A G E N D A CIBMTR WORKING COMMITTEE FOR … · Dr. Alvaro Urbano-Ispizua reviewed the four studies...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR GRAFT-VERSUS-HOST DISEASE Salt Lake City, Utah Wednesday, February 13, 2013, 12:15 – 2:15 PM

Co-Chair: Alvaro Urbano-Ispizua, MD; Hospital Clinic of Barcelona, Spain Phone: +34 93-227-5475, Fax: +34 93-227-9811, E-mail: [email protected] Co-Chair: Corey Cutler, MD, MPH, Dana Farber Cancer Institute, Boston, MA Phone: 617-632-5946, Fax: 617-632-5168, E=mail: [email protected] Co-Chair: Mary Flowers, MD, Fred Hutchinson Cancer Research Center, Seattle, WA Phone: 206-667-5191, Fax: 206-667-1034, E-mail: [email protected] Statisticians: Michael Hemmer, MS, CIBMTR Statistical Center, Milwaukee, WI Phone : 414-805-4638, Fax : 414-805-0714, E-mail : [email protected] Tao Wang, PhD, CIBMTR, Medical College of Wisconsin, Milwaukee, WI Phone : 414-456-4339, Fax : 414-456-4339, E-mail : [email protected] Scientific Directors: Mukta Arora, MD, MS, CIBMTR, Minneapolis, MN Phone: 612-626-4105, Fax: 612-625-6919, E-mail: [email protected] Stephen Spellman, MS, CIBMTR, Minneapolis, MN Phone: 612-617-8334, Fax: 612-362-3488, E-mail: [email protected]

1. Introduction a. 2012 Tandem Minutes for approval (Attachment 1) b. Newly appointed chair: Daniel Couriel, MD; The University of Michigan Medical Director;

E-mail: [email protected].

2. Accrual Summary (Attachment 2)

3. Presentation, published or submitted papers a. GV05-02 Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS, Urbano-Ispizua A, Pavletic SZ, Haagenson MD, Zhang MJ, Antin JH, Bolwell BJ, Bredeson C, Cahn JY, Cairo M, Gale RP, Gupta V, Lee SJ, Litzow M, Weisdorf DJ, Horowitz MM, Hahn T. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 119(1):296-307, January 5, 2012 b. GV08-01 Battiwalla M, Ellis K, Li P, Pavletic SZ, Akpek G, Hematti P, Klumpp TR, Maziarz RT, Savani BN, Aljurf MD, Cairo MS, Drobyski WR, George B, Hahn T, Khera N, Litzow MR, Loren AW, Saber W, Arora M, Urbano-Ispizua A, Cutler C, Flowers ME, Spellman SR. HLA DR15 antigen status does not impact graft-versus-host disease or survival in HLA-matched sibling transplantation for hematologic malignancies. BBMT 18(8):1302-8, August 2012 c. GV04-02/05-03c Boyiadzis M, Arora M, Klein JP, Hassebroek A, Hemmer M, Antin JH, Bolwell BJ, Cahn JY, Cairo MS, Cutler CS, Flowers ME, Gale RP, Herzig R, Isola LM, Jacobsohn DA, Jagasia MH, Klumpp TR, Lee SJ, Petersdort EW, Santarone S, Schouten HC, Verdonck LF, Wingard JR, Weisdorf DJ, Horowitz MM, Pavletic SZ. Impact of chronic graft-versus-host disease on late relapse, treatment related mortality, and survival after allogeneic hematopoietic cell transplantation for hematological malignancies. (Submitted to JAMA on 12-20-12.)

1

Not for publication or presentation

4. Studies in progress (Attachment 3)

a. GV06-04 Current trends in chronic GVHD – updated report from the CIBMTR/NMDP (Sally

Protocol Development

b. GV08-02 Balancing acute GVHD and survival after allogeneic hematopoietic progenitor cell transplantation in hematological malignancies: A potential for graft engineering by T cell dose control (A Saad)


c. GV11-02 Acute and chronic GVHD after unrelated umbilical cord blood transplantation: Analysis of risk factors and outcomes (Y-B Chen)


d. GV11-03 A retrospective comparison of tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic HCT according to graft and donor type (Y Inamoto)


e. GV11-04 Validation of chronic GVHD CIBMTR Risk Score (M Flowers)

Data File Preparation

f. GV12-01 Outcomes of grades 3-4 acute graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation: How

much progress was achieved? (HJ Khoury)


g. GV12-02 Prognostic implications of acute upper gastrointestinal graft-versus-host disease in patients undergoing myeloablative hematopoietic cell transplantation (S Nikiforow/C Cutler)


5. Proposed Studies a. PROP 1112-69 Impact of donor sex, parity, and sibling/unrelated status on outcomes of allogeneic

hematopoietic stem cell transplantation (A Kumar/A Loren) (Attachment 4) b. Dropped Proposals

a) PROP 1112-50 Determining the effects of early donor T-cell reconstitution on relapse and GVHD in pediatric leukemia patients (Dropped because data not collected on CD3/4/8 at early time points. T-cell chimerism also not collected by CIBMTR. There is also heterogeneity in the methodology used to estimate donor chimerism amongst transplant centers.)

b) PROP 1112-59 A retrospective CIBMTR study to compare tacrolimus/sirolimus (+/- methotrexate) with tacrolimus/methotrexate as GVHD prophylaxis after unrelated donor hematopoietic stem cell transplantation (Dropped because approximately 70% of patients who received sirolimus came from 2 transplant centers. It was recommended to PI to pursue this study independently with those centers.)

c) PROP 1112-66 Prognostic implications of prior GVHD in patients undergoing donor leukocyte infusion for relapse after allogeneic hematopoietic cell transplantation. (Dropped because there was an overlap with an ongoing CIBMTR study, R02-09 “Evaluation of DLIs to treat relapsed hematologic malignancies after related and unrelated donor myeloablative allogeneic HCTs” and the goals of this proposal could be implemented within R02-09).

6. Other business

2

Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR GRAFT-VERSUS-HOST DISEASE San Diego, California Saturday, February 4, 2012, 2:45 PM-4:45 PM Co-Chair: Mary Evelyn D. Flowers, MD, Fred Hutchinson Cancer Research Center,

Seattle, WA Telephone: 206-667-5191; Fax: 206-667-1034; E-mail: [email protected] Co-Chair: Alvaro Urbano-Ispizua, MD, Hospital Clínic of Barcelona, SPAIN

Telephone: +34 93 227 5475; FAX: +34 93 227 9811; E-mail: [email protected] Co-Chair: Corey Cutler, MD, Dana Farber Cancer Institute, Boston, MA

Telephone: 617-632-5946; FAX: 617-632-5168; E-mail: [email protected]

Statisticians: Tao Wang, PhD, CIBMTR, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-456-4339; Fax: 414-456-4339; E-mail: [email protected] Scientific Directors: Mukta Arora, MD, MS, CIBMTR, Minneapolis, MN Telephone: 612-626-4105; Fax: 612-625-6919; E-mail: [email protected] Stephen Spellman, MBS, CIBMTR, Minneapolis, MN Telephone: 612-617-8334; Fax: 612-362-3488; E-mail: [email protected] 1. Introduction

Dr. Mary Flowers opened the working committee meeting at 2:45 pm by thanking everyone attending the meeting. She introduced the GVHD working group. A motion to approve the February, 2011 GVWC minutes was made, seconded and approved. Dr. Flowers reminded everyone to get their presence registered electronically on today’s meeting which will also allow broadcasting emails from the GVHD WC to all members. She discussed the voting that will be casted today for prior approved studies that have not yet initiated and on the new proposals and reviewed the voting sheet criteria which is based on a scale from 1 to 9 for scientific impact with 1 being the highest impact and 9 being the lowest scientific impact. The voting will help the committee to assign priorities to the studies in the upcoming year. Dr. Flowers then mentioned that the CIBMTR will be revising current forms. She encouraged GVHD members to review what GVHD data are currently been collected in the current forms and encouraged comments about any changes about GVHD questions in these forms to be sent by March 2, 2012. Please send suggestions to Emilie Meissner at [email protected], and to volunteer to help, either contact Emilie or one of the GVHD WC chairs.

3


2. Accrual summary Steve Spellman discussed the Accrual Summary in Attachment 2. He started by discussing the Research Repository update. Unrelated donor and recipient sample collection began in 1988 for NMDP transplants. Related donor sample collection began in 2007 as part of the SCTOD, which has been expanded to BMT-CTN core sites, and 46 sites have agreed to participate. Over 12,000 sample aliquots were distributed in 2011. The repository receives 10-20 ml of whole blood from donors and recipients, and any source of DNA from infused cord blood units. The samples are stored as frozen aliquots (-80 degrees C and liquid Nitrogen) and whole blood spotted on filter paper. In the summer of 2008, 2 milliliters of ACD-A plasma is stored. Prior to 2002, samples collected were B-LCL, PBMC, granulocytes and serum. For unrelated donor transplants there are over 22,700 pairs, of which over 15,000 are first transplants and most with high-resolution HLA typing. For umbilical cord blood transplants, there are 775 single UCBT pairs and 128 double UCBT triplets. Mr. Spellman also discussed costs of samples, both at the academic rate and the industry rate. Grants through the NMDP Immunobiology group are available to help in deferring some of the costs. Support also exists through CIBMTR for NIH/other grant submissions. Sample usage requirements are such that investigators are required to submit the interpreted results of all testing back to the NMDP. Data must be made available to HCT research community, which eliminates or reduces duplicative testing to preserve resources and sample inventory. Data is captured in the NMDP Immunobiology database and linked to the sample inventory.

3. Presentations, published or submitted papers

a. Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis. Blood. 2011 Jun 16;117(24):6714-20.

b. Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease. Blood 118:4472-4479, 2011.

c. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 2011 blood-2011-06-364265; published ahead of print October 18, 2011

d. HLA DR15 Antigen Status Does Not Impact Graft-Versus-Host Disease or Disease-Free Survival in HLA-Matched Sibling Transplantation for Hematologic Malignancies. BBMT (Accepted for publication as a short paper). ASH 2011. ASH Abstract # 3094

Dr. Alvaro Urbano-Ispizua reviewed the four studies presented and published this past year in the GVHD WC. He went through the results of each of these four studies.

4. Studies in progress

a. GV04-02/GV05-03b: Chronic Graft-Versus-Host Disease - Relapse and Risk Factor Analyses (S Pavletic/Michael Boyiadzis): Dr. Mukta Arora presented this study. This study proposes to determine factors associated with leukemia relapse in patients with cGVHD, with specific focus on cGVHD related characteristics. The analysis is complete and the results will be presented in the Allogeneic Transplantation session February 4, 2012 at 4.45 p.m.

b. GV06-04: Current trends in chronic GVHD - updated report from the CIBMTR/NMDP (S Arai): Dr. Arora presented the update on this study. This study proposes to observe GVHD incident trends of last 10 years and evaluate markers such as type of onset, organ involvement, disease status at diagnosis, cGVHD specific mortality, and overall mortality. The study is in data file preparation stage – the final protocol is provided in your attachment.

c. GV11-04: Validation of chronic GVHD CIBMTR Risk Score (M Flowers): Dr. Arora presented this study, which will validate the cGVHD risk score predicting NRM and overall survival in patients with cGVHD. The outcomes to be studied are non-relapse mortality (NRM) and overall survival (OS). The final protocol is available for review.

4


Dr. Arora then, discussed the voting sheets. She mentioned that everyone should put an asterisk by the study that is of the highest importance to help the GVHD working group determine which studies are the most important to work on in the upcoming year. Dr. Arora then called Dr. Marcelo Pasquini to the podium to present his study.

d. GV06-01: Comparison Of GVHD Prophylaxis Regimens With And Without Methotrexate in Matched, Related and Unrelated Donor Transplantation with Reduced Intensity Conditioning (C Cutler / J Antin /M Pasquini): Dr. Pasquini started the presentation by introducing the problems with the original proposal, which looked at comparing Methotrexate (MTX) vs. non-Methotrexate (sirolimus) GvHD prophylaxes in myeloablative intensity matched related donors (MRD) and unrelated donor (URD) HCT. The study will now look at MTX vs. non-MTX in the reduced intensity/nonmyeloablative setting, and it will include cases from 1998 through 2006, with diseases of AML, ALL, CML and MDS. Cord blood transplants will be excluded. Outcomes to be analyzed are acute GVHD, TRM, transplant-related complications, overall survival, relapse and relapse-free survival. There is mainly PBSC and reduced intensity regimens in the current data base. Dr. Pasquini had concerns if the current focus of this study is still of scientific interest of the committee. Proposed changes could include focusing the study to PBSC and RIC population, years of transplant from 2002 – 2011 and outcomes of early toxicity composite and the previous outcomes as mentioned. Expectations would be to explore new toxicity outcome, determine the impact of conditioning regimens and GVHD prophylaxis type and to describe the role of MTX in the RIC setting.

e. GV08-02: Balancing acute GVHD and survival after allogeneic hematopoietic progenitor cell transplantation in hematological malignancies: a potential for graft engineering by T cell dose control (A Saad/ M Sharma): Dr. Ayman Saad presented this study where the purpose is to attempt to identify of the ideal components of the allogeneic stem cells (progenitor cells) graft in hematological malignancies. This study has the hypothesis that Grade III-IV severe acute GvHD and the graft-versus-tumor effect are separable, and that there exists a cell dose range of both CD4(+) and/or CD8(+) T-cell which promotes graft-vs.-tumor effect, while levels above these ranges result in unacceptable Grade III-IV aGvHD. The purpose of this study is to correlate the dose of CD3(+), CD4(+), and CD8(+) T-cells in the progenitor cell graft with incidence and grade of acute GVHD, overall survival and disease-free survival. Outcomes include the primary outcomes of Grades II-IV acute GvHD, Grades III - IV acute GvHD, overall survival and disease-free survival as well as the secondary outcomes of chronic GvHD, extensive chronic GvHD, relapse rate and time to engraftment. The eligibility criteria include adult patients at least 18 years old with a diagnosis of hematological malignancy with at least one year of follow-up after allogeneic transplant. Based on adults (18 and older) only data reviewed, there are 160 bone marrow and 963 PBSC that have CD3 (+), CD4 (+) and CD8 (+) cell dose data available. This year, Dr. Saad is proposing to include pediatric patients and exclude cord blood transplants. No comments were made for this study.

f. GV11-01: Analysis of graft versus Lymphoma effect after allogeneic HCT (A Urbano-Ispizua): Dr. Urbano-Ispizua presented this study, which looks at lymphoma cases. Lymphoma occurs at a much higher incidence rate than acute leukemia. Lymphoma patients have a median age of 60-65, so for this aged set of patients, reduced intensity conditioning (RIC) transplants would be an excellent platform of immunotherapy, if a graft-vs.-lymphoma (GvLy) effect is clearly demonstrated. The hypothesis of this study is that there is a potent GvLy effect associated with acute and chronic GvHD, and its intensity is different depending on the subtype of B and T cell lymphoma. If such an association is demonstrated, the results would be of particular usefulness in RIC transplants. This study would evaluate the effect of GvHD on relapse rate (primary outcome) and on progression-free survival (secondary outcome) with six groups being considered: All cases (N=1746), Follicular

5


(N=714), Diffuse large (N=414), Mantle cell (N=336), Peripheral T (N=116) and Hodgkin’s (N=166). The plan of the study would be to evaluate cumulative incidence of relapse in individual groups (1 to 6) for patients with "no GVHD", with "aGVHD", with "cGVHD", and with "aGVHD+cGVHD“. The relative risks will be derived from multivariate regression adjusting for phase of disease, HLA identity, type of transplant, source of HPC, etc., and multivariate analysis will be performed in time-dependent fashion. Questions were raised as to why this is not being presented in the lymphoma working committee.

g. GV11-02 : Acute and chronic GVHD after unrelated umbilical cord blood transplantation: analysis of risk factors and outcomes (Y-B Chen): Dr. Yi-Bin Chen presented this study, which plans to evaluate GvHD after cord blood transplants (UCBT). GVHD after UCBT appears to be different than GVHD after BMT or PBSCT: 1) acute GVHD appears to be milder, and 2) chronic GVHD may not have an effect on DFS. Aims of this study include establishing incidence of significant acute and chronic GVHD after UCBT, identifying the risk factors which are associated with its development, and investigating the influence of acute and chronic GVHD on patient outcomes. Outcomes include the primary outcomes of acute Grade II-IV GvHD, acute Grade III-IV GvHD, limited vs. extensive chronic GvHD and mild vs. moderate vs. severe chronic GvHD. The secondary outcomes are non-relapse survival, overall survival, disease-free survival and relapse. There appears to be a large number of cases (at least 2000) that will help determine factors that affect relapse/aGvHD/cGvHD. This study will define the risk factors for GvHD in UCBT.

5. Proposed studies

a. PROP 0911-04 Outcomes of grades 3-4 acute graft-versus-host disease (aGVHD) post-allogeneic hematopoietic stem cell transplantation (HSCT): how much progress was achieved? (HJ Khoury) Dr. Hanna Jean Khoury presented this proposal. Rationales for this proposal: Grades III-IV aGvHD is a limiting factor for successful transplant, steroid-refractory Grades 3-4 aGvHD is common, there are responses after 2nd line agents in steroid-refractory aGVHD, but mortality is high (usually due to infections), and major progress has been made in antimicrobials mainly in antifungal therapy. Aims of this proposal include 1) to determine overall survival (OS) of allogeneic HSCT recipients who develop severe (grades 3-4) aGVHD before and after 2003; 2) to determine disease-free survival (DFS) of allogeneic HSCT who develop severe (grades 3-4) aGVHD before and after 2003; 3) to determine causes of death of allogeneic HSCT recipients who develop severe (grades 3-4) aGVHD before and after 2003. There are approximately 3057 cases before and in 2003 while there are 1280 after 2003 that fit the proposal criteria. A suggestion was made to limit to United States patients only. Another concern raised was to have a center specific analysis with this data. Another suggestion was to exclude GvHD after DLI, while another suggestion was to look at different time points of overall survival (e.g. – 3 months, 6 months, 1 year, etc.). Another suggestion was to use the same numbers of years before 2003 and after 2003 (i.e., one cohort would be from 2003-2011 and the other from 1995 to 2002).

b. PROP 1111-43 Prognostic Implications of Acute Upper Gastrointestinal Graft-versus-Host Disease in Patients undergoing Myeloablative Hematopoietic Cell Transplantation (S Nikiforow/C Cutler) Dr. Sarah Nikiforow presented this proposal, which looks at upper gastrointestinal tract (UGI) acute GvHD. UGI aGVHD was recognized as a syndrome in 1983, with anorexia, dyspepsia, food intolerance, nausea and vomiting as symptoms. The histology is single cell epithelial necrosis and dilation of mucosal crypts/glands. The differential diagnosis of UGI is extensive

6


among clinical symptoms. Currently, persistent nausea “with histologic evidence of GVHD in the stomach or duodenum” is considered Stage 1 gut GvHD which translates to Grade 2 acute GvHD. There is the question of the validation of UGI in current practice. In 1999, a Japanese group led by Wakui et al. BMT determined that routine EGD revealed UGI aGVHD in 46% of allo recipients, but it did not impact cGVHD, OS, transplant outcome. 1/3rd resolve without treatment. Current reporting criteria do not require histologic confirmation, and the impact on staging and prognostic implications of UGI aGVHD has never been validated in a large patient population. Aims of this proposal would be to 1) establish incidence of UGI aGVHD in isolation and in combination with other manifestations of GVHD; 2) establish influence of UGI aGVHD on transplant-related outcomes; and 3) evaluate the current placement of UGI aGVHD within GVHD staging and grading schema. The study population is proposed to be adults with myeloablative conditioning regimens and calcineurin-based GVHD prophylaxis, bone marrow or PBSC, non-T-cell depleted, matched related donor or 8/8 URD with diseases of AML/ALL/ MDS/CML. The outcomes would be TRM, relapse, DFS and overall survival, along with development of chronic GvHD. The main effects of the proposal would be to compare A) isolated UGI aGVHD (Grade II) with 1) Grade 0, 2) Grade 1, 3) Grade II without UGI, 4) Grade III without UGI, 5) Grade IV without UGI; B) Grade II GVHD with UGI to Grade II without; C) Grade III GVHD with UGI to Grade III without; and D) Grade IV GVHD with UGI to Grade IV without. Not everyone gets UGI endoscopy to determine UGI GVHD. It was suggested to open this study to mismatched transplant cohort such as 7/8 and possibly 6/8 HLA-match. What is currently captures in the CIBMTR form limits the scope of this study. For instance, there is no specific time point that is currently captured for UGI. A time-dependent analysis cannot be done.

c. PROP 1111-58 Correlative study of myeloid-derived suppressor cells (MDSC) and GVHD or leukemia relapse in AML patients after HCT (X-Z Yu/FL Locke/J Pidala) – Dr. Joseph Pidala presented this proposal, which looks at Myeloid-Derived Suppressor Cells (MDSC). MDSCs are a group of myeloid cells comprised of hematopoietic progenitors, immature macrophages, dendritic cells and granulocytes. They play a critical role in induction of T cell tolerance in tumor environment, but the role in GVHD and leukemia relapse is not defined. Preclinical studies suggest that increases in MDSC leads to decreased GVHD while decreases in MDSC lead to increased GVL effect. Preliminary murine data in Dr. Yu’s lab show 1) MDSCs (CD11b+/Gr-1+) accumulated in peripheral blood and spleen during the development of acute GVHD; 2) the level of MDSCs was positively correlated with severity of acute GVHD induced by titrated numbers of donor T cells; 3) accumulated MDSCs under GVHD were suppressive to naïve T cells in response to alloantigen in vitro; 4) high levels of MDSCs in peripheral blood were closely associated with and preceded leukemia relapse; and 5) accumulated MDSCs under leukemia were highly immunosuppressive. The study objective of this proposal is to study the relationship between MDSC and HCT outcome in human samples. Methods include obtaining peripheral blood samples where the criteria for patient selection are first transplant for AML, age >20 years, CR1, well matched or partially matched donors, myeloablative conditioning, marrow graft and 100 most recent selected. The study design includes the measuring of the phenotype of patient samples with the following steps: 1) stain for expression of HLA-DR, CD11b, CD33, CD14, CD15, and CD124, and perform multi-color FACS analysis; 2) define HLA-DRlowCD11b+CD33+ as MDSC, CD14lowCD15+ as granulocytic, and CD14+CD15- as monocytic; 3) analyze CD124 (IL-4R) expression (positively correlates with suppressive activity); and 4) control blood samples will be obtained from healthy donors from local blood bank. The analysis would include looking for a study association between day 100 total MDSC and MDSC subsets and a) incidence and severity of chronic GVHD; b) leukemia relapse. In a secondary analysis, the relationship between day 100 MDSC and prior acute GVHD (none vs.

7


resolved vs. ongoing at day 100) would be explored. Anticipated results and pitfalls include a) human MDSC post-HCT will have significant association with GVHD and leukemia relapse; and b) single sample design, which would provide initial insight, but serial time points would be needed to address dynamic shifts in MDSC during GVHD and relapse. The samples are 100 days post-transplant. Comments included that human studies results would be needed before exploring this proposal using samples from the NMDP repository.

6. Other business

Dr. Cutler ended the meeting at 4:45 pm by reminding people to vote.

8


Accrual Summary for GVHD Working Committee

Characteristic of leukemia patients reported to the CIBMTR between 1990 and 2012

Characteristics of patients HLA-identical

sibling

Other related donor

Unrelated donor

Identical twin

Umbilical cord blood

Number of patients 20256 1457 20075 264 3665Number of centers 406 233 331 141 221Age at transplant, median (range), years

35 (<1 - 77) 22 (<1 - 77) 36 (<1 - 79) 36 (1 - 73) 15 (<1 - 83)

Disease AML 8745 (43) 598 (41) 8521 (42) 115 (44) 1732 (47) ALL 4710 (23) 489 (34) 5077 (25) 64 (24) 1520 (41) Other leukemia 1036 ( 5) 55 ( 4) 1209 ( 6) 26 (10) 201 ( 5) CML 5765 (28) 315 (22) 5268 (26) 59 (22) 212 ( 6)Gender Male 11750 (58) 856 (59) 11612 (58) 161 (61) 2022 (55) Female 8505 (42) 600 (41) 8460 (42) 103 (39) 1643 (45) Missing 1 (<1) 1 (<1) 3 (<1) 0 0Graft source Bone marrow 12656 (62) 922 (63) 12697 (63) 159 (60) 0 Peripheral blood 7560 (37) 529 (36) 7336 (37) 103 (39) 0 Cord blood 0 0 0 0 3665 Missing 40 (<1) 6 (<1) 42 (<1) 2 (<1) 0Conditioning regimen Myeloablative 14587 (72) 813 (56) 13506 (67) 180 (68) 1474 (40) RIC 330 (2 ) 71 ( 5) 403 ( 2) 0 1099 (30) Non-myeloablative 3085 (15) 459 (32) 4458 (22) 55 (21) 731 (20) TBD 1834 ( 9) 85 ( 6) 1477 ( 7) 18 ( 7) 184 ( 5) Missing cond regimen 420 ( 2) 29 ( 2) 231 ( 1) 11 ( 4) 177 ( 5)GVHD prophylaxis None 100 (<1) 16 ( 1) 51 (<1) 169 (64) 12 (<1) FK506+MTX+-other 1780 ( 9) 37 ( 3) 5197 (26) 4 ( 2) 192 ( 5) FK506+-other 702 ( 3) 55 ( 4) 1591 ( 8) 2 (<1) 681 (19) CsA+MTX+-other 10932 (54) 548 (38) 7678 (38) 33 (13) 220 ( 6) CsA+-other 2911 (14) 161 (11) 1333 ( 7) 30 (11) 2228 (61) T-cell depletion 1473 ( 7) 471 (32) 3637 (18) 4 ( 2) 242 ( 7) Other 635 ( 3) 55 ( 4) 359 ( 2) 10 ( 4) 47 ( 1) Missing 1723 ( 9) 114 ( 8) 229 ( 1) 12 ( 5) 43 ( 1)

9


Continued.


sibling

Other related donor

Unrelated donor

Identical twin


Severity of Acute GVHD None 9942 (49) 632 (43) 6722 (33) 215 (81) 1568 (43) Grade A 2189 (11) 129 ( 9) 1783 ( 9) 16 ( 6) 303 ( 8) Grade B 4727 (23) 342 (23) 5261 (26) 23 ( 9) 906 (25) Grade C 2108 (10) 217 (15) 3985 (20) 10 ( 4) 658 (18) Grade D 1290 ( 6) 137 ( 9) 2324 (12) 0 230 ( 6)Any cGVHD None 12716 (63) 1086 (75) 11213 (56) 242 (92) 2650 (72) Yes 7359 (36) 364 (25) 8298 (41) 21 ( 8) 956 (26) Missing 181 (<1) 7 (<1) 564 ( 3) 1 (<1) 59 ( 2)Year of transplant 1990-1995 8423 (42) 549 (38) 3589 (18) 134 (51) 69 ( 2) 1996-2000 4867 (24) 442 (30) 5159 (26) 70 (27) 378 (10) 2001-2005 3827 (19) 267 (18) 5827 (29) 45 (17) 825 (23) 2006-2010 2932 (14) 191 (13) 5201 (26) 15 ( 6) 1921 (52) 2011-2012 207 ( 1) 8 (<1) 299 ( 1) 0 472 (13)Median follow-up of survivors, median (range), months 73 (<1 - 269) 68 (2 - 243) 71 (<1 - 270) 79 (2 - 260) 36 (1 - 225)

10


Characteristic of non-leukemia patients reported to the CIBMTR between 1990 and 2012


sibling

Other related donor

Unrelated donor

Identical twin


Number of patients 12551 1020 8649 314 2464Number of centers 395 190 286 162 198Age at transplant, median (range), years 30 (<1 - 77) 5 (<1 - 74) 35 (<1 - 79) 42 (<1 - 76) 4 (<1 - 73)Disease MDS 2621 (21) 149 (15) 3683 (43) 27 ( 9) 500 (20) NHL 2488 (20) 103 (10) 1633 (19) 97 (31) 227 ( 9) HD 212 ( 2) 11 ( 1) 90 ( 1) 21 ( 7) 17 (<1) SAA 2950 (24) 123 (12) 1271 (15) 53 (17) 162 ( 7) Other 4280 (34) 634 (62) 1972 (23) 116 (37) 1558 (63)Gender Male 7423 (59) 640 (63) 5286 (61) 157 (50) 1495 (61) Female 5128 (41) 380 (37) 3360 (39) 157 (50) 969 (39) Missing 0 0 3 (<1) 0 0Graft source Bone marrow 7921 (63) 689 (68) 5124 (59) 152 (48) 0 Peripheral blood 4586 (37) 323 (32) 3497 (40) 162 (52) 0 Cord blood 0 0 0 0 2464 Missing 44 (<1) 8 (<1) 28 (<1) 0 0Conditioning regimen Myeloablative 6770 (54) 541 (53) 3221 (37) 161 (51) 1163 (47) RIC 2101 (17) 149 (15) 2227 (26) 88 (28) 398 (16) Non-myeloablative 697 ( 6) 91 ( 9) 717 ( 8) 2 (<1) 445 (18) TBD 2440 (19) 138 (14) 2228 (26) 39 (12) 264 (11) Missing cond regimen 543 ( 4) 101 (10) 256 ( 3) 24 ( 8) 194 ( 8)GVHD prophylaxis None 164 ( 1) 20 ( 2) 26 (<1) 220 (70) 15 (<1) FK506+MTX+-other 1019 ( 8) 22 ( 2) 2118 (24) 4 ( 1) 90 ( 4) FK506+-other 484 ( 4) 52 ( 5) 822 (10) 1 (<1) 334 (14) CsA+MTX+-other 6247 (50) 317 (31) 2663 (31) 22 ( 7) 190 ( 8) CsA+-other 2542 (20) 171 (17) 990 (11) 37 (12) 1569 (64) T-cell depletion 990 ( 8) 326 (32) 1805 (21) 8 ( 3) 189 ( 8) Other 307 ( 2) 35 ( 3) 132 ( 2) 3 (<1) 41 ( 2) Missing 798 ( 6) 77 ( 8) 93 ( 1) 19 ( 6) 36 ( 1)

11


Continued.


sibling

Other related donor

Unrelated donor

Identical twin


Severity of Acute GVHD None 7288 (58) 555 (54) 3625 (42) 281 (89) 1280 (52) Grade A 1044 ( 8) 79 ( 8) 630 (7 ) 11 ( 4) 192 ( 8) Grade B 2342 (19) 190 (19) 1859 (21) 16 ( 5) 450 (18) Grade C 1203 (10) 135 (13) 1617 (19) 6 ( 2) 410 (17) Grade D 674 ( 5) 61 ( 6) 918 (11) 0 132 ( 5)Any cGVHD None 9048 (72) 803 (79) 5217 (60) 298 (95) 1842 (75) Yes 3365 (27) 201 (20) 3198 (37) 11 ( 4) 574 (23) Missing 138 ( 1) 16 ( 2) 234 ( 3) 5 ( 2) 48 ( 2)Year of transplant 1990-1995 3868 (31) 309 (30) 1059 (12) 112 (36) 48 ( 2) 1996-2000 3295 (26) 287 (28) 1735 (20) 118 (38) 253 (10) 2001-2005 3130 (25) 239 (23) 2689 (31) 66 (21) 683 (28) 2006-2010 2035 (16) 166 (16) 2765 (32) 17 ( 5) 1199 (49) 2011-2012 223 ( 2) 19 ( 2) 401 ( 5) 1 (<1) 281 (11)Median follow-up time, median (range), months 70 (<1 - 269) 56 (1 - 255) 60 (<1 - 249) 94 (3 - 239) 39 (<1 - 231)Abbreviations: RIC=reduced intensity conditioning, GVHD=graft-versus-host disease, FK506=tacrolimus, MTX=methotrexate, CsA=cyclophosphamide a: First transplant reported to CIBMTR, 2012 data are incomplete.

12


To: Graft-Versus-Host Disease Working Committee Members From: Mukta Arora, Scientific Director for GVHD WC RE: 2013 Studies in Progress Summery Studies in progress GV06-04 Current trends in chronic GVHD – updated report from the CIBMTR/NMDP (S Arai) This study will observe cGVHD incidence as a time trend in transplants done from 1995 to 2007. In addition, the study will also estimate temporal trends in non-relapse mortality and overall survival, as well as the proportion of cGVHD patients receiving systemic steroid immunosuppression over the same time frame. The analysis results were approved at the CIBMTR Statistical Meeting, with minor comments for possible changes, on January 8th, 2013. GV11-02: Acute and chronic GVHD after unrelated umbilical cord blood transplantation: Analysis of risk factors and outcomes (Y-B Chen) This study will examine the effect of risk factors on the incidences and grades of aGVHD (grade II-IV and grade III-IV) and cGVHD following an unrelated umbilical cord blood (UCB) transplant was performed for hematological malignancies. Both single and double UCB transplants will be evaluated. The proposed aim is to develop a multivariate predictive model to prognosticate the development of aGVHD and to study the effect of cGVHD and its interaction with other variables on clinical post-transplant outcomes. The protocol was presented at the CIBMTR Statistical Meeting on October 23rd, 2012, where feedback was provided to add more patients to the population. At that time, the study only considered an UCB population from a pre-existing study from the Graft Sources Working Committee. The population has been opened to include all UCB transplants reported to the CIBMTR and NMDP from 2000 – 2009. The draft protocol is currently being revised. GV11-04: Validation of chronic GVHD CIBMTR Risk Score (M Flowers) This study will validate the cGVHD CIBMTR risk score predicting non-relapse mortality and overall survival in patients with cGVHD. There were issues discovered between 2 generations of CIBMTR forms and the different information that was collected at time of cGVHD diagnosis. In order to calculate the risk score, only transplants that used an older generation of CIBMTR forms could be considered, so the scope of the study was narrowed to transplants from 2005 – 2007. Data file preparation is underway. GV12-01: Outcomes of grades 3-4 acute graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation: How much progress was achieved? (HJ Khoury) This study proposes to determine the overall survival of patients who develop severe (grade III-IV) aGVHD and compare the disease free survival and causes of death between patients who developed severe aGVHD before and after 2003, when more effective anti-fungal therapy agents became available. The draft protocol is currently being revised.

13


Studies previously proposed, but not initiated GV08-02: Balancing acute GVHD and survival after allogeneic hematopoietic progenitor cell transplantation in hematological malignancies: A potential for graft engineering by T cell dose control (A Saad) This study hypothesizes that high grade (III-IV) aGVHD and the graft versus tumor effect (GvT) are separable. It specifically theorizes that there exists an optimal cell dose range of both CD4(+) and CD8(+) T-cell that will promote GvT while any greater doses will result in high grade aGVHD with subsequent decreased survival. GV11-03: A retrospective comparison of tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic HCT according to graft and donor type (Y Inamoto) This study will compare tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation among patients with hematological malignancies, as well as to perform retrospective replications of previous randomized studies with the same objective and similar patient eligibility criteria and adjustment by propensity group. GV12-02: Prognostic implications of acute upper gastrointestinal graft-versus-host disease in patients undergoing myeloablative hematopoietic cell transplantation (S Nikiforow/C Cutler) This study proposes to compare the outcomes of treatment-related mortality, cGVHD incidence, disease-free survival and overall survival between those patients with isolated upper gastrointestinal (UGI) aGVHD and those who have aGVHD without UGI involvement at each individual grade of aGVHD.

14


CIBMTR Study Proposal: 1112-69 Study Title: Impact of donor sex, parity, and sibling/unrelated status on outcomes of allogeneic hematopoietic stem cell transplantation 1st PI Information: PI Name Anita J. Kumar Degree(s): MD Email Address: [email protected] Institution Name: Hospital of University of Pennsylvania, Abramson Cancer Center 2nd PI Information if applicable: PI Name (First, Middle, Last): Alison W. Loren Degree(s): MD Email Address: [email protected] Institution Name: Hospital of University of Pennsylvania, Abramson Cancer Center Specific Aims:

To compare the incidence of acute GVHD, chronic GVHD, and overall survival in recipients of allogeneic SCT who received stem cells from 1) female parous HLA identical sibling donors or 2) male unrelated HLA identical donors

To determine whether the sex of SCT recipients impacts the incidence of acute GVHD, chronic GVHD, and overall survival after allogeneic SCT

To determine whether the relationship between parity, sex & related/sibling donor and other transplant variables affects incidence of acute and chronic GVHD

This study will help delineate specific risks when performing donor selection for patients who are undergoing allogeneic SCT.

Scientific Justification: Allogeneic stem cell transplant (SCT) is a potentially curative therapy for patients with hematologic malignancies. Successful SCT depends on both the conditioning therapy and the graft versus leukemia effect, but can also result in significant morbidity and mortality. Donor selection is an important factor in reducing risks of morbidity & mortality from SCT: specific qualities within donor selection include HLA matching, cytomegalovirus status, ABO incompatibility, age, sex, and parity. Donor sex and parity have been an increasingly studied risk factor specifically for development of acute and chronic GVHD (aGVHD, cGVHD). Studies have shown an increased risk of chronic GVHD with female donors [1] [2]. Although some studies have shown no association between parity and GVHD [3], many studies have found an increased risk of GVHD with multiparous donors [4] [5] [6] [7]. This increased risk has also been seen among syngeneic recipients [8]. In 2006, a large CIBMTR study was completed, in which it investigated both donor and recipients’ sex & parity in HLA identical sibling stem cell transplants. The study demonstrated an increased risk of cGVHD in all recipients from parous female donors, and that nulliparous female donors confer an increased risk of cGVHD in male donors. There was no significant increased risk for acute GVHD. Interestingly, the study did not find a significant relationship between recipient parity and incidence of GVHD [5]. It is thought that the association between parity and GVHD is related to alloimmunization and exposure to fetal antigens during pregnancy, and this is an evolving area of research [9]. SCT from a matched unrelated donor (URD) also is known to carry higher risks than from a matched sibling donor. Historically, matched sibling donors have been preferred for SCT over unrelated donors

15


for a lower risk of GVHD. Recently, a large study was completed with the CIBMTR investigating outcomes for sibling versus URD donors for AML, with the finding that there is a higher risk of early mortality and GVHD among unrelated donors, but overall survival was not significantly different [10]. To date, there is a known increased risk of GVHD from both multiparous donors and unrelated donors. However, there is no study directly comparing outcomes from using multiparous female sibling donors and unrelated male donors. We feel that this is an important study because if there is an elevated risk in multiparous sibling donors, this may shift a practice paradigm of donor selection towards using unrelated male donors over female sibling donors. If a patient has a matched sibling female donor, (s)he may ultimately opt for an unrelated male donor despite the risks associated with an unrelated donor to avoid the risks of GVHD due to multiparity and female sex. The goals of the study (as detailed below) will be to primarily assess incidence of acute GVHD, chronic GVHD, and overall survival. We hypothesize that multiparous female sibling donors will be associated with more GVHD than unrelated male donors. This study will further the understanding of factors involved in donor selection, and methods in selection to reduce the risks of GVHD associated with allogeneic SCT. Patient Eligibility Population: Patients will be eligible if they underwent a non-T cell depleted myeloablative allogeneic stem cell transplant from an HLA identical sibling or matched unrelated donor between January 1, 2000 and December 31, 2006 for acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). Patients will be at least 18 years old at time of transplant and both peripheral blood and bone marrow grafts will be included. Data Requirements: The data forms that will be required are:

Recipient Baseline Data Hematopoietic Stem Cell Transplant (HSCT) Infusion Hematopoietic Stem Cell Transplant (HSCT) Infusion Acute Lymphoblastic Leukemia Pre-HSCT Data Acute Myeloid Leukemia Pre-HSCT Data 100 Day Post-HSCT Data Acute Myelogenous Leukemia Post-HSCT Data Acute Lymphocytic Leukemia Post-HSCT Data Study R02-09 AML/ALL - Supplemental Form Six Months to Two Years Post-HSCT Data Yearly Follow-Up for Greater than Two Years Post-HSCT Data Pre-Transplant Essential Data Selective Post-Transplant Essential Data Recipient Death Data

The study will not require collection of supplemental data. The study will not combine data from another group. Sample Requirements: None

16


Study Design: The study will be a cohort study that examines incidence of acute and chronic GVHD & overall survival among patients who receive stem cell infusion from either 1) unrelated male donors or 2) female parous HLA-identical sibling. The study will also examine the exposure of sex in the recipient and its impact on these outcomes. Transplant related variables will be evaluated for possible confounding.

The following information will be obtained from Data Collection forms: -Donor: Age, sex, parity, race, CMV status, ABO type -Recipient: Age, sex, parity, race, CMV status, ABO type, disease type -Incidence and stage of acute GVHD, chronic GVHD, date of relapse, date of death The primary outcomes of the study will be incidence of acute and chronic GVHD, and overall survival. The secondary outcomes of the study will be relapse-free survival and transplant related mortality. To examine the impact of parity and sibling versus unrelated donor the following groups will be analyzed: -Donor: male unrelated donors, female parous sibling donors, female parous unrelated doors, and male sibling donors. It is hypothesized that female parous unrelated donors will confer the highest risk of GVHD and that male sibling donors will confer the lowest risk of GVHD among these groups, thereby allowing a comparison of female parous sibling donors to male sibling donors. -Recipient: males and females -Possible confounders/effect modifiers: 1) Donor & Recipient variables: age, race, sex, CMV status, transfusion history. 2) Disease related variables: Disease type and risk. 3) Transplant-related variables: sex-mismatched transplant, GVHD prophylaxis, conditioning, ABO compatibility, stem cell source, time from diagnosis to transplant.

Statistics: The variables listed above will be compared between donor and recipient groups (males, females, sibling, unrelated, multiparous females). Categorical variables will be compared using the chi-squared test. These include but will not necessarily be limited to disease type, GVHD prophylaxis, ABO incompatibility, source of stem cells, CMV status, transfusion history, and sex-mismatch). Continuous data that is not normally distributed will be analyzed with the Kruskal-Willis test. If a significant difference is found between two variables, post hoc testing will use pairwise comparisons. Overall survival will be measured with the Kaplan-Meier method. We will test for interaction effects between transplant variables.

17


References 1. Carlens, S., et al., Risk factors for chronic graft-versus-host disease after bone marrow

transplantation: a retrospective single centre analysis. Bone Marrow Transplant, 1998. 22(8): p. 755-61.

2. Randolph, S.S., et al., Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood, 2004. 103(1): p. 347-52.

3. Przepiorka, D., et al., Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation. Blood, 1999. 94(4): p. 1465-70.

4. Kollman, C., et al., Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood, 2001. 98(7): p. 2043-51.

5. Loren, A.W., et al., Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 2006. 12(7): p. 758-69.

6. Nash, R.A., et al., Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate. Blood, 1992. 80(7): p. 1838-45.

7. Remberger, M., et al., Risk factors for moderate-to-severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 2002. 8(12): p. 674-82.

8. Adams, K.M., et al., Risk factors for syngeneic graft-versus-host disease after adult hematopoietic cell transplantation. Blood, 2004. 104(6): p. 1894-7.

9. Lo, Y.M., et al., Two-way cell traffic between mother and fetus: biologic and clinical implications. Blood, 1996. 88(11): p. 4390-5.

10. Saber, W., et al., Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood, 2012. 119(17): p. 3908-16.

18


Characteristics of adult patients undergoing first allogeneic HCT for AML or ALL between 2000-2006 from an HLA-identical sibling or matched related donor with a non T-cell depleted bone

marrow or peripheral blood graft source

Characteristics of patients:

F parous HLA-id

donor M URD donorPatient-related Number of patients 533 1238Number of centers 127 115Age at transplant, median (range), years 45 (18 - 68) 43 (18 - 70)Age at transplant, years 18-19 9 ( 2) 39 ( 3) 20-29 55 (10) 270 (22) 30-39 115 (22) 222 (18) 40-49 181 (34) 332 (27) 50-59 148 (28) 294 (24) 60+ 25 ( 5) 81 ( 7)Gender Male 288 (54) 686 (55) Female 245 (46) 552 (45)Race Caucasian 402 (75) 1123 (91) African-American 17 ( 3) 13 ( 1) Other 92 (17) 76 ( 6) Unknown/Missing 22 ( 4) 26 ( 2)Karnofsky score prior to transplant <90% 178 (33) 382 (31) >=90% 341 (64) 744 (60) Missing 14 ( 3) 112 ( 9)Disease-related Disease AML 412 (77) 928 (75) ALL 121 (23) 310 (25)Disease Status at Transplant Early 289 (54) 542 (44) Intermediate 91 (17) 325 (26) Advanced 138 (26) 366 (30) Other/Unknown 15 ( 3) 5 (<1)

19


Continued.


F parous HLA-id

donor M URD donorDonor-related Donor age, median (range), years 44 (<1 - 82) 33 (18 - 61)Donor age, years 18-29 47 ( 9) 472 (38) 30-39 117 (22) 439 (35) 40-49 178 (33) 240 (19) 50-59 126 (24) 54 ( 4) 60+ 33 ( 6) 2 (<1) TBD (availability of data in progress) 32 ( 6) 31 ( 3)D-R sex match M-M 0 686 (55) M-F 0 552 (45) F-M 288 (54) 0 F-F 245 (46) 0Number of donor pregnancies Male donor 0 1238 1 pregnancy 92 (17) 0 2 pregnancies 164 (31) 0 3 pregnancies 101 (19) 0 >=4 pregnancies 101 (19) 0 Unknown 21 ( 4) 0 Missing 54 (10) 0D-R race match Caucasian - Caucasian 111 (21) 764 (62) African-American - African-American 6 ( 1) 7 (<1) Other - Other 29 ( 5) 22 ( 2) Caucasian donor 2 (<1) 43 ( 3) African-American donor 0 3 (<1) Other donor 1 (<1) 25 ( 2) TBD (availability of data in progress) 384 (72) 374 (30)D-R CMV status +/+ 245 (46) 205 (17) +/- 77 (14) 95 ( 8) -/+ 96 (18) 455 (37) -/- 96 (18) 386 (31) TBD (availability of data in progress) 19 ( 4) 97 ( 8)

20


Continued.


F parous HLA-id

donor M URD donor

D-R ABO match ABO Matched 345 (65) 565 (46)

ABO Minor mismatch 78 (15) 299 (24) ABO Major mismatch 81 (15) 281 (23)

ABO Bidirectional mismatch 23 ( 4) 87 ( 7) ABO Undetermined 6 (1 ) 6 (<1)

Transplant-related Graft type

Bone Marrow 90 (17) 411 (33) Peripheral Blood 443 (83) 827 (67)

ATG/Campath used in regimen or GVHD prophylaxis ATG + Campath 0 1 (<1)

ATG only 1 (<1) 0 Campath only 4 (<1) 14 (1 )

Neither ATG nor Campath 1 (<1) 0 TBD 527 (99) 1223 (99)

Conditioning Regimen CY + BU alone 227 (43) 541 (44)

CY + TBI alone 25 ( 5) 73 ( 6) CY + TBI +/- others 11 ( 2) 14 ( 1)

CY +/- others (not TBI) 199 (37) 376 (30) BU +/- others (not CY) 65 (12) 222 (18)

TBI +/- others (not CY, BU, FLU) 4 (<1) 12 (<1) Other 2 (<1) 0

GVHD Prophylaxis Cyclophosphamide + others 2 (<1) 8 (<1)

FK506 + MTX alone 136 (26) 560 (45) FK506 + MTX +- others 17 ( 3) 170 (14)

FK506 + MMF +- others (not MTX) 35 ( 7) 112 ( 9) FK506 + others (except MTX, MMF) 31 ( 6) 71 ( 6)

CsA + MTX +-others (not FK506) 251 (47) 275 (22) CsA + MMF +-others (not FK506,MTX) 5 (<1) 10 (<1)

CsA +-others (not FK506,MTX,MMF) 32 ( 6) 23 ( 2) Other GVHD prophylaxis 10 ( 2) 6 (<1)

Missing 14 ( 3) 3 (<1)

21


Continued.

Abbreviations: AML=Acute Myeloid Leukemia, ALL=Acute Lymphoblastic Leukemia, MDS=Myelodysplastic Syndromes, CMV=Cytomegalovirus, HLA=Human Leukocyte Antigen, URD=Unrelated, CY=Cyclophosphamide, BU=Busulfan, TBI=Total Body Irradiation, FLU=Fludarabine, LPAM=Melphalan, ARAC=Cytarabine, FK506=Tacrolimus, MMF=Mycophenolate mofetil, MTX=Methotrexate, CSA=Cyclosporine, *Disease status is categorized as follows: Early = AML/ALL (CR1); MDS (RA/RARS/pre-HCT marrow blasts <5%) Intermediate = AML/ALL (>=CR2) Advanced = AML/ALL (REL/PIF); MDS (RAEB/RAEB-t/CMML or marrow blasts >=5%)

Characteristics of patients

F parous HLA-id

donor M URD

donorYear of transplant 2000 46 ( 9) 71 ( 6)

2001 49 ( 9) 63 ( 5) 2002 50 ( 9) 62 ( 5)

2003 33 ( 6) 69 ( 6) 2004 44 ( 8) 120 (10)

2005 64 (12) 172 (14) 2006 50 ( 9) 192 (16)

2007 36 ( 7) 204 (16) 2008 50 ( 9) 91 ( 7)

2009 57 (11) 108 ( 9) 2010 54 (10) 86 ( 7)

Post-transplant-related Acute GVHD Grade

No aGVHD 248 (47) 432 (35) I 51 (10) 110 ( 9)

II 140 (26) 367 (30) III 66 (12) 238 (19)

IV 22 ( 4) 88 ( 7) Missing 6 ( 1) 3 (<1)

Chronic GVHD Grade No cGVHD 263 (49) 578 (47)

Limited 71 (13) 146 (12) Extensive 194 (36) 502 (41)

Missing 5 (<1) 12 (<1)

22


Donor group distribution

Donor Frequency Percent

Cumulative

Frequency

Cumulative

Percent

F parous HLA-id donor 541 11.20 541 11.20

F parous URD donor 245 5.07 786 16.27

F non-parous HLA-id donor 659 13.64 1445 29.92

F non-parous URD donor 367 7.60 1812 37.52

M HLA-id donor 1473 30.50 3285 68.01

M URD donor 1239 25.65 4524 93.66

TBD 306 6.34 4830 100.00

Selection Criteria Exclusion N First allogeneic HCT for ALL or AML between 2000-2010

17604

At least 18 years old 4270 13334 BM or PBSC graft source 1020 12314 HLA-id sibling or Matched unrelated donor 4281 8033 Myeloablative conditioning regimen intensity 3020 5013 Non T-cell depleted grafts 183 4830

23

A G E N D A CIBMTR WORKING COMMITTEE FOR … · Dr. Alvaro Urbano-Ispizua reviewed the four studies...

Documents

Transcript of A G E N D A CIBMTR WORKING COMMITTEE FOR … · Dr. Alvaro Urbano-Ispizua reviewed the four studies...