MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION San Diego, CA Thursday, February 12, 2015, 12:15 2:15 pm

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1 MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION San Diego, CA Thursday, February 12, 2015, 12:15 2:15 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: Daniel Fowler, MD, NIH-NCI Experimental Transplantation and Immunology Branch, Bethesda, MD; Telephone: ; Fax: ; Miguel-Angel Perales, MD, Memorial Sloan Kettering Cancer Center, New York NY; Telephone: ; Fax: ; Vanderson Rocha, MD, PhD, Churchill Hospital, Oxford, United Kingdom; Telephone: ; Fax: ; Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: ; Fax: ; Junfang Chen, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: ; Fax: ; Mary Eapen, MBBS, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: : Fax: ; 1. Introduction Dr. Fowler opened the meeting at 12:15 pm by welcoming the working committee members for attending the Graft Sources and Manipulation working committee (GSWC). He welcomed Dr. Asad Bashey as newly appointed GSWC chair starting from March 2014, then introduced the GSWC s leadership, goals, expectations and limitations, the voting process, rule of membership/ authorship, and working committee evaluation information. The minutes of the February 2013 meeting were approved as written. Members were referred to the accrual summary, which reflects potentially eligible cases when considering submitting study proposals to this committee. 2. Published/submitted papers and presentations Dr. Fowler led this section. The committee has 5 publications and 1 paper under review. Two other studies are completed, their results were presented at the 2014 American Society of Hematology meetings and the manuscripts are being prepared. a. GS05-01 Karen K. Ballen, Brent R. Logan, Mary J. Laughlin, Wensheng He, Daniel R. Ambruso, Susan E. Armitage, Rachel L. Beddard, Deepika Bhatla, William Y.K. Hwang, Joseph E. Kiss, Gesine Koegler, Joanne Kurtzberg, Arnon Nagler, David Oh, Lawrence D. Petz, Thomas H. Price, Ralph R. Quinones, Voravit Ratanatharathorn, J. Douglas Rizzo, Kathleen Sazama, Andromachi Scaradavou, Michael W. Schuster, Leonard S. Sender, Elizabeth J. Shpall, Stephen R. Spellman, Millicent Sutton, Lee Ann Weitekamp, John R. Wingard, Mary Eapen. Effect of Cord Blood Processing on Transplant Outcomes after Single Myeloablative Umbilical Cord Blood Transplantation. Biol Blood Marrow Transplant, In press, 2015.

2 b. SC11-02b Mary Eapen, Brent R. Logan, Fredrick R. Appelbaum, Joseph H. Antin, Claudio Anasetti, Daniel R. Couriel, Junfang Chen, Richard T. Maziarz, Philip L. McCarthy, Ryotaro Nakamura, Voravit Ratanatharathorn, Ravi Vij, Richard E. Champlin. Long-Term Survival after Transplantation of Unrelated Donor Peripheral Blood or Bone Marrow Hematopoietic Cells for Hematologic Malignancy. Biol Blood Marrow Transplant. 21(1): c. SC11-02a Mary Eapen, Brent R. Logan, Mary M. Horowitz, Xiaobo Zhong, Miguel Angel Perales, Stephanie J. Lee, Vanderson Rocha, Robert J. Soiffer, Richard E. Champlin. Bone Marrow or Peripheral Blood for Reduced Intensity Conditioning Unrelated Donor Transplantation. J Clin Oncol. 33 (4): d. GS12-01 Johan Törlén, Olle Ringdén, Jennifer Le Rademacher, Minoo Batiwalla, Junfang Chen, Tom Erkers, Vincent Ho, Partow Kebriaei, Carolyn Keever-Taylor, Tamila Kindwall-Keller, Hillard M. Lazarus, Mary J. Laughlin, Michael Lill, Tracey O Brien, Miguel-Angel Perales, Vanderson Rocha, Bipin N. Savani, David Szwajcer, David Valcarcel, Mary Eapen. Low CD34 Dose Is Associated with Poor Survival after Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant 20 (9): e. GS12-03 Daniel Weisdorf, Mary Eapen, Annalisa Ruggeri, Mei-Jie Zhang, Xiaobo Zhong, Claudio Brunstein, Celalettin Ustun, Vanderson Rocha, Eliane Gluckman. Alternative Donor Transplantation for Older Patients with Acute Myeloid Leukemia in First Complete Remission: a Center for International Blood and Marrow Transplant Research-Eurocord Analysis. Biol Blood Marrow Transplant 20 (6): f. GS08-01 Craig Kollman, Stephen R. Spellman, Mei-Jie Zhang, Anna Hassebroek, Claudio Anasetti, Joseph H. Antin, Richard E. Champlin, Dennis Confer, John DiPersio, Marcelo Fernandez-Vina, Robert Hartzman, Mary M Horowitz, Carolyn K Hurley, Chatchada Karanes, Martin Maiers, Carlheinz Mueller, Michelle Setterholm, Ann Woolfrey, Neng Yu, Mary Eapen. The Effect of Donor Characteristics on Survival after Unrelated Donor Transplantation for Hematologic Malignancy. Submitted. g. GS13-01 Doris M. Ponce, Rodney Sparapani, Junfang Chen, Vanderson Rocha, Daniel H. Fowler, Mary Eapen, Juliet N. Barker, Migule-Angel Perales. Comparable 3-Year Disease-Free Survival Regardless of Anti-Thymocyte Globulin Inclusion in Pediatric Myeloablative Cord Blood Transplantation for Acute Lymphoblastic Leukemia. Presented at the 56 th annual meeting of the American Society of Hematology, San Francisco, CA, December 2014 (Poster presentation). h. GS14-01a Stefan Ciurea, Mei-Jie Zhang, Andrea Bacigalupo, Asad Bashey, Fredrick Appelbaum, Philippe Armand, Joseph Antin, Omar Altijwa, Junfang Chen, Steve Devine, Daniel Fowler, Ryotaro Nakamura, Miguel-Angel Perales, Ravi Pingali, David Porter, Marcie Riches, Olle Ringden, Vanderson Rocha, Ravi Vij, Daniel Weisdorf, Richard Champlin, Ephraim Fuchs, Mary Eapen. Survival after T-cell Replete Haploidentical Related Donor Transplant with Post-transplant Cyclophosphamide Compared with Matched Unrelated Donor Transplant for Acute Myeloid Leukemia. Presented at the 56 th annual meeting of the American Society of Hematology, San Francisco, CA, December 2014 (Oral presentation).

3 3. Studies in Progress Dr. Rocha led this section. On behalf of the committee, Dr. Rocha thanked Dr. Fowler for his contributions to GSWC as co-chair. Then he presented the findings and conclusions of study GS14-01a (see summary below), and briefly discussed the status of three other approved studies. GS13-01 was not discussed as the results were presented at the Tandem 2014 meeting. a. GS14-01a: Haploidentical vs. matched unrelated HCT (S Ciurea/ O Ringden/E Fuchs/A Bacigalupo). This study compared transplant outcomes of 2,174 adults with acute myeloid leukemia (AML) after haploidentical and 8/8 HLA-matched unrelated donor transplantation. All haploidentical transplant recipients received post-transplant cyclophosphamide; n=104 received myeloablative (MAC) and 88, reduced intensity conditioning (RIC) regimens. Among unrelated donor transplant recipients n=1,245 received MAC and 737, RIC regimens. The primary endpoint was overall survival. The 3-year probabilities of overall survival were 50% (95% CI 47-53) after MAC unrelated donor compared with 45% (95% CI 36-54) after haploidentical transplants (p=0.38). The corresponding rates after RIC transplants were 44% (95% CI ) and 46% (95% CI 35-56), respectively (p=0.71). However, other outcomes differed: Day-30 neutrophil recovery was 97% after MAC unrelated donor compared with 90% haploidentical transplants (p=0.02). The corresponding rates after RIC transplants were 96% and 93%, respectively (p=0.25). In the MAC setting, 3-month grade 2-4 acute graft-versus-host disease (GVHD) (33% versus 16%; p<0.0001) and 3-year chronic GVHD (53% versus 30%, p<0.0001) were higher after unrelated donor compared with haploidentical transplants. A similar trend was observed after RIC transplants, 28% versus 19%, p=0.05 and 52% versus 34%, p=0.002, respectively. In conclusion, in this retrospective analysis, the available data suggest that survival for AML patients after haploidentical transplantation was comparable with HLA-matched unrelated donor transplantation. b. GS13-02: Matching between cord blood units in double cord blood unit transplantation Does this affect hematopoietic recovery, acute GVHD and early survival? (C Brunstein). This study is currently under study file preparation, we would anticipate completing the analysis by June c. GS14-02: Association between recipient and donor sex and clinical outcomes after allogeneic HCT (P Armand/H Kim): This study will explore whether recipient gender or recipient/donor gender match is associated with clinical outcomes after allogeneic HSCT, and whether this association varies by disease. This study is currently under analysis and we expect to submit the manuscript by June d. GS14-01b: Compare haplo-hct verses double cord blood transplantation for AML/NHL with reduced intensity condition regimens (A Mussette/M Perales). The haplo-/transplant cohort is confounded with transplant center. This makes it impossible to separate transplant center effect from the effects of donor source on transplant outcomes. Therefore we have decided to defer this study until several more centers are performing reduced intensity conditioning haplo-identical transplants for AML and NHL. 4. New proposals Dr. Perales led this section, reinforcing to the committee to select proposals likely to have a high impact and feasible. a. PROP / / / / All five proposals are seeking to study the influence of donor selection on outcomes after haplo-identical transplantation followed by high-dose of post-transplant Cyclophosphamide. Proposal was presented by Dr.

4 Wingard. Proposal was presented by Dr. Kekre. Proposal was presented by Dr. Hanna. Proposal and were presented by Dr. Perales and Dr. Rocha, respectively. The CIBMTR statistical group along with the co-chairs decided there will be one study rather than 5 studies each addressing an aspect of donor selection. Based on CIBMTR database, we identified ~ 600 adults with hematologic malignancy transplanted between 2008 and 2013 in the US. Patients received either myeloablative or reduced intensity regimens. The primary objective of these proposals are to identify donor characteristics associated with better engraftment, lower acute and chronic GVHD risks and better survival. The donor characteristics of interest include the following: donor sex, donor age, donor weight, donor parity (female donors), donor-patient relationship (sister, brother, mother or father), donor CMV serostatus, donor ABO blood group and donor-recipient HLA typings for assign HLA-match status. These variables are captured on CIBMTR forms research level data. However, due to financial constrains / burden of reporting the CIBMTR selects only a subset of patients for their research track. Haploidentical transplants are relatively new and being performed at a few centers in the U.S. In discussions prior to the committee meeting, centers performing haploidentical transplants are very interested in providing the CIBMTR, the additional donor-related variables that were not captured for transplants reported on the TED track. There were two additional variables of interest which was considered challenging to collect: the effect of non-inherited maternal and paternal antigen matching/mismatching and donor specific HLA antibodies. We will not be requesting data on donor specific HLA antibodies. It is unlikely we will be able to study an effect of HLA-matching final determination will be after review of HLA data jointly with the Immunobiology Program of the CIBMTR. This proposal received the highest priority score. The proposal was accepted and we will begin the process of supplemental data collection. Supplemental data collection adds about 6-9 additional months to a study. We will review data received after 6 months of initiating data collection. If data collection is unsatisfactory we will not be able to proceed. b. PROP DRI-guided graft source selection for allogeneic hematopoietic cell transplantation in adults with leukemia and lymphoma (N Bejanyan/D Weisdorf). The purpose is to study the effect of graft source on disease-free survival (DFS) of adult allograft recipients with hematological malignancies based on DRI assignment, and to stratify DRI-based models of graft choice by disease-group (leukemia and lymphoma). The primary outcome of interest is disease-free survival (DFS) and the secondary outcomes of interest are neutrophil recovery, platelet recovery, acute and chronic GVHD, treatment-related mortality, malignancy relapse and overall survival. The study population will include patients in the DRI validation dataset ( ). Of note, the DRI has only being validated for overall survival. Therefore using the DRI index for patient selection we will study overall survival by graft source. As graft source primarily affects recipients of unrelated donor transplantation, the analysis will be restricted to this group of transplants. The primary outcome of interest would be overall survival. While we can study other outcomes, the DRI has not been tested/validated for these outcomes. These issues will be discussed further during protocol development stage. Several committee members suggested we include pediatric patients with AML/ALL, the most common indication for unrelated donor transplantation in children. Dr. Armand has conducted preliminary analysis/validation of DRI. The CIBMTR will discuss with Dr. Armand regarding his findings on the pediatric group and whether it is feasible to test the DRI index assignment for graft selection for pediatric unrelated donor transplant. There was interest in pursuing this study; proposal accepted.

5 c. PROP Likelihood of survival for patients with acute leukemia who are alive and diseasefree at 3, 6, & 12 months post-transplant: Are there differences by donor source? (W Hwang). Dr. Hwang presented the proposal. The aim of the study is to determine whether cord blood transplant recipients have better long term outcomes if they have survived the first 100 days after their transplant. The outcomes are overall survival, disease-free survival, and chronic GVHD. The study population includes AML/ALL adult patients who underwent first allogenic transplant and who were alive and disease free at 3 months. The proposal also wanted to compare outcomes amongst those who survived for at least 3-months to HLA-matched sibling and HLA-matched unrelated donor transplants. The primary concern regarding comparing donor/graft sources was that one could not select a donor or graft based on outcomes beyond 3-months after transplantation. Decisions such as donor/graft choices should begin at time of transplantation. The only exception being, the late effect studies which tend to select patients alive and disease-free at about 2 years after transplantation. Of note, there is a recent CIBMTR paper (Lee SJ et al) that addressed a similar question after HLA-matched sibling and unrelated donor transplantation. Data were shown on potentially eligible patients at 6-months and 12-months. Much of the discussion centered on conducting this study for recipients of cord blood transplants as there are no papers that address this issue currently. While the results of the study will not allow for donor / graft selection upfront (ie, time of transplant), the study may generate information that may be valuable to counsel patients. Of note, Dr. Brunstein had proposed a similar study last year but was interested in leukemia-free and overall survival at later time points. In the current population about 800 CB transplant recipients are alive and disease-free at 3-months, 590, at 6- months and 400 at 12-months. This would allow for assessment at these three time-points. The proposal was accepted. As there was a similar proposal last year, the committee leadership will invite Dr. Brunstein to join Dr. Hwang. d. PROP What should be the minimum required stem cell dose for successful autologous peripheral blood HCT after myeloablative conditioning? (G Akpek). Dr. Akpek presented the proposal. The aim of this study is to identify the minimum CD34+ cell dose for successful autologous transplantation with peripheral blood. The primary endpoint is delayed neutrophil (> 14 days) recovery, the secondary endpoints includes delayed platelet (>30 days) recovery, and day+100 transplant-related mortality. The study population will include all patients who received peripheral blood autologous HCT multiple myeloma, non-hodgkin and Hodgkin lymphoma. The transplant period would include 2008 to 2013 and for transplants in the U.S. The main discussion/concern was how would be establish a new threshold? In reviewing the frequency Table, only about a quarter of transplants used a graft that contained <3 x 10^6/kg CD34 cells. Therefore, to establish a new threshold we would have to test for a cell dose effect at <2 x 10^6/kg CD34 cells. In addition disease heterogeneity may play a role. The other concern was the definition of engraftment. The PI would like to use neutrophil recovery (>0.5 x 10^9/L). Others felt we should consider platelet recovery (platelet transfusion independence). We would have to use the variable for recovery >20 x 10^9/L to assess platelet engraftment. There was limited enthusiasm for this proposal; therefore this was not approved to proceed further. Below is the distribution of CD34 cell dose categories: <1, , , by disease.

6 CD34 cell dose x 10 6 /kg NHL HL MM Total < Total e. PROP What is the optimal stem cell source (peripheral blood versus bone marrow) for recipients aged 20 years with HLA-matched sibling donors? (George Chen). The purpose of the study is to compare outcomes after bone marrow versus peripheral blood transplant by recipient age in young adults (aged years). Transplants limited to HLAmatched siblings and for AML/ALL. Reviewing the CIBMTR data, only 46 patients aged received bone marrow compared to 372 who received peripheral blood. In the year age group, 68 patients received bone marrow compared to 942, peripheral blood. The CIBMTR included patients transplanted between 2005 and 2011 and it appears very few patients are receiving bone marrow grafts. The study proposal is not feasible considering transplants over the last 10 years. To be able to address this issue one would have to study transplants performed in a much earlier period (like the late nineties) but one would argue transplant strategies/patient selection/supportive care has evolved so much that results of transplants performed in the nineties is not necessarily applicable to transplants after 2010 or later period. There was limited enthusiasm for this proposal; therefore this was not approved to proceed further. Meeting adjourned at 2:15 PM.