaja MA, Lazarus HM, Miller AM, Olsson R, Pedersen TL, Pidala J, Pulsipher MA, Rowe JM, Saber W, van Besien KW, Waller EK, Weisdorf DJ. Reduced‐Intensity and Non‐Myeloablative Hematopoietic Cell Transplantation in Older Patients with Non‐Hodgkin Lymphoma (NHL): Encouraging Survival even in Advanced Age. Submitted.

h. LK12‐03 Bejanyan N, Weisdorf DJ, Logan B, Wang HL, Devine S, de Lima M, Bunjes D, Zhang MJ. Survival of AML patients Relapsing after Allogeneic Stem Cell Transplantation. Presentation at ASH meeting in New Orleans, LA, December 2013. Manuscript in preparation.

i. LK11‐01 Goyal S, Zhang MJ, Wang HL, Weisdorf DJ, Uy G. Extramedullary Involvement does not Affect the Outcome of Allogeneic Transplantation for Acute Myeloid Leukemia: a CIBMTR Analysis. Presentation at BMT Tandem meeting in Grapevine, Tx, February 2014. Manuscript in preparation.

4. Studies in progress (Attachment 3) a. LK09‐02 Monosomal karyotype and chromosomal 7

abnormalities in allo HCT for AML/MDS (M Pasquini/ M Battiwala)

Manuscript preparation

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b. LK11‐01 Extramedullary disease and outcome in AlloHCT for

AML (S Goyal/ G Uy) Manuscript preparation

c. LK12‐01 Chemo vs. AlloHCT for Ph‐ ALL (M Seftel) Data file preparation

d. LK12‐02 Allotx for FLT3/ITD positive AML in CR1 (S Sengsayadeth/ A Deol/ B Savani/ M Jagasia)

Data file preparation

e. LK12‐03 Survival after relapse in AML (N Bejanyan/ D Weisdorf/ MJ Zhang)

Manuscript preparation

f. LK13‐01 Outcomes after RIC AlloHCT in older adult ALL (A Rosko/ V Bachanova)

Protocol development

g. LK13‐02 Impact of cytogenetic abnormalities in AlloHCT for Ph‐ ALL in CR1 (A Lazaryan)


h. LK13‐03 Outcomes after allotx for acute biphenotypic leukemia (R Munker)


5. Proposed studies (Attachments 4 through 12) AML a. PROP 1310‐07 Outcome of allogeneic hematopoietic cell transplantation in patients with

acute myeloid leukemia with antecedent history of Philadelphia‐negative myeloproliferative Neoplasm (G Vikas) (Attachment 4)

b. PROP 1310‐19 Allogeneic transplantation to treat secondary AML diagnosed after autologous transplant (L Metheny, M de Lima, H Mohty) (Attachment 5)

c. PROP 1311‐50 Outcome of umbilical cord blood transplantation (CBT) in adults with high risk acute myeloid leukemia (I Lewis) (Attachment 6)

d. PROP 1311‐56 Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first and second complete remission (FV Michelis, V Gupta) (Attachment 7)

e. PROP 1310‐02/1310‐04/1312‐01 Risk index for Acute Leukemia Patients Receiving Allogeneic Hematopoietic Cell Transplantation (F Anwer, YX Hu, H Huang, R Krishnadasan, C Ustun, D Weisdorf, A Yeager) (Attachment 8)

ALL f. PROP 1311‐34 The graft versus leukemia effect following reduced intensity allotransplant for

acute lymphoblastic leukemia (V Bachanova) (Attachment 9) g. PROP 1311‐43 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 (N Bejanyan, A Lazaryan, D Weisdorf) (Attachment 10)

h. PROP 1312‐09 Comparison of total body irradiation (TBI)‐based with intravenous (i.v.) busulfan (Bu) containing chemotherapy‐only myeloablative transplant conditioning regimens in patients with acute lymphoblastic leukemia (P Kebriaei, D Marks) (Attachment 11)

ALL LEUKEMIAS i. PROP 1311‐05 Second Allogeneic Transplantation using a Reduced Intensity Conditioning

Preparative Regimen in the Case of Relapse or Graft Failure in Patients with Acute Leukemia (R Salit, C Delaney, T Gooley) (Attachment 12)

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Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA Salt Lake City, Utah Saturday, February 16, 2013, 2:45 pm ‐ 4:45 pm

Co‐Chair: Donald Bunjes, MD, University Hospital Ulm, Ulm, GERMANY

Telephone: +49‐731‐500‐45532; Fax: +49‐731‐500‐45655; E‐mail: [email protected]

Co‐Chair: Steven Devine, MD, Ohio State Medical Center ‐ James Cancer Center, Columbus, OH Telephone: 614‐293‐9868; Fax: 614‐293‐6690; E‐mail: [email protected]

Co‐Chair: John F. DiPersio, MD, PhD, Washington University School of Medicine, St. Louis, MO

Telephone: 314‐454‐8491; Fax: 314‐454‐8315; E‐mail: [email protected] Statisticians: Hailin Wang, MPH, CIBMTR Statistical Center, Milwaukee, WI

Telephone: 414‐805‐0647; Fax: 414‐805‐0714; E‐mail: [email protected] Mei‐Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414‐456‐8375; Fax: 414‐456‐6530; E‐mail: [email protected]

Scientific Director: Daniel Weisdorf, MD, University of Minnesota, Minneapolis, MN Telephone: 612‐624‐3101; Fax: 612‐625‐6919; E‐mail: [email protected] 1. Introduction

The CIBMTR Acute Leukemia Working Committee was called to order at 2:45 pm on Saturday, February 16, 2013, by Dr. Daniel Weisdorf. The chairs, scientific director and statisticians were presented. Attendees were asked to have their name badges scanned for attendance purposes and to maintain the committee membership roster, and to fill out the Working Committee evaluations and voting sheets for proposals. The CIBMTR guidelines for voting on proposals were discussed. The guidelines are based on a scale from 1 to 9; 1= high scientific impact, 9= low scientific impact. The meeting was limited to presentation and discussion of proposals. Dr. Donald Bunjes introduced the accrual summary, committee’s accomplishments for the past year and progress of ongoing studies. Each proposal presentation was limited to 5 minutes (maximum 3‐4 slides) to allow for adequate time for discussion (5‐7 minutes). The minutes of the February 2012 meeting were approved without modifications.

Dr. Donald Bunjes welcomed Dr. Marcos de Lima as newly appointed ALWC chair starting from March 2013 and presented a souvenir to departing chair Dr. John DiPersio. Dr. Daniel Weisdorf announced the principles established by advisory committee to improve the quality and efficiency of working committees: 1) peer‐reviewed publications of high scientific impact as target 2) work product to be finished within a reasonable time period 3) ensuring inclusiveness and fairness of the process.

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2. Accrual summary

Due to the full agenda, the accrual summary of registration and research cases between 1995 and 2012 were not presented to the committee but were available as part of the Working Committee attachments:

Registration only Research

AML allogeneic 22776 19854

ALL allogeneic 12710 10827

AML autologous 4582 1304

ALL autologous 730 218

3. Published/submitted papers and presentations

Due to the full agenda, the 2012 presentations and published papers were mentioned, but not presented. Three papers were published; one submitted and two ASBMT tandem presentations were given during the past year. These include:

a. LK04‐03 Keating A, DaSilva G, Perez WS, Gupta V, Cutler CC, Ballen KK, Cairo MS, Camitta BM,

Champlin RE, Gajewski JL, Lazarus HM, Lill M, Marks DI, Nabhan C, Schiller GJ, Socie G, Szer J, Tallman MS, Weisdorf DJ. Autologous blood cell transplantation versus HLA‐identical sibling transplantation for acute myeloid leukemia in first complete remission: A registry study from the Center for International Blood and Marrow Transplant Research. Haematologica 98(2):185‐192, 2013.

b. LK07‐03b Warlick E, Ahn KW, Pedersen TL, Artz A, DeLima M, Pulsipher M, Akpek G, Aljurf M, Cahn JY, Cairo M, Chen YB, Cooper B, Deol A, Giralt S, Gupta V, Khoury HJ, Kohrt H, Lazarus H, Lewis I, Olsson R, Pidala J, Savani B, Seftel M, Socie G, Tallman M, Ustun C, Vij R, Vindel?v L, Weisdorf DJ. RIC is superior to NMA conditioning for older Chronic Myelogenous Leukemia patients undergoing hematopoietic cell transplant during the TKI Era. Blood 119(17):4083‐4090, 2012.

c. R02‐05 Foran JM, Pavletic SZ, Logan BR, Agovi‐Johnson MA, Pérez WS, Bolwell BJ, Bornhäuser M, Bredeson CN, Cairo MS, Camitta BM, Copelan EA, Dehn J, Gale RP, George B, Gupta V, Hale G, Lazarus HM, Litzow MR, Maharaj D, Marks DI, Martino R, Maziarz RT, Rowe JM, Rowlings PA, Savani BN, Savoie ML, Szer J, Waller EK, Wiernik PH, Weisdorf DJ. Unrelated Donor allogeneic transplantation after failure of autologous transplantation for acute myeloid leukemia: a study from the CIBMTR. Submitted, revised.

d. LK08‐02 Koreth J, Pidala J, Pérez WS, Deeg JH, Garcia‐Manero G, Malcovati L, Cazzola M, Park S, Itzykson R, Ades L, Fenaux P, Jadersten M, Hellstrom‐Lindberg E, Gale RP, Beach CL, Greenberg PL, Tallman MS, DiPersio JF, Bunjes D, Weisdorf DJ, Cutler C. A Decision Analysis of Reduced‐Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Older Patients with de‐novo Myelodysplastic Syndrome (MDS): Early Transplantation Offers Survival Benefit in Higher‐Risk MDS. Journal of Clinical Oncology. In Press.

e. LK08‐01 Lee SJ, Storer B, Wang HL, Lazarus HM, Waller E, Isola L, Klumpp T, Savani B, Loren A, Cairo MS, Camitta B, Cutler CC, George B, Khoury J, Marks DI, Rizzieri D, Copelan E, Gupta V, Liesveld J, Litzow MR, Miller A, Shouten H, Gale R, Cahn JY, Weisdorf DJ. Factors significantly

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associated with leukemia‐free survival (LFS) and chronic graft‐versus‐host disease in adult patients more than 1 year after myeloablative allogeneic transplantation for acute leukemia. Submitted.

f. LK10‐02 Warlick ED, Litzow M, Paulson K, Weisdorf DJ. Pre‐transplant consolidation chemotherapy does not improve outcomes following reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) in CR1 (E Warlick/ M Litzow).Presentation at the ASBMT Tandem Meetings in Salt Lake City, Utah, February 2013. Manuscript in preparation.

g. LK10‐03 Bachanova V, Marks DI, Zhang MJ, Wang HL, Weisdorf DJ. Older patients with Ph+ acute lymphoblastic leukemia (ALL) in first remission (CR1) have prolonged survival with either myeloablative or reduced intensity conditioning allogeneic transplantation: Impact of imatinib and minimal residual disease (MRD) on outcomes: a CIBMTR matched‐pair study (V Bachanova). Presentation at the ASBMT Tandem Meetings in Salt Lake City, Utah, February 2013. Manuscript in preparation.

4. Studies in progress The studies which made progress during the past year were 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. These were:

a. R02‐09 Evaluation of donor leukocyte infusions to treat relapsed hematologic malignancies after

related and unrelated donor myeloablative allogeneic hematopoietic stem cell transplantation (A Loren) The value of related and unrelated donor DLI in treatment of acute leukemia relapsed after allografting will be examined, including the impact of disease status, timing, dose response, and comparative efficacy of the two donor sources. Secondary data collection is required and is underway. The supplemental data collection is finished and data file preparation is underway.

b. LK04‐01 Comparison of autologous and allogeneic hematopoietic stem cell transplantation for patients with acute promyelocytic leukemia (APL) in second complete remission (M Rubinger/M Tallman) This project analyzes outcome of APL in second CR including details of molecular remission prior to transplant. The analysis is finished and currently under manuscript preparation.

c. LK07‐03 Reduced intensity or non‐ablative hematopoietic cell transplantation in older patients with Non‐Hodgkin Lymphoma: encouraging survival for patients ≥55 years (B McClune) This study proposes to analyze outcome of NHL in older patients who received NMA/RIC conditioning. The draft manuscript has been circulated within writing committee and the PI is currently revising the manuscript for submission.

d. LK09‐02 Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation for Acute Myeloid Leukemia and Myelodysplasia (M Pasquini/ M Battiwala) The purpose of this study is to identify the impact of high risk cytogenetic subsets: specifically chromosome 7 abnormalities (either monosomy7 or del(7q)) and monosomal karyotype in outcomes for AML and MDS after allogeneic HCT and to evaluate the impact of conditioning intensity in the outcome of patients with AML and monosomal karyotype. The draft protocol is

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currently being reviewed by PI.

e. LK10‐02 Effect of pre‐transplant consolidation chemotherapy on outcomes of RIC Allogeneic transplant for adults with AML in CR1 (E Warlick) The purpose of this study is to (1) compare the outcomes of adults with AML in first remission who have received no consolidation, standard‐dose cytarabine consolidation, or high‐dose cytarabine consolidation followed by reduced intensity conditioning related or unrelated donor allogeneic stem cell transplantation (HCT) and (2) to determine if there is an exposure threshold (number of cycles of consolidation) that impacts post‐transplant outcomes. The draft manuscript has been circulated within the WrC and is currently being revised by PI for submission.

f. LK10‐03 The outcome of adults with Philadelphia positive acute lymphoblastic leukemia

comparing reduced intensity conditioning and myeloablative conditioning allogeneic stem cell transplantation (V Bachanova) The purpose of this study is to (1) to compare outcomes of adults with Ph+ ALL who received reduced intensity versus myeloablative conditioning followed by sibling or matched unrelated donor HCT; (2) to examine the effect of pre‐transplant treatment with tyrosine kinase inhibitors (TKI) on transplant outcomes using RIC and MA conditioning and (3) to examine the prognostic significance of patient, disease and transplant related characteristics on transplant outcomes. Supplemental data collection regarding TKI use was required and supported by external funding. The draft manuscript has been circulated and is currently being revised by PI for submission.

g. LK11‐01 Impact of extramedullary disease on the outcome of allogeneic HCT in AML (S Goyal/ G

Uy) The purpose of this proposal is (1) to describe the outcome of patients undergoing alloHSCT for AML with extramedullary involvement and (2) to assess patient, disease and transplant related factors which influence the outcome of alloHSCT in AML. There are 935 AML patients ≥18 years of age with extramedullary disease prior to HCT reported to the CIBMTR between 1995 and 2010. Protocol development and data file review is underway.

The following studies were previously proposed, but not initiated: a. LK12‐01 Chemotherapy versus Allogeneic Hematopoietic Cell Transplantation in Philadelphia

negative chromosome negative adult ALL (M Seftel) The purpose of the study is to compare HSCT outcomes of younger adults with Philadelphia chromosome negative (Ph‐) Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) treated with either allogeneic hematopoietic cell transplantation (alloHCT) or with a pediatric style chemotherapy regimen.

b. LK12‐02 FLT3/ITD mutation in AML remains a poor prognostic factor compared to conventional cytogenetics with increased risk of relapse and decreased overall survival after allogeneic stem cell transplantation in first complete remission (S Sengsayadeth) The purpose of this study is to (1) To study the prognostic significance of FLT3/ITD mutation in AML in patients receiving allo‐HSCT in CR1 and (2) To study the impact of FLT3/ITD mutation on incidence of relapse, disease‐free survival (DFS), overall survival (OS) after allo‐SCT in CR1.

5. Future/ Proposed studies Drs. Devine and DiPersio led this section. The proposals were the following:

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a. PROP 1012‐02 To Determine whether In‐vivo T Cell Depletion with Alemtuzumab Affects

Outcome after Myeloablative TBI‐based Conditioning in Children and Young Adults who Received Unrelated Donor Transplants for AML (S Samarasinghe/ P Veys/ M Eapen) Dr. Veys presented the proposal. The purpose of this study is to compare transplant outcomes including aGVHD/ cGVHD/ OS/ LFS/ 1 year TRM/ viral infection in children and AYA who have undergone a myeloablative HSCT for AML, the incidence of acute GVHD and chronic GVHD between regimens with in vivo T cell depletion using Alemtuzumab/ATG or T cell replete. There are 2225 patients who are under age of 40 and underwent 1st allo unrelated donor T‐cell replete myeloablative conditioning HSCT between 1997 and 2010. Drs. Weisdorf and Eapen commented that CIBMTR forms do not capture the administration dates or specific doses of Alemtsuzumab/ATG but only the product name and total dose. The proposal was not approved because concerns raised about the arbitrary age limit of 40 years old and also lack of novelty.

b. PROP 1112‐06 Comparing Autologous to Allogeneic Transplant in APL Patients with

Extramedullary Disease who Achieve a Second or Subsequent Complete Remission (CR) (C Ganzel/ M Tallman/ D Douer) Dr. Douer presented the proposal. The purpose of this study is to compare the OS, DFS and toxicity between auto HSCT and ATO‐based treatment in relapsed APL patients, using large databases. There are 129 patients (allo n=106; auto n=23) in the CIBMTR dataset who had 1st HSCT for APL with extramedullary involvement. Comparatively there are 46 patients treated with ATO in an available Indian cohort. The issue of high percentage of earlier patients (year<=1995, 62%) with different HSCT therapy approaches was commented. The proposal was not approved because 1) small number (n=23) in extramedullary group 2) overlap with ongoing study LK04‐01

c. PROP 1112‐10 Comparing Autologous Transplant to Arsenic Trioxide (ATO) for Patients with

Acute Promyelocytic Leukemia (APL) in First and Subsequent Relapse (C Ganzel/ M Tallman/ D Douer) Dr. Douer presented the proposal. The purpose of this study is to compare the OS, DFS, TRM, hematological toxicity, infectious disease, cardiovascular events, arrhythmias, neurologic events and APL differentiation syndrome between auto HSCT and ATO‐based treatment in relapsed APL patients and 2) identify predictive patient characteristics for favorable outcome. There are 125 patients who relapsed before 1st auto HSCT for APL. This proposal was not approved because concerns were raised about the potential selection bias of patients who received transplant vs. ATO treatment. Also the ATO group likely had a high proportion of transplanted patients with no further available information thus confounding the comparisons.

d. PROP 1112‐38 Allogeneic Transplantation For Older Patients with Acute Lymphoblastic Leukemia: Impact of Age on Transplant Outcomes (V Bachanova) Dr. Bachanova presented the proposal. The purpose of this study is to 1) analyze outcomes of allogeneic donor transplantation for older patients with acute lymphoblastic leukemia comparing 3 age groups: 40‐50, 51‐60 and ≥61 years of age; 2) define the prognostic factors (patient, disease and transplant related (including graft choice and conditioning regimen intensity)) impacting on mortality, relapse and survival. There are 1216 patients older than 40 years of age who had 1st allo HSCT for ALL between 01/01/2000 and 06/30/2011.

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e. PROP 1112‐35 Prognostic Significnace of Cytogenetic Abnormalities in Patients with Philadelphia‐negative Acute Lymphoblastic Leukemia undergoing Allogeneic Hematopoietic Stem Cell Transplantation in Complete Remission: A CIBMTR Study (A Lazaryan) Dr. Lazaryan presented the proposal. The purpose of this study is to 1) develop a novel HCT‐specific cytogenetic classification scheme for prognostication of relapse and survival outcomes following allo‐HCT in patients with Philadelphia‐negative ALL; 2) validate major existing cytogenetic groupings of Ph‐ALL among the recipients of allo‐HCT from multicenter cohort of CIBMTR patients; 3) compare the performance of novel and existing classification schemes in an independent cohort of HCT patients from CIBMTR patient database. There are 3062 adult patients who had 1st allo BM/PB graft HSCT for Ph‐negative and non‐L3 ALL in remission. EBMT cytogenetic data was suggested to be used as validation set. PI will need to review cytogenetic report to determine proper category for analysis.

f. PROP 1112‐41 Outcomes of Allogeneic Stem Cell Transplantation in T cell Acute Lymphoblastic Leukemia (W Rasheed) Dr. Rasheed presented the protocol. The purpose of this study is to analyze outcomes of allo HSCT in adult patients with T‐Cell ALL including OS, DFS and NRM. There are 821 adult patients who received 1st allo BM/PB graft HLA‐id sibling or unrelated donor HSCT for T‐ALL between 1990 and 2010. The proposal was not approved due to lack of novelty compared with the recently published EBMT study (Cahu et al). Also there was concern about correlation between years of HSCT, conditioning intensity and disease status prior to HSCT.

g. PROP 0712‐04 Allogeneic Transplantation for Acute Biphenotypic Leukemia (ABiL): Disease Characteristics, Complications and Outcomes (R Munker) Dr. Munker presented the proposal. The purpose of this study is to describe frequency of allogeneic transplant for ABiL, demographics and disease characteristics before transplant, describe outcomes of transplant for ABiL. There are 278 patients younger than 70 years of age who had 1st allo HSCT for biphenotypic leukemia (per CIBMTR disease category) since 1996. It was suggested that detailed diagnostic reports need to be reviewed for every patient to determine the specifics and diagnostic subsets of biphenotypic leukemia. It was considered as an interesting and unique study since no similar publication is available.

h. PROP 1112‐26 The Impact of Peripheral Blood Chimerism on Transplant Outcomes in Patients with Acute Leukemia and Myelodysplastic Syndrome (P Kebriaei) Dr. Kebriaei presented the proposal. The purpose of the study is to 1) assess the impact of persistent mixed chimerism at 3 months following allogeneic HSCT on the rate of relapse post HSCT; 2 ) assess the impact of persistent mixed chimerism on the rate of GVHD; 3) describe the kinetics of donor chimerism in the first year following transplant. There are 6262 patients who had 1st allo T‐cell replete BM/PB graft HCT for AML/ALL/MDS. This study was not approved because chimerism data is not readily available in CIBMTR database, although there is potential interest in chimerism studies.

Three additional proposals were submitted to the committee, but not presented as stated below: a. PROP 1012‐06 Evaluation of Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell

Neoplasm (BPDCN) / Leukemia after Transplantation (S Ahmed/ P Kebriaei/ R Champlin): Hard to define cases/ insufficient number of cases.

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b. PROP 1112‐54 Outcomes of Hematopoietic Cell Transplantation for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (Nishihori T): similar proposal as p1012‐06 and dropped for same reason.

c. PROP 1112‐57 Comparative outcome of nonmyeloablative allogeneic hematopoietic stem cell

transplantation combined with pre‐emptive donor lymphocyte infusion and myeloablative allogeneic hematopoietic stem cell transplantation in older patients with high‐risk leukemia (Huang H): Hard to define post‐tx DLI cases/ insufficient detail available and insufficient number of cases.

6. 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:

a. PROP 1112‐35 Prognostic Significance of Cytogenetic Abnormalities in Patients with Philadelphia‐negative Acute Lymphoblastic Leukemia undergoing Allogeneic Hematopoietic Stem Cell Transplantation in Complete Remission: A CIBMTR Study

b. PROP1112‐38 Allogeneic Transplantation for Acute Biphenotypic Leukemia (ABiL): Disease

Characteristics, Complications and Outcomes

c. PROP 0712‐04 Allogeneic Transplantation For Older Patients with Acute Lymphoblastic

Leukemia: Impact of Age on Transplant Outcomes

Dr. Bunjes expressed gratitude to the Committee members for their active role and valuable support to the Committee. Without additional comments, the meeting was adjourned at 4:35 pm. Working Committee Overview Plan for 2013‐2014

a. R02‐09 Evaluation of donor leukocyte infusions to treat relapsed hematologic malignancies after

related and unrelated donor myeloablative allogeneic hematopoietic stem cell transplantation. The study will be combined with a similar proposal and transferred to cellular therapy working committee. Previously collected supplemental data collection will be used to enhance the study.

b. LK04‐01 Comparison of autologous and allogeneic hematopoietic stem cell transplantation for patients with acute promyelocytic leukemia (APL) in second complete remission.The analysis is completed and manuscript is under preparation. We plan to submit the paper by June 2013.

c. LK07‐03c: Reduced intensity or non‐ablative hematopoietic cell transplantation in older patients with Non‐Hodgkin Lymphoma: encouraging survival for patients ≥55 years. The revised manuscript is nearly completed. We plan to submit the paper by June 2013.

d. LK09‐02: Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation

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for Acute Myeloid Leukemia and Myelodysplasia. Protocol will be finalized in April 2013 and since the data file preparation is almost complete already, we plan to finish analysis by June 2013. Submission is anticipated by June 2014.

e. LK10‐02: Effect of pre‐transplant consolidation chemotherapy on outcomes of RIC Allogeneic transplant for adults with AML in CR1. Draft manuscript has been circulated with feedback received. Additional modest analysis is needed from PhD statistician and we plan to submit paper before June 2013.

f. LK10‐03: The outcome of adults with Philadelphia positive acute lymphoblastic leukemia comparing reduced intensity conditioning and myeloablative conditioning allogeneic stem cell transplantation. The draft manuscript is complete and has been circulated within the Writing Committee in March. Submission of paper is expected by June 2013.

g. LK11‐01: Impact of extramedullary disease on the outcome of allogeneic HCT in AML. Data file preparation ongoing and will be ready for analysis by June 2013. Submission of paper is expected by June 2014.

h. LK12‐01: Chemotherapy versus Allogeneic Hematopoietic Cell Transplantation in Philadelphia negative chromosome negative adult ALL. Protocol revision is underway and plan to move to data file preparation by June 2013. We plan to finish analysis and complete the manuscript by June 2014.

i. LK12‐02: FLT3/ITD mutation in acute myeloid leukemia remains a poor prognostic factor compared to conventional cytogenetics with increased risk of relapse and decreased overall survival after allogeneic stem cell transplantation in first complete remission. Protocol revision is underway and will be moved to data file preparation by June 2013. We plan to finish analysis and complete the manuscript by June 2014.

j. LK13‐01 (PROP 1112‐38): Evaluating outcomes of reduced intensity conditioning allogeneic SCT in older adult lymphoblastic leukemia patients reported to the CIBMTR and EBMT. We anticipate developing the study protocol after July 2013 and prepare data file to be ready for analysis by June 2014.

k. LK13‐02 (PROP 1112‐35): Prognostic significance of cytogenetic abnormalities in patients with Philadelphia‐ negative acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission. We anticipate developing the study protocol after July 2013 and prepare data file for detailed review by the PI and to be ready for analysis by June 2014.

l. LK13‐03 (PROP 0712‐04): Allogeneic transplantation for Acute Biphenotypic Leukemia: Disease characteristics, complications and outcomes. We anticipate developing the study protocol after July 2013. All cases will have a pathology report reviewed by PI. We plan to finish data file preparation and review of cases by June 2014.

11


Oversight Assignments for Working Committee Leadership (February 2013)

Daniel Weisdorf LK07‐03c: Reduced intensity or non‐ablative hematopoietic cell

transplantation in older patients with Non‐Hodgkin Lymphoma: encouraging survival for patients ≥55 years LK12‐01: Chemotherapy versus Allogeneic Hematopoietic Cell Transplantation in Philadelphia negative chromosome negative adult ALL LK13‐02: Prognostic significance of cytogenetic abnormalities in patients with Philadelphia‐negative acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission

Marcos de Lima LK09‐02: Impact of monosomal karyotype in the outcome of

hematopoietic cell transplantation for Acute Myeloid Leukemia and Myelodysplasia LK11‐01: Impact of extramedullary disease on the outcome of allogeneic HCT in AML LK13‐01: Evaluating outcomes of reduced intensity conditioning allogeneic SCT in older adult lymphoblastic leukemia patients reported to the CIBMTR and EBMT

Steven Devine LK04‐01: Comparison of autologous and allogeneic hematopoietic stem

cell transplantation for patients with acute promyelocytic leukemia (APL) in second complete remission LK10‐02: Effect of pre‐transplant consolidation chemotherapy on outcomes of RIC Allogeneic transplant for adults with AML in CR1 LK10‐03: The outcome of adults with Philadelphia positive acute lymphoblastic leukemia comparing reduced intensity conditioning and myeloablative conditioning allogeneic stem cell transplantation

Donald Bunjes LK12‐02: FLT3/ITD mutation in acute myeloid leukemia remains a poor

prognostic factor compared to conventional cytogenetics with increased risk of relapse and decreased overall survival after allogeneic stem cell transplantation in first complete remission LK13‐03: Allogeneic transplantation for Acute Biphenotypic Leukemia: Disease characteristics, complications and outcomes

12


Accrual Summary for Acute Leukemia Working Committee

Characteristics of recipients of allogeneic transplants for AML and ALL reporteda to the CIBMTR between 1995 and 2013

Variable AML ALL

Number of patients 16733 9544

Number of centers 377 363

Age in decades

<10 1619 (10) 2429 (25)

10‐19 1822 (11) 2381 (25)

20‐29 2128 (13) 1692 (18)

30‐39 2487 (15) 1247 (13)

40‐49 3314 (20) 1034 (11)

50‐59 3442 (21) 606 (6)

60‐69 1767 (11) 150 (2)

>=70 154 (<1) 3 (<1)

Missing 0 2 (<1)

Gender

Male 8795 (53) 5859 (61)

Female 7936 (47) 3682 (39)

Missing 2 (<1) 3 (<1)

HCT‐CI

0 14338 (86) 8398 (88)

1 1923 (11) 895 (9)

2 191 (1) 91 (<1)

3 21 (<1) 5 (<1)

4 2 (<1) 0

Missing 258 (2) 155 (2)

Disease status prior to HCT

Primary induction failure 2081 (12) 322 (3)

CR1 7702 (46) 3693 (39)

CR2 3596 (21) 3303 (35)

>=CR3 293 (2) 859 (9)

Relapse 2728 (16) 1201 (13)

Missing 333 (2) 166 (2)

Time from diagnosis to HCT, months

Median (range) 6 (<1‐607) 12 (<1‐279)

<6 months 7780 (46) 2599 (27)

6 ‐ 12 months 4192 (25) 2172 (23)

>12 months 4709 (28) 4751 (50)

Missing 52 (<1) 22 (<1)

Conditioning regimen intensity

13


Variable AML ALL

Myeloablative 12614 (75) 8547 (90)

RIC 2414 (14) 387 (4)

NMA 853 (5) 139 (1)

Unknown 852 (5) 471 (5)

Graft type

Bone marrow 6091 (36) 4616 (48)

Peripheral blood 8757 (52) 3282 (34)

Umbilical cord blood 1860 (11) 1640 (17)

Missing 25 (<1) 6 (<1)

Type of donor

HLA‐identical sibling 5937 (35) 2899 (30)

Identical twin 77 (<1) 52 (<1)

Other relative 787 (5) 516 (5)

Unrelated 9804 (59) 6009 (63)

Missing 128 (<1) 68 (<1)

Year of HCT

1995‐1996 1651 (10) 1301 (14)

1997‐1998 1457 (9) 1128 (12)

1999‐2000 1446 (9) 1070 (11)

2001‐2002 1812 (11) 1134 (12)

2003‐2004 2119 (13) 1143 (12)

2005‐2006 2573 (15) 1291 (14)

2007‐2008 2598 (16) 1210 (13)

2009‐2010 2047 (12) 706 (7)

2011‐2012b 786 (5) 458 (5)

2013‐currentb 244 (1) 103 (1)

Median follow‐up of survivors (range), months 69 (1‐221) 72 (<1‐223)a Patients have available comprehensive research form b Cases continue to be reported in this interval

14


Accrual Summary for Acute Leukemia Working Committee

Characteristics of recipients of autologous transplants for AML and ALL reporteda to the CIBMTR between 1995 and 2013

Variable AML ALL



Age in decades

<10 95 (7) 28 (13)

10‐19 103 (7) 46 (21)

20‐29 184 (13) 56 (25)

30‐39 251 (18) 27 (12)

40‐49 275 (20) 34 (15)

50‐59 297 (21) 23 (10)

60‐69 188 (13) 8 (4)

>=70 9 (<1) 0

Gender

Male 706 (50) 146 (66)

Female 695 (50) 76 (34)

Missing 1 (<1) 0


Primary induction failure 12 (<1) 2 (<1)

CR1 812 (58) 123 (55)

CR2 293 (21) 52 (23)

>=CR3 19 (1) 10 (5)

Relapse 73 (5) 5 (2)

Missing 193 (14) 30 (14)


Myeloablative 874 (62) 182 (82)

RIC 12 (<1) 3 (1)

NMA 4 (<1) 1 (<1)

TBD 512 (37) 36 (16)


Median (range) 6 (<1‐584) 9 (<1‐172)

<6 months 611 (44) 35 (16)

6 ‐ 12 months 373 (27) 100 (45)

>12 months 403 (29) 85 (38)

Missing 15 (1) 2 (<1)

Graft type

Bone marrow 204 (15) 37 (17)


Missing 131 (9) 25 (11)

15


Variable AML ALL

Year of HCT

1995‐1996 324 (23) 80 (36)

1997‐1998 277 (20) 62 (28)

1999‐2000 162 (12) 25 (11)

2001‐2002 149 (11) 20 (9)

2003‐2004 138 (10) 8 (4)

2005‐2006 138 (10) 9 (4)

2007‐2008 141 (10) 12 (5)

2009‐2010 46 (3) 3 (1)

2011‐2012a 22 (2) 2 (<1)

2013‐currenta 5 (<1) 1 (<1)

Median follow‐up of survivors (range), months 85 (1‐218) 114 (2‐217)a Patients have available comprehensive research form b Cases continue to be reported in this interval

16


To: Acute Leukemia Working Committee Members

From: Daniel Weisdorf, MD and Wael Saber, MD, MS, Scientific Directors for the Acute Leukemia WC

RE: 2013‐2014 Studies in Progress Summary

LK09‐02: Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation for Acute Myeloid Leukemia and Myelodysplasia (M Pasquini/ M Battiwala): The purpose of this study is to identify the impact of high risk cytogenetic subsets: specifically chromosome 7 abnormalities (either monosomy7 or del(7q)) and monosomal karyotype in outcomes for AML and MDS after allogeneic HCT and to evaluate the impact of conditioning intensity in the outcome of patients with AML and monosomal karyotype. Analysis is completed and draft manuscript is being prepared by PI.

LK11‐01: Impact of extramedullary disease on the outcome of allogeneic HCT in AML (S Goyal/ G Uy): The purpose of this proposal is (1) to describe the outcome of patients undergoing alloHSCT for AML with extramedullary involvement and (2) to assess patient, disease and transplant related factors which influence the outcome of alloHSCT in AML. There are 935 AML patients ≥18 years of age with extramedullary disease prior to HCT reported to the CIBMTR between 1995 and 2010. Analysis is completed and draft manuscript is being prepared by PI. LK12‐01: Chemotherapy versus Allogeneic Hematopoietic Cell Transplantation in Philadelphia negative chromosome negative adult ALL (M Seftel): The purpose of the study is to compare HSCT outcomes of younger adults with Philadelphia chromosome negative (Ph‐) Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) treated with either allogeneic hematopoietic cell transplantation (alloHCT) or with a pediatric style chemotherapy regimen. Draft protocol has been circulated within Working Committee. Protocol finalization and data file preparation is underway. LK12‐02: FLT3/ITD mutation in acute myeloid leukemia remains a poor prognostic factor compared to conventional cytogenetics with increased risk of relapse and decreased overall survival after allogeneic stem cell transplantation in first complete remission (S Sengsayadeth): The purpose of this study is to (1) To study the prognostic significance of FLT3/ITD mutation in AML in patients receiving allo‐HSCT in CR1 and (2) To study the impact of FLT3/ITD mutation on incidence of relapse, disease‐free survival (DFS), overall survival (OS) after allo‐SCT in CR1. Protocol has been finalized and data file preparation is underway. LK12‐03: Survival of AML patients relapsing after allogeneic stem cell transplantation (N Bejanyan/ D Weisdorf/ MJ Zhang): The purpose of this study is to (1) study the clinical outcomes including overall survival (OS) after post‐transplant relapse among allogeneic transplant recipients with AML and (2) to identify prognostic factors for survival after post‐transplant relapse. Analysis is completed and draft manuscript is being prepared by PI.

17


LK13‐01: Allogeneic Transplantation for older patients with Acute Lymphoblastic Leukemia reported to the CIBMTR and EBMT: Impact of age on transplant outcomes (A Rosko/ M de Lima/ M Mohty/ V Bachanova): The purpose of this study is to (1) To analyze outcomes of allogeneic donor transplantation for older patients with acute lymphoblastic leukemia ages 55 years and older who underwent reduced intensity conditioning (2) To define the prognostic factors (patient, disease and transplant related) that impact mortality, relapse and survival. Protocol development is underway. 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 to (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. Protocol development is underway. LK13‐03: Allogeneic transplantation for Acute Biphenotypic Leukemia (ABiL): Disease characteristics, complications and outcomes (R Munker): The purpose of this study is to (1) Describe frequency of allogeneic transplant for ABiL, demographics and disease characteristics before transplant (2) Assess patient‐, disease‐ and transplant‐ related factors which influence the outcome of allogeneic transplant for ABiL. Protocol development is underway.

18


Study Proposal 1310‐07 Study Title: Outcome of allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia with antecedent history of Philadelphia‐negative myeloproliferative Neoplasm Vikas Gupta, MD, Princess Margaret Cancer Center, Canada, [email protected] Study Hypothesis: Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for selected patients with leukemic transformation from Philadelphia‐negative myeloproliferative Neoplasm (MPN); and prognostic factors for outcome of HCT in this setting are not known. Objectives: Primary

1. Outcome of HCT in patients with leukemic transformation from Philadelphia‐negative MPN 2. To identify patient, disease and transplant related factors associated with outcome

Secondary 3. To study the graft‐versus‐leukemia effect in this setting

Scientific Rationale: Philadelphia‐negative MPNs are a group of phenotypically related clonal hematopoietic cell diseases characterized by overproduction of mature myeloid cells and a prolonged clinical course. Transformation to AML occurs in approximately 5‐10% of these neoplasms after 10 years, and is associated with extremely poor prognosis3, 5‐8.

The median survival of patients after leukemic transformation is 3‐4 months; and none of the conventional treatment options are known to improve the survival of these patients. There are few small case series which have shown that HCT has the potential of long‐term disease control in some selected patients with leukemic transformation from Ph negative MPN.

In a study from Princess Margaret Cancer Center, Toronto, 75 consecutive patients diagnosed with LT from ph‐MPN were studied3. Out of these 75 patients, 39 patients were treated with curative intent (chemotherapy +/‐HCT); and subsequently 17 patients were able to undergo HCT in either CR or chronic MPN phase. The survival of patients post‐HCT was significantly improved compared to patients who achieved CR/cMPN phase but did not receive HCT (2‐year OS 47% versus 15%, p=0.03).

All the studies reporting on HCT outcomes in patients with LT from ph‐ negative MPN are summarized in table 11‐7. The largest cohort of transplant patients reported in these studies was from Princes Margaret, and had only 17 patients. It is not known which patients with this complication benefit from the option of HCT. Due to small sample size, it was not possible to analyze prognostic factors associated with outcomes in any of these studies.

Due to rarity of this complication, prospective studies pose a logistic challenge as even the major centers with special interest in MPNs treat a few patients with MPN every year. Therefore, observational studies through a large data source such as CIBMTR will be important to study the transplant outcomes of this rare disease. The outcomes of this study will help in understanding which patients with LT benefit from HCT; and will assist leukemia and transplant physician in decision making as well as improving the transplant practices in this group of patients.

19


Study Population: Using the CIBMTR database, patients with AML and a preceding h/o Philadelphia negative MPN undergoing HCT between 1996 and 2012 and meet the following criteria will be identified. Inclusion Criteria

Diagnosis of AML prior to HCT

Age 18 years and above

Prior to AML transformation, patients had preceding h/o one of the following: o Polycythemia rubra vera (PV) or post‐PV myelofibrosis o Essential thrombocythemia (ET) or post ET myelofibrosis o Primary Myelofibrosis (PMF)

HCT using any type of donor Exclusion Criteria

Syngeneic transplantation

Positive for Philadelphia chromosome or BCR‐ABL

In Vitro T‐cell depletion Outcomes of Interest: Hematopoietic recovery: Time to neutrophils (ANC) >0.5 x 109/L (first of 3 consecutive days) and time to platelets ≥20 x 109/L (first of 3 consecutive days and no platelet transfusions 7 days prior)

Acute GVHD: Occurrence of grade II, III and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD. Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the criteria of chronic GVHD

Relapse: disease recurrence or persistence. This event will be summarized by cumulative incidence estimate with TRM as the competing risk

Treatment‐related mortality: time to death without evidence of disease relapse. This event will be summarized as cumulative incidence estimate with relapse/progression as the competing risk.

Leukemia‐free survival: will be defined as time to relapse, leukemia transformation or death from any cause. Patients are censored at last follow‐up.

Overall survival: Time to death, patients censored at last follow‐up Variables to be analysed: Patient‐related:

Age

Gender

Performance scores: <90 vs ≥90

Co‐morbidities (depending on availability of data) Disease‐related:

Aetiology of MPN: PV vs. PPV‐MF vs. ET vs. PET‐MF vs. PMF

Remission status prior to HCT: CR versus Blasts in BM<5% but not meeting CR definition (chronic MPN phase) vs. active leukemia

20


Type of leukemic reduction therapy prior to HCT: 3+7 or high‐dose cytarabine based versus hypomethylating agent (decitabine or azacytidine) or others

Duration between diagnosis of MPN and AML: >5‐years versus 2‐5 years versus <2‐years

MPN therapies: none versus ≤2 versus ≥3

Spleen status : Splenectomy versus not palpable spleen versus splenomegaly

Cytogenetics: abnormal versus normal versus unknown

Cytogenetics (classified as SWOG) favorable versus intermediate‐normal versus intermediate abnormal versus adverse versus unknown

Cytogenetics (only in patients with available cytogenetics results): normal karyotype versus abnormal but not monosomal karyotype versus monosomal karyotype

Time from diagnosis of AML to transplant: <6 months versus 6‐12 months versus >12 months

WBC count at the diagnosis of AML

JAK 2 mutation status any time prior to HCT: present/absent/unknown Transplant‐related:

Conditioning therapy: Myeloablative versus reduced intensity

Graft type: BM versus PB versus CB

Donor type: HLA identical sibling versus other related versus well matched URD vs. partially matched URD/ mismatched URD vs. cord blood

GVHD prophylaxis: Calcineurin inhibitor (CsA or FK 506) + Methotrexate versus calcineurin inhibitor (CsA or FK 506) + mycophenolate versus others

Serotherapy used (ATG or alemtuzumab or campath): yes/no

Year of transplant: 1991‐1995 vs. 1996‐2000 vs. 2001‐2005 vs. 2006‐2011

Donor‐recipient gender match: M‐M vs M‐F vs F‐M vs F‐F

Donor‐recipient CMV serostatus: +/+ vs. +/‐ vs. ‐/+ vs. ‐/‐

CD34+cell dose x 106/kg for PB Tx / TNC for BM grafts

Planned Growth factor initiated within 7 days post‐transplant: yes/no Analysis Plan: Patient‐, disease‐, and transplant‐related variables for the study cohort will be described. Univariate probabilities of LFS and survival will be calculated using the Kaplan‐Meier estimator; the log‐rank test will be used for univariate comparisons. Probabilities of hematopoietic recovery, acute and chronic GVHD, treatment‐related mortality and relapse will be calculated using cumulative incidence curves to accommodate competing risks. Assessment of potential risk factors for outcomes of interest will be evaluated in multivariate analyses using Cox proportional hazards regression

21


Summary of literature review on outcome of LT from Philadelphia negative MPN Studies including all patients with LT from MPN Patients treated with induction

therapy Patients undergoing HCT

STUDY PRECEEDING MPN

n Median OS n Favorable response

Median OS n % pre‐treated

% in CR/CRi/cMPN

2‐year OS

Mesa et al. (2005)5

PMF, PPV‐MF, PET‐MF

91 2.6 24 10 (42%) 3.9 0 ‐ ‐ ‐

Tam et al. (2008)7

all Ph‐MPNs

74 5 41 18 (46%) not reported

8 62.5% 75% 73%

Noor et al. (2010)6

all Ph‐MPNs

23 4.6 20 12 (60%) 6 3 100% not reported

not reported

Cherington et al. (2012)1

ET, PV, PMF

13 not reported

10 6 (60%) not reported

8 100% 62.5% 75%

Princess Margaret Toronto data3

all Ph‐MPNs

75 6.5 38 29 (76%) 9.2 17 94% 100% 47%

Transplant‐focused studies Ciurea et al. (2010)2


‐ ‐ ‐ ‐ ‐ 14 93% 43% 49%

Mascarenas et al. (2010)4


‐ ‐ ‐ ‐ ‐ 5 20% ≤20% 53%

22


References: 1. C. Cherington, J. L. Slack, J. Leis, R. H. Adams, C. B. Reeder, J. R. Mikhael, J. Camoriano, P.

Noel, V. Fauble, J. Betcher, M. S. Higgins, G. Gillette‐Kent, L. D. Tremblay, M. E. Peterson, J. J. Olsen, R. Tibes, and R. A. Mesa, 'Allogeneic Stem Cell Transplantation for Myeloproliferative Neoplasm in Blast Phase', Leuk Res, 36 (2012), 1147‐51.

2. S. O. Ciurea, M. de Lima, S. Giralt, R. Saliba, C. Bueso‐Ramos, B. S. Andersson, C. M. Hosing, S. Verstovsek, R. E. Champlin, and U. Popat, 'Allogeneic Stem Cell Transplantation for Myelofibrosis with Leukemic Transformation', Biol Blood Marrow Transplant, 16 (2010), 555‐9.

3. J. A. Kennedy, E. G. Atenafu, H. A. Messner, K. J. Craddock, J. M. Brandwein, J. H. Lipton, M. D. Minden, A. D. Schimmer, A. C. Schuh, K. W. Yee, and V. Gupta, 'Treatment Outcomes Following Leukemic Transformation in Philadelphia‐Negative Myeloproliferative Neoplasms', Blood, 121 (2013), 2725‐33.

4. J. Mascarenhas, S. Navada, A. Malone, A. Rodriguez, V. Najfeld, and R. Hoffman, 'Therapeutic Options for Patients with Myelofibrosis in Blast Phase', Leuk Res, 34 (2010), 1246‐9.

5. R. A. Mesa, C. Y. Li, R. P. Ketterling, G. S. Schroeder, R. A. Knudson, and A. Tefferi, 'Leukemic Transformation in Myelofibrosis with Myeloid Metaplasia: A Single‐Institution Experience with 91 Cases', Blood, 105 (2005), 973‐7.

6. S. J. Noor, W. Tan, G. E. Wilding, L. A. Ford, M. Barcos, S. N. Sait, A. W. Block, J. E. Thompson, E. S. Wang, and M. Wetzler, 'Myeloid Blastic Transformation of Myeloproliferative Neoplasms‐‐a Review of 112 Cases', Leuk Res, 35 (2011), 608‐13.

7. C. S. Tam, R. M. Nussenzveig, U. Popat, C. E. Bueso‐Ramos, D. A. Thomas, J. A. Cortes, R. E. Champlin, S. E. Ciurea, T. Manshouri, S. M. Pierce, H. M. Kantarjian, and S. Verstovsek, 'The Natural History and Treatment Outcome of Blast Phase Bcr‐Abl‐ Myeloproliferative Neoplasms', Blood, 112 (2008), 1628‐37.

8. S. Thepot, R. Itzykson, V. Seegers, E. Raffoux, B. Quesnel, Y. Chait, L. Sorin, F. Dreyfus, T. Cluzeau, J. Delaunay, L. Sanhes, V. Eclache, C. Dartigeas, P. Turlure, S. Harel, C. Salanoubat, J. J. Kiladjian, P. Fenaux, and L. Ades, 'Treatment of Progression of Philadelphia‐Negative Myeloproliferative Neoplasms to Myelodysplastic Syndrome or Acute Myeloid Leukemia by Azacitidine: A Report on 54 Cases on the Behalf of the Groupe Francophone Des Myelodysplasies (Gfm)', Blood, 116 (2010), 3735‐42.

23


Characteristics of Study Population

Variable N (%)

Number of patients 164

Number of centers 80

Age in decades

Median (range) 56 (20‐74)

20‐29 6 (4)

30‐39 11 (7)

40‐49 33 (20)

50‐59 70 (43)

60‐69 37 (23)

>=70 7 (4)

Gender

Male 94 (57)

Female 70 (43)

Karnofsky score

90‐100% 86 (52)

< 90% 72 (44)

Missing 6 (4)

White blood count at diagnosis

<= 30 101 (62)

30 ‐ 100 18 (11)

> 100 3 (2)

Missing 42 (26)

Aetiology of MPN

Polycythemia vera 42 (26)

Essential thrombocythemia 48 (29)

Myelofibrosis with myeloid metaplasia 37 (23)

Other myelofibrosis or myelosclerosis 22 (13)

Chronic idiopathic myelofibrosis 15 (9)


Blasts in BM < 5% but not CR 19 (12)

CR 77 (47)

Active leukemia (PIF and relapse) 64 (39)

Missing 4 (2)

Cytogenetics scoring

Normal 35 (21)

Favorable 7 (4)

Intermediate 24 (15)

Poor 41 (25)

TBD (needs review) 19 (12)

24


Variable N (%)

Not tested 11 (7)

Missing 27 (16)

Induction therapy

7+3 39 (24)

7+3 + other 11 (7)

Hypomethylating agent 2 (1)

Other 112 (68)

Duration between diagnosis of MPN and AML (years)

Median (range) 4 (<1‐10)

< 2 years 51 (31)

2 ‐ 5 years 32 (20)

> 5 years 63 (38)

Missing 18 (11)

Time from diagnosis to HCT (months)


0 ‐ 3 months 105 (64)

3 ‐ 6 months 37 (23)

>= 6 months 22 (13)


Myeloablative 92 (56)

RIC 45 (27)

NMA 17 (10)

TBD 10 (6)

Graft type

Bone marrow 37 (23)

Peripheral blood 118 (72)

Cord blood 9 (5)

Type of donor

HLA‐identical sibling 59 (36)

Other related 5 (3)

Well‐matched unrelated 47 (29)

Partially matched unrelated 31 (19)

Mismatched unrelated 5 (3)

Unrelated TBD 7 (4)

Cord blood 9 (5)

Missing 1 (<1)

GVHD prophylaxis

(CsA or FK506) + MMF 44 (27)

(CsA or FK506) + MTX 89 (54)

Other 31 (19)

25


Variable N (%)

ATG or campath

ATG alone 22 (13)

CAMPATH alone 10 (6)

No ATG or CAMPATH 80 (49)

Missing 52 (32)

Donor/Recipient CMV match

‐/‐ 43 (26)

‐/+ 48 (29)

+/‐ 15 (9)

+/+ 46 (28)

TBD 12 (7)

Donor/Recipient sex match

M/M 58 (35)

M/F 36 (22)

F/M 36 (22)

F/F 32 (20)

TBD 2 (1)

Year of HCT

1996 ‐ 2000 28 (17)

2001 ‐ 2005 57 (35)

2006 ‐ 2010 72 (44)

2011 ‐ 2012 7 (4)

Planned growth factor initiated within 7 days post‐HSCT

No 100 (61)

Yes 64 (39)

Median follow‐up of survivors (range), months 71 (4‐179)

The following selection criteria was applied for HSCT cohort: Excluded Included

INCLUSION:

1st allo HSCT for AML transformed from Ph‐ MPN between 1996 and 2012 197

Age 18 years and above 8 189

All donor except HLA‐identical sibling 2 187

T‐cell replete graft 18 169

EXCLUSION:

Patient didn’t consent 2 167

No 100‐day comprehensive research form 3 164

26


Study Proposal 1310‐19 Study Title: Allogeneic transplantation to treat secondary AML diagnosed after autologous transplant Leland Metheny, MD, University Hospitals Case Medical Center, [email protected] Marcos de Lima, MD, University Hospitals Case Medical Center, [email protected] Mohammed Mohty, MD, PhD, Saint‐Antoine Hospital and University Pierre & Marie Curie, France, [email protected] Specific Aims: Primary

1. To evaluate overall survival of adult allogeneic HSCT patients with secondary AML following autologous transplant.

Secondary 2. To assess leukemia‐free‐survival, treatment‐related mortality and non‐relapse mortality. 3. To describe acute and chronic GVHD rates in this setting. 4. To assess the effect of preparative regimen intensity.

Scientific Justification: The risk of treatment‐related myelodysplasia (t‐MDS) and treatment‐related acute myeloid leukemia (t‐AML) following autologous stem cell transplant (auto‐SCT) is not insignificant, and the combined incidence has been estimated at up to 24%. (1‐3). t‐MDS and t‐AML are more frequent following auto‐SCT than following allogeneic stem cell transplantation (allo‐SCT) (4‐5). In a case control study, Krishnan demonstrated that patients who underwent chemo‐mobilization with etoposide had a significant increase in t‐MDS/t‐AML (4), while Metayer et al. demonstrated that t‐MDS/t‐AML occurred at a median of 2.5 years following auto‐SCT. Overall survival following t‐MDS and t‐AML in this setting was 12 and 6 months, respectively (5). Both alkylating agents and topoisomerase II inhibitors have been linked with t‐MDS/t‐AML (7). Alkylating agent t‐MDS/AML is associated with 5q and 7q deletions and has a median survival of 0.4 years (8‐10). While etoposide t‐MDS/AML is associated with rearrangements of the MLL gene, t(8;21), t(15;17), and inv(16) and survival is poor as well (11‐ 13). Even though allo‐SCT is a curative treatment option in these circumstances, there is relatively little published data specifically addressing this subgroup of patients. A retrospective analysis of patients with t‐MDS/t‐AML was undertaken in 2001 at Fred Hutchinson Cancer Center. The 5 year survival was 8% following allo‐SCT (mostly using myeloablative regimens). (14). Reduced intensity conditioning regimens have also been evaluated in patients with secondary AML or MDS, with overall survival of 36% at 2 years (7). In 2009, Kroger published a retrospective review on 461 patients who underwent allo‐SCT for t‐MDS and t‐AML. The authors indicated that age less than 40 years and normal cytogenetics were predictive of improved outcomes. However, neither of these two retrospective studies focused solely on patients who developed t‐MDS/t‐AML following auto‐SCT (15). Litzow et al reported the CIBMTR data on 868 patients underwent allo‐SCT for t‐MDS/t‐AML. TRM at 5 years was 48% and was associated with age > 35 years, prior MDS, poor performance status and non‐HLA matched grafts. Incidence of grade II‐IV acute graft‐versus‐host disease (aGVHD) was 39%, while 5‐year cumulative incidence of chronic GHVD was 30%. Relapse incidence at 5 years was 31%; probability

27


of relapse was associated with age > 35 years, diagnosis of ALL, poor risk cytogenetics and active disease at transplant. Overall survival at 5 years was 37% (16). Recent retrospective data from the European Group for Blood and Marrow Transplantation demonstrated that 31% of patients over the age of 50 could be cured of high‐risk MDS and t‐AML (17). Furthermore, a retrospective study from Platzbecker suggests an improvement in overall survival in elderly patients undergoing allo‐SCT for high‐risk MDS and t‐AML when compared to azacitidine (18). Again, none of these studies looked specifically at patients who underwent auto‐SCT and later developed t‐MDS/t‐AML. One of the remarkable advances in our field is the reduction of TRM in the setting of autologous transplants. Improved early survival has left a larger population at risk of relapse and long‐term complications such as t‐MDS or t‐AML. The only curative approach to this feared complication is an allo‐SCT, but there is a lack of specific data describing outcomes and possibly, best practices for this high‐risk population. Here we propose to analyze data from the EBMT and CIBMTR databases, to investigate the hypothesis that secondary AML/MDS after autologous transplant can be cured with allogeneic HSCT as well as evaluate the risks of this therapy. Patient Eligibility Population: Inclusion Criteria

All patients with t‐AML and t‐MDS who have received allogeneic HSCT, after having undergone autologous SCT for multiple myeloma, Hodgkin’s disease and non‐Hodgkin’s lymphoma, and reported to the CIBMTR and EBMT will be included for evaluation

Transplant between year 2000 and 2011 Data Requirements: Patient‐related:

Age

Gender

Race Autologous Transplant:

Age at autologous HSCT

Diagnosis (MM, HD, NHL)

Disease status at autologous transplant

Cytogenetics prior to transplant

Stem cell source

Peripheral blood mobilization (chemo mobilization: yes vs no)

Chemo mobilization type

Preparative regimen

Transplant date

Disease response

Date of relapse (if applicable)

28


AML‐MDS‐related:

Date of AML/MDS diagnosis

Disease status at time of HSCT

Induction / consolidation therapy

Laboratory assessment at time of transplant : WBC, Blast % (blood and bone marrow)

Cytogenetics risk group

Status of central nervous system prior to preparative regimen Treatment‐related:

Date of allo HSCT

HSCT type

Preparative regimen and preparative regimen intensity

Donor type

Stem cell source

GVHD prophylaxis

Use of ATG

Donor lymphocyte infusion (as part of planned therapy)

Date of relapse (if applicable)

Date of death or last known contact

Cause of death (if known)

Study Design: Retrospectively detailed information on each patient’s clinical characteristics and outcome will be

tabulated and compared utilizing the CIBMTR and EBMT registries.

Statistical Analysis:

2 or Fisher’s exact test will be used to examine the association between two categorical factors. The event free survival will be measured from the date of transplantation to the date of death or relapse and censored at the date of last follow‐up for survivors without relapse. Survival distribution will be estimated using Kaplan‐Meier methods and difference between/among groups will be tested using log rank. The effect of conditioning regimens on time‐to‐event outcomes will be analyzed by Cox model with time‐dependent covariates after adjusting for the effects of other confounders. References:

1. Pedersen‐Bjergaard J, Andersen MK, Christiansen DH. Therapy related acute myeloid leukemia and myelodysplasia after high dose chemotherapy and autologous stem cell transplantation. Blood. 2000;95: 3273‐3279.

2. Stone RM. Myelodysplastic syndrome after autologous transplantation for lymphoma: the price of progress. Blood. 1994; 83: 3437‐3440.

3. Traweek ST, Slovak ML, Nademanee AP, et al. Myelodysplasia and acute myeloid leukemia occurring after autologous bone marrow transplantation for lymphoma. Leuk Lymphoma. 1996;20:365‐372.

4. Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy‐related leukemia and myelodysplasia following autologous transplantation for lymphoma: An assessment of risk factors. Blood 95:1588‐1593, 2000.

5. Metayer C, Curtis RE, Vose J, et al: Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: A multicenter case‐control study. Blood 101:2015‐2023, 2003.

29


6. Witherspoon RP, Deeg HJ, Storer B, et al. Hematopoietic Stem‐Cell Transplantation for Treatment‐Related Leukemia or Myelodysplasia. JCO April 15, 2001 vol. 19 no. 8 2134‐2141.

7. van Leeuwen FE, Chorus AM, van den Belt‐ Dusebout AW, et al. Leukemia risk following Hodgkin’s disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage. J Clin Oncol. 1994;12:1063‐1073.

8. Pedersen‐Bjergaard J, Andersen MK, Andersen MT, et al. Genetics of therapy‐related myelodysplasia and acute myeloid leukemia. Leukemia. 2008;22:240‐248.

9. Larson RA, Le Beau MM. Therapy‐related myeloid leukaemia: a model for leukemogenesis in humans. Chem Biol Interact. 2005;153‐154:187‐195.

10. 31.Ng AK, Bernardo MVP, Weller E, et al. Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long‐term risks and risk factors. Blood. 2002;100:1989‐1996

11. Bloomfield CD, Archer KJ, Mrozek K, et al. 11q23 balanced chromosome aberrations in treatment‐related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002;33:362‐378.

12. Andersen MK, Larson RA, Mauritzson N, et al. Balanced chromosome abnormalities inv(16) and t(15;17) in therapyrelated myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002;33:395‐400.

13. Dissing, M., Le Beau, M.M., Pedersen‐Bjergaard, J. (1998) Inversion of chromosome 16 and uncommon rearrangements of the CBFB and MYH11 genes in therapy‐related acute myeloid leukemia: rare events related to DNA‐topoisomerase II inhibitors?Journal of Clinical Oncology, 16, 1890 1896.

14. Kröger N, Shimoni A, Zabelina T, et al. Reduced‐toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS). Bone Marrow Transplant. 2006 Feb;37(4):339‐44.

15. Kroger N, Brand R, van Biezen A, et al. Risk factors for therapy‐related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation. Haematologica.

16. 2009;94(4):542‐549. 17. Litzow MR, Tarima S, Pérez WS, et al. Allogeneic transplantation for therapy‐related

myelodysplastic syndrome and acute myeloid leukemia. Blood. 2010 Mar 4;115(9):1850‐7. 18. Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem‐cell transplantation for patients

50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010 Jan 20;28(3):405‐11.

19. Platzbecker U, Schetelig J, Finke J, et al. Allogeneic hematopoietic cell transplantation in patients age 60‐70 years with de novo high‐risk myelodysplastic syndrome or secondary acute myelogenous leukemia: comparison with patients lacking donors who received azacitidine. Biol Blood Marrow Transplant. 2012 Sep;18(9):1415‐21

30



Variable t‐AML t‐MDS



Autologous transplant data

Age

Median (range) 47 (21‐64) 48 (21‐62)

20‐29 3 (13) 1 (3)

30‐39 5 (25) 6 (19)

40‐49 4 (17) 11 (34)

50‐59 9 (38) 11 (34)

60‐69 2 (8) 3 (9)

Year of HCT

1986‐1990 1 (4) 0

1991‐1995 2 (13) 4 (13)

1996‐2000 7 (29) 10 (31)

2001‐2005 12 (50) 18 (56)

2006‐2010 1 (4) 0

Disease

Non Hodgkin Lymphoma 10 (42) 22 (69)

Hodgkin Lymphoma 11 (50) 8 (25)

Multiple Myeloma 2 (8) 2 (6)

Graft type

Bone marrow 2 (13) 5 (16)


Missing 2 (8) 2 (6)



NMA 2 (8) 4 (13)

Unknown 15 (62) 21 (66)

Relapse after transplant

No 20 (88) 29 (91)

Yes 3 (13) 3 (9)

Allogeneic transplant data

Age in decades

Median (range) 52 (25‐67) 52 (28‐65)

20‐29 2 (8) 1 (3)

30‐39 3 (13) 4 (13)

40‐49 5 (21) 6 (19)

50‐59 9 (42) 16 (50)

60‐69 4 (17) 5 (16)

31



Year of HCT

2000‐2005 14 (58) 24 (75)

2006‐2010 9 (42) 8 (25)


Median (range) 4 (1‐43) 3 (<1‐12)

<= 10 19 (83) 28 (88)

10 ‐ 100 4 (17) 1 (3)

Missing 0 3 (9)

Blasts % in marrow at HSCT, median (range) 5 (0‐80) 2 (0‐15)

Blasts % in blood at HSCT, median (range) 0 (0‐58) 0 (0‐9)

Disease status prior to HCT for AML

Primary induction failure 11 (46)

CR1 9 (38)

Relapse 1 (8)

Missing 2 (8)

Disease status prior to HCT for MDS

MDS early 17 (53)

MDS advanced 15 (47)


Favorable 2 (8) 2 (6)

Intermediate 0 2 (6)

Poor 11 (46) 19 (59)

TBD (needs review) 5 (25) 3 (9)

Not tested 1 (4) 2 (6)

Missing 4 (17) 4 (13)



RIC 11 (48) 20 (63)

NMA 2 (9) 3 (9)

Unknown 2 (9) 0

Type of donor


Well‐matched unrelated 13 (57) 22 (69)

Partially matched unrelated 4 (17) 4 (13)

Mismatched unrelated 2 (9) 3 (9)

Unrelated TBD 2 (9) 0

Missing 0 1 (3)

Graft type

Bone marrow 8 (38) 5 (16)


32



Umbilical cord blood 0 1 (3)

GVHD prophylaxis

Ex vivo T‐cell depletion alone 1 (4) 0

FK506 + MMF +‐ others 6 (26) 9 (28)

FK506 + MTX +‐ others (except MMF) 9 (39) 13 (41)

FK506 alone 0 1 (3)

CSA + MMF +‐ others (except FK506) 4 (17) 5 (16)

CSA + MTX +‐ others (except FK506, MMF) 3 (13) 4 (13)

ATG or campath

ATG alone 8 (35) 11 (34)

CAMPATH alone 1 (4) 3 (9)

No ATG or CAMPATH 14 (61) 18 (56)

Median follow‐up of survivors (range), months 96 (73‐120) 95 (29‐119)


INCLUSION:

1st allo HSCT for AML/MDS between 2000 to 2011 after 1 or more previous auto HSCT, CAP modeled

477

Auto HSCT for multiple myeloma, HD and NHL 402 75

Therapy linked AML/MDS 19 56

EXCLUSION:

No 100 day comprehensive form 1 55

33


Study Proposal 1311‐50 Study Title: Outcome of umbilical cord blood transplantation (CBT) in adults with high risk acute myeloid leukemia (AML) Ian D. Lewis, MBBS, PhD, Royal Adelaide Hospital, [email protected] Specific Aims: 1. To study the prognostic significance of high risk cytogenetic or molecular markers in AML compared

to other conventional prognostic markers in patients receiving CBT. Specifically to identify the

impact of:

a) chromosome 7 abnormalities [either monosomy7 or del(7q)] and monosomal karyotype

(MK)

b) fms‐like tyrosine kinase 3/internal tandem mutation (FLT3/ITD) mutation; on outcomes for

AML after CBT

2. To study the impact of high risk cytogenetics or FLT3/ITD mutation on incidence of relapse, disease‐

free survival, and overall survival after CBT

Scientific Justification: The recognition that high risk AML is rarely cured by standard chemotherapy has led to more aggressive transplant approaches being used in 1st complete remission (CR1), including use of alternative donors in recipients who do not have a suitably matched sibling donor. While the definition of high risk AML is constantly in evolution, particularly with the identification of increasing numbers of molecular markers, the presence of an adverse cytogenetic profile at diagnosis, and in particular MK, or the presence of a FLT3/ITD mutation in normal karyotype AML are well recognised markers of high risk disease. A number of studies have demonstrated benefit for CR1 transplant in patients with high risk AML. A meta‐analysis of randomised studies confirmed the benefit of allogeneic hematopoietic cell transplantation (HCT) for patients with poor‐risk cytogenetics1. In MK‐AML, allogeneic HCT in CR1 produced an OS of 19% compared to 9% for patients treated with chemotherapy alone or autologous transplantation2. In patients with adverse cytogenetics, similar outcomes following allogeneic HCT have been seen with sibling donors or well‐matched unrelated donors (URD)3. The benefit of CR1 transplant in patients with FLT3/ITD AML has been shown in a donor – no‐donor analysis, although in this study transplant was restricted to recipients with sibling donors4. Easy and rapid availability of umbilical CB is an attractive option for patients without a suitable HLA‐matched sibling or URD. The use of multiple CB units has expanded the use of CB in adults. However, studies of CBT in adults are difficult to interpret because of the inclusion of different disease states, different haematologic malignancies and different conditioning regimens. Early registry studies of CBT in haematological malignancies demonstrated the feasibility of CBT in adults. The EBMT study demonstrated similar outcomes for patients treated with CBT compared with URD bone marrow (BM) transplantation5, whereas the CIBMTR study demonstrated reduced transplant‐related mortality (TRM), treatment failure and mortality for URD BM recipients compared to CB recipients6. Recent studies of CBT in adult patients with acute leukemia have demonstrated recipients of a double unit CBT having a low dose TBI, cyclophosphamide and fludarabine conditioning regimen have an equivalent outcome compared to recipients of a 7/8 or 8/8 unrelated peripheral blood progenitor cell transplant7.

34


Furthermore, adult recipients of a single CB unit of adequate size have an equivalent 2 year survival compared to recipients of a double unit CBT8. Considering these results it is now apparent that CBT in adults with acute leukemia is a viable treatment option with comparable outcomes to recipients of HCT from other sources. Defining specific response rates in high risk AML patients would potentially lead to increased use of CBT in adult patients without an identified sibling or URD earlier in the disease course, thereby potentially improving outcome. Patient Eligibility Population: Adult patients ≥ 18 years of age who have had a single or multi unit CBT for AML at any disease stage. Data Requirements: The lack of molecular data and detailed information on FLT3 may restrict/limit the analysis. It is unclear whether it is feasible to approach transplant center’s for supplemental data.

Data to be analyzed will be from data collected in the CIBMTR Report Forms. Patient, disease and transplant variables include: Patient‐related:

Age

Gender

Karnofsky performance score Disease‐related:

Disease status at time of transplant

Cytogenetic/molecular risk group Transplant‐related:

Preparative regimen

Single or double unit cord transplant

Cell dose

HLA match Outcomes:

Time to engraftment

Transplant‐related mortality

Leukemia‐free survival

Overall Survival

Cause of Death

Chimerism

Incidence of grade 2‐4 and grade 3‐4 acute GVHD

Incidence of chronic GVHD Sample Requirements: No samples required Study Design: This is a retrospective cohort study evaluating outcomes of adult patients with high risk AML who have received a CBT at any time in the disease course. The outcomes studied will be TRM, relapse, leukemia‐free survival and overall survival. Comparisons will include outcomes correlated with disease stage.

35


The purpose of the study is to study the prognostic significance of MK or FLT3/ITD mutation in AML patients receiving CBT. Cohorts to be studied are:

1) patients with and without MK‐AML 2) FLT3‐ITD mutation in cytogenetically normal AML compared to other conventional prognostic

markers in patients receiving CBT.

References: 1. Yanada et al Cancer (2005) 103:1652 2. Cornelissen et al J Clin Oncol (2012) 30: 2140 3. Basara et al Leukemia (2009) 23: 635 4. Schlenk et al New Engl J Med (2008) 358: 1909 5. Rocha et al New Engl J Med (2004) 351: 2276 6. Laughlin et al New Engl J Med (2004) 351: 2265 7. Brunstein et al Blood (2012) 119: 5591 8. Scaradavou et al Blood (2013) 121: 752

36



Variable N (%)



Age in decades


18‐29 197 (24)

30‐39 141 (17)

40‐49 158 (19)

50‐59 191 (23)

60‐69 140 (17)

>=70 14 (2)

Gender

Male 380 (45)

Female 461 (55)

Recipient race

Caucasian 640 (76)

African‐American 97 (12)

Asian 73 (9)

Pacific islander 2 (<1)

Native American 4 (<1)

Other 1 (<1)

Unknown 24 (3)

Karnofsky score

<90% 225 (27)

>=90% 541 (64)

Missing 75 (9)

White blood count at diagnosis (x10^9/L)


<= 30 450 (54)

30 ‐ 100 131 (16)

> 100 62 (7)

Missing 198 (24)



CR1 347 (41)

37


Variable N (%)

CR2 237 (28)

>=CR3 37 (4)

Relapse 100 (12)

Missing 32 (4)


Normal 229 (27)

Favorable 69 (8)


Poor 192 (23)


Not tested 17 (2)

Missing 123 (15)

FLT3 mutation

No 274 (33)

Yes 85 (10)

Normal cytogenetics 52

Abnormal cytogenetics 31

Unknown cytogenetics 2

Not collected before 2007 190 (23)

Missing 292 (35)

Monosomal karyotype

MK+: more than 1 monosomy 32 (4)

MK+: 1 monosomy + other 26 (3)

Other cytogenetic abnormalities 313 (37)

Normal cytogenetics 229 (27)

TBD 104 (12)

Missing 137 (17)



RIC 102 (12)

NMA 219 (26)

TBD 54 (6)

Conditioning regimen

TBI 562 (67)

Bu + Cy 65 (8)

Bu + Mel 12 (1)

38


Variable N (%)

Bu + Thio 5 (<1)

Mel + Thio 40 (5)

Mel + Flud 54 (6)

Cy + Flud 4 (<1)

Bu + Flud 44 (5)

Treosulfan 2 (<1)

CBV 1 (<1)

Others 52 (6)

Single vs. double cord

Single 280 (33)

3/6 3 (1)

4/6 90 (32)

5/6 49 (18)

6/6 20 (7)

Missing 118 (42)

Double 561 (67)

2/6 1 (<1)

3/6 5 (<1)

4/6 268 (48)

5/6 144 (26)

6/6 24 (4)

Missing 119 (21)

GVHD prophylaxis

Ex vivo T‐cell depletion + post‐tx immune supression 2 (<1)

CD34 selection alone 12 (1)

CD34 selection + post‐tx immune supression 4 (<1)

FK506 + MMF +‐ others 223 (27)

FK506 + MTX +‐ others (except MMF) 27 (3)

FK506 + others (except MTX, MMF) 46 (5)

FK506 alone 28 (3)

CSA + MMF +‐ others (except FK506) 344 (41)

CSA + MTX +‐ others (except FK506, MMF) 26 (3)

CSA + others (except FK506, MTX, MMF) 48 (6)

CSA alone 17 (2)

Other GVHD prophylaxis 64 (8)

ATG or campath

39


Variable N (%)

ATG alone 280 (33)

CAMPATH alone 7 (<1)


Missing 30 (4)

Year of HCT

2001‐2005 129 (15)

2006‐2011 712 (85)



INCLUSION:

1st allo transplant for AML from 2001 to 2011 11531


UCB graft (single or double) 8764 936

EXCLUSION:



Crosstab of Disease Status by Risk

Variable Low risk High risk† Missing

Number of patients 274 260 307


Primary induction failure 26 (9) 26 (10) 36 (12)

CR1 164 (60) 87 (33) 96 (31)

CR2 46 (17) 97 (37) 94 (31)

>=CR3 12 (4) 17 (7) 8 (3)

Relapse 24 (9) 33 (13) 43 (14)

Missing 2 (<1) 0 30 (10)†High risk defined as: poor cytogenetics, MK+, or FLT3+, considered missing if any of 3 characteristics is

missing with no high risk is identified

40


Study Proposal 1311‐56 Study Title: Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first and second complete remission Fotios Vasilios Michelis, MD, PhD, Allogeneic Blood and Marrow Transplant Program, Princess Margaret Hospital, Canada, [email protected] Vikas Gupta, MD, FRCP, FRCPath, Allogeneic Blood and Marrow Transplant Program, Princess Margaret Hospital, Canada, [email protected] Specific Aim: To identify patient, disease, and transplant related characteristics associated with outcomes for older patients in particular (≥60 years) with AML undergoing allogeneic hematopoietic cell transplantation (HCT) in CR1 and CR2. Outcomes of Interest:

Overall survival (OS)

Leukemia‐free survival (LFS)

Cumulative Incidence of Relapse (CIR)

Non‐relapse mortality (NRM) Scientific Justification: The prognosis of younger patients with AML has improved significantly over the last two decades.1 This improvement is the result of better supportive care strategies and increased use of allogeneic transplants in younger patients. In comparison, the outcomes of older patients continue to remain dismal.2,3 Conventional myeloablative conditioning (MAC) is associated with high post‐transplant mortality in older patients4. The introduction of reduced‐intensity conditioning (RIC) has enabled to overcome the barrier of early TRM, and several studies have reported an OS post‐HCT using RIC or non‐myeloablative (NMA) conditioning in the range of 30‐35% at 2‐3 years in CR15‐10. Data on outcomes in older patients undergoing HCT in CR2 are very limited. In our own experience at Princess Margaret Hospital, we recently analyzed the outcomes of 242 patients undergoing HCT for AML from 1999‐2011, of which 116 were <60 years of age in CR1, 78 were <60 in CR2, 32 patients were ≥60 years of age in CR1 and 16 were ≥60 in CR2 (manuscript submitted, available on request). OS at 2‐years was 43% and 23% for the older patients in CR1 and CR2, respectively, while LFS at 2‐years was 34% and 19% for the older patients in CR1 and CR2, respectively. There were no survivors in the ≥60 years CR2 group at 4 years post‐HCT (See the outcome data in Appendix 1 and 2). Moreover, in a recently published study examining risk factors for outcome of HCT for 94 patients with AML in CR2 at our institution, older age was associated with inferior OS, as well as brief duration of CR1 and a high comorbidity score 11. Clearly, older CR2 patients do not appear to benefit from the curative potential of HCT. One of the limitations of our study has been the small number of patients in CR2. Therefore we would like to use a larger database to evaluate the usefulness of transplantation in CR2 patients. Due to modest results of transplantation, many physicians are hesitant to refer these patients for transplant. Graft‐versus‐host disease (GvHD) and infectious complications are major problems in the ≥60 age group. Further improvement in outcomes may come from newer approaches addressing various post‐transplant complications in older patients. Given that 2/3 of older patients undergoing HCT in CR1 will fail transplant due to either relapse or NRM, identifying patients likely to benefit from the option of transplantation as well as patients for whom transplant procedure is likely to be futile will be of

41


importance. At present, this information is not available due to small sample sizes of the current studies. Large‐scale studies to investigate the role of allo‐HCT in older patients with AML in CR2 in particular are not available. Information is mostly derived from subset analyses of studies that include patients in both CR1 and CR2. The large size of the CIBMTR registry provides an opportunity to study these prognostic factors in a well powered study. The data from this study will provide useful information as below:

a. Identifying patients likely to benefit from HCT will give confidence to the referring physicians in the option of HCT, and improve the referral of these patients to transplant centers.

b. Identifying patients unlikely to benefit from HCT will spare these patients side‐effects associated with HCT. In addition, these patients could benefit from novel transplant or non‐transplant related treatment options.

c. Patient counseling d. Design of future clinical trials comparing allogeneic and non‐allogeneic treatment options, as well

as clinical trials designed to improve the dismal outcome post‐HCT of older patients in CR2. Patient Eligibility Population: Using the CIBMTR database, patients with AML who underwent HCT between 1999 and 2013 and meet the following criteria will be identified. Eligible Patients: Inclusion criteria:

Age 18 years and older at the time of HCT (will be divided into <60 and ≥60 years of age)

First allogeneic transplant

Diagnosis of AML

CR1 or CR2

Transplant from either a matched related donor or matched volunteer unrelated donor (9/10 or 10/10)

Exclusion criteria:

Syngeneic transplants

In vitro T cell depletion

Cord‐blood transplants

Haplo‐identical transplants

Acute promyelocytic leukemia

Previous allogeneic transplant Variables to be analyzed: Patient‐related:

Age at HCT

Gender

Karnofsky Performance scores: <90 vs ≥90

Hematopoietic cell transplant‐comorbidity index12(HCT‐CI)(depending on availability of data) Disease‐related:

Type of AML: de‐novo versus therapy related versus secondary AML with previous diagnosis of MDS/MPD

Previous autologous transplant (yes/no)

Cytogenetics: good risk vs. intermediate vs. poor risk vs. unknown/not available (defined according to SWOG/ECOG definition13)

42


Time from diagnosis of AML to transplant

For CR1 patients, number of courses of chemotherapy to CR1

For CR2 patients, duration of first CR in months Transplant‐related:

Conditioning regimen: MAC vs. RIC vs. NMA as defined by CIBMTR14

TBI in conditioning regimen: no TBI versus TBI with dose in cGY included

Donor age

Donor type: MSD vs. 9/10 MUD vs 10/10 MUD

Donor‐recipient gender: M‐M vs. M‐F vs. F‐M vs. F‐F

CMV status of donor and recipient: +/+ vs. +/‐ vs. ‐/+ vs. ‐/‐

ABO incompatibility: none vs. minor vs. major vs. bidirectional

Source of hematopoietic cells: BM vs. PBSC

Median CD34 cell dose, x 106/kg

Date of transplant

GVHD prophylaxis: Calcineurin inhibitor (CNI) + MTX vs. CNI + MMF vs. others

Received Serotherapy with either campath or ATG: yes/no Outcomes of Interest:

1. Hematopoietic recovery (neutrophil and platelet recovery) 2. Acute GVHD 3. Chronic GVHD 4. Cumulative incidence of Relapse 5. Cumulative incidence of NRM 6. LFS 7. OS

Statistical Analysis: This is a retrospective study of CIBMTR data between 1999 and 2013.

The purpose of the proposed study is to compare the outcomes of patients undergoing allo‐HCT for AML depending on the combination of age at transplant (<60 vs ≥60 years) and remission status (CR1 vs CR2). The patients would be divided into four groups: <60 CR1, <60 CR2, ≥60 CR1, ≥60 CR2. Patient, disease and transplant related variables will be compared between the groups using chi‐square test for categorical variables and Mann‐Whitney test for continuous variables. Statistical endpoints will be calculated using Kaplan‐Meier Method and will be compared using log‐rank test for overall survival, while non‐relapse mortality (NRM), cumulative incidence of relapse (CIR) and GVHD incidence will be calculated using the cumulative incidence method considering competing risks and will be compared using Gray method. Multivariate analysis will also be performed using Cox’s proportional hazard model for overall survival, and using Fine‐Gray method for NRM, CIR and GVHD incidence. All variables with a p‐value <0.1 in the univariate analysis will be considered for entry into multivariate analysis, in which all p‐values will be tested as two‐sided and p‐value <0.05 will be used as statistically significant. Further plan will be developed depending on sample size after discussion with statistical team at CIBMTR.

References: 1. Derolf AR, Kristinsson SY, Andersson TM, Landgren O, Dickman PW, Bjorkholm M. Improved

patient survival for acute myeloid leukemia: a population‐based study of 9729 patients diagnosed in Sweden between 1973 and 2005. Blood. 2009;113:3666‐3672

43


2. Hiddemann W, Kern W, Schoch C, Fonatsch C, Heinecke A, Wormann B, Buchner T. Management of acute myeloid leukemia in elderly patients. J Clin Oncol. 1999;17:3569‐3576

3. Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, Anderson JE, Petersdorf SH. Age and acute myeloid leukemia. Blood. 2006;107:3481‐3485

4. Wallen H, Gooley TA, Deeg HJ, Pagel JM, Press OW, Appelbaum FR, Storb R, Gopal AK. Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol. 2005;23:3439‐3446

5. Gupta V, Daly A, Lipton JH, Hasegawa W, Chun K, Kamel‐Reid S, Tsang R, Yi QL, Minden M, Messner H, Kiss T. Nonmyeloablative stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia in patients 60 years or older. Biol Blood Marrow Transplant. 2005;11:764‐772

6. Bertz H, Potthoff K, Finke J. Allogeneic stem‐cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol. 2003;21:1480‐1484

7. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010;28:2859‐2867

8. Koreth J, Aldridge J, Kim HT, Alyea EP 3rd, Cutler C, Armand P, Ritz J, Antin JH, Soiffer RJ, Ho VT. Reduced‐intensity conditioning hematopoietic stem cell transplantation in patients over 60 years: hematologic malignancy outcomes are not impaired in advanced age. Biol Blood Marrow Transplant. 2010;16:792‐800

9. McClune BL, Weisdorf DJ, Pedersen TL, Tunes da Silva G, Tallman MS, Sierra J, Dipersio J, Keating A, Gale RP, George B, Gupta V, Hahn T, Isola L, Jagasia M, Lazarus H, Marks D, Maziarz R, Waller EK, Bredeson C, Giralt S. Effect of age on outcome of reduced‐intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010;28:1878‐1887

10. Spyridonidis A, Bertz H, Ihorst G, Grullich C, Finke J. Hematopoietic cell transplantation from unrelated donors as an effective therapy for older patients (> or = 60 years) with active myeloid malignancies. Blood. 2005;105:4147‐4148

11. Michelis FV, Atenafu EG, Gupta V, et al. Duration of first remission, hematopoietic cell transplantation‐specific comorbidity index and patient age predict survival of patients with AML transplanted in second CR. Bone Marrow Transplant. 2013 May 20. doi:10.1038/bmt.2013.71. [Epub ahead of print]

12. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)‐specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.

13. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075‐4083

14. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, Pasquini M, Sandmaier BM, Barrett J, Blaise D, Lowski R, Horowitz M. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628‐1633

44


Appendix 1:

Appendix 1. a) Overall Survival following univariate analysis, stratified by CR status and age (p=0.003), b)

Leukemia Free Survival, stratified by CR status and age (p=0.0005).

45


Appendix 2:

Appendix 2. a) Cumulative Incidence Rate of NRM, stratified by CR status and age (p=0.04), b)

Cumulative Incidence Rate of Relapse, stratified by CR status and age (p=0.05).

46



Variable 18‐60 yr >=60 yr



Age in decades

Median (range) 45 (18‐60) 64 (60‐78)

18‐29 659 (18) 0

30‐39 656 (18) 0

40‐49 1116 (30) 0

50‐59 1281 (35) 0

60‐69 0 628 (92)

>=70 0 56 (8)

Gender

Male 1914 (52) 415 (61)

Female 1798 (48) 269 (39)

Karnofsky score

<90% 958 (26) 218 (32)

>=90% 2567 (69) 428 (63)

Missing 187 (5) 38 (6)

HCT‐CI

0 1109 (30) 252 (37)

1 304 (8) 82 (12)

2 33 (<1) 16 (2)

3 8 (<1) 2 (<1)

4 0 1 (<1)

Not collected before 2007 2258 (61) 331 (48)

Type of AML

De‐novo 3086 (83) 439 (64)

Transformed from MDS/MPS 416 (11) 206 (30)

Therapy linked 210 (6) 39 (6)


CR1 2745 (74) 526 (77)

CR2 967 (26) 158 (23)


Normal 1185 (32) 224 (33)

Favorable 262 (7) 18 (3)

47



Intermediate 430 (12) 72 (11)

Poor 623 (17) 149 (22)

TBD (needs review) 543 (15) 65 (10)

Not tested 136 (4) 21 (3)

Missing 533 (14) 135 (20)

Time from diagnosis to transplant, median (range), months 5 (<1‐193) 6 (<1‐90)

Duration of CR1 for CR2 cases 11 (<1‐187) 11 (<1‐82)

Number of lines of induction for CR1 cases

1 837 (22) 224 (32)

2 207 (6) 57 (8)

3 27 (<1) 6 (<1)

4 4 (<1) 4 (<1)


Number of cycles of induction for CR1 cases

1 1104 (30) 208 (30)

2 465 (13) 64 (9)

3 67 (2) 9 (1)

4 13 (<1) 10 (1)

>=5 29 (1) 5 (<1)

Missing 1067 (29) 230 (34)



RIC 530 (14) 364 (53)

NMA 150 (4) 159 (23)

TBD 116 (3) 46 (7)


TBI 1420 (38) 176 (26)

Bu + Cy 1174 (32) 52 (8)

Bu + Mel 13 (<1) 0

Mel + Thio 7 (<1) 0

Mel + Flud 163 (4) 87 (13)

Cy + Flud 54 (1) 39 (6)

Bu + Flud 746 (20) 267 (39)

Cy + Thio 4 (<1) 0

Treosulfan 11 (<1) 0

BEAM 1 (<1) 0

48



TLI 18 (<1) 21 (3)

Others 101 (3) 42 (6)

Total body irradiation

No 2236 (60) 498 (73)

Yes 1420 (38) 176 (26)

Missing 56 (2) 10 (1)

Type of donor




‐/‐ 927 (25) 158 (23)

‐/+ 979 (26) 238 (35)

+/‐ 399 (11) 57 (8)

+/+ 1272 (34) 206 (30)

TBD 135 (4) 25 (4)


M/M 1227 (33) 267 (39)

M/F 1068 (29) 149 (22)

F/M 684 (18) 148 (22)

F/F 727 (20) 119 (17)

TBD 6 (<1) 1 (<1)

Donor/recipient ABO match

Matched 1953 (53) 276 (40)

Minor mismatch 634 (17) 118 (17)

Major mismatch 668 (18) 118 (17)

Bidirectional mismatch 189 (5) 25 (4)

TBD 268 (7) 147 (21)

Graft type

Bone marrow 854 (23) 62 (9)


GVHD prophylaxis

CD34 selection alone 26 (<1) 4 (<1)

CD34 selection + post‐tx immune supression 72 (2) 22 (3)

Cyclophosphamide alone 16 (<1) 3 (<1)

Cyclophosphamide + others 3 (<1) 0

FK506 + MMF +‐ others 359 (10) 123 (18)

49




FK506 + others (except MTX, MMF) 144 (4) 17 (2)

FK506 alone 86 (2) 21 (3)



CSA + others (except FK506, MTX, MMF) 73 (2) 13 (2)

CSA alone 126 (3) 25 (4)

Other GVHD prophylaxis 72 (2) 16 (2)

ATG or campath

ATG + CAMPATH 1 (<1) 0

ATG alone 665 (18) 213 (31)


No ATG or CAMPATH 2962 (80) 434 (63)

Year of HCT

1999‐2003 1066 (29) 107 (16)

2004‐2007 1521 (41) 313 (46)

2008‐2011 1125 (30) 264 (39)



INCLUSION:

1st allo transplant for AML from 1999 to 2011 12896


CR1 or CR2 prior to transplant 3554 7222

BM/PB graft 594 6628

HLA‐id sib or well‐matched unrelated 1873 4755

EXCLUSION:

FAB M3 50 4705

Ex‐vivo T‐cell depletion 40 4575



50


Study Proposal 1310‐02/1310‐04/1312‐01 Study Title:

Risk index for Acute Leukemia Patients Receiving Allogeneic Hematopoietic Cell Transplantation PI Information: (PIs were given in alphabetic order regarding authors’ last name) Faiz Anwer1, Yongxian Hu2, He Huang2, Ravi Krishnadasan1, Celalettin Ustun3, Daniel Weisdorf3, Andrew Yeager1 1Division of Hematology, Oncology & Stem Cell Transplantation, The University of Arizona Cancer Center, University of Arizona ([email protected], [email protected], and [email protected]) 2Bone marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China ([email protected]) 3University of Minnesota Medical Center, Fairview, Minneapolis, MN, USA ([email protected] and [email protected])

Specific Aim: Primary Objective: To create a risk index for acute leukemia patients (AL‐RI) receiving allogeneic hematopoietic cell transplantation Secondary objectives:

1. To create Risk Index for Risk index for Acute Myeloid Leukemia Patients (AML‐RI) Receiving Allogeneic Hematopoietic Cell Transplantation

2. To create Risk Index for Risk index for Acute Lymphoblastic Leukemia Patients (ALL‐RI) Receiving Allogeneic Hematopoietic Cell Transplantation

3. To evaluate time to transplant variable as DCT index (Time from Diagnosis to CR ÷ Time from CR to Transplant) in patients with CR1 predicts outcomes better than conventional time‐to‐transplant (TtT) variable.

Scientific Justification: Allogeneic hematopoietic cell transplantation (alloHCT) is curative for patients with acute leukemia (AL). Outcomes after allogeneic hematopoietic cell transplantation (alloHCT), however, vary largely depending upon disease‐, patient‐, and transplantation‐characteristics.1‐6 Therefore, disease risk index and comorbidity index have been created and validated.7,8 Within time, progress in alloHCT (conditioning intensity, donor use other than unrelated or siblings) as well as understanding of molecular biology of AL has been made.9‐12 In this study proposal, molecular marker, importance of intensity of conditioning regimens as well as alternative donors will be included. In this proposed study we would like to combine all potential factors and create an index for Risk Index for patients with acute leukemia receiving alloHCT. Given the fact that ALL and AML are different diseases with different alloHCT outcomes, as a secondary end point we aimed to create RI for each AML (AML‐RI) and ALL (ALL‐RI). Time to Transplant (TT) has been used for a factor in allogeneic hematopoietic cell transplantation outcome (alloHCT).13,14 The longer TT is associated with better outcome given the patients with poor risk AML will relapse before alloHCT. (Because favorable patient group will remain in longer CR) will receive

51


alloHCT.). However, TT is composed of 2 components: each component opposes the other. First component is “time from diagnosis to CR” (TDC) and second component is “ time from CR to alloHCT” (TCT). The shorter duration of the first component is associated with most favorable outcome, on the other hand, the longer duration of the second component is associated with most favorable outcome; therefore these 2 components cancel out each other. Therefore we propose a new index, DCTI (from Diagnosis to CR to Transplant). It is arguable that some patients would receive consolidations while others would not in component 2. However there has been no study showing that consolidation therapy before either reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) alloHCT improves outcome.15‐17 Study Period: From Jan 1996 to Dec 2012. For molecular analysis from January 2007 to December 2012. Patient Eligibility Population: Adult patients (≥18 years) with diagnosis of AL who underwent first alloHCT over defined years. Exclusion:

• Identical twin

• Second or greater alloHCT

Variables to be Analyzed: Patient‐related:

• Age: continuous; by decades

• Gender: male vs. female

• Weight and BMI:

• Karnofsky performance score: <90% vs 90‐100%

• Hematopoietic cell transplantation (HCT)‐specific comorbidity index (HCT‐CI) Disease‐related:

WBC at diagnosis

Bone marrow blast count at alloHCT (<1% vs. 1‐3% vs. 3‐4% vs. ≥5%)

CR number (CR≤2 vs. CR>2)

TDC, TCT and DCTI

Cytogenetic

Molecular markers (after 2007)

Hypomethylating therapy before transplant (Cycles Zero ‐2 /2‐4 / 4‐6 / >6 cycles.)

Extramedullary disease, CNS involvement

De novo or secondary AML Transplant‐related:

• Conditioning regimen intensity (NST vs. RIC vs. conventional myeloablative)

• In vivo or in vitro T‐cell depletion

• Donor age

• Donor‐recipient gender match: M‐M vs. M‐F vs. F‐M vs. F‐F

• Donor type (Sibling vs. URD vs. UCB vs. Haploidentical)

• Donor‐recipient CMV status: +/+ vs. +/‐ vs. ‐/‐

• GVHD prophylaxis (CNI + MTX vs. CNI + MMF vs. no CNI regimens

• CD 34+ cell count or mononuclear cell count infused

• HLA match status (well‐matched vs. partial‐match vs. mismatched)

52


• ABO‐compatibility between donor and recipient

• Year of transplant (1996‐2001 vs. 2002‐2007 vs. 2008‐2012)

• Stem cell source (BM or PBSC) Outcome‐related:

• TRM at year 1 and 5 years

• Progression rate at year1 and 5 years

• PFS at 1 year and 5 years

• OS at 1 year and 5 years

• Acute and chronic graft‐versus‐host disease (GVHD) rate and severity Study Design: The goal of this study is to identify risk factors associated with relapse after allogeneic hematopoietic stem cell transplantation for acute leukemia patients with normal karyotype in first and second complete remission. Descriptive tables of patient‐, disease‐, and transplant‐related factors by relapsed and non‐relapsed patients posttransplantation will be prepared. Statistical analyses will be done per CIBMTR statisticians recommendations. However briefly, overall survival (OS) and progression‐free survival (PFS) will be calculated with the Kaplan‐Meier method. OS was defined as the time from day of alloHCT (stem cell infusion, day 0) to death from any cause. Patients who were alive or lost to follow‐up were censored at the time last seen alive. PFS was defined as the time from day0 to disease relapse or progression or death from any cause, whichever occurred first. Patients who were alive without disease relapse or progression were censored at the time last seen alive and progression‐free. The log‐rank test was used for comparisons of Kaplan‐Meier curves. Cumulative incidence curves for nonrelapse mortality (NRM) and relapse with or without death were constructed reflecting time to relapse and time to NRM, respectively, as competing risks. Time to relapse and time to NRM were measured from the date of stem cell infusion. The difference between cumulative incidence curves in the presence of a competing risk was tested. Potential prognostic factors for OS, PFS, relapse, and NRM were examined in the proportional hazards model as well as in the competing risks regression model. References: 1. Armand P, Kim HT, Zhang MJ, et al. Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant. 2012;18(2):280‐288. 2. Bachanova V, Marks DI, Zhang MJ, 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. 2013. 3. Ustun C, Wiseman AC, Defor TE, et al. Achieving stringent CR is essential before reduced‐ intensity conditioning allogeneic hematopoietic cell transplantation in AML. Bone Marrow Transplant. 2013;48(11):1488. 4. Jaglowski SM, Ruppert AS, Heerema NA, et al. Complex karyotype predicts for inferior outcomes following reduced‐intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia. Br J Haematol. 2012;159(1):82‐87. 5. Hu YX, Cui Q, Liang B, Huang H. Relapsing hematologic malignancies after haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2011;17(8):1099‐1111. 6. Nagler A, Rocha V, Labopin M, et al. Allogeneic hematopoietic stem‐cell transplantation for

53


acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total‐body irradiation plus Cy as conditioning regimen‐‐a report from the acute leukemia working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013;31(28):3549‐3556. 7. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood. 2012;120(4):905‐913. 8. Sorror ML, Giralt S, Sandmaier BM, et al. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood. 2007;110(13):4606‐4613. 9. Pratcorona M, Brunet S, Nomdedeu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low‐allelic burden FLT3‐ITD mutation and concomitant NPM1 mutation: relevance to post‐remission therapy. Blood. 2013;121(14):2734‐2738. 10. Luger SM, Ringden O, Zhang MJ, et al. Similar outcomes using myeloablative vs reduced‐ intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant. 2012;47(2):203‐ 211. 11. Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA‐mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118(2):282‐288. 12. Di Bartolomeo P, Santarone S, De Angelis G, et al. Haploidentical, unmanipulated, G‐CSF‐primed bone marrow transplantation for patients with high‐risk hematologic malignancies. Blood. 2013;121(5):849‐857. 13. Foran JM, Pavletic SZ, Logan BR, et al. Unrelated donor allogeneic transplantation after failure of autologous transplantation for acute myelogenous leukemia: a study from the center for international blood and marrow transplantation research. Biol Blood Marrow Transplant. 2013;19(7):1102‐1108. 14. Peffault de Latour R, Brunstein CG, Porcher R, et al. Similar overall survival using sibling, unrelated donor, and cord blood grafts after reduced‐intensity conditioning for older patients with acute myelogenous leukemia. Biol Blood Marrow Transplant. 2013;19(9):1355‐1360. 15. Tallman MS, Rowlings PA, Milone G, et al. Effect of postremission chemotherapy before human leukocyte antigen‐identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood. 2000;96(4):1254‐1258. 16. Warlick E, Paulson K, Brazauskas R, et al. Pre‐Transplant Consolidation Chemotherapy Does Not Improve Outcomes Following Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplant (HCT) for Acute Myeloid Leukemia (AML) in CR1. Biology of Blood and Marrow Transplantation. 2013;19(2):S231‐S231. 17. McCormack SE, Cao Q, Oran B, Weisdorf DJ, Warlick ED. Pre‐transplant consolidation chemotherapy may not improve outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission. Leukemia Research. 2011;35(6):757‐761.

54



Variable AML ALL



Age in decades

Median (range) 48 (18‐78) 35 (18‐72)

18‐29 951 (16) 877 (38)

30‐39 881 (15) 507 (22)

40‐49 1433 (24) 479 (21)

50‐59 1737 (29) 346 (15)

60‐69 899 (15) 91 (4)

>=70 80 (1) 1 (<1)

Gender

Male 3151 (53) 1367 (59)

Female 2830 (47) 934 (41)

Karnofsky score

<90% 1543 (26) 595 (26)

>=90% 4106 (69) 1596 (69)

Missing 332 (6) 110 (5)

HCT‐CI

0 2021 (34) 635 (28)

1 562 (9) 170 (7)

2 63 (1) 18 (<1)

3 16 (<1) 4 (<1)

4 1 (<1) 0


White blood count at diagnosis, (x10^9/L)

Median (range) 9 (<1‐2420) 12 (<1‐4870)

<= 30 3663 (61) 1234 (54)

30 ‐ 100 989 (17) 334 (15)

> 100 492 (8) 270 (12)

Missing 837 (14) 463 (20)

Blasts in BM prior to transplant

0‐1 % 1777 (30) 739 (32)

1‐3 % 2240 (37) 695 (30)

3‐5 % 933 (16) 258 (11)

>=5 % 336 (6) 306 (13)

Missing 695 (12) 303 (13)


CR1 4130 (69) 1484 (64)

CR2 1719 (29) 698 (30)

55


Variable AML ALL

>=CR3 132 (2) 119 (5)

TDC, median (interquartile range) 1.4 (1.0‐2.3) 1.5 (1.0‐3.2)

TCT, median (interquartile range) 4.1 (2.2‐9.6) 4.5 (2.6‐11.9)

DCTI, median (interquartile range) 0.3 (0.1‐0.8) 0.3 (0.1‐1.0)

Cytogenetics scoring (AML)

Normal 1767 (30) N/A

Favorable 503 (8)


Poor 1087 (18)


Not tested 144 (2)

Missing 845 (14)

Cytogenetics scoring (ALL)

Normal N/A 499 (22)

Poor 813 (35)

Other 149 (6)


Not tested 110 (5)

Missing 406 (18)

FLT3 mutation at diagnosis (AML)

No 1078 (18) N/A

Yes 284 (5)


Missing 1318 (22)

BCR/ABL any time prior to HSCT

Negative N/A 259 (11)

Positive 157 (7)

Not tested 240 (10)


Missing 189 (8)

TEL/AML/AML1 any time prior to HSCT

Negative N/A 33 (1)

Positive 8 (<1)

Not tested 614 (27)


Missing 190 (8)

Other molecular testing any time prior to HSCT

Negative N/A 63 (3)

Positive 34 (1)

Not tested 559 (24)

56


Variable AML ALL


Missing 189 (8)

Extramedullary disease at diagnosis

No 5554 (93) 1936 (84)

Yes 321 (5) 273 (12)

Missing 106 (2) 92 (4)

EMD at CNS at diagnosis

No 5788 (97) 2079 (90)

Yes 87 (1) 130 (6)

Missing 106 (2) 92 (4)

EMD at other site at diagnosis

No 5627 (94) 2048 (89)

Yes 248 (4) 161 (7)

Missing 106 (2) 92 (4)

Type of AML

Transformed from MDS 857 (14) N/A

Therapy linked (secondary) 337 (6)

De‐novo 4664 (78)

Missing 123 (2)


Myeloablative 4022 (67) 2008 (87)

RIC 1309 (22) 176 (8)

NMA 456 (8) 63 (3)

TBD 194 (3) 54 (2)

Graft type

Bone marrow 1290 (22) 694 (30)


Type of donor


Other related 200 (3) 75 (3)


Partially matched unrelated 461 (8) 240 (10)

Mismatched unrelated 103 (2) 67 (3)

Unrelated TBD 1738 (29) 567 (25)

Related donor age

Median (range) 46 (<1‐85) 37 (<1‐80)

0‐18 80 (1) 102 (4)

18‐29 282 (5) 196 (9)

30‐39 403 (7) 184 (8)

40‐50 640 (11) 208 (9)

57


Variable AML ALL

50‐59 577 (10) 143 (6)

60‐70 363 (6) 43 (2)

N/A 3567 (60) 1392 (60)

Missing 69 (1) 33 (1)

Unrelated donor age

Median (range) 34 (18‐62) 34 (<1‐61)

18‐29 1009 (17) 396 (17)

30‐39 1039 (17) 430 (19)

40‐50 697 (12) 274 (12)

50‐59 198 (3) 76 (3)

60‐70 4 (<1) 2 (<1)

N/A 2414 (40) 909 (40)

Missing 620 (10) 214 (9)


M/M 2053 (34) 882 (38)

M/F 1643 (27) 519 (23)

F/M 1093 (18) 481 (21)

F/F 1182 (20) 413 (18)

TBD 10 (<1) 6 (<1)


‐/‐ 1436 (24) 578 (25)

‐/+ 1734 (29) 580 (25)

+/‐ 625 (10) 274 (12)

+/+ 1982 (33) 779 (34)

TBD 204 (3) 90 (4)

GVHD prophylaxis

Ex vivo T‐cell depletion alone 88 (1) 32 (1)

Ex vivo T‐cell depletion + post‐tx immune supression 107 (2) 38 (2)

CD34 selection alone 46 (<1) 15 (<1)

CD34 selection + post‐tx immune supression 119 (2) 40 (2)

Cyclophosphamide alone 22 (<1) 4 (<1)

Cyclophosphamide + others 21 (<1) 8 (<1)

FK506 + MMF +‐ others 663 (11) 195 (8)


FK506 + others (except MTX, MMF) 221 (4) 102 (4)

FK506 alone 153 (3) 30 (1)



CSA + others (except FK506, MTX, MMF) 97 (2) 35 (2)

CSA alone 181 (3) 55 (2)

58


Variable AML ALL

Other GVHD prophylaxis 137 (2) 61 (3)

ATG or campath

ATG + CAMPATH 2 (<1) 0

ATG alone 1534 (26) 450 (20)


No ATG or CAMPATH 4219 (71) 1788 (78)

Missing 20 (<1) 6 (<1)

Year of HCT

2001‐2004 1900 (32) 881 (38)

2005‐2008 2743 (46) 1048 (46)

2009‐2012 1338 (22) 372 (16)



INCLUSION:

1st allo transplant for AML/LLL from 2001 to 2012 17798


BM/PB graft 1371 12100

Patients in complete remission prior to transplant 3446 8654

EXCLUSION:

Syngeneic transplant 57 8597



59


Study Proposal 1311‐34 Study Title: The graft versus leukemia effect following reduced intensity allotransplant for acute lymphoblastic leukemia (ALL) Veronika Bachanova, MD, PhD, University of Minnesota, [email protected] Specific Aim: To identify a graft vs. leukemia (GVL) effect after reduced intensity (RIC) HCT for T and B‐ALL by comparing leukemia recurrence in patients with and without acute and/or chronic GVHD Scientific Justification: GVL. Allogeneic donor HCT following myeloablative conditioning is a curative treatment option for patients with ALL (1). Potent antileukemia effect occurs from the combination of high dose chemo‐radiation therapy and immune‐mediated GVL effect (1). CIBMTR study by Passweg at el. in 1998 demonstrated clear associations between graft versus host disease (GVHD) and GVL in ALL (2). 1132 patients with ALL transplanted in CR1 or CR2 with bone marrow from HLA identical sibling were analyzed. For CR1 patients, relative risk of relapse for patients with and without GVHD was 0.34 for T‐ALL and 0.44 was B‐ALL. The study confirmed lower risk of relapse in ALL patients who experienced both acute and chronic GVHD. These findings applied to both pre‐B ALL and T –lineage ALL (2).

RIC HCT for Ph+ ALL. Reduced intensity conditioning has been explored to limit the non‐relapse mortality (NRM) while extending allograft to older individuals and those with significant co‐morbidities unable to tolerate myeloablation. The goal of RIC HCT is to harness GVL. Two recent CIMTR studies reported anti‐leukemic potential of RIC allografting in adult ALL (Ph‐ and Ph+ cohorts) with acceptable rates of donor engraftment and favorable NRM, protection from relapse and promising overall survival (3,4). Similar study from EBMTR on 127 patients transplanted on RIC HCT protocols suggested acceptable NRM but trend toward increased relapse rate (47% in RIC vs 31% in MA) (5).

The potency of GVL effect after RIC for ALL has not been well studied. Here, we propose CIBMTR registry analysis to examine the influence of GVHD on NRM, relapse, PFS and OS in patients with and without acute and/or chronic GVHD. We can determine the effect separately for pre‐B and pre‐T cell ALL. Patient Eligibility Population: Patient eligibility/selection criteria include: Adult patients (older than 16) undergoing allogeneic donor HCT for ALL reported to the CIBMTR.

HCT period between 1998 and 2011

CR1 and CR2

NMA and RIC conditioning regimens only

Donor grafts: BM or PBSC or UCB Exclusion:

Patients who received pre‐emptive DLI

Ex‐vivo depleted graft

Patients who failed to engraft

60


Outcomes: Acute and chronic GVHD: Occurrence of grade II, III, and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD, and limited and extensive chronic GVHD.

Non‐relapse mortality: death without relapse or progression, where relapse or progression are competing risks. Those who survive without recurrence or progression are censored at the time of last contact.

Relapse/progression: progressive disease or recurrence of disease are counted as events. Treatment related death, defined as death without relapse or progression, is the competing event. Those who survive without recurrence or progression are censored at the time of last contact.

Progression‐free survival (PFS): survival without recurrence or tumor progression. Recurrence of progression of disease and death are counted as events. Those who survive without recurrence or progression are censored at the time of last contact. Overall survival: time to death. Death from any cause will be considered an event. Surviving patients will be censored at the time of last follow‐up. Variables to be analyzed: Time dependent acute (Grade II‐IV) and chronic GVHD (limited and extensive) Patient‐related:

Age at transplant, decades

Gender: male vs. female

Karnofsky performance status transplant: <90% vs. ≥90%

Co‐morbidity index 0‐1 vs ≥2 Disease‐related:

Cytogenetics: t(9:22) vs other high risk vs intermediate risk

WBCx109/L: <30 vs. 30‐100 vs. >100

Extramedullary disease at diagnosis: CNS (yes/no), other (yes/no)

Time to achieve CR1: <4 weeks vs. 4‐8 weeks vs. >8 weeks Transplant‐related:

Time from diagnosis to transplant

Time from remission to transplant :

Conditioning regimen: o TBI vs non‐TBI‐based

Type of donor: HLA‐identical sibling vs. unrelated donor

Donor‐recipient gender match: F‐M vs. M‐F vs. M‐M vs. F‐F

Donor age : continuous median (range)

Donor‐recipient CMV status: ‐/‐ vs. others

Source of stem cells: BM vs. PBSC vs UCB

Year of transplant 1998‐2005 vs 2006‐2011

GVHD prophylaxis: CSA‐based vs Tacro‐based vs other

T cell depletion (in vivo) yes vs no Data Requirements: None

61


Sample Requirements: No Study Design: Patient and transplant related variables will be compared using Chi‐square test for categorical variables and Mann‐Whitney test for continuous variables. GVHD will be treated as time‐dependent covariate. We will only consider GVHD which occurred before relapse. For estimating cumulative incidence of GVHD, death will be considered as competing risk. Patients who were reported to develop GVHD will be divided to 4 groups:

1. no GVHD 2. acute GVHD alone 3. chronic GVHD alone 4. both acute and chronic GVHD

We will examine influence of GVHD on NRM, relapse, PFS and OS. Kaplan‐Meier curves will be used to estimate the probability of OS and LFS, cumulative incidence will be used to estimate NRM, GVHD and relapse. Relapse will be summarized by the cumulative incidence estimate with NRM as a competing risk. For LFS and OS patients will be censored at the time of last follow‐up. Association of patient and graft characteristics with grade II‐IV acute GVHD and chronic GVHD will be evaluated using multivariate logistic regression. Association of patient, disease and transplant characteristics with other outcomes (NRM, relapse, DFS,OS) will be evaluated in multivariate analysis using Cox proportional hazards. Time to onset of GVHD will be determined as time to onset to aGVHD or cGVHD, whichever came first. Patients in CR1 and CR2 will analyzed together. Models will include patient‐,disease‐, transplant‐ related variables that were significantly (P,0.05) associated with relapse. We will also perform landmark analysis for relapse and OS for all patients who are leukemia free at 100 days and 1 year. SAS programs will be used in all the analyses. References:

1. Passweg JR, Tiberghien P, Cahn JY, Barrett AJ.Graft‐versus‐leukemia effects in T lineage and B lineage acute lymphoblastic leukemia. Bone Marrow Transplant. 1998 Jan;21(2):153‐8.

2. Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, et al. In adults with standard‐risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008 Feb 15;111(4):1827‐1833.

3. Marks DI, Wang T, Perez W, Bunjes D, DiPersio JF et al. Comparison of Outcomes for Non‐Myeloablative (NMA) and Myeloablative (MA) Conditioning for Adults with Acute Lymphoblastic Leukemia (ALL) in First and Second Complete Remission (CR): a Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis. Blood. 2010 Apr 19

4. Bachanova V, Marks DI, Zhang MJ, et al. Weisdorf DJ. 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. 2013 Aug 30. doi: 10.1038/leu.2013.253. [Epub ahead of print]

62


5. Mohty M, Labopin M, Volin L, Gratwohl A, Socié G, Esteve J, Tabrizi R, Nagler A, Rocha V; Acute Leukemia Working Party of EBMT.Reduced‐intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood. 2010 Nov 25;116(22):4439‐43.

63



Variable N (%)



Age in decades

16‐19 22 (7)

20‐29 44 (15)

30‐39 26 (9)

40‐49 46 (15)

50‐59 102 (34)

60‐69 57 (19)

Gender

Male 149 (50)

Female 148 (50)

FAB classification

T‐cell 42 (14)

B‐cell 237 (80)

Unspecified 18 (6)

Karnofsky score

<90% 109 (37)

>=90% 179 (60)

Missing 9 (3)

White blood count at diagnosis (x10^9/L)


<= 30 163 (55)

30 ‐ 100 37 (12)

> 100 26 (9)

Missing 71 (24)

HCT‐CI

0‐1 100 (34)

>=2 5 (2)

Earlier than 2007, not collected 192 (65)

Cytogenetics

t(9:22) only 60 (20)

t(9:22) and other 52 (18)

Other 126 (42)

Not tested 12 (4)

Missing 47 (16)


No 254 (86)

Yes 32 (11)

64


Variable N (%)

Missing 11 (4)


No 267 (90)

Yes 19 (6)

Missing 11 (4)


No 270 (91)

Yes 16 (5)

Missing 11 (4)

Time from diagnosis to transplant, median (range), months 7 (2‐174)

Time from CR1 to transplant, median (range), months 5 (<1‐97)

Time to achieve CR1 (weeks)


<4 weeks 37 (12)

4‐8 weeks 103 (35)

>8 weeks 136 (46)

Missing 21 (7)


RIC 205 (69)

NMA 92 (31)


TBI 149 (50)

Mel + Flud 69 (23)

Cy + Flud 22 (7)

Bu + Flud 48 (16)

Treosulfan 3 (1)

CBV 1 (<1)

BEAM 1 (<1)

TLI 4 (1)


No 148 (50)

Yes 149 (50)

TBI dose (cGy), median (range) 200 (200‐800)

Type of donor


Other related 23 (8)




Unrelated TBD 13 (4)

65


Variable N (%)

Cord blood 53 (18)

Graft type

Bone marrow 51 (17)


Umbilical cord blood 53 (18)

GVHD prophylaxis

CD34 selection alone 2 (<1)

CD34 selection + post‐tx immune supression 7 (2)

Cyclophosphamide + others 4 (1)

FK506 + MMF +‐ others 59 (20)



FK506 alone 8 (3)




CSA alone 19 (6)


ATG or campath

ATG alone 79 (27)

CAMPATH alone 13 (4)


GVHD occurance

aGVHD + cGVHD before relapse 54 (18)

aGVHD before relapse 48 (16)

cGVHD before relapse 67 (23)

No GVHD before relapse 124 (42)

aGVHD or cGVHD occured but time unknown 4 (1)

Year of HCT

1998‐2002 58 (20)

2003‐2006 105 (35)

2007‐2011 134 (45)


66



INCLUSION:

1st allo transplant for ALL from 1998 to 2011 7342


CR1 and CR2 prior to transplant 1215 3294

RIC/NMA conditioning 2974 320

EXCLUSION:

Ex‐vivo depleted graft 5 315

Pre‐emptive DLI recipients 1 314

Engraftment failure (never achieved CR post‐HSCT) 1 313



67


Study Proposal 1311‐43

Study Title: 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 Nelli Bejanyan, MD, University of Minnesota, [email protected] Aleksandr Lazaryan, MD, MPH, PhD, University of Minnesota, [email protected] Daniel Weisdorf, MD, University of Minnesota, [email protected]

Specific Aims: Primary

1. To study overall survival (OS) of acute lymphoblastic leukemia (ALL) patients in first complete remission (CR1) receiving 0 vs. 1 vs. ≥2 post‐remission consolidation cycles prior to alloHCT.

Secondary 2. To study treatment‐related mortality (TRM), incidence of relapse and leukemia‐free survival

(LFS) among above 0 vs. 1 vs. ≥2 consolidation cycle groups. 3. To study TRM, incidence of relapse, LFS and OS in subgroup of ALL patients with MRD positivity

(as questioned by cytogenetic and molecular remission status in CIBMTR ALL form) who receive 0 vs. 1 vs. ≥2 post‐remission consolidation cycles prior to alloHCT.

Scientific Justification: Allogeneic hematopoietic cell transplantation (alloHCT) is potential curative treatment for adult ALL patients achieving remission with cytoreductive chemotherapy.(1‐3) However, the role of pre‐transplant post‐remission consolidation chemotherapy on clinical outcomes of ALL patients remains uncertain. European MRC UKALL XII/ECOG 2993 large prospective study protocol mandated 2 cycles of induction chemotherapy (phase I and phase II) followed by 3 cycles of consolidation with high‐dose Methotrexate for CR1 ALL patients in alloHCT group even when remission (CR1) was achieved with initial phase 1 induction cycle. (1, 4) Similarly, GRAALL‐2003 and LALA‐94 studies allowed alloHCT per protocol for high‐risk CR1 ALL only after completion of several cycles of post‐induction consolidation chemotherapy.(6, 7) In contrast, other ALL induction protocols allowed patients with available donor proceeding with alloHCT whenever CR1 was achieved with chemotherapy.(8‐10) Since time from CR to post‐remission therapy has been found to be an independent predictor for relapse and OS in adults with ALL,(11) post‐remission consolidation chemotherapy is routinely used in clinical practice while donor search is in progress. In addition, MRD positivity has been identified to be an adverse independent predictor for ALL relapse and OS in multiple studies.(12‐14) Thus studying the role of pre‐transplant consolidation chemotherapy among MRD positive patients would help us guide an early vs. delayed (post‐consolidation) alloHCT therapeutic strategy. CIBMTR’s large ALL transplant dataset will provide us with unique opportunity to establish the importance of pre‐transplant post‐remission consolidation chemotherapy in ALL patients with available donor. In addition, this study can help us identifying a subset of ALL patients (e.g. MRD+ or MRD‐) who would potentially benefit from post‐remission chemotherapy prior to transplantation. Patient Eligibility Population: Inclusion Criteria:

Adult ALL patients age 16 years or older who underwent alloHCT in CR1 at participating CIBMTR centers between 2008 and 2011

Both MA and RIC transplants

68


Exclusion Criteria:

Patients with French American British (FAB) type L3 ALL (Burkitt's leukemia) Data Requirements:

All necessary study data are available for extraction from the ALL‐specific CIBMTR data collection forms

o (http://www.cibmtr.org/DataManagement/DataCollectionForms/Documents/2011/Rev2.0/combine‐2011%20ALL%20r2.pdf)

Demographic and clinical characteristics (Supplementary Table 1) will be abstracted from the CIBMTR data forms.

o As possible, data sets utilized will include already analyzed (and/or published) ALL HCT outcomes to minimize the need for subsequent data re‐review and cleanup.

Sample Requirements: None Study Design: We propose an observational retrospective cohort study of adult CR1 ALL recipients of alloHCT. Chi‐square test for categorical variables and the Wilcoxon two sample tests for continuous variables will be used to compare patient, disease, chemotherapy and transplant related characteristics between patients receiving 0 vs. 1 vs. ≥2 post‐remission consolidation cycles prior to alloHCT. The Kaplan‐Meier method will be used to estimate univariate LFS and OS probabilities. Cumulative incidence curves will be used to calculate probabilities of TRM and relapse. Patient and disease related risks factors of post‐remission consolidation chemotherapy will be tested using Cox proportional hazards regression model. A backward elimination method will be used to build the regression model for the outcomes of TRM, relapse, LFS and OS. The Cox regression model will be used to estimate adjusted probability of LFS and OS.

Characteristics of CR1 ALL patients receiving alloHCT from 2008‐2011 Variables: Patient‐related:

Age

Median (IQR)

Gender: Male or Female

Karnofsky score: <90%, ≥90%, unknown Disease‐related:

White blood count at diagnosis: ≤10, 10‐100, >100, unknown

Cytogenetics (modified MRC classification) (15) o Very high o High o Intermediate o Standard o Unknown

Molecular o Philadelphia (Ph) positive o Ph negative o Unknown

Extramedullary disease at diagnosis: yes, no, unknown

69


CNS involvement at diagnosis: yes, no, unknown

Time From Diagnosis to CR1 median(range), months o 0‐2 o 2‐6 o >6

Characteristics of Complete Remission (CR):

Minimal residual disease (MRD) status* o MRD positive o MRD negative o Unknown

Cytogenetic CR status: yes, no, unknown

Molecular CR status: yes, no, unknown Chemotherapy‐related:

Number of chemotherapy cycles prior of CR1: 1, 2, >2

Cycles of consolidation chemotherapy (post‐CR1): 0, 1, ≥2 Transplant‐related:

Year of Transplant

Time from diagnosis to HCT in months

o Median (IQR)

Donor relation o Matched Sibling Donor o Matched URD o Partially Matched URD o UCB

Graft source o Marrow o PBSC

Recipient CMV Serostatus: positive, negative, unknown

Type of Conditioning o Myeloablative o Reduced Intensity (RIC)

Conditioning regimen o TBI‐based regimen o Non‐TBI regimens

GVHD prevention o ATG used o No ATG

Survival status o Alive o Dead

Cause of death o Relapse o Infection o GVHD o Organ damage o Other

* As questioned by cytogenetic and molecular remission status in CIBMTR ALL form

70


References:

1. Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, et al. In adults with standard‐risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827‐33.

2. Cornelissen JJ, van der Holt B, Verhoef GE, van't Veer MB, van Oers MH, Schouten HC, et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no‐donor comparison. Blood. 2009 Feb 5;113(6):1375‐82.

3. Kako S, Morita S, Sakamaki H, Ogawa H, Fukuda T, Takahashi S, et al. A decision analysis of allogeneic hematopoietic stem cell transplantation in adult patients with Philadelphia chromosome‐negative acute lymphoblastic leukemia in first remission who have an HLA‐matched sibling donor. Leukemia. 2011 Feb;25(2):259‐65.

4. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760‐7.

5. Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, et al. Pediatric‐inspired therapy in adults with Philadelphia chromosome‐negative acute lymphoblastic leukemia: the GRAALL‐2003 study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 Feb 20;27(6):911‐8.

6. Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA‐94 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004 Oct 15;22(20):4075‐86.

7. Thomas DA, O'Brien S, Faderl S, Garcia‐Manero G, Ferrajoli A, Wierda W, et al. Chemoimmunotherapy with a modified hyper‐CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome‐negative precursor B‐lineage acute lymphoblastic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 Aug 20;28(24):3880‐9

8. Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, et al. First report of phase 2 study of dasatinib with hyper‐CVAD for the frontline treatment of patients with Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070‐7.

9. Stock W, Johnson JL, Stone RM, Kolitz JE, Powell BL, Wetzler M, et al. Dose intensification of daunorubicin and cytarabine during treatment of adult acute lymphoblastic leukemia: results of Cancer and Leukemia Group B Study 19802. Cancer. 2013 Jan 1;119(1):90‐8.

10. Advani AS, Jin T, Ramsingh G, Tiu R, Saber W, Theil K, et al. Time to post‐remission therapy is an independent prognostic factor in adults with acute lymphoblastic leukemia. Leuk Lymphoma. 2008 Aug;49(8):1560‐6.

11. Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, et al. Improved risk classification for risk‐specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009 Apr 30;113(18):4153‐62.

12. Patel B, Rai L, Buck G, Richards SM, Mortuza Y, Mitchell W, et al. Minimal residual disease is a significant predictor of treatment failure in non T‐lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol. 2010 Jan;148(1):80‐9.

13. Bachanova V, Burke MJ, Yohe S, Cao Q, Sandhu K, Singleton TP, et al. Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant. 2012 Jun;18(6):963‐8.

14. Campana D, Leung W. Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. Br J Haematol. 2013 Jul;162(2):147‐61.

15. Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood 2008;111(5):2563‐72.

71



Variable N (%)



Age in decades


10‐19 31 (8)

20‐29 76 (20)

30‐39 69 (18)

40‐49 109 (29)

50‐59 71 (19)

60‐69 23 (6)

Gender

Male 228 (60)

Female 151 (40)

Karnofsky score

<90% 117 (31)

>=90% 255 (67)

Missing 7 (2)

White blood count at diagnosis (10^9/L)


<= 10 151 (40)

10 ‐ 100 81 (21)

> 100 27 (7)

Missing 120 (32)


Normal 75 (20)

Poor 196 (52)

Other 35 (9)


Not tested 10 (3)

Missing 13 (3)

Philadelphia positive

No 219 (58)

Yes 160 (42)


72


Variable N (%)

No 311 (82)

Yes 55 (15)

Missing 13 (3)


No 335 (88)

Yes 31 (8)

Missing 13 (3)

Time from diagnosis to CR1


0‐2 months 193 (51)

2‐6 months 130 (34)

>=6 months 33 (9)

Missing 23 (6)

Cytogenetic CR status

No 27 (7)

Yes 296 (78)

Missing 56 (15)

Molecular CR status

No 53 (14)

Yes 166 (44)

Missing 160 (42)

Number of induction cycles

1 320 (85)

2 46 (12)

3 12 (3)

4 1 (<1)

Number of consolidation cycles

0 239 (63)

1 116 (31)

2 17 (4)

3 4 (1)

4 3 (<1)


No 55 (15)

Yes 324 (85)


73


Variable N (%)


RIC 33 (9)

NMA 12 (3)

TBD 3 (<1)


TBI 324 (85)

Bu + Cy 10 (3)

Bu + Mel 7 (2)

Bu + Thio 1 (<1)

Mel + Flud 11 (3)

Cy + Flud 2 (<1)

Bu + Flud 21 (6)

Others 3 (<1)

ATG or campath

ATG alone 74 (20)

CAMPATH alone 5 (1)




0‐3 months 20 (5)

3‐6 months 232 (61)

6‐12 months 110 (29)

>12 months 16 (4)

Missing 1 (<1)

Type of donor




Mismatched unrelated 3 (<1)


Graft type

Bone marrow 63 (17)



‐/‐ 105 (28)

‐/+ 96 (25)

74


Variable N (%)

+/‐ 51 (13)

+/+ 123 (32)

TBD 4 (1)


M/M 147 (39)

M/F 96 (25)

F/M 81 (21)

F/F 55 (15)

GVHD prophylaxis

FK506 based 279 (74)

CsA based 80 (21)

Other 20 (5)

Year of transplant

2008 148 (39)

2009 99 (26)

2010 58 (15)

2011 74 (20)



INCLUSION:

1st allo transplant for ALL from 2008 to 2011 1552


CR1 prior to transplant 438 590

BM/PB graft 121 469

EXCLUSION:

Identical twin and haplo‐identical related donor 25 444

FAB L3 30 414



75


Study Proposal 1312‐09 Study Title: Comparison of total body irradiation (TBI)‐based with intravenous (i.v.) busulfan (Bu) containing chemotherapy‐only myeloablative transplant conditioning regimens in patients with acute lymphoblastic leukemia Partow Kebriaei, MD, MD Anderson Cancer Center, [email protected] David Marks, MD, University Hospitals Bristol Foundation Trust, [email protected] Hypothesis: We hypothesise that i.v. Bu containing regimens will achieve similar survival to TBI based regimens in patients with ALL Objectives: Primary

1. Compare transplant outcomes in patients receiving myeloablative TBI‐based transplant conditioning with a chemotherapy‐only regimen consisting of i.v. Bu and nucleoside analogue therapy. Specifically, we will look at differences in overall survival (OS), disease‐free survival (DFS), incidence of graft versus host disease (GVHD), and treatment‐related mortality (TRM)

Scientific Justification: TBI‐based transplant conditioning regimens are considered the standard of care for patients undergoing hematopoietic cell transplantation (HCT) for ALL, with expected survival of 50% to 60% in first complete remission (CR1)(1, 2). However, TBI is associated with acute and long‐term toxicity (including secondary malignancy), with non‐relapse mortality (NRM) rates of 20%‐45% following SCT (2‐4). In efforts to minimize toxicity, the combination of oral Bu and cyclophosphamide (Cy) was developed. But a retrospective (5) and prospective analysis (6) in children comparing Cy‐TBI with Bu‐Cy demonstrated that although relapse rates were equivalent in the two groups, TRM was actually increased in the Bu‐Cy group with greater rates of veno‐occlusive disease and interstitial pneumonitis, and thus survival was better with Cy‐ TBI. Since these studies, the intravenous formulation of Bu has been developed and increasingly used, and study results across disease types show a better safety profile(7, 8) (ref). Furthermore, PK‐ directed dosing of intravenous Bu affords even greater safety (9, 10) (Ansari EBMT 2012) and efficacy (Andersson ASH 2011). Interestingly, a recent CIBMTR multicenter cohort analysis in patients with acute myeloid leukemia (AML) receiving HCT following Cy‐TBI or myeloablative, intravenous Bu‐based conditioning regimens found superior survival for the Bu‐ based group (56% vs. 48%, p=.02) (Bredeson ASBMT 2013). Several phase II studies have reported excellent transplant outcomes with intravenous Bu combined with fludarabine (11, 12) and clofarabine(13) in patients receiving SCT for ALL. An updated analysis of our data with Bu and clofarabine SCT conditioning for ALL patients in CR1 (n=44) and CR2 (n=21) revealed that 70% and 52%, respectively, of patients are alive and in remission with a median follow‐up of 18 months. Thus, we would like to do a comparison of myeloablative TBI‐based conditioning regimens versus intravenous Bu‐based regimens in patients receiving allogeneic HCT for ALL. We propose to limit the Bu‐based regimens to those combined with a nucleoside analogue. Data for intravenous Bu combined with another alkylator,

76


most commonly Cy, may not show similar results to the nucleoside analogue. We, and others, showed excellent disease control but increased toxicity in the form of interstitial pneumonia and hemorrhagic cystitis with the combination of Bu and melphalan (14, 15). Patient Eligibility Population: Patients with ALL who received a first peripheral blood or bone marrow sibling or well‐matched unrelated donor SCT following myeloablative transplant conditioning. Patients with L3 ALLwill be excluded. The study will be limited to adults due to lack of sufficient cases of i.v. Bu‐ based regimens in children (>16 years‐old). Furthermore, due to lack of i.v. Bu‐based cases generally in the CIBMTR database, we will compare patients in the MD Anderson database (CR1, n=58; CR2, n=36) who received i.v. BuClo to the patients who received TBI‐based regimens in the CIBMTR. Data Requirements: Data collection from standard CIBMTR forms. Sample Requirements: None Study Design: We propose a comparison of patients receiving radiation‐based, myeloablative conditioning (TBI>500cGy in a single fraction or >800 cGy fractionated plus Cy >60 mg/kg or etoposide >30 mg/kg) compared with intravenous Bu >9 mg/kg plus fludarabine or clofarabine at >80 mg/m2 for HCT in CR1 or CR2. Due to the relatively few cases of i.v. Bu‐based regimens, we will do a retrospective case‐controlled analysis, with the majority of patients receiving Bu based regimens coming from MD Anderson. Primary outcomes: Overall survival, DFS, GVHD (acute and chronic), NRM at 2 years Study Variables:

Patient related

- Age (by decades, or as a continuous variable) - Gender (M vs F) - Karnofsky PS (<90% vs 90% or more)

Disease related

- Cytogenetic abnormalities: t(4;11), t(9;22), hypodiploidy or near triploidy, complex cytogenetics (>5 abnormalities) vs. diploid vs. other abnormalities vs. not known

- Lineage (T vs. B vs. not known) - WBC at diagnosis <25, 25‐100, 100‐200, >200 - Time to achieve CR1: <4 weeks, >8 weeks, 4‐8 weeks - Time from diagnosis to transplant for CR1 patients - Relapse on chemotherapy (yes/no) - Extramedullary disease at diagnosis: CNS (yes/no), testis (yes/no), other (yes/no)

Transplant‐related

- Time from remission to transplant (CR1 and CR2) - Duration of CR1 for CR2 transplants

77


- Alemtuzamab vs ATG (dose to be collected) - GVHD prophylaxis for UD transplants: ex vivo T cell depletion vs. CsA+MTX vs.

tacrolimus+MTX vs. post SCT cytoxan - Donor age for unrelated donors (continuous variable) - Gender match (F‐M vs M‐F vs M‐M vs F‐F) - CMV status: ‐/‐ vs +/‐ vs _/+ vs +/+ - Year of transplant - Matching of unrelated donors: well matched vs. partly matched vs. mismatched (CIBMTR

criteria) - Post‐transplant therapy: DLI (yes/no); chemotherapy (yes/no); intrathecal chemotherapy

(yes/no) - PBSC vs. BM - Busulfan PK monitoring, yes/no - Daily Busulfan dose <130 mg/2 vs. > 130 or AUC <5000 vs. > 5000 - Dose of TBI <13 Gy vs. >13 Gy - Cytoxan vs.VP16 vs. others + TBI - cell dose data

References: 1. Marks DI, Forman SJ, Blume KG, Perez WS, Weisdorf DJ, Keating A, et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2006;12(4):438‐53. Epub 2006/03/21.

2. Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, et al. In adults with standard‐risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111(4):1827‐33. Epub 2007/12/01.

3. Sutton L, Kuentz M, Cordonnier C, Blaise D, Devergie A, Guyotat D, et al. Allogeneic bone marrow transplantation for adult acute lymphoblastic leukemia in first complete remission: factors predictive of transplant‐related mortality and influence of total body irradiation modalities. Bone marrow transplantation. 1993;12(6):583‐9. Epub 1993/12/01.

4. Oliansky DM, Camitta B, Gaynon P, Nieder ML, Parsons SK, Pulsipher MA, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence‐based review. ASBMT Position Statement. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2012;18(7):979‐81. Epub 2012/04/12.

5. Davies SM, Ramsay NK, Klein JP, Weisdorf DJ, Bolwell B, Cahn JY, et al. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2000;18(2):340‐7. Epub 2000/01/19.

78


6. Bunin N, Aplenc R, Kamani N, Shaw K, Cnaan A, Simms S. Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone marrow transplantation. 2003;32(6):543‐8. Epub 2003/09/04.

7. Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W, et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD‐related mortality, and overall 100‐day mortality. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2002;8(9):493‐500. Epub 2002/10/11.

8. Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C, et al. Once‐daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2002;8(9):468‐76. Epub 2002/10/11.

9. Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT, et al. Busulfan systemic exposure relative to regimen‐related toxicity and acute graft‐versus‐host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2002;8(9):477‐85. Epub 2002/10/11.

10. Geddes M, Kangarloo SB, Naveed F, Quinlan D, Chaudhry MA, Stewart D, et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2008;14(2):220‐8. Epub 2008/01/25.

11. Russell JA, Savoie ML, Balogh A, Turner AR, Larratt L, Chaudhry MA, et al. Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 CGY total‐body irradiation, and thymoglobulin. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2007;13(7):814‐21. Epub 2007/06/21.

12. Santarone S, Pidala J, Di Nicola M, Field T, Alsina M, Ayala E, et al. Fludarabine and pharmacokinetic‐targeted busulfan before allografting for adults with acute lymphoid leukemia. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2011;17(10):1505‐11. Epub 2011/03/10.

13. Kebriaei P, Basset R, Ledesma C, Ciurea S, Parmar S, Shpall EJ, et al. Clofarabine combined with busulfan provides excellent disease control in adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2012;18(12):1819‐26. Epub 2012/07/04.

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14. Kebriaei P, Madden T, Wang X, Thall PF, Ledesma C, de Lima M, et al. Intravenous BU plus Mel: an effective, chemotherapy‐only transplant conditioning regimen in patients with ALL. Bone marrow transplantation. 2013;48(1):26‐31. Epub 2012/06/27.

15. Small TN, Young JW, Castro‐Malaspina H, Prockop S, Wilton A, Heller G, et al. Intravenous busulfan and melphalan, tacrolimus, and short‐course methotrexate followed by unmodified HLA‐matched related or unrelated hematopoietic stem cell transplantation for the treatment of advanced hematologic malignancies. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2007;13(2):235‐44. Epub 2007/01/24.

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Characteristics of study population

Variable CIBMTR MDACC



Age in decades

20‐29 185 (30) 35 (37)

30‐39 150 (25) 18 (19)

40‐49 162 (27) 16 (17)

50‐59 106 (17) 19 (20)

60‐69 8 (1) 6 (6)

Gender

Male 364 (60) 57 (61)

Female 247 (40) 37 (39)

Karnofsky score

<90% 172 (28) 17 (18)

>=90% 414 (68) 76 (81)

Missing 25 (4) 1 (1)


<= 30 347 (57) 48 (51)

30 ‐ 100 72 (12) 18 (19)

> 100 72 (12) 15 (16)

Missing 120 (20) 13 (14)

FAB classification

T‐cell 100 (16) 13 (14)

B‐cell 500 (82) 77 (82)

Unspecified 11 (2) 4 (4)


CR1 458 (75) 58 (62)

CR2 153 (25) 36 (38)

Time from diagnosis to HSCT

Median (range) 6 (<1‐229) 8 (2‐117)

<6 months 334 (55) 26 (28)

6 months ‐ 1 year 138 (23) 32 (34)

>1 year 139 (23) 36 (38)

Duration of CR1 for CR2 patients


81



<6 months 30 (5)

6 months ‐ 1 year 19 (3)

>1 year 68 (11)

Missing 36 (6)

Time to achieve CR1

Median (range) 7 (<1‐612) 5 (<1‐148)

<4 weeks 76 (12) 24 (26)

4‐8 weeks 246 (40) 40 (43)

>=8 weeks 258 (42) 29 (31)

Missing 31 (5) 1 (1)

Time from remission to HSCT

Median (range) 3 (<1‐139) 6 (1‐113)

<3 months 251 (41) 18 (19)

>=3 months 330 (54) 75 (80)

Missing 30 (5) 1 (1)


No 506 (83) 69 (73)

Yes 102 (17) 18 (19)

Missing 3 (<1) 7 (7)


No 573 (94) 78 (83)

Yes 35 (6) 9 (10)

Missing 3 (<1) 7 (7)


No 537 (88) 77 (82)

Yes 71 (12) 10 (11)

Missing 3 (<1) 7 (7)

ATG or campath

ATG alone 51 (8) 43 (46)

CAMPATH alone 5 (<1) 0

No ATG or CAMPATH 555 (91) 51 (54)

Conditioning regimen for CIBMTR cases

TBI + VP16 151 (25)

TBI + Cy 433 (71)

IV Bu + Fludara 27 (4)

Conditioning regimen for MDACC cases

82



Busulfan+Clofarabine 48 (51)

Busulfan+Clofarabine+ATG 43 (46)

Fludarabine+Busulfan 3 (3)


No 27 (4) 94

Yes 584 (96) 0

TBI dose


<13 Gy 343 (56)

>=13 Gy 241 (39)

Not applicable 27 (4)


‐/‐ 168 (27)

‐/+ 155 (25)

+/‐ 83 (14)

+/+ 195 (32)

TBD 10 (2)


M/M 228 (37)

M/F 150 (25)

F/M 136 (22)

F/F 97 (16)

TBD 0

Type of donor



Graft type

Bone marrow 113 (18) 22 (23)


Year of HSCT

2005 121 (20) 0

2006 111 (18) 0

2007 86 (14) 0

2008 96 (16) 0

2009 68 (11) 3 (3)

2010 44 (7) 18 (19)

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2011 65 (11) 25 (27)

2012 20 (3) 21 (22)

2013 0 26 (28)

2014 0 1 (1)

Median follow‐up of survivors (range), months 59 (3‐98) 18 (<1‐45)

The following selection criteria was applied for HSCT cohort Excluded Included

1st allo HCT for non‐L3 ALL between 2005 and 2012 after CAP modeling 3641

Age>=20 1585 2056

Patient in CR1 or CR2 prior to HCT 448 1608

BM or PB graft 234 1374

HLA‐id sib or well matched unrelated donor 396 978

Myeloablative conditioning 152 826

TBI/VP16 or TBI/Cy or i.v.Bu/Fludrabine as conditioning regimen 173 653

Patient with at least 100‐day comprehensive research form 10 643

Patient consent 15 628

Exclude MDACC cases 17 611

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Study Proposal 1311‐05

Study Title:

Second Allogeneic Transplantation using a Reduced Intensity Conditioning Preparative Regimen in the Case of Relapse or Graft Failure in Patients with Acute Leukemia Rachel Salit, MD, Fred Hutchinson Cancer Research Center, University of Washington Medical Center, [email protected]

Colleen Delaney, MD, Fred Hutchinson Cancer Research Center, Seattle Children’s Medical Center, [email protected]

Ted Gooley, PhD, Fred Hutchinson Cancer Research Center, [email protected]

Specific Aims: 1. To examine the early outcomes of patients receiving a second allogeneic stem cell transplant (HCT)

with reduced intensity conditioning (RIC) for relapse of acute leukemia or myelodysplastic syndrome (MDS) following their initial allogeneic transplant.

2. To examine the early outcomes of patients receiving second allogeneic stem cell transplantation with RIC for graft failure following their initial allogeneic transplant.

Scientific Justification:

Leukemia recurs in 20‐70% of patients after HCT. Prognosis of patients who relapse is poor.

Current treatment options include chemotherapy, donor lymphocyte infusion (DLI) and second transplant.

Results of DLI in relapsed acute leukemia leads to remission in only 10‐20% of patients.

Most studies of second transplants are small.

CIBMTR conducted a retrospective analysis in 2004 for patients with acute and chronic leukemia.

All patients included in that study had received an HLA‐matched sibling transplant as their first transplant and only 16% of patients had received an RIC preparative regimen; these patients did worse than the group as a whole.

Due to RIC we are doing more and more second transplants for patients with relapsed MDS/acute leukemia and graft failure.

The data published on RIC second transplants in the last 10 years is lacking.

The current health care environment will unlikely support the continued management of patients with multiple transplantation procedures due to cost. Therefore it is important to prospectively design studies that determine the patient population that will benefit most and the treatment regimen that is the most effective.

Patient Eligibility Population (at the time of second transplant):

Age 6 months to 75 years Diseases to include acute myeloid leukemia and acute lymphoid leukemia and myelodysplastic

syndrome Patients who have received prior allogeneic transplant Patients may be in complete remission (CR), have minimal residual disease (MRD) or be in frank

relapse. Donor types may include matched related donor, matched unrelated donor, mismatched

unrelated donor, umbilical cord blood transplant and haploidentical transplant.

85


Conditioning may have been myeloablative or nonmyleoablative (NMA) or reduced intensity (RIC) for first transplant.

Data Requirements:

Data should be able to be compiled from the following forms:

2010: Acute Myelogenous Leukemia Pre‐HSCT 2011: Acute Lymphoblastic Leukemia Pre‐HSCT 2014: MDS Pre‐HSCT 2000: Recipient Baseline Data 2110: Acute Myelogenous Leukemia Post‐HSCT 2111: Acute Lymphoblastic Leukemia Post‐HSCT 2114: MDS Post‐HSCT No collection of supplemental data will be necessary

Patient‐related:

Age at first transplant

Age at second transplant

Gender

CMV serostatus

Comorbidity score at 1st transplant

Comorbidity score at 2nd transplant Disease‐related:

Disease: AML, ALL, or MDS

Disease status at second transplant (ie relapsed/persistent disease vs complete remission (CR))

Time from 1st transplant to relapse or graft failure

Time from relapse or graft failure to 2nd transplant Transplant‐related:

1st transplant

Year of transplant: 1995‐present patients only

Disease status at 1st transplant

For those in CR: minimal residual disease status (MRD) vs no MRD if available

Conditioning intensity: ie myeloablative (MAC), reduced intensity (RIC), or nonmyeloablative (NMA)


Donor source: (ie) HLA matched sibling, HLA‐matched and mismatched unrelated donor (URD), umbilical cord blood (UCB), haploidentical

Graft source: bone marrow (BM), peripheral blood (PBSCT), UCB

Locus of mismatch if exists (for URD and UCB)

GVHD prophylaxis regimen

Overall grade of acute graft versus host disease (GVHD) after 1st transplant

Maximum severity of chronic GVHD after 1st transplant (by NIH criteria if available)

2nd transplant

Year of transplant: 2000‐present patients only

Indication for second transplant: ie relapse, graft failure

Time from 1st transplant to relapse

86


Time from 1st transplant to graft failure

Treatment for post‐transplant relapse

Time from 1st transplant to second transplant

Disease status at 2nd transplant

For those in CR: MRD vs no MRD if available

Conditioning intensity: RIC and NMA only


Donor source: (ie) HLA matched sibling, URD, UCB, haploidentical

Donor source: same vs different as first transplant

Graft source: BM vs PBSCT vs UCB

Locus of mismatch if exists (for URD and UCB)

GVHD prophylaxis regimen

Overall grade of acute GVHD after 2nd transplant

Maximum severity of chronic GVHD after 2nd transplant (by NIH criteria if available)

Sample Requirements (if study will use biologic samples from the NMDP Research Sample Repository):

No biologic samples will be required

Study Design (Scientific Plan):

This is a retrospective cohort study with the objective to identify risk factors for various outcomes following 2nd transplant for eligible patients as detailed above. The outcomes examined will be relapse, NRM, treatment failure (relapse or death), overall mortality, and acute and chronic GVHD. Univariate and multivariable analyses will be used to assess the association of various factors with outcome. Factors to be examined will include those listed above. Standard methods for time‐to‐event outcomes will be used to assess these associations.

Using the results from these analyses, we aim to identify populations of patients with acute leukemia and MDS who relapsed after a previous allogeneic transplant that might benefit from a second transplant, as well as groups that do not appear to benefit from a second transplant. Such results will allow us set a benchmark for outcome and identify a target population for the development of a prospective clinical trial using cord blood and reduced‐intensity conditioning for a second transplant among patients who relapsed or experienced graft failure following a first allogeneic transplant. To facilitate this effort, we are seeking data only and will obtain statistical support from inside our Center.

References:

Eapen M et al Second Transplant for acute and chronic leukemia relapsing after first HLA‐identical sibling transplant. BBMT 2004.

87



Variable N (%)



Gender

Male 160 (60)

Female 107 (40)

Characteristics of 1st HSCT

Age at 1st HSCT

<10 41 (15)

10‐19 34 (13)

20‐29 39 (15)

30‐39 31 (12)

40‐49 41 (15)

50‐59 55 (21)

60‐69 26 (10)

Year of 1st HSCT

1995‐2000 28 (10)

2001‐2005 99 (37)

2006‐2011 140 (52)

Disease

AML 143 (54)

ALL 85 (32)

MDS 39 (15)

Disease status prior to HSCT for AML or ALL


CR1 102 (38)

CR2 61 (23)

>=CR3 3 (1)

Relapse 26 (10)

Missing 15 (6)

Disease status prior to HSCT for MDS

MDS early 8 (3)

MDS advanced 30 (11)

Missing 1 (<1)



RIC 45 (17)

NMA 16 (6)

TBD 33 (12)


88


Variable N (%)

TBI 112 (42)

Bu + Cy 66 (25)

Mel + Thio 1 (<1)

Mel + Flud 12 (4)

Cy + Flud 1 (<1)

Bu + Flud 42 (16)

TLI 1 (<1)

Others 32 (12)

Type of donor


Identical twin 7 (3)

Other related 8 (3)





Missing 24 (9)

Graft type

Bone marrow 77 (29)



GVHD prophylaxis

Ex vivo T‐cell depletion alone 3 (1)

Ex vivo T‐cell depletion + post‐tx immune supression 4 (1)


CD34 selection + post‐tx immune supression 1 (<1)

Cyclophosphamide alone 1 (<1)

FK506 + MMF +‐ others 21 (8)



FK506 alone 8 (3)




CSA alone 7 (3)


Time from 1st HSCT to relapse (months) 11 (1‐90)

Time from relapse to 2nd HSCT (months) 4 (<1‐58)

Characteristics of 2nd HSCT

Age at 2nd HSCT

89


Variable N (%)

<10 36 (13)

10‐19 33 (12)

20‐29 40 (15)

30‐39 30 (11)

40‐49 35 (13)

50‐59 59 (22)

60‐69 32 (12)

>=70 2 (<1)

Year of 2nd HSCT

2000‐2005 83 (31)

2006‐2011 184 (69)

Disease

AML 150 (56)

ALL 85 (32)

MDS 32 (12)

Disease status prior to HSCT for AML or ALL


CR1 9 (3)

CR2 77 (29)

>=CR3 65 (24)

Relapse 73 (27)

Missing 2 (<1)

Disease status prior to HSCT for MDS

MDS early 9 (3)

MDS advanced 20 (7)

Missing 3 (1)


RIC 199 (75)

NMA 68 (25)


TBI 99 (37)

Mel + Flud 87 (33)

Cy + Flud 16 (6)

Bu + Flud 54 (20)

Treosulfan 9 (3)

CBV 1 (<1)

BEAM 1 (<1)

Type of donor


Other related 22 (8)

90


Variable N (%)





Missing 9 (3)

Graft type

Bone marrow 40 (15)



PB + UCB 4 (1)

GVHD prophylaxis

Ex vivo T‐cell depletion alone 1 (<1)


CD34 selection + post‐tx immune supression 5 (2)

Cyclophosphamide + others 3 (1)

FK506 + MMF +‐ others 55 (21)



FK506 alone 19 (7)




CSA alone 18 (7)


Median follow‐up of survivors since 2nd HSCT, months 84 (5‐157)


INCLUSION:

1st allo HSCT for AML/ALL/MDS between 1995 to 2011, CAP modeled 28273

All related and unrelated donors Syngeneic (n=136) 28137

Relapsed or persistant disease after HSCT 18791 9346

2nd allo HSCT between 2000 to 2011 8207 1139

RIC/NMA for 2nd HSCT 829 310

EXCLUSION:

No consent 11 299

No 100 day comprehensive form 32 267

91