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1 MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION Grapevine, TX Thursday, February 27, 2014, 2:45 4:45 pm Co Chair: Co Chair: Co Chair: Statisticians: Scientific Director: Daniel H. Fowler, MD, National Cancer Institute, Bethesda, MD Telephone: ; Fax: ; E mail: dhfowler@helix.nih.gov Miguel Angel Perales, MD, Memorial Sloan Kettering Cancer Center, New York, NY Telephone: ; Fax: ; E mail: peralesm@mskcc.org Vanderson Rocha, MD, PhD; Churchill Hospital, Oxford, UK Telephone: ; Fax: ; E mail: vanderson.rocha@ouh.nhs.uk Mei Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; E mail: meijie@mcw.edu Junfang Chen, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; E mail: juchen@mcw.edu Mary Eapen, MD, MS, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; E mail: meapen@mcw.edu 1. Introduction Dr. Fowler opened the meeting at 2:45 pm by welcoming the working committee members for attending the Graft Sources and Manipulation working committee (GSWC). He then briefly introduced the GSWC s leadership, goals, expectations and limitations. He also presented 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 papers Dr. Perales reviewed publications (shown below), and summarized the findings and conclusions of on going studies described below. There were two presentations at the 2013 American Society of Hematology meetings and one, at the 2013 European Group for Blood and Marrow Transplantation meeting. a. GS08 02 Alousi AM, Le Rademacher J, Saliba RM, Appelbaum FR, Artz A, Benjamin J, Devine SM, Kan F, Laughlin MJ, Lazarus HM, Liesveld J, Perales MA, Maziarz RT, Sabloff M, Waller EK, Eapen M, Champlin RE. Who is the better donor for older hematopoietic transplant recipients: an older aged sibling or a young, matched unrelated volunteer? Blood 121(13): , 2013.

2 b. GS09 02 Eapen M, Klein JP, Ruggeri A, Spellman S, Lee SJ, Anasetti C, Arcese W, Barker JN, Baxter Lowe LA, Brown M, Fernandez Vina MA, Freeman J, He W, Iori AP, Horowitz MM, Locatelli F, Marino S, Maiers M, Michel G, Sanz GF, Gluckman E, Rocha V. Impact of allele level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood 123(1):133 40, c. GS11 01 Marks DI, Ahn KW, Xiaobo Z, Appelbaum, Bachanova V, Barker JN, Brunstein CG, Gibson J, Kebriaei P, Lazarus HM, Olsson R, Perales, Pidala J, Savani B, Rocha V, Eapen M. Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors. Haematologica 99(2): , Studies in Progress Four studies were completed in 2013 and manuscripts circulated to writing committee members with submission planned in the next 6 8 weeks. These studies are summarized below: a. GS05 01: The effect of cord blood processing and thawing techniques on transplant outcomes after single myeloablative umbilical cord blood (UCB) transplantation (KK Ballen). UCB banking practices were separated into four groups based on whether processing was manual or automated, units were plasma/ red cell reduced or plasma reduced and whether hespan was added to the bag. Neutrophil recovery at day 28 was significantly lower after transplantation of units that were manually processed and plasma reduced. However, this did not affect day 100 mortality. b. GS08 01: Effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy (C Kollman). In this dataset of almost 7000 donor recipient pairs, we identified three donor characteristics associated with better survival: 1) donors aged 32 years or younger, HLA matched at HLA A, B, C and DRB1 and blood group ABO matched. Importantly, each of these donor characteristics had an independent prognostic value. Transplantation of grafts from male donor or female nulliparous donors were associated with lower risks of chronic GVHD; donor sex was not associated with survival. Donor CMV seropositivity was also not associated with survival. c. GS12 01: Low CD34 cell dose is associated with higher non relapse and overall mortality after reduced intensity HCT for AML and MDS (J Thörlén/O Ringden). CD34 dose was associated with overall mortality and non relapse mortality but the dose threshold differed by donor source. Peripheral blood grafts that contained less than 4 x 10 6 /kg was associated with higher risks of overall mortality and non relapse mortality after HLA matched sibling donor transplants. In the setting of unrelated donor transplantation, grafts that contained CD34 dose less than 6 x 10 6 /kg were associated with higher overall and non relapse mortality. CD34 dose was not associated with acute or chronic GVHD risks. d. GS12 03: Alternative donor transplantation for older patients with acute myeloid leukemia in 1 st complete remission (D Wesidorf). This is a joint study with Eurocord. UCB grafts were associated with slower hematopoietic recovery and lower rates of chronic GVHD. Compared to HLA matched unrelated donor transplant, leukemia free and overall survival was lower after UCB transplants. Nevertheless, for those without a fully matched adult unrelated donor, UCB

3 transplants extend leukemia free survival for over a third of patients. This paper is now in press (Biol Blood Marrow Transplant; 2014). Studies in Progress: Analysis e. GS13 01: Comparison of cord blood transplantation outcomes testing for an effect of antithymocyte globulin to transplant conditioning regimen (D Ponce/ M Perales/J Barker). The study will compare outcomes after single or double UCB transplantation for AML, ALL and MDS patients testing for the effect of ATG on outcomes. Patient age, use to ATG and regimen intensity are confounding factors. Therefore, we will conduct two separate analyses. The first, in a pediatric population (n = 588), that received myeloablative transplant conditioning. Results of analyses confirmed lower risks of acute and chronic GVHD with regimens that included ATG. However, there were no differences in non relapse mortality, relapse, disease free or overall survival. The members suggested we study the effect of ATG on hematopoietic recovery and grade 3 4 acute GVHD. V Rocha has questioned that the effect of ATG on the incidence of GVHD and not impact on survival can be related to higher incidence of infection. Infections related death should be investigated. The CIBMTR captures data on infections within the first 3 months; thereafter infection related data are not collected consistently as patients may not be followed up regularly at the tertiary center (transplant center). Studying causes of death using data submitted to an observation registry is challenging and unreliable. While these data can be reviewed, past precedence suggests this to be of low scientific merit. The second part of the study will focus on adults who received reduced intensity regimens and test the effect of ATG. This analysis is ongoing. Studies in Progress: Protocol Development f. 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). 4. New study proposals Dr. Rocha has conducted the discussion of the new proposals, reinforcing that the committee would select proposals with high impact score and have greatest impact on clinical practice. a. PROP / / All three proposals are seeking to study outcomes after transplantation of haplo identical donor transplants to HLA matched unrelated adult donor transplantation or umbilical cord blood transplantation. Prop was presented by S Ciurea in collaboration with investigators at Johns Hopkins, Genova and Atlanta. Prop was presented by O Ringden and Prop , Alberto Mussetti and Miguel Perales. As haploidentical donor transplants are relatively recent, the study population will be limited to and adult patients with AML. The study will be limited to adults and when possible, we will identify transplant packages. There are few patients with ALL, who received haplo identical donor or UCB transplants. The haplo identical donor transplant group will be divided into CD34 selected grafts and post transplant cyclophosphamide. Further, we will make appropriate adjustments for transplant conditioning regimen intensity. These proposals will be combined together for efficiency. The committee was keen to conduct these analyses and assigned a high priority score. It is likely that there will be two separate publications, one comparing outcomes after haplo identical donor transplantation to that after unrelated donor transplantation and

4 the second, comparing outcomes after haplo identical donor transplantation to that after cord blood transplantation. Within the committee, we have prioritized this proposal over GS b. PROP Trends in HLA haplo identical allogeneic hematopoietic stem cell transplantation for hematologic malignancies: a CIBMTR analysis (G Akpek). The purpose of the study is to compare trends and transplant outcomes among 5 cohorts of patients who received haploidentical allo transplants for hematologic malignant diseases based on their year of transplantation from the 1980s to current. The primary outcome of interest is transplantrelated mortality at day+100 and 1 year. However, transplant strategies and supportive care have evolved over the decades making it impossible to attribute survival differences to transplant strategy alone. This proposal received a low priority score. Therefore the proposal was dropped. c. PROP Association between recipient and donor sex and chronic GVHD, relapse and survival after allogeneic hematopoietic stem cell transplantation (P Armand/ H Kim). The aim of the study is to determine whether recipient gender or recipient/donor gender match is associated with clinical outcomes after allogeneic HSCT, and whether this association varies by disease. Drs. Armand and Kim will utilize an existing dataset that they have worked on to validate the disease risk index developed by this group. The DRI index was predictive for overall survival. They would like to extend to other outcomes relapse and GVHD. We are unable to study acute GVHD for the entire population as registration level data does not capture the date of onset of acute GVHD. Therefore acute GVHD will be evaluated in a subset for whom we have organ staging and date of onset. The proposal received a high priority score; we will update the existing dataset for Drs. Armand and Kim. d. PROP Peripheral stem cell graft composition of female donors and transplant outcome (J Schetelig/ A Nagler/ A Shimoni/ G Ehninger). Dr. Schetelig presented the proposal. The aim of this study is to challenge the preferential activation of unrelated male peripheral blood stem cell (PBSC) donors, and to describe the effect of sex mismatch in matched unrelated donorrecipient peripheral blood stem cell transplantation (PBSCT). The research question is whether donor recipient mismatch (female donor/male recipient) is associated with a higher incidence of GVHD, non relapse mortality and disease free survival compared to transplantation from male donors to male or female recipients or female donors to female recipients in the setting of HLA matched unrelated adult PBPC transplants. The investigators are interested in CD34 and CD3 dose; the later is not reported for about 60% of eligible HLA matched sibling donor transplants. The NMDP does not collect CD3 dose the CIBMTR does not collect graft characteristics for transplants facilitated by the NMDP. On the other hand, CD3 dose is available for DKMS facilitated transplants in the US. Study population will include patients with AML, ALL or MDS. The committee was interested in pursuing this proposal further but we are unsure as to whether we will be able to identify a cohort for whom we have CD34 and CD3 dose. The proposal was conditionally approved to assess feasibility which will require the CIBMTR prepare a study file and thereafter identify those transplants facilitated by the DKMS through the NMDP. We will test feasibility and only if feasible will we proceed to protocol development. e. PROP The impact of graft T cell subset doses on the outcomes of allogeneic peripheral blood stem cell transplants after reduced intensity conditioning in patients with hematologic

5 malignancies (R Reshef/ D Porter). The purpose of the study is to assess the impact of CD3, CD4 and CD8 cell doses on overall survival, relapse free survival, acute and chronic GVHD and, treatment related mortality in patients with hematologic malignancies undergoing allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning. Only T cell replete transplants will be included. As with the above mentioned proposal, CD3 dose is not readily available but if obtained for the above study we would use those data for this proposal. However, CD8 counts are not routinely performed in the US; a show of hands at the meeting concluded only 3 centers report CD8 dose. Although this proposal is interesting it is not feasible. As Drs. Reshef and Potter have pilot data from their institution, they will discuss with investigators at the two other centers for a collaborative study. f. PROP Using landmark analysis to provide updated relapse and leukemia free survival estimates to patients after umbilical cord blood transplantation (C Brunstein/ S Lee). Dr. Brunstein presented this proposal, which is similar to the recent publication by Drs. Lee and Weisdorf. It is clear there are very few long term survivors because adult UCB transplant is relatively recent and it would take several hundreds of adult UCB transplant with long term follow up to undertake this study. The purpose of presentation was to gauge interest within the committee. There is enthusiasm from the committee members consequently, Dr. Brunstein will present a separate proposal in a few years. Meeting adjourned at 4:38 PM.

6 Working Committee Overview Plan for a. GS13 01: Comparison of cord blood transplantation outcomes testing for an effect of antithymocyte globulin to transplant conditioning regimen. Manuscript submission June b. GS13 02: Matching between cord blood units in double cord blood unit transplantation Does this affect hematopoietic recovery, acute GVHD and early survival? Data file preparation/data analysis January 2015; Manuscript submission June c. GS14 01 (PROP / / ): Evaluation of three alternative donor strategies for AML. This study is a priority we anticipate developing a protocol and study file by July 2014 and plan on submitting abstracts to the 2014 American Society of Hematology meeting. Manuscript submission June 2015 d. GS14 02 (PROP ): Association between recipient and donor sex and clinical outcome after allogeneic hematopoietic stem cell transplantation. Updating the existing study file will be completed by September Manuscript submission December e. GS14 03 (PROP ): Peripheral stem cell graft composition of female donors and transplant outcome. We will determine feasibility by June 2014; if feasible we will proceed with protocol development thereafter and plan to complete analysis January 2015; manuscript submission June Working Assignments for Working Committee Leadership (March 2014) Miguel Perales Vanderson Rocha Mary Eapen Mary Eapen Daniel Fowler GS13 01: Comparison of cord blood transplantation outcomes testing for an effect of anti thymocyte globulin to transplant conditioning regimen. GS13 02: Matching between cord blood units in double cord blood unit transplantation Does this affect hematopoietic recovery, acute GVHD and early survival? GS14 01: Evaluation of three alternative donor strategies for AML. GS14 02: Association between recipient and donor sex and clinical outcome after allogeneic hematopoietic stem cell transplantation. GS14 03: Peripheral stem cell graft composition of female donors and transplant outcome.