a g e n d a cibmtr working committee for ......2018/02/23 · loren aw. graft versus host disease...

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A G E N D A CIBMTR WORKING COMMITTEE FOR GRAFT-VERSUS-HOST DISEASE Salt Lake City, UT Friday, February 23, 2018, 12:15 – 2:15 pm

Co-Chair: Daniel Couriel, MD, University of Utah, Salt Lake City, UT; Telephone: 801-585-7121; E-mail: [email protected]

Co-Chair: Amin Alousi, MD, MD Anderson Cancer Center, Houston, TX; Telephone: 713-745-8613; E-mail: [email protected]

Co-Chair: Joseph Pidala, MD, PhD, H. Lee Moffitt Cancer Center and Research Institute; Telephone: 813-745-2556; E-mail: [email protected]

Scientific Director: Mukta Arora, MD, MS, University of Minnesota Medical Center, Minneapolis, MN; Telephone: 612-626-4105; E-mail: [email protected]

Scientific Director: Stephen Spellman, MBS, CIBMTR Statistical Center, Minneapolis, MN; Telephone: 763-406-8334; E-mail: [email protected]

Statistical Director: Tao Wang, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-4339; E-mail: [email protected]

Statistical Director: Ying Liu, PhD, CIBMTR, Medical College of Wisconsin, Milwaukee, WI; Telephone: 414-955-8280, E-mail: [email protected]

Statistician: Michael Hemmer, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-4638; E-mail: [email protected]

1. Introduction

a. Minutes and Overview Plan from February 2017 meeting (Attachment 1)

b. Introduction of new incoming Co-Chair:Madan Jagasia, MBBS, MSVanderbilt University Medical CenterTelephone: (615) 936-8422E-mail: [email protected]

Thank you to Daniel Couriel for all of his contributions and input to the GVWC.

2. Accrual Summary (Attachment 2)

3. Presentations, published or submitted papers

a. GV14-02 Qayed M, Arora M, Wang T, Spellman SR, Hemmer MT, Pidala J, Couriel DR, Alousi AM, HoranJ. Influence of age on acute and chronic GVHD in children undergoing HLA-identical sibling BMT for acute leukemia: Implications for prophylaxis. Biology Blood Marrow Transplant. 2017 Nov; [Epub ahead of print].

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b. GV13-01 Kumar AJ, Soyoung K, Hemmer MT, Arora M, Spellman SR, Pidala J, Couriel DR, Alousi AM,Loren AW. Graft versus host disease in recipients of male unrelated donor compared to parous femalesibling donor transplants. Submitted.

c. GV15-01a Turcotte L, Wang T, Hemmer MT, Spellman SR, Arora M, Couriel DR, Alousi AM, Pidala J,Knight JM, Verneris M. Donor body mass index does not predict graft-versus-host-disease followinghematopoietic cell transplantation. Submitted.

d. GV15-02 Alousi AM, Wang T, Hemmer MT, Spellman SR, Arora M, Couriel DR, Pidala J, Weisdorf D.Peripheral blood versus bone marrow from unrelated donors: Bone marrow allografts have improvedlong-term overall and graft-versus-host disease, relapse-free survival. Submitted.

e. GV16-01 Mehta R, Holtan S, Wang T, Hemmer MT, Arora M, Spellman SR, Alousi AM, Couriel DR, PidalaJ, Weisdorf D. Graft-versus-host disease-free relapse-free survival and chronic GVHD in alternativedonor hematopoietic cell transplantation in adults and pediatric patients. Oral and posterpresentation at ASH meeting in Atlanta, GA, December 2017.

4. Future/proposed studiesa. PROP 1710-24 Predictive value of pre-transplant gene expression profile in unrelated stem cell donor

on recipient risk and severity of post-transplant GVHD (S Lachance/A Brasey) (Attachment 3)b. PROP 1711-122 Impact of GVHD prophylaxis on outcome of single UCB transplantation in patients with

non-malignant disorders (M Ayas) (Attachment 4)c. PROP 1711-04 Risk stratification by time to onset of acute GVHD. (H Choe/ S Lee) (Attachment 5)d. PROP 1711-163 Comparison of antibacterial prophylaxis strategies and outcomes in alloHCT patients

with acute GVHD (W Wallis/ A Alousi/ A Gulbis) (Attachment 6)e. PROP 1710-10 Evaluating different ATG dosing of anti-thymocyte globulin in conditioning regimens for

matched related and unrelated donor transplants (L Metheny/ M de Lima) (Attachment 7)f. PROP 1709-04 Impact of chronic GVHD on non-relapse mortality and disease relapse (V Bhatt/S Lee)

(Attachment 8)

g. PROP 1711-162 Comparison of late effects among alloHCT survivors with and without cGVHD (C Lee/D

Couriel) (Attachment 9)

Dropped proposed studiesh. PROP 1710-01 Comparison of GVHD-free, relapse-free survival of haploidentical transplants using

post-transplant Cyclophosphamide versus HLA-matched donor transplants in patients with hematologic malignancies. Overlapped with current study GV17-03.

i. PROP 1711-89 Impact of pre-allogeneic HCT checkpoint inhibition on development of GVHD. Small sample size, due to recent FDA approval of checkpoint inhibition.

j. PROP 1711-108 Outcomes of haploidentical alloHCT with post-transplant Cy versus single-locus HLA-mismatched related alloHCT without post-transplant Cy. Small sample size of single-locus HLA-mismatched related donors.

k. PROP 1711-159 Impact of donor source on 5-year GRFS in pediatric patients with high-risk hematological malignancies (K Page/ J Kurtzberg). Lack of 5-year follow-up and small sample size of haploidentical pediatric patients. Overlap with GV16-01.

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5. Studies in progress (Attachment 10)a. GV14-01 Comparison of mycophenolate versus methotrexate in combination with a calcineurin

inhibitor for GVHD prophylaxis in allogeneic HCT (B Hamilton/ S Chhabra/ N Majhail/ L Costa/ R Stuart/D Kim/ O Ringden) Manuscript Preparation

b. GV 15-01b Pro-inflammatory cytokine and adipokine levels in adult unrelated marrow donors are not associated with HCT outcomes (L Turcotte/ M Verneris/ J Knight) Manuscript Preparation

c. GV16-02 The impact of the graft T cell dose on the outcome of allogeneic HLA-matched peripheral blood stem cell transplantation (A Saad/ S Hashmi/ M Sharma/ L Lamb) Manuscript Preparation

d. GV17-01 Investigating antibiotic exposure and risk of acute GVHD in children undergoing HCT for acute leukemia (C Elgarten/ B Fisher/ R Aplenc) Protocol Development

e. GV17-02 Risk factors of GVHD in T-replete haploidentical HCT using post-transplant Cy (A Im/ B Hamilton/ A Rashidi/ N Majhail/ S Pavletic/ D Weisdorf) Data File Preparation

f. GV17-03 Alterations in the characteristics and outcomes of GVHD following post-transplant Cy for haploidentical HCT and in patients over 60 at high risk for GVHD (R Saliba/ S Ciurea/ J Schriber) Data File Preparation

6. Other Business

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MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR GRAFT-VERSUS-HOST DISEASE Orlando, FL Friday, February 24, 2017, 12:15 – 2:15 pm

Co-Chair: Daniel Couriel, MD, University of Utah, Salt Lake City, UT; Telephone: 801-585-7121; E-mail: [email protected]

Co-Chair: Amin Alousi, MD, MD Anderson Cancer Center, Houston, TX; Telephone: 713-745-8613; E-mail: [email protected]

Co-Chair: Joseph Pidala, MD, PhD, H. Lee Moffitt Cancer Center and Research Institute; Telephone : 813-745-2556 ; E-mail : [email protected]

Scientific Director: Mukta Arora, MD, MS, University of Minnesota Medical Center, Minneapolis, MN; Telephone: 612-626-4105; E-mail: [email protected]

Scientific Director: Stephen Spellman, MBS, CIBMTR Statistical Center, Minneapolis, MN; Telephone: 763-406-8334; E-mail: [email protected]

Statistical Director: Tao Wang, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-4339; E-mail: [email protected]

Statistical Director: Ying Liu, PhD, CIBMTR, Medical College of Wisconsin, Milwaukee, WI; Telephone: 414-955-8280, E-mail: [email protected]

Statistician: Michael Hemmer, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-4638; E-mail: [email protected]

1. IntroductionMinutes and Overview Plan from February 2016 meeting (Attachment 1)Dr. Amin Alousi began meeting at 12:15pm by introducing the GVWC leadership and reviewing the goals,expectations and limitations of the GVWC.

2. Accrual summary (Attachment 2)Dr. Alousi referenced that the Accrual Summary tables could be found online.

3. Presentations, published or submitted papersa. GV11-02 Chen Y, Wang T, Hemmer MT, Couriel DR, Alousi AM, Pidala J, Urbano-Ispizua A, Choi SW,

Nishihori T, Teshima T, Inamoto Y, Wirk B, Marks D, Abdel-Azim H, Lehmann L, Yu L, Bitan M, Cairo MS,Qayed M, Salit R, Gale PR, Martino R, Jaglowski S, Bajel A, Savani B, Frangoul H, Lewis I, Storek J, AskarM, Kharfan-Dabaja MA, Aljurf M, Ringden O, Reshef R, Olsson R, Hashmi SK, MacMillan M, Lazaryan A,Spellman SR, Arora M, Cutler CS. Acute and chronic GVHD after umbilical cord blood transplantationfor acute leukemia: An analysis of risk factors and effect on outcomes. Bone Marrow Transplant. 2016Dec; [Epub ahead of print].

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b. GV13-02 Krakow E, Hemmer MT, Wang T, Logan BR, Arora M, Spellman SR, Last M, Lachance S, Moodie E. Tools for the Precision Medicine Era, How to Develop Highly personalized treatment recommendations from cohort and registry data using Q-learning. Accepted by American Journal of Epidemiology.

c. GV12-01 Khoury HJ, Wang T, Hemmer MT, Couriel DR, Alousi AM, Cutler CS, Aljurf M, Antin JH, Ayas M, Battiwalla M, Jean-Yves C, Cairo M, Chen Y, Gale RP, Hashmi S, Hayashi RJ, Jagasia M, Juckett M, Kamble RT, Kharfan-Dabaja M, Litzow M, Majhail N, Miller A, Nishihori T, Qayed M, Schoemans H, Schouten HC, Carabasi GM, Dandoy C, Gergie U, Hematti P, Solh M, Jamani K, Lehmann L, Savani B, Schultz KR, Wirk BM, Spellman SR, Arora M, Pidala J. Outcomes of grades II-IV acute graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation: How much progress was achieved? Accepted by Haematologica.

d. GV12-02 Nikiforow S, Wang T, Hemmer MT, Spellman SR, Akpek G, Choi SW, Inamoto Y, Khoury HJ, MacMillan M, Marks D, Meehan K, Nakasone H, Nishihori T, Olsson R, Paczesny S, Przepiorka D, Reddy V, Reshef R, Schoemans H, Waller N, Weisdorf D, Wirk BM, Horowitz MH, Alousi AM, Couriel DR, Pidala J, Arora M, Cutler CS. Upper gastrointestinal acute graft-versus-host disease adds minimal prognostic value when present in isolation or with other GVHD manifestations. Submitted

e. GV13-01 Kumar AJ, Soyoung K, Hemmer MT, Arora M, Spellman SR, Pidala J, Couriel DR, Alousi AM, Loren AW. Unrelated male donors versus sibling parous female donors: Impact on transplant-related outcomes. Presentation at ASH meeting in San Diego, CA, December 2016.

f. GV14-02 Qayed M, Arora M, Wang T, Spellman SR, Hemmer MT, Pidala J, Couriel DR, Alousi AM, Horan J. Influence of age on acute and chronic GVHD in children receiving HLA-identical sibling BMT. Presentation at ASH meeting in San Diego, CA, December 2016. Dr. Alousi also highlighted the 6 studies that have been presented, published or submitted for publication during the 2016 calendar year.

4. Future/proposed studies Dr. Joseph Pidala introduced the proposal section of the meeting with some explanation on how the Voting Sheet works and a reminder to the presenters that they will each have 5 minutes to present and then allow for 5 minutes of questions and discussion.

a. PROP 1611-04 Risk stratification by time to onset of acute GVHD. (H Choe/ S Lee) (Attachment 3) Dr. Hannah Choe presented the proposal. Dr. Choe stated that the timing of aGVHD onset relative to neutrophil engraftment has not been examined yet utilizing the CIBMTR database. The hypothesis of the study is that early onset of aGVHD will indicate a higher risk of other outcomes, namely OS, NRM and cGVHD, and the analysis will aim to identify risk factors associated with the development of each time to onset category. A question from the GVWC was asking why the study population was restricted to patients developing aGVHD within 100 days post-transplant. Dr. Choe suspected that aGVHD reported beyond 100 days post-transplant are not as reliable instances of aGVHD as those reported within 100 days, but would be open to considering them in the population if they’re thoroughly reviewed. Another question asked if the proposal would evaluate sample typing and the GVWC leadership answered that sample typing data would only be available in a subset of the population. A concern was expressed that very early aGVHD could be an incorrect diagnosis.

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b. PROP 1611-05 Analysis of the risk factors for hepatic acute GVHD after allogeneic stem cell transplantation (Y Arai) (Attachment 4) Dr. Yasuyuki Arai presented the proposal. Dr. Arai stated the exact incidence and impact of risk factors of hepatic aGVHD are still unknown and that the number of hepatic aGVHD patients found in the CIBMTR database would make the proposal statistically viable. This proposal could provide early therapeutic and diagnostic interventions in high-risk patients and the findings from this study could provide baseline data for future investigations. A member of the GVWC noted that a prior publication showed that incidence of hepatic aGVHD has been decreasing in recent years. Another member of the GVWC asked why pediatric patients were excluded from the population and encouraged including them in the population. Dr. Arai clarified that hepatic aGVHD will include patients who experienced liver-based and/or other organ involvement in aGVHD. The CIBMTR does not collect timing of each organ involved in aGVHD, so the proposal cannot analyze timing of liver involvement relative to other organs. Another comment was to consider creating a score of some kind that can provide more weight for patients who have multiple aGVHD organs involved.

c. PROP 1611-108 The cumulative incidence and risk factors for renal GVHD after allogeneic hematopoietic cell transplantation (A Alousi/ A Abudayyeh/ R Saliba) (Attachment 5) Dr. Amin Alousi presented the proposal. Dr. Alousi emphasized that renal cGVHD is a very rare event, and the largest case study published had 12 patients included. The CIBMTR database allows the opportunity to investigate far more renal cGVHD cases than has been examined before. The hypothesis of the proposal is that renal cGVHD is associated with increased mortality and has discrete risk factors when compared to other manifestations of cGVHD. The GVWC leadership clarified a comment that while there is no variable on the CIBMTR follow-up forms asking for kidney involvement in cGVHD, there was a variable for other organ involvement and the renal cGVHD cohort had indicated renal or kidney involvement in the other, specify field on the forms. Dr. Alousi agreed with a comment from the GVWC that renal involvement is underreported and answered that the CIBMTR forms do collect whether biopsies were obtained for the other organs (on which renal or kidney involvement was specified). A question was whether the CIBMTR collects treatment response, which the forms do not collect. A member of the GVWC expressed concern over the small number of patients (n=37) who indicated renal cGVHD and had biopsies available.

d. PROP 1611-109 Impact of baseline renal sufficiency on the rate of acute GVHD following allogeneic HCT and a determination of risk factors on and the impact for decline in glomerular filtration rate post-HCT (A Alousi/ A Abudayyeh/ R Saliba) (Attachment 6) Dr. Amin Alousi presented the proposal. Dr. Alousi cited several publications that show conflicting findings of baseline renal insufficiency and its impact on NRM. The goal of this proposal is to determine if there is a threshold of glomerular filtration rate (GFR) for increased risk for aGVHD and NRM. A comment from the GVWC was that GFR decreases with age and that adding pediatric patients would add more interest to examining this variable. It was further suggested to consider adding a maximum age cut-off to the population. When a member of the GVWC expressed concern for how to account for decreased kidney function with increasing age, and how to handle confounding variables (especially conditioning intensity), Dr. Alousi responded that those concerns will be accounted for in the statistical analysis. Another comment was to consider different cut-off points for the GFR distribution, to which Dr. Alousi agreed that would be under consideration. Another comment was to examine conditioning regimen drugs and doses thoroughly to see if certain combinations arise with connections to GFR or study’s outcomes.

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e. PROP 1611-113 Investigating antibiotic exposure and risk of acute GVHD in children undergoing hematopoietic stem cell transplantation for acute leukemia (C Elgarten/ B Fisher/ R Aplenc) (Attachment 7) Dr. Caitlin Elgarten presented the proposal. The aims of the proposal are to determine the association of antibiotics commonly administered for neutropenic fever and the differential impact of antibiotic exposures before transplant with subsequent development of aGVHD among pediatric patients undergoing transplant for acute leukemia. The hypothesis is that exposure to antibiotics with activity against anaerobic commensal microorganisms in the peri-transplant period is associated with an increased risk of aGVHD. In order to obtain the detailed data required for this proposal, Dr. Elgarten proposes merging the patients fitting the population from CIBMTR registry with the Pediatric Health Information System (PHIS) database. Dr. Elgarten said this would be the first pediatric study to assess differential impact of broad spectrum antibiotics on GVHD. A question was asked whether the CIBMTR forms can discern as to what purpose antibiotics were administered (whether for prophylaxis or treatment for active infection). While the CIBMTR forms do not collect the purpose for which the treatment was given, the investigators may be able to make assumptions based on the timing of the administration of the treatment. A question was asked whether infection data was collected by the CIBMTR, which it is, but the study will rely on the FISK database for those data. A member of the GVWC warned that there will likely be patients who have constantly escalating antibiotics and the exposure will be difficult to quantify. Another concern expressed was whether the proposal would be able to account for patients who were started on antibiotics for a different factor than infection, say GVHD, and Dr. Elgarten answered that yes, she will be able to account for those different instances of use of antibiotic use.

f. PROP 1608-01 Evaluate the relationship between clostridium difficile colitis and subsequent gastrointestinal graft versus host disease in recipients of allogeneic stem cell transplantation (D Bhutani/ A Deol) (Attachment 8) Dr. Divaya Bhutani presented the proposal. The hypothesis of the proposal is that development of clostridium difficile infection (CDI) post-transplant increases the risk of subsequent development of gastrointestinal (GI) aGVHD. The incidence and major risk factors of CDI were covered by Dr. Bhutani. There are reports, including an analysis of 300 patients that Dr. Bhutani worked on, that demonstrated that patients who developed CDI had a statistically significantly higher chance of developing subsequent GI aGVHD. Dr. Bhutani is proposing to perform a similar analysis to compare the incidence of GI aGVHD in patients with a preceding history of CDI versus those with no CDI history in a much larger population, which the CIBMTR can provide. A concern was expressed by the GVWC that different centers may have reported CDI differently based on different thresholds. Dr. Bhutani clarified that the time frame of this proposal predates the PCR test, which should result in more consistent reporting across centers. A GVWC member recommended to exclude patients with viruses that cause diarrhea, to create a more focused group on which to focus the analysis. Dr. Pidala informed the GVWC that the remaining two proposals are each the results of separate proposals of similar topics that were merged together, at the request of the GVWC leadership. All of the proponents were very respectful and collaborated successfully.

g. PROP 1610-08/1611-24 Risk factors for GVHD and outcomes in T-replete HLA-haploidentical HCT using post-transplant cyclophosphamide (A Im/ B Hamilton/ A Rashidi/ S Pavletic/ N Majhail/ D Weisdorf) (Attachment 9) Dr. Annie Im presented the proposal, stating that she was a part of a team that presented this topic last year, but did not proceed due to small sample sizes that have since increased in the CIBMTR research database. Dr. Im stated that while studies in haploidentical transplantation (haploHCT) have become more common, there has yet to be a large analysis comparing myeloablative (MA) versus

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reduced intensity or non-myeloablative (RIC/NMA) conditioning intensity on aGVHD incidence following haploHCT with post-transplant cyclophosphamide (PTCy). This proposal will describe the incidence and identify risk factors for aGVHD and cGVHD after haploHCT using PTCy, separately for MA and RIC/NMA as well as BM and PB graft sources. The hypothesis is that there will be a low incidence of both aGVHD and cGVHD following haploHCT using PTCy, with MA and RIC/NMA having similar incidences of aGVHD while PB grafts may experience a higher incidence of cGVHD compared to BM grafts. Clarifications were made that donor characteristics, TBI use and GVHD prophylaxis will be included in the analysis. There was a concern expressed that even though the numbers have increased since last year, that there might be too few events of severe aGVHD (Grade III-IV) but it’s expected that the RIC/NMA cohort (n=330 patients) would have sufficient numbers to evaluate aGVHD Grade II-IV.

h. PROP 1611-15/1611-131 Characteristics and outcomes of acute and chronic GVHD after haploidentical related donor allogeneic stem cell transplantation (R Saliba/ S Ciurea/ J Schriber) (Attachment 10) Dr. Rima Saliba presented the proposal. The goal of the proposed study is to compare GVHD outcomes between patients receiving post-transplant Cyclophosphamide (PTCy)-based GVHD prophylaxis versus those receiving standard (Tacrolimus/Cyclosporine + MTX) GVHD prophylaxis. The hypothesis brought forward by Dr. Saliba is that PTCy-based GVHD prophylaxis is associated with lower incidence of severe aGVHD, severe cGVHD, and mortality among patients with GVHD, when compared to standard GVHD prophylaxis. Furthermore, Dr. Saliba speculates that this difference in mortality is more pronounced in patients 60 years or older at time of transplant. It was further clarified that the analysis will compare haploidentical donors receiving PTCy-based GVHD prophylaxis versus matched unrelated donors who received standard calcineurin inhibitor-based GVHD prophylaxis. A GVWC member asked if the proposal will investigate HLA data for the haploidentical donors, but Steve Spellman expressed concern about the clarity of the HLA data on those patients. It was also further clarified that the analysis will perform a subset analysis to specifically examine the effect of donor type and GVHD prophylaxis among patients 60 years or older at transplant.

Dropped proposed studies Dr. Mukta Arora introduced the proposals that were submitted to the GVWC but were determined by the GVWC leadership that they were not feasible for the specified reasons.

i. PROP 1611-28 Outcomes of acute and chronic GVHD treated with mesenchymal stromal cells. Small sample size and insufficient data on response to GVHD treatment.

j. PROP 1611-35 Impact of stem cell source on GVHD outcome. Insufficient data on response to GVHD treatment.

k. PROP 1611-45 Impact of the use of ATG as prophylaxis of acute and chronic GVHD in patients undergoing allogeneic hematopoietic cell transplant. Insufficient data on ATG dose collected for GVHD prophylaxis.

l. PROP 1611-76 Combination of etanercept and photopheresis as treatment for steroid refractory GVHD of the lower GI tract following allogeneic hematopoietic stem cell transplantation. Small sample size and insufficient data on timing of GVHD treatment.

m. PROP 1611-78 Comparison of calcineurin inhibitors with post-transplant cyclophosphamide alone as GVHD prophylaxis in patients undergoing allogeneic hematopoietic cell transplant. Small sample size.

n. PROP 1611-123 Incidence and risk factors for severe aGVHD in the perfect HLA match setting. Overlapped with current study GV12-01.

o. PROP 1611-128 Risk of chronic GVHD with use of Rituximab-based regimen. Overlap with current study in the Lymphoma Working Committee LY16-05.

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p. PROP 1611-129 Amphiregulin, the amphiregulin/epidermal growth factor ratio, and clinical outcomes after classic acute GVHD: A biomarker study of BMT CTN 0302 and 0802. Dropped with referral to BMT CTN.

q. PROP 1611-156 Incidence of chronic GVHD in myelofibrosis after prior Ruxolitinib therapy. Small sample size, due to pre-transplant Ruxolitinib not being reliably captured until 2013.

5. Studies in progress (Attachment 11) Dr. Dan Couriel introduced our studies in progress by reviewing a slide summarizing the activity accomplished by the GVWC so far in the current academic year and what remained to be accomplished before July 2017.

a. GV15-02 Peripheral blood versus bone marrow from unrelated donors: Bone marrow grafts are best for survival and graft-versus-host disease, relapse-free survival (AM Alousi) Manuscript Preparation

b. GV 13-01 Unrelated male donors versus parous sibling female donors: Impact on transplant-related outcomes (AJ Kumar/ A Loren) Manuscript Preparation

c. GV14-02 Influence of age on acute and chronic GVHD in children receiving HLA-identical sibling BMT for acute leukemia: Implications for prophylaxis (M Qayed/ J Horan) Manuscript Preparation

d. GV15-01 Impact of donor obesity and inflammation on acute and chronic GVHD among HCT recipients (L Turcotte/ M Verneris/ J Knight) Manuscript Preparation

e. GV14-01 Comparison of mycophenolate versus methotrexate in combination with a calcineurin inhibitor for GVHD prophylaxis in allogeneic HCT (B Hamilton/ S Chhabra/ N Majhail/ L Costa/ R Stuart/ D Kim/ O Ringden) Analysis

f. GV16-01 GVHD-free relapse-free survival in alternative donor hematopoietic cell transplantation (Mehta R/ Holtan S/ Weisdorf D) Data File Preparation

g. GV16-02 The impact of the graft T cell dose on the outcome of allogeneic HLA-matched peripheral blood stem cell transplantation (Saad A/ Hashmi S/ Sharma M/ Lamb L) Data File Preparation

6. Other Business Repository summary Steve Spellman presented a summary slideshow on the repository, and encouraged GVWC members to utilize these data if they believe it will enhance their proposals or studies. Hearing no other calls for business to discuss, Steve Spellman ended the meeting at 2:15pm.

Working Committee Overview Plan for 2017 - 2018

a.

GV14-01 Comparison of MMF vs. MTX in combination with a CNI for GVHD prophylaxis in allogeneic HCT (B Hamilton / S Chhabra / N Majhail / L Costa / R Stuart / D Kim / O Ringden) This study will compare the incidence of grade 2-4 aGVHD between patients receiving a GVHD prophylaxis regimen of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) with mycophenolate mofetil (MMF) versus methotrexate (MTX). Incidence of grade 3-4 aGVHD, cGVHD and rates of relapse, TRM, DFS, OS and hematopoietic recovery will also be evaluated. We anticipate revising the initial draft of the manuscript by August 2017. We also anticipate submitting an abstract for ASH. After circulating to the Writing Committee for feedback, we expect to submit the final manuscript by November 2017. 70 statistical hours have been allocated to accomplish these goals.

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b. GV15-01 Impact of donor obesity and inflammatory cytokine levels on GVHD (L Turcotte / M Verneris / J Knight) This study aims to evaluate the impact of donor inflammatory status as a function of donor serum inflammatory cytokine concentration on the development of GVHD in patients undergoing allogeneic HCT for AML, ALL, CML, MDS from an 8/8-matched unrelated donor. We anticipate the samples and data file to be prepared for analysis by July 2017 and the analysis to be completed by September 2017. We further anticipate submitting an abstract for Tandem by October 2017 and receiving the initial draft of the manuscript by November 2017. The initial draft will be revised by December 2017 and circulated to the Writing Committee by January 2018. We finally expect to submit the final manuscript for publication by March 2018. 70 statistical hours have been allocated to accomplish these goals.

c. GV16-01 GRFS in alternative donor HCT (R Mehta/ S Holtan/ D Weisdorf) This study will compare GRFS at 1- and 2-years post-transplant among patients with hematological malignancies who underwent HCT in one of the following “alternative donor” categories – (a) UCB transplant (b) haploidentical donor (c) PB related/unrelated donor with 1-antigen HLA mismatch and (d) BM related/unrelated donor with 1-antigen HLA mismatch. The study will further describe the distribution of contributing events of GRFS at 1- and 2-years post-transplant. The study will also analyze OS and DFS at 1- and 2-years post-transplant. We anticipate that the data file will be prepared for analysis by July 2017. We further anticipate that the analysis will be completed by August 2017, so that an ASH abstract can be submitted. We further anticipate an initial draft of the manuscript will be received by September 2017 and a final manuscript submitted for publication by January 2018. 150 statistical hours have been allocated to accomplish these goals.

d. GV16-02 The impact of the graft T cell dose on the outcome of allogeneic HLA-matched peripheral blood stem cell transplantation (A Saad/ S Hashmi/ M Sharma/ L Lamb) This study will test the hypothesis that the graft dose of CD3+, CD4+ and CD8+ T cells, and the CD4+/CD8+ ratio, will correlate with the incidence and grade of aGVHD and cGVHD after allogeneic PBSC transplantation. The study will also test the correlation of those graft doses with OS and DFS among allogeneic PBSC transplants. We anticipate that the protocol will be finalized by July 2017. We further anticipate preparing the data file by January 2018 and have preliminary results from analysis by February 2018. 100 statistical hours have been allocated to accomplish these goals.

e. GV17-01 Investigating antibiotic exposure and risk of acute GVHD in children undergoing HCT for acute leukemia (C Elgarten / B Fisher / R Aplenc) The aims of the study are to determine the association of antibiotics commonly administered for neutropenic fever with subsequent development of post-HCT aGVHD among pediatric patients undergoing HCT for acute leukemia. The hypothesis is that these patients who are exposed to antibiotics with activity against anaerobic commensal microorganisms are associated with an increased risk of aGVHD. We anticipate receiving the draft protocol by August 2017. We then expect to develop and finalize the protocol by November 2017. We further anticipate preparing the data file for analysis by February 2018. 100 statistical hours have been allocated to accomplish these goals.

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f. GV17-02 Risk factors for GVHD and outcomes in T-replete HLA-haploidentical HCT using post-transplant Cyclophosphamide (A Im / B Hamilton / A Rashidi / S Pavletic / N Majhail / D Weisdorf) The aims of the study are to describe the incidence, characteristics and risk factors for acute and chronic GVHD in patients undergoing post-transplant Cyclophosphamide-based T-replete haploidentical HCT, specifically evaluating the impact of conditioning regimen intensity and graft source on GVHD. Secondary aims are to evaluate the incidence of other outcomes, including OS, relapse, TRM, GRFS, hematopoietic recovery and CMV viremia. We anticipate receiving the draft protocol by August 2017. We then expect to develop and finalize the protocol by December 2017. We further anticipate preparing the data file for analysis by March 2018. 160 statistical hours have been allocated to accomplish these goals.

g. GV17-03 Characteristics and outcomes of acute and chronic GVHD after haploidentical related donor allogeneic HCT (R Saliba / S Ciurea / J Schriber) The aims of the study are to compare aGVHD, cGVHD, OS and TRM between patients receiving post-transplant Cyclophosphamide-based GVHD prophylaxis with those receiving standard GVHD prophylaxis. Patients over the age of 60, and therefore at greater risk for GVHD, will also be specifically examined in a subset analysis. We anticipate receiving the draft protocol by August 2017. We then expect to develop and finalize the protocol by January 2018. 60 statistical hours have been allocated to accomplish these goals.

The top three proposals were selected based on priority scores provided by committee attendees, and post-meeting deliberation by the GVWC Chairs with attention to the proposals’ novelty, design, impact, and feasibility.

Joseph Pidala GV16-02: The impact of the graft T cell dose on the outcome of allogeneic HLA-matched peripheral blood stem cell transplantation GV17-01: Investigating antibiotic exposure and risk of acute GVHD in children undergoing HCT for acute leukemia GV17-02: Risk factors for GVHD and outcomes in T-replete HLA-haploidentical HCT using post-transplant Cyclophosphamide

Daniel Couriel GV17-03: Characteristics and outcomes of acute and chronic GVHD

after haploidentical related donor allogeneic HCT

Amin Alousi GV14-01 Comparison of MMF vs. MTX in combination with a CNI for GVHD prophylaxis in allogeneic HCT GV16-01: GRFS in alternative donor HCT

Oversight Assignment for Working Committee Leadership (March 2017)

11


Accrual Summary for the Graft-vs-Host Disease Working Committee

Characteristics of leukemia patients receiving allogeneic HCT between 1990-2017

Accrual Table 1. Leukemia patients: HLA-identical

sibling Haplo

identical Other

related Unrelated

donor Cord

blood Number of patients 28605 3554 1244 33239 6562 Number of centers 442 302 274 395 248 Age at transplant, years, median (range) 38 (<1-78) 36 (<1-82) 37 (<1-77) 41 (<1-83) 19 (<1-83) Disease

AML 11090 (39) 1609 (45) 513 (41) 12817 (39) 2992 (46) ALL 5442 (19) 824 (23) 286 (23) 6351 (19) 2151 (33) Other leukemia 1369 (5) 135 (4) 74 (6) 1687 (5) 280 (4) MDS 4090 (14) 590 (17) 189 (15) 6531 (20) 854 (13) CML 6614 (23) 396 (11) 182 (15) 5853 (18) 285 (4)

Sex Male 16698 (58) 2136 (60) 728 (59) 19502 (59) 3644 (56) Female 11904 (42) 1418 (40) 516 (41) 13734 (41) 2918 (44) Missing 3 (<1) 0 0 3 (<1) 0

Graft source Bone marrow 14930 (52) 1530 (43) 494 (40) 16707 (50) - Peripheral blood 12842 (45) 1915 (54) 708 (57) 16075 (48) - Missing 833 (3) 109 (3) 42 (3) 457 (1) -

GVHD prophylaxis None 1580 (6) 170 (5) 334 (27) 781 (2) 128 (2) Ex-vivo T-cell depletion 1621 (6) 617 (17) 106 (9) 2929 (9) 34 (<1) CD34 selection 427 (1) 240 (7) 39 (3) 575 (2) 202 (3) Post-transplant Cy + others 177 (<1) 1068 (30) 44 (4) 365 (1) 5 (<1) Tac + MTX alone 3027 (11) 111 (3) 109 (9) 7313 (22) 209 (3) Tac + MTX + others 713 (2) 27 (<1) 25 (2) 3148 (9) 80 (1) Tac + MMF alone 546 (2) 276 (8) 49 (4) 1477 (4) 937 (14) Tac + MMF + others 158 (<1) 77 (2) 11 (<1) 699 (2) 258 (4) Tac alone 407 (1) 34 (<1) 22 (2) 858 (3) 191 (3) Tac + others 398 (1) 17 (<1) 20 (2) 844 (3) 242 (4) CsA + MTX alone 13111 (46) 579 (16) 184 (15) 8469 (25) 242 (4) CsA + MTX + others 601 (2) 39 (1) 23 (2) 1819 (5) 91 (1) CsA + MMF alone 793 (3) 33 (<1) 34 (3) 1259 (4) 1875 (29) CsA + MMF + others 42 (<1) 5 (<1) 3 (<1) 313 (<1) 365 (6) CsA alone 3297 (12) 120 (3) 77 (6) 864 (3) 1153 (18) CsA + others 284 (<1) 23 (<1) 9 (<1) 335 (1) 256 (4) Others 565 (2) 32 (<1) 38 (3) 343 (1) 112 (2) Missing 858 (3) 86 (2) 117 (9) 848 (3) 182 (3)

12



sibling Haplo

identical Other

related Unrelated

donor Cord

blood Number of patients 28605 3554 1244 33239 6562 Conditioning regimen intensity Myeloablative 23396 (82) 2143 (60) 894 (72) 24022 (72) 4798 (73) RIC 2409 (8) 387 (11) 127 (10) 6012 (18) 657 (10) NMA 1256 (4) 795 (22) 99 (8) 1905 (6) 969 (15) Missing 1544 (5) 229 (6) 124 (10) 1300 (4) 138 (2) Grade of aGVHD None 13033 (46) 1494 (42) 677 (54) 10734 (32) 2624 (40) Grade I 4656 (16) 554 (16) 154 (12) 5497 (17) 1005 (15) Grade II 3887 (14) 658 (19) 109 (9) 7177 (22) 1336 (20) Grade III 3526 (12) 379 (11) 117 (9) 5080 (15) 834 (13) Grade IV 1270 (4) 180 (5) 36 (3) 2699 (8) 358 (5) Missing 2233 (8) 289 (8) 151 (12) 2052 (6) 405 (6) Organ involvement of aGVHD Skin 866 (11) 225 (20) 30 (13) 2445 (17) 439 (18) Skin + Liver 1221 (15) 82 (7) 12 (5) 1485 (11) 109 (5) Skin + Liver + UGI 67 (<1) 8 (<1) 3 (1) 197 (1) 23 (<1) Skin + Liver + LGI 1759 (22) 174 (16) 45 (20) 2483 (18) 230 (10) Skin + Liver + UGI + LGI 245 (3) 38 (3) 13 (6) 632 (4) 96 (4) Skin + UGI 309 (4) 50 (5) 11 (5) 940 (7) 169 (7) Skin + LGI 1483 (18) 212 (19) 50 (22) 2524 (18) 471 (20) Liver 249 (3) 11 (1) 6 (3) 226 (2) 41 (2) Liver + UGI 37 (<1) 3 (<1) 0 47 (<1) 12 (<1) Liver + LGI 302 (4) 24 (2) 1 (<1) 303 (2) 60 (3) Liver + UGI + LGI 82 (1) 12 (1) 2 (<1) 127 (<1) 34 (1) UGI 265 (3) 60 (5) 7 (3) 634 (4) 144 (6) LGI 638 (8) 81 (7) 22 (10) 869 (6) 207 (9) UGI + LGI 225 (3) 43 (4) 14 (6) 441 (3) 140 (6) Missing 275 (3) 76 (7) 12 (5) 784 (6) 210 (9) Incidence of cGVHD No 18390 (64) 2626 (74) 928 (75) 19067 (57) 4821 (73) Yes 9108 (32) 814 (23) 259 (21) 12560 (38) 1554 (24) Missing 1107 (4) 114 (3) 57 (5) 1612 (5) 187 (3) Maximum grade of cGVHD Limited 2754 (30) 233 (29) 64 (25) 2595 (21) 561 (36) Extensive 5754 (63) 512 (63) 156 (60) 9402 (75) 858 (55) Missing 600 (7) 69 (8) 39 (15) 563 (4) 135 (9)

13



sibling Haplo

identical Other

related Unrelated

donor Cord

blood Number of patients 28605 3554 1244 33239 6562 Overall severity of cGVHD Mild 3556 (39) 359 (44) 81 (31) 4174 (33) 828 (53) Moderate 3072 (34) 248 (30) 81 (31) 3570 (28) 356 (23) Severe 1819 (20) 134 (16) 55 (21) 2374 (19) 216 (14) Missing 661 (7) 73 (9) 42 (16) 2442 (19) 154 (10) Year of transplant 1990-1994 8197 (29) 450 (13) 207 (17) 3104 (9) 33 (<1) 1995-1999 7079 (25) 523 (15) 290 (23) 6237 (19) 406 (6) 2000-2004 5346 (19) 420 (12) 187 (15) 7798 (23) 921 (14) 2005-2009 4229 (15) 373 (10) 211 (17) 8625 (26) 2139 (33) 2010-2014 2421 (8) 671 (19) 181 (15) 4656 (14) 2248 (34) 2015-2017 1333 (5) 1117 (31) 168 (14) 2819 (8) 815 (12) Follow-up of survivors, months, median (range)

76 (<1-319) 19 (<1-300) 47 (<1-316) 72 (<1-314) 58 (<1-265)

Abbreviations: AML=Acute myelogenous leukemia, ALL=Acute lymphoblastic leukemia, CML=Chronic myelogenous leukemia, MDS=Myelodysplastic-myeloproliferative diseases, RIC=Reduced intensity conditioning, NMA=Non-myeloablative, Cy=Cyclophosphamide, Tac=Tacrolimus, MTX=Methotrexate, MMF=Mycophenolate mofetil, CsA=Cyclosporine, UGI=Upper gastrointestinal, LGI=Lower gastrointestinal.

14


Characteristics of non-leukemia patients receiving allogeneic HCT between 1990-2017

Accrual Table 2. Non-leukemia patients: HLA-identical

sibling Haplo

identical Other

related Unrelated

donor Cord

blood Number of patients 12923 1530 1069 8751 3168 Number of centers 432 222 264 316 210 Age at transplant, years, median (range) 26 (<1-77) 10 (<1-76) 26 (<1-77) 27 (<1-79) 5 (<1-73) Disease NHL 3239 (25) 297 (19) 245 (23) 2902 (33) 503 (16) HD 423 (3) 71 (5) 48 (4) 653 (7) 133 (4) SAA 3287 (25) 225 (15) 162 (15) 1447 (17) 185 (6) MM 1721 (13) 42 (3) 184 (17) 661 (8) 45 (1) Inherited abnormalities of

erythrocyte diff-or function 2692 (21) 238 (16) 151 (14) 857 (10) 523 (17)

SCID & other immune system disorders

602 (5) 478 (31) 170 (16) 885 (10) 715 (23)

Inherited abnormality of platelets 27 (<1) 4 (<1) 2 (<1) 38 (<1) 40 (1) Histiocytic disorders 121 (<1) 47 (3) 18 (2) 366 (4) 233 (7) Inherited disorders of metabolism 209 (2) 86 (6) 23 (2) 537 (6) 686 (22) Others 602 (5) 42 (3) 66 (6) 405 (5) 105 (3) Sex Male 7712 (60) 957 (63) 609 (57) 5477 (63) 1921 (61) Female 5211 (40) 573 (37) 460 (43) 3274 (37) 1247 (39) GVHD prophylaxis None 743 (6) 70 (5) 369 (35) 175 (2) 108 (3) Ex-vivo T-cell depletion 593 (5) 390 (25) 81 (8) 873 (10) 17 (<1) CD34 selection 234 (2) 172 (11) 33 (3) 337 (4) 51 (2) Post-transplant Cy + others 309 (2) 306 (20) 24 (2) 74 (<1) 2 (<1) Tac + MTX alone 892 (7) 27 (2) 31 (3) 1448 (17) 99 (3) Tac + MTX + others 242 (2) 15 (<1) 10 (<1) 694 (8) 22 (<1) Tac + MMF alone 275 (2) 84 (5) 19 (2) 470 (5) 321 (10) Tac + MMF + others 84 (<1) 24 (2) 8 (<1) 182 (2) 116 (4) Tac alone 174 (1) 18 (1) 13 (1) 296 (3) 111 (4) Tac + others 133 (1) 4 (<1) 3 (<1) 183 (2) 114 (4) CsA + MTX alone 5377 (42) 187 (12) 152 (14) 1742 (20) 151 (5) CsA + MTX + others 308 (2) 27 (2) 12 (1) 341 (4) 34 (1) CsA + MMF alone 667 (5) 31 (2) 31 (3) 644 (7) 796 (25) CsA + MMF + others 28 (<1) 1 (<1) 3 (<1) 112 (1) 109 (3) CsA alone 1962 (15) 94 (6) 110 (10) 513 (6) 820 (26) CsA + others 310 (2) 13 (<1) 13 (1) 193 (2) 145 (5) Others 188 (1) 18 (1) 23 (2) 134 (2) 44 (1) Missing 404 (3) 49 (3) 134 (13) 340 (4) 108 (3)

15



sibling Haplo

identical Other

related Unrelated

donor Cord

blood Number of patients 12923 1530 1069 8751 3168 Graft source Bone marrow 7782 (60) 785 (51) 498 (47) 4849 (55) - Peripheral blood 4833 (37) 696 (45) 554 (52) 3735 (43) - Missing 308 (2) 49 (3) 17 (2) 167 (2) - Conditioning regimen intensity Myeloablative 8615 (67) 737 (48) 657 (61) 4072 (47) 2014 (64) RIC 1283 (10) 176 (12) 149 (14) 2320 (27) 492 (16) NMA 1757 (14) 411 (27) 100 (9) 1736 (20) 568 (18) Missing 1268 (10) 206 (13) 163 (15) 623 (7) 94 (3) Grade of aGVHD None 7294 (56) 781 (51) 728 (68) 3742 (43) 1553 (49) Grade I 1724 (13) 197 (13) 88 (8) 1230 (14) 480 (15) Grade II 1408 (11) 201 (13) 80 (7) 1472 (17) 517 (16) Grade III 1229 (10) 144 (9) 64 (6) 1113 (13) 293 (9) Grade IV 424 (3) 65 (4) 16 (1) 621 (7) 141 (4) Missing 844 (7) 142 (9) 93 (9) 573 (7) 184 (6) Organ involvement of aGVHD Skin 436 (15) 82 (22) 27 (18) 574 (19) 237 (26) Skin + Liver 419 (14) 31 (8) 14 (10) 248 (8) 45 (5) Skin + Liver + UGI 25 (<1) 0 0 33 (1) 6 (<1) Skin + Liver + LGI 528 (18) 67 (18) 13 (9) 480 (16) 83 (9) Skin + Liver + UGI + LGI 72 (2) 7 (2) 7 (5) 117 (4) 32 (3) Skin + UGI 83 (3) 7 (2) 1 (<1) 174 (6) 53 (6) Skin + LGI 651 (22) 73 (20) 37 (25) 630 (21) 199 (21) Liver 87 (3) 8 (2) 4 (3) 48 (2) 7 (<1) Liver + UGI 10 (<1) 0 0 10 (<1) 2 (<1) Liver + LGI 110 (4) 9 (2) 4 (3) 98 (3) 28 (3) Liver + UGI + LGI 15 (<1) 7 (2) 2 (1) 35 (1) 8 (<1) UGI 73 (3) 13 (3) 5 (3) 125 (4) 30 (3) LGI 257 (9) 24 (6) 18 (12) 259 (8) 81 (9) UGI + LGI 50 (2) 18 (5) 9 (6) 83 (3) 47 (5) Missing 88 (3) 26 (7) 6 (4) 156 (5) 68 (7)

16



sibling Haplo

identical Other

related Unrelated

donor Cord

blood Number of patients 12923 1530 1069 8751 3168 Incidence of cGVHD No 9581 (74) 1223 (80) 922 (86) 5477 (63) 2371 (75) Yes 2856 (22) 257 (17) 102 (10) 2888 (33) 702 (22) Missing 486 (4) 50 (3) 45 (4) 386 (4) 95 (3) Maximum grade of cGVHD Limited 988 (35) 95 (37) 39 (38) 680 (24) 306 (44) Extensive 1630 (57) 129 (50) 47 (46) 2027 (70) 337 (48) Missing 238 (8) 33 (13) 16 (16) 181 (6) 59 (8) Overall severity of cGVHD Mild 1232 (43) 115 (45) 43 (42) 1024 (35) 370 (53) Moderate 881 (31) 71 (28) 26 (25) 804 (28) 169 (24) Severe 497 (17) 38 (15) 15 (15) 591 (20) 99 (14) Missing 246 (9) 33 (13) 18 (18) 469 (16) 64 (9) Year of transplant 1990-1994 2785 (22) 220 (14) 140 (13) 577 (7) 23 (<1) 1995-1999 3136 (24) 218 (14) 234 (22) 1176 (13) 205 (6) 2000-2004 3457 (27) 239 (16) 155 (14) 2442 (28) 523 (17) 2005-2009 2128 (16) 232 (15) 191 (18) 2748 (31) 1070 (34) 2010-2014 687 (5) 256 (17) 201 (19) 1033 (12) 980 (31) 2015-2017 730 (6) 365 (24) 148 (14) 775 (9) 367 (12) Follow-up of survivors, months, median (range)

77 (1-316) 34 (<1-313) 52 (1-297) 72 (<1-312) 61 (<1-268)

Abbreviations: NHL=Non-Hodgkin lymphoma, HD=Hodgkin disease, SAA=Severe aplastic anemia, MM=Multiple myeloma, SCID=Severe combined immunodeficiency, RIC=Reduced intensity conditioning, NMA=Non-myeloablative, Cy=Cyclophosphamide, Tac=Tacrolimus, MTX=Methotrexate, MMF=Mycophenolate mofetil, CsA=Cyclosporine, UGI=Upper gastrointestinal, LGI=Lower gastrointestinal.

17


Unrelated Donor HCT Research Sample Inventory - Summary for First Allogeneic Transplants in CRF and TED with biospecimens available through the CIBMTR Repository stratified by availability of paired samples, recipient only samples and donor only samples.

Accrual Table 3.

Samples Available for Recipient and Donor

Samples Available for Recipient Only

Samples Available for Donor Only

Unrelated donor research sample: N (%) N (%) N (%) Number of patients 17958 3888 3382 CRF 9787 (54) 2119 (54) 1932 (57) TED 8171 (46) 1769 (46) 1450 (43) Number of centers 206 174 224 Disease at transplant AML 12188 (68) 2688 (69) 2209 (65) ALL 5404 (30) 1112 (29) 1102 (33) Other acute leukemia 366 (2) 88 (2) 71 (2) Disease status at transplant First complete remission 8778 (49) 1831 (47) 1497 (44) Second, or greater, complete remission 4595 (26) 1009 (26) 895 (26) Active disease 2737 (15) 639 (16) 559 (17) Other 1848 (10) 409 (11) 431 (13) Recipient age at transplant 0-9 years 1428 (8) 340 (9) 364 (11) 10-19 years 1942 (11) 408 (10) 445 (13) 20-29 years 2311 (13) 484 (12) 497 (15) 30-39 years 2203 (12) 461 (12) 463 (14) 40-49 years 2800 (16) 564 (15) 524 (15) 50-59 years 7274 (41) 1631 (42) 1089 (32) Median (Range) 44 (0-84) 45 (0-79) 38 (0-76) Recipient race/ethnicity Caucasian 14938 (85) 3239 (85) 2550 (83) African-American 669 (4) 162 (4) 131 (4) Asian 409 (2) 87 (2) 155 (5) Pacific islander 25 (<1) 1 (<1) 8 (<1) Native American 71 (<1) 14 (<1) 9 (<1) Hispanic 1358 (8) 281 (7) 228 (7) Other 17 (<1) 10 (<1) 9 (<1) Missing 471 (N/A) 94 (N/A) 292 (N/A) Recipient sex Male 9900 (55) 2226 (57) 1920 (57) Female 8058 (45) 1662 (43) 1462 (43) Karnofsky score 10-80 6109 (34) 1411 (36) 970 (29) 90-100 11175 (62) 2334 (60) 2157 (64) Missing 674 (4) 143 (4) 255 (8)

18


Accrual Table 3.




Unrelated donor research sample: N (%) N (%) N (%) Number of patients 17958 3888 3382 HLA-A B DRB1 groups - low resolution ≤ 3/6 14 (<1) 3 (<1) 0 4/6 87 (<1) 36 (1) 15 (<1) 5/6 2651 (15) 589 (16) 507 (16) 6/6 15042 (85) 3128 (83) 2701 (84) Missing 164 (N/A) 132 (N/A) 159 (N/A) High-resolution HLA matches available out of 8 ≤ 5/8 354 (2) 38 (1) 29 (1) 6/8 798 (5) 57 (2) 71 (3) 7/8 3666 (21) 541 (20) 551 (25) 8/8 12435 (72) 2103 (77) 1596 (71) Missing 705 (N/A) 1149 (N/A) 1135 (N/A) HLA-DPB1 Match Double allele mismatch 4324 (30) 277 (30) 157 (29) Single allele mismatch 7616 (54) 457 (49) 307 (56) Full allele matched 2254 (16) 198 (21) 86 (16) Missing 3764 (N/A) 2956 (N/A) 2832 (N/A) High resolution release score No 148 (1) 4 (2) 1 (1) Yes 13220 (99) 163 (98) 113 (99) Missing 4590 (N/A) 3721 (N/A) 3268 (N/A) KIR typing available No 13231 (74) 3835 (99) 3366 (>99) Yes 4727 (26) 53 (1) 16 (<1) Graft type Bone marrow (BM) 6488 (36) 1525 (39) 1426 (42) Peripheral blood stem cells (PBSC) 11461 (64) 2321 (60) 1949 (58) BM+PBSC 3 (<1) 1 (<1) 2 (<1) PBSC+UCB 6 (<1) 41 (1) 5 (<1) Conditioning regimen Myeloablative 11089 (62) 2305 (59) 2116 (63) RIC 1712 (10) 398 (10) 383 (11) Nonmyeloablative 444 (2) 81 (2) 80 (2) TBD 4713 (26) 1104 (28) 803 (24) Donor age at donation TBD/NA 0 50 (1) 0 0-9 years 14 (<1) 31 (1) 1 (<1) 10-19 years 514 (3) 109 (3) 87 (3) 20-29 years 7902 (44) 1663 (43) 1314 (39) 30-39 years 5124 (29) 1176 (30) 1031 (30) 40-49 years 3337 (19) 669 (17) 725 (21) 50+ years 1067 (6) 190 (5) 224 (7) Median (Range) 31 (0-66) 31 (1-73) 33 (3-64)

19


Accrual Table 3.




Unrelated donor research sample: N (%) N (%) N (%) Number of patients 17958 3888 3382 Donor/Recipient CMV serostatus Negative/Negative 3668 (20) 816 (21) 629 (19) Negative/Positive 4575 (25) 992 (26) 863 (26) Positive/Negative 2045 (11) 440 (11) 419 (12) Positive/Positive 4540 (25) 989 (25) 839 (25) Missing 3130 (17) 651 (17) 632 (19) GvHD Prophylaxis Ex vivo T-cell depletion 1016 (6) 275 (7) 249 (7) CD34 selection 298 (2) 96 (2) 63 (2) Tacrolimus + MMF +- others 2078 (12) 449 (12) 254 (8) Tacrolimus + MTX +- others (except MMF) 8179 (46) 1629 (42) 1120 (33) Tacrolimus + others (except MTX, MMF) 947 (5) 205 (5) 134 (4) Tacrolimus alone 421 (2) 101 (3) 65 (2) CSA + MMF +- others (except Tacrolimus) 965 (5) 178 (5) 241 (7) CSA + MTX +- others (except Tacrolimus, MMF) 2959 (16) 700 (18) 930 (27) CSA + others (except Tacrolimus, MTX, MMF) 194 (1) 46 (1) 82 (2) CSA alone 123 (1) 25 (1) 64 (2) Other GVHD prophylaxis 216 (1) 42 (1) 37 (1) Missing 562 (3) 142 (4) 143 (4) Donor/Recipient sex match Male/Male 7003 (39) 1580 (41) 1276 (38) Male/Female 4865 (27) 1039 (27) 857 (25) Female/Male 2896 (16) 639 (16) 644 (19) Female/Female 3193 (18) 619 (16) 605 (18) Missing 1 (N/A) 11 (N/A) 0 (N/A) Year of transplant 1986-1990 141 (1) 11 (<1) 21 (1) 1991-1995 769 (4) 200 (5) 192 (6) 1996-2000 1372 (8) 525 (14) 339 (10) 2001-2005 2463 (14) 514 (13) 720 (21) 2006-2010 4559 (25) 692 (18) 854 (25) 2011-2015 6698 (37) 1310 (34) 978 (29) 2016-2017 1956 (11) 636 (16) 278 (8) Follow-up among survivors, Months N Eval 7192 1484 1131 Median (Range) 47 (1-337) 37 (3-289) 45 (3-313) Abbreviations: CRF = Comprehensive report form, TED = Transplant essential data, AML=Acute myelogenous leukemia, ALL=Acute lymphoblastic leukemia, UCB=Umbilical cord blood, RIC=Reduced intensity conditioning, TBD = To be determined, MMF=Mycophenolate mofetil, MTX=Methotrexate, CsA=Cyclosporine. * Biospecimens include: whole blood, serum/plasma and limited quantities of viable cells and cell lines (collected prior to 2006). Specific inventory queries available upon request through the CIBMTR Immunobiology Research Program

20


Unrelated Cord Blood Transplant Research Sample Inventory - Summary for First Allogeneic Transplants in CRF and TED with biospecimens available through the CIBMTR Repository stratified by availability of paired, recipient only and cord blood only samples.

Accrual Table 4.




Unrelated cord blood research sample: N (%) N (%) N (%) Number of patients 2831 336 695 CRF 2132 (75) 260 (77) 497 (72) TED 699 (25) 76 (23) 198 (28) Number of centers 130 94 121 Disease at transplant AML 1772 (63) 213 (63) 402 (58) ALL 983 (35) 116 (35) 274 (39) Other acute leukemia 76 (3) 7 (2) 19 (3) Disease status at transplant First complete remission 1383 (49) 153 (46) 332 (48) Second, or greater, complete remission 911 (32) 121 (36) 234 (34) Active disease 285 (10) 39 (12) 62 (9) Other 252 (9) 23 (7) 67 (10) Recipient age at transplant 0-9 years 653 (23) 111 (33) 186 (27) 10-19 years 422 (15) 49 (15) 130 (19) 20-29 years 324 (11) 26 (8) 56 (8) 30-39 years 322 (11) 33 (10) 70 (10) 40-49 years 318 (11) 35 (10) 82 (12) 50-59 years 792 (28) 82 (24) 171 (25) Median (Range) 30 (0-81) 22 (0-75) 25 (0-78) Recipient race/ethnicity Caucasian 1596 (59) 196 (62) 389 (61) African-American 356 (13) 36 (11) 78 (12) Asian 176 (7) 20 (6) 55 (9) Pacific islander 12 (<1) 2 (1) 8 (1) Native American 12 (<1) 1 (<1) 4 (1) Hispanic 537 (20) 63 (20) 107 (17) Other 0 0 1 (<1) Missing 142 (N/A) 18 (N/A) 53 (N/A) Recipient sex Male 1489 (53) 189 (56) 391 (56) Female 1342 (47) 147 (44) 304 (44) Karnofsky score 10-80 744 (26) 77 (23) 161 (23) 90-100 2032 (72) 243 (72) 512 (74) Missing 55 (2) 16 (5) 22 (3)

21


Accrual Table 4.




Unrelated cord blood research sample: N (%) N (%) N (%) Number of patients 2831 336 695 HLA-A B DRB1 groups - low resolution ≤ 3/6 15 (1) 2 (1) 2 (<1) 4/6 1253 (45) 154 (47) 283 (41) 5/6 1232 (44) 135 (41) 326 (47) 6/6 315 (11) 38 (12) 80 (12) Missing 16 (N/A) 7 (N/A) 4 (N/A) High-resolution HLA matches available out of 8 ≤ 5/8 1479 (59) 147 (58) 324 (57) 6/8 595 (24) 64 (25) 132 (23) 7/8 308 (12) 29 (11) 83 (15) 8/8 143 (6) 15 (6) 28 (5) Missing 306 (N/A) 81 (N/A) 128 (N/A) HLA-DPB1 Match Double allele mismatch 355 (38) 27 (46) 19 (36) Single allele mismatch 494 (53) 26 (44) 28 (53) Full allele matched 82 (9) 6 (10) 6 (11) Missing 1900 (N/A) 277 (N/A) 642 (N/A) High resolution release score No 17 (2) 0 1 (50) Yes 807 (98) 46 (100) 1 (50) Missing 2007 (N/A) 290 (N/A) 693 (N/A) KIR typing available No 2109 (74) 327 (97) 693 (>99) Yes 722 (26) 9 (3) 2 (<1) Cord blood number of units Single units 1820 (64) 0 515 (74) Double units 1008 (36) 0 180 (26) Triple units 3 (<1) 0 0 Missing 0 (N/A) 336 (N/A) 0 (N/A) Graft type UCB 2734 (97) 295 (88) 658 (95) BM+UCB 1 (<1) 0 1 (<1) PBSC+UCB 96 (3) 41 (12) 36 (5) Conditioning regimen Myeloablative 1954 (69) 230 (68) 434 (62) RIC 245 (9) 52 (15) 73 (11) Nonmyeloablative 334 (12) 27 (8) 88 (13) TBD 298 (11) 27 (8) 100 (14)

22


Accrual Table 4.




Unrelated cord blood research sample: N (%) N (%) N (%) Number of patients 2831 336 695 Donor age at donation TBD/NA 14 (<1) 12 (4) 10 (1) 0-9 years 2658 (94) 280 (83) 631 (91) 10-19 years 128 (5) 24 (7) 38 (5) 20-29 years 7 (<1) 3 (1) 4 (1) 30-39 years 12 (<1) 9 (3) 6 (1) 40-49 years 5 (<1) 4 (1) 3 (<1) 50+ years 7 (<1) 4 (1) 3 (<1) Median (Range) 3 (0-64) 4 (0-73) 4 (0-67) Donor/Recipient CMV serostatus Negative/Negative 192 (7) 10 (3) 56 (8) Negative/Positive 321 (11) 15 (4) 78 (11) Positive/Negative 200 (7) 7 (2) 47 (7) Positive/Positive 580 (20) 36 (11) 122 (18) Missing 1538 (54) 268 (80) 392 (56) GvHD Prophylaxis Ex vivo T-cell depletion 14 (<1) 6 (2) 2 (<1) CD34 selection 100 (4) 32 (10) 36 (5) Tacrolimus + MMF +- others 795 (28) 82 (24) 115 (17) Tacrolimus + MTX +- others (except MMF) 111 (4) 15 (4) 40 (6) Tacrolimus + others (except MTX, MMF) 114 (4) 13 (4) 20 (3) Tacrolimus alone 52 (2) 7 (2) 9 (1) CSA + MMF +- others (except Tacrolimus) 1316 (46) 119 (35) 339 (49) CSA + MTX +- others (except Tacrolimus, MMF) 50 (2) 10 (3) 16 (2) CSA + others (except Tacrolimus, MTX, MMF) 117 (4) 36 (11) 59 (8) CSA alone 19 (1) 5 (1) 14 (2) Other GVHD prophylaxis 61 (2) 1 (<1) 7 (1) Missing 82 (3) 10 (3) 38 (5) Donor/Recipient sex match Male/Male 749 (27) 98 (29) 207 (30) Male/Female 646 (23) 77 (23) 159 (23) Female/Male 709 (26) 90 (27) 174 (26) Female/Female 669 (24) 68 (20) 139 (20) Missing 58 (N/A) 3 (N/A) 16 (N/A) Year of transplant 1996-2000 0 2 (1) 3 (<1) 2001-2005 54 (2) 59 (18) 10 (1) 2006-2010 1000 (35) 66 (20) 240 (35) 2011-2015 1465 (52) 142 (42) 378 (54) 2016-2017 312 (11) 67 (20) 64 (9) Follow-up among survivors, Months N Eval 1253 156 303 Median (Range) 46 (2-154) 24 (3-170) 46 (1-145)

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Abbreviations: CRF=Comprehensive report form, TED=Transplant essential data, AML=Acute myelogenous leukemia, ALL=Acute lymphoblastic leukemia, UCB=Umbilical cord blood, BM=Bone marrow, PBSC=Peripheral blood stem cells, RIC=Reduced intensity conditioning, TBD=To be determined, MMF=Mycophenolate mofetil, MTX=Methotrexate, CsA=Cyclosporine. * Biospecimens include: whole blood, serum/plasma and limited quantities of viable cells and cell lines (collected prior to 2006). Specific inventory queries available upon request through the CIBMTR Immunobiology Research Program

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Related Donor HCT Research Sample Inventory - Summary for First Allogeneic Transplants in CRF and TED with biospecimens available through the CIBMTR Repository stratified by availability of paired, recipient only and donor only samples.

Accrual Table 5.




Related donor research sample: N (%) N (%) N (%) Number of patients 2442 380 182 CRF 800 (33) 77 (20) 44 (24) TED 1642 (67) 303 (80) 138 (76) Number of centers 74 48 38 Disease at transplant AML 1625 (67) 238 (63) 111 (61) ALL 746 (31) 127 (33) 68 (37) Other acute leukemia 71 (3) 15 (4) 3 (2) Disease status at transplant First complete remission 1520 (62) 243 (64) 110 (60) Second, or greater, complete remission 455 (19) 52 (14) 30 (16) Active disease 393 (16) 73 (19) 35 (19) Other 74 (3) 12 (3) 7 (4) Recipient age at transplant 0-9 years 145 (6) 14 (4) 15 (8) 10-19 years 242 (10) 17 (4) 14 (8) 20-29 years 250 (10) 50 (13) 18 (10) 30-39 years 245 (10) 45 (12) 18 (10) 40-49 years 382 (16) 66 (17) 28 (15) 50-59 years 1178 (48) 188 (49) 89 (49) Median (Range) 49 (1-76) 50 (1-76) 49 (1-73) Recipient race/ethnicity Caucasian 1567 (67) 194 (55) 109 (64) African-American 223 (9) 33 (9) 8 (5) Asian 119 (5) 33 (9) 18 (11) Pacific islander 8 (<1) 1 (<1) 0 Native American 9 (<1) 3 (1) 0 Hispanic 422 (18) 90 (25) 36 (21) Missing 94 (N/A) 26 (N/A) 11 (N/A) Recipient sex Male 1396 (57) 216 (57) 103 (57) Female 1046 (43) 164 (43) 79 (43) Karnofsky score 10-80 899 (37) 158 (42) 72 (40) 90-100 1472 (60) 216 (57) 106 (58) Missing 71 (3) 6 (2) 4 (2)

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Accrual Table 5.




Related donor research sample: N (%) N (%) N (%) Number of patients 2442 380 182 Donor type from retrieval HLA-identical sibling 1788 (73) 284 (75) 130 (71) Identical twin 3 (<1) 3 (1) 0 HLA-matched other relative 61 (2) 11 (3) 11 (6) HLA-mismatched relative 590 (24) 82 (22) 41 (23) Graft type BM 605 (25) 68 (18) 41 (23) PBSC 1835 (75) 310 (82) 138 (76) BM+PBSC 0 2 (1) 0 BM+UCB 2 (<1) 0 0 PBSC+UCB 0 0 3 (2) Conditioning regimen Myeloablative 1145 (47) 185 (49) 80 (44) RIC 213 (9) 24 (6) 15 (8) Nonmyeloablative 83 (3) 12 (3) 6 (3) TBD 1001 (41) 159 (42) 81 (45) Donor age at donation TBD/NA 1636 (67) 303 (80) 137 (75) 0-9 years 37 (2) 1 (<1) 3 (2) 10-19 years 62 (3) 5 (1) 4 (2) 20-29 years 125 (5) 9 (2) 5 (3) 30-39 years 127 (5) 8 (2) 6 (3) 40-49 years 146 (6) 18 (5) 9 (5) 50+ years 309 (13) 36 (9) 18 (10) Median (Range) 44 (1-76) 47 (8-79) 45 (6-69) Donor/Recipient CMV serostatus Negative/Negative 244 (10) 21 (6) 18 (10) Negative/Positive 432 (18) 44 (12) 25 (14) Positive/Negative 132 (5) 16 (4) 9 (5) Positive/Positive 655 (27) 92 (24) 56 (31) Missing 979 (40) 207 (54) 74 (41)

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Accrual Table 5.




Related donor research sample: N (%) N (%) N (%) Number of patients 2442 380 182 GvHD Prophylaxis No GVHD prophylaxis 12 (<1) 2 (1) 1 (1) Ex-vivo T-cell depletion 37 (2) 3 (1) 5 (3) CD34 selection 34 (1) 12 (3) 5 (3) Post-CY + other(s) 400 (16) 61 (16) 21 (12) TAC + MMF +- other(s) (except post-CY) 279 (11) 32 (8) 22 (12) TAC + MTX +- other(s) (except MMF, post-CY) 1118 (46) 132 (35) 93 (51) TAC + other(s) (except MMF, MTX, post-CY) 248 (10) 107 (28) 13 (7) TAC alone 17 (1) 4 (1) 1 (1) CSA + MMF +- other(s) (except post-CY) 31 (1) 2 (1) 3 (2) CSA + MTX +- other(s) (except MMF, post-CY) 191 (8) 11 (3) 12 (7) CSA alone 15 (1) 3 (1) 3 (2) Other(s) 39 (2) 7 (2) 1 (1) Missing 21 (1) 4 (1) 2 (1) Donor/Recipient sex match Male/Male 771 (32) 138 (36) 65 (36) Male/Female 552 (23) 72 (19) 44 (24) Female/Male 625 (26) 78 (21) 38 (21) Female/Female 492 (20) 92 (24) 35 (19) Missing 2 (N/A) 0 (N/A) 0 (N/A) Year of transplant 2006-2010 231 (9) 27 (7) 16 (9) 2011-2015 1479 (61) 220 (58) 124 (68) 2016-2017 732 (30) 133 (35) 42 (23) Follow-up among survivors, Months N Eval 1389 215 100 Median (Range) 24 (2-275) 13 (3-79) 25 (3-73) Abbreviations: CRF=Comprehensive report form, TED=Transplant essential data, AML=Acute myelogenous leukemia, ALL=Acute lymphoblastic leukemia, UCB=Umbilical cord blood, BM=Bone marrow, PBSC=Peripheral blood stem cells, RIC=Reduced intensity conditioning, TBD=To be determined, MMF=Mycophenolate mofetil, MTX=Methotrexate, CsA=Cyclosporine. * Biospecimens include: whole blood, serum/plasma and limited quantities of viable cells and cell lines (collected prior to 2006). Specific inventory queries available upon request through the CIBMTR Immunobiology Research Program

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Proposal 1710-24

Title: Predictive Value of Pre-Transplant Gene Expression Profile in Unrelated Stem Cell Donor on Recipient Risk and Severity of Post-Transplant Graft-Versus-Host-Disease.

Silvy Lachance MD, FRCPC, [email protected], Université de Montréal Montréal Ann Brasey, PhD, [email protected], Hôpital Maisonneuve-Rosemont

Hypothesis: Gene expression in healthy hematopoietic stem cell donors regulates the risk of graft-versus-host disease (GVHD) in recipients following HLA-identical hematopoietic stem cell transplantation.

Scientific impact: A priori knowledge of GVHD risk would allow better donor selection, and to tailor immunosuppression according to GVHD risk and should significantly improve transplant outcome.

Specific aims: By studying the gene expression profile of CD4 T cells from HLA-identical unrelated stem cell donors, our study aims to identify donors presenting a greater risk of eliciting significant graft versus host disease in their recipient.

• Primary objective:The primary objective of the study is to confirm the predictive value of the expression ofcandidate genes in unrelated stem cell donors on the development and severity of graftversus host disease in their recipient following Hematopoietic stem cell transplantation.

• Secondary Objective:o To identify and select the most informative genes to include in a predictive assay.o To build a GVHD genomic predictive algorithm and test for unrelated donor

selection.o To explore new pathways for GVHD diagnosis and treatment.

Scientific justification: Graft-versus-Host disease (GVHD), an immune reaction of donor T cells directed against antigenic determinants in the recipient, constitutes a major and potentially lethal complication following unrelated stem cell transplantation leading to tissue and organ damage, prolonged immunosuppression and significant morbidity and mortality. Many factors are known to increase the risk of post-transplant GVHD, the most obvious one being HLA disparities (incompatibilities) between the donor and recipient. Our team previously demonstrated in HLA identical sibling transplant setting, that some genes expressed by the donor could increase the GVHD risk in the recipient (1).

We recently confirmed our first observation by performing RNA-sequencing on purified CD4 T cells from 330 AHCT donors from three centers (Boston, Calgary, Montreal). Donor and recipient were 8/8 HLA matched siblings. CD4 T lymphocytes were isolated from blood samples collected from donors prior to hematopoietic stem cell mobilization and collection. RNA was poly-A enriched and sequenced on an Ion Proton to an average depth of 40M reads. Expression profiles obtained from donors were computed using TopHat and cuffquant. A nested cross-

28


validation protocol was used to train a logistic regression with either L1 or L2 regularization to predict the onset of acute GVHD of IBMTR grade C and above. An outer 10-fold cross-validation was used for the selection of hyper-parameters (number of genes considered, type and weight of the regularization) and an inner leave-one-out cross validation was used for the predictor training. Areas under the ROC curve (AUC) and relative risks were computed based on out-of-sample predicted risk of GVHD. Depending on the selected threshold applied to our predictive score, we were able to identify donors whose relative risk to trigger severe aGVHD in their recipient (IBMTR grade ≥ C) was increased by 1.8- to 4-fold (95% confidence intervals for relative risks derived for all possible thresholds). (ASH 2017 abstract no.103385).

This study aims to validate, in the unrelated setting, the capacity, reliability and robustness of candidate genes expressed in stem cell donor, to identify strong “alloresponders” and consequently, donors more likely to elicit significant GVHD in their recipient. It will confirm that pre-transplant gene expression profile patterns in donor CD4 lymphocytes will allow the identification of distinct gene transcripts able to predict recipient risk, type and severity of post-transplant GVHD development.

Study population: Adult patients (≥ 18 years) who have received, a non-T cell depleted myeloablative (MA) or reduced- intensity (RIC) allogeneic HSCT from a 10/10 matched unrelated donor for acute leukemia, myelodysplastic syndrome or myeloproliferative disorder and for whom donor PBMC or lymphocytes were collected prior stem cell mobilization and donation and are available for study. To be included in the study, recipient must have engrafted and survived for a minimum of 100 days post transplantation. The exclusion criteria are: T cell depleted graft, HLA mismatch, planned post transplant DLI and death before engraftment. Data Requirements: The results of the donor genes expression profile will be correlated to the grade and severity of acute GVHD in the recipient and to other known risk factors for GVHD. Followed are the data requirements for both donor and recipient. Unrelated Donor information

• Date of birth or Age • HLA typing (if available) • Ethnic group (race) • Gender • If Female, number of pregnancies • ABO blood group • CMV status: +/- • Date of PBMC-lymphocytes collection: Date of stem cell donation

Recipient information • Age • HLA typing: (A, B, C, DR, DQ and DP if available) • Ethnic group (race) • Gender • ABO blood group • CMV status: +/- • Diagnosis • State of disease at transplantation:

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• Disease risk • Conditioning regimen: myeloablative (MA) or reduced intensity (RIC) • TBI containing: yes/no • Source of stem cells: marrow or PBSC • GVHD prophylaxis: • ATG uses as part of GVHD prophylaxis: yes/no

Sample requirements: To proceed with the gene expression profiling tests, blood samples collected from the matched unrelated donor, prior to hematopoietic stem cell mobilization and collection are requested. Frozen PBMC total 10 to 20x 10e6/donor or CD4+ lymphocytes 5x 10e6/donor collected and cryopreserved according to standard procedure.

Methodology summary: Cryopreserved peripheral blood mononuclear cells are thawn, CD4+ lymphocytes selected by magnetic bead pull-down (EasySep Human CD4 positive selection kit, StemCell Technologies) and RNA is isolated by Trizol-column (PureLink system, ThermoFisher Scientific). The CD4 T cell RNA is then poly-A enriched to be analyzed by next-generation sequencing on the Ion Torrent Platform to an average depth of 40M reads. Expression profiles obtained from donors will be computed using TopHat and cuffquant.

Study design: We used the RNA-Seq sample size analysis {PMID: 25374457} to compute the sample size needed to identify a predictor at a false discovery rate of 0.05 assuming an effect size of 2.0 (rho). Input for the remaining function parameters were calculated from our current dataset (maximal dispersion / phi0 = 0.31522, average read count per gene / lambda0 = 20745). Under these parameters, and assuming equal representation of each group, a power of 90% is obtained with 32 samples per group (Group 1: no severe acute GVHD grade ≤ 1 or A; Group 2: severe aGVHD grade ≥ 3 or C), for a total sample size of 64.

A conservative estimate for the incidence of aGVHD IBMTR grade ≥ 3 or C for unrelated HSCTs is roughly 15%. If a manual selection of the positive and negative cases is not possible, a dataset of ≥214 samples would be required in order to yield a robust predictor (~32 positive and ~182 negative cases). Under a more optimistic incidence estimate of aGVHD grade ≥ 3 or C) 25%, 128 samples would be required (~32 positive and ~96 negative cases).

References: 1. Baron, Chantal, et al. "Prediction of graft-versus-host disease in humans by donor gene-

expression profiling." PLoS Med. 2007;4(1):e23. 2. Petersdorf E. The Genetics of Graft-versus-Host-Disease: The Major Histocompatibility complex.

Blood Reviews. 2013;27:1-12. 3. Biesecker LG, Green RC. Diagnostic Clinical Genome and Exome sequencing. NEJM. 2014;19:2418. 4. Jagasia M. Et al. Risks Factors for Graft-versus-Host-Disease and Survival after Haematopoietic

Cell Transplantation. Blood. 2012;119:296-307.

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5. Cahn J-Y, Klein JP, Lee SJ, Horowitz MM, and Socié G. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Société Française de Greffe de Moëlle et Thérapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106:1495-1500.

6. Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016;34(5):525-7.

7. Snoek, Jasper, Larochelle H, Adams RP. "Practical bayesian optimization of machine learning algorithms." Advances in Neural Information Processing Systems. 2012.

8. Ni T, Yang W, Han M, Zhang Y, Shen T, Nie H, Zhou Z, Dai Y, Yang Y, Liu P, et al. Global intron retention mediated gene regulation during CD4+ T cell activation. Nucleic Acids Res. 2016;44:6817–6829.

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Characteristics of adult patients undergoing first allogeneic transplant for AML, ALL, CML, MDS with a T-cell replete PB graft from a 10/10-matched unrelated donor, and for whom there are at least 2

donor sample vials available, between 2000-2005, as reported to the CIBMTR. Variable aGVHD 0-I aGVHD II aGVHD III-IV Number of patients 45 41 23 Number of centers 26 20 16 Age at transplant, years Median (range) 51 (22-68) 40 (19-66) 48 (21-63) 18-29 9 (20) 10 (24) 2 (9) 30-39 5 (11) 9 (22) 2 (9) 40-49 4 (9) 9 (22) 10 (43) 50-59 18 (40) 4 (10) 8 (35) 60-70 9 (20) 9 (22) 1 (4) Disease AML 14 (31) 16 (39) 12 (52) ALL 9 (20) 5 (12) 2 (9) CML 9 (20) 7 (17) 5 (22) MDS 4 (9) 5 (12) 3 (13) MPS 9 (20) 8 (20) 1 (4) Conditioning regimen intensity Myeloablative 25 (56) 26 (63) 14 (61) RIC 8 (18) 5 (12) 4 (17) NMA 9 (20) 8 (20) 5 (22) TBD 3 (7) 2 (5) 0 GVHD prophylaxis TAC + MMF + other(s) (except PT-Cy) 6 (13) 4 (10) 2 (9) TAC + MTX + other(s) (except MMF, PT-Cy) 13 (29) 10 (24) 5 (22) TAC + others (except MMF, MTX, PT-Cy) 0 0 1 (4) TAC alone 1 (2) 1 (2) 0 CSA + MMF + other(s) (except PT-Cy) 13 (29) 8 (20) 5 (22) CSA + MTX + other(s) (except MMF, PT-Cy) 9 (20) 17 (41) 7 (30) CSA + other(s) (except MMF, MTX, PT-Cy) 1 (2) 0 2 (9) CSA alone 2 (4) 1 (2) 1 (4) Year of transplant 2000 5 (11) 8 (20) 6 (26) 2001 14 (31) 13 (32) 8 (35) 2002 19 (42) 16 (39) 8 (35) 2003 0 2 (5) 0 2004 1 (2) 1 (2) 0 2005 6 (13) 1 (2) 1 (4)

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Variable aGVHD 0-I aGVHD II aGVHD III-IV Number of patients 45 41 23 Acute GVHD grade None 27 (60) 0 0 I 18 (40) 0 0 II 0 41 0 III 0 0 17 (74) IV 0 0 6 (26) Chronic GVHD No 17 (38) 5 (12) 6 (26) Yes 27 (60) 35 (85) 17 (74) Missing date 1 (2) 1 (2) 0 Follow-up of survivors, months, median (range) 147 (72-192) 169 (157-192) 162 (145-171) Abbreviations: AML=Acute myelogenous leukemia, ALL=Acute lymphoblastic leukemia, CML=Chronic myelogenous leukemia, MDS=Myelodysplastic-myeloproliferative diseases, MPS=Myelofibrosis, RIC = Reduced intensity, NMA = Non-myeloablative, TBD = To be determined, TAC = Tacrolimus, MMF = Mycophenolate mofetil, PT-Cy = Post-transplant Cyclophosphamide, MTX = Methotrexate, CSA = Cyclosporine.

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Proposal 1711-122

Title: Impact of the GVHD prophylaxis regimen on outcome of Single Unrelated Cord Blood Transplantation in patients with non-malignant disorders

Mouhab Ayas, MD, [email protected], King Faisal Specialist Hospital and Research Center

Hypothesis: Different GVHD prophylaxis regimens used in unrelated cord blood transplantation may have different impacts on outcome of transplant: Rate of rejection, rate of GVHD acute and chronic, rate of opportunistic infections.

Scientific impact: This study will help shed more light on what might be the optimal GVHD prophylaxis regimen in these patients if any.

Specific aims: • Analyze the incidence of Acute GVHD and Chronic GVHD after single unrelated cord blood unit

transplantation in patients with non-malignant disorders according to the GVHD prophylaxisregimen used, namely Calcineurin inhibitors/Mycophenolic Acid, Calcineurin inhibitors/Steroids,Calcineurin inhibitors/MTX.

• The secondary aim is to look at the incidence graft rejection in this cohort of patients as well asthe incidence of opportunistic infections with each GVHD prophylaxis regimen (Fungal, Viral-CMV, EBV)

• Some regimens are more expensive than others; if no difference is found, it might justify use ofthe less expensive regimens.

Scientific justification: • There is currently no consensus regarding the best GVHD prophylaxis regiment to be used in

unrelated cord blood transplant.• In non-malignant disorders, there is theoretically no need for the GVL effect; therefore, it is

essential to maximize the GVHD prophylaxis.• Some agents in the GVHD prophylaxis regimens maybe associated with a higher incidence of

opportunistic infections (steroids).• Some agents in the GVHD prophylaxis regimens are less preferred because of presumed

interference with engraftment (Methotrexate).• Some GVHD prophylaxis regimens are less expensive that the others and if the GVHD incidence

in this study is no different amongst the used regimens, it is more economical to use the lessexpensive regimens i.e. steroids instead of Mycophenolic Acid.

• A recent CIBMTR analysis looked at the GVHD after cord blood transplant in acute leukemiapatients only; it concluded that absence of ATG was associated with acute GVHD, but the GVHDprophylaxis regimen was not associated with acute GVHD.

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Study population: • All patients with who underwent single unrelated cord blood transplantation for a non-

malignant condition. • Patients who received cord blood infusion with no conditioning are not eligible (such as patients

with immune deficiency disorders). Data requirements:

• To use post HCT data forms. • No collection of supplemental data is needed.

Sample requirements (if study will use biologic samples from the NMDP Research Sample Repository): • N/A

Study design (Scientific Plan): I suggest dividing the patients into 3 main categories:

• Calcineurin inhibitors with Mycophenolic Acid. • Calcineurin inhibitors with Steroids. • Calcineurin inhibitors with Methotrexate.

Mainly analyze in these 3 groups: • Incidence of graft failure. • Incidence of acute and chronic GVHD. • Incidence of opportunistic infections (CMV, EBV, fungal)

Data source:

• CIBMTR Research Database

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Characteristics of patients undergoing first allogeneic transplant in patients for non-malignancies with a single UCB graft from an unrelated donor between 2000-2016, as reported to the CIBMTR.

Variable N (%) Number of patients 797 Number of centers 111 Age at transplant, years Median (range) 2 (<1-65) < 1 292 (37) 1 91 (11) 2-4 126 (16) 5-9 194 (24) 10-17 77 (10) 18-29 9 (1) 30+ 8 (1) Primary disease code Severe aplastic anemia 78 (10) Inherited abnormalities erythrocyte diff-function 195 (24) SCID & other immune system disorders 401 (50) Inherited disorders of metabolism 116 (15) Histiocytic disorders 7 (<1) Conditioning regimen intensity Myeloablative 491 (62) RIC 133 (17) NMA 115 (14) TBD 50 (6) Missing 8 (1) GVHD prophylaxis No GVHD prophylaxis 27 (3) Ex-vivo T-cell depletion 2 (<1) CD34 selection 1 (<1) TAC + MMF +- other(s) (except PT-CY) 82 (10) TAC + MTX +- other(s) (except MMF, PT-Cy) 46 (6) TAC + other(s) (except MMF, MTX, PT-Cy) 44 (6) TAC alone 12 (2) CSA + MMF +- other(s) (except PT-Cy) 218 (27) CSA + MTX +- other(s) (except MMF, PT-Cy) 49 (6) CSA + other(s) (except MMF, MTX, PT-Cy) 272 (34) CSA alone 29 (4) Other(s) 14 (2) Missing 1 (<1)

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Variable N (%) Number of patients 797 Year of transplant 2000 14 (2) 2001 39 (5) 2002 28 (4) 2003 55 (7) 2004 43 (5) 2005 46 (6) 2006 30 (4) 2007 40 (5) 2008 75 (9) 2009 103 (13) 2010 80 (10) 2011 60 (8) 2012 69 (9) 2013 51 (6) 2014 30 (4) 2015 19 (2) 2016 15 (2) Follow-up of survivors, months, median (range) 71 (3-193) Abbreviations: RIC = Reduced intensity, NMA = Non-myeloablative, TBD = To be determined, TAC = Tacrolimus, MMF = Mycophenolate mofetil, PT-CY = Post-transplant Cyclophosphamide, MTX = Methotrexate, CSA = Cyclosporine.

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Proposal 1711-04

Title: Risk stratification by time to onset of acute GVHD

Hannah Kyung Choe, MD, [email protected], The Ohio State University – James Cancer Center Stephanie J. Lee, MD, MPH, [email protected], Fred Hutchinson Cancer Research Center

Hypothesis: Early onset of acute GVHD indicates a higher risk of resistance to treatment, NRM, and chronic GVHD

Scientific impact: Acute GVHD remains the most common cause of non-relapse mortality post-transplant, affecting approximately 50% of transplant cases. There is currently no consensus on the risk associated with the timing of acute GVHD onset. Understanding the time to onset of acute GVHD and its risk for resistance to first line therapy, non-relapse mortality, survival, and chronic GVHD could directly affect treatment approaches and design of future clinical trials.

Specific aims: • To analyze the survival, rate of relapse, and chronic GVHD in patients with early onset acute

GVHD defined as engraftment +/- 10 days, classic acute GVHD defined as 11-56 days afterengraftment, and later acute GVHD defined as 57 or more days after engraftment.

• To identify risk factors associated with the development of each time to onset category. Toidentify nonmodifiable risk factors (i.e., race, gender, age) and modifiable risk factors (i.e.,conditioning regimen intensity, transplant type, HLA mismatch, donor/recipient sex match, grafttype, and GVHD prophylaxis).

Scientific justification: Early onset acute GVHD or “hyperacute” GVHD was first reported in 1986, associated with lack of post-transplant immunosuppression. Fifteen of 15 cases in HLA-matched sibling transplants developed biopsy-proven aGVHD with a median 8 days of onset after engraftment1. While some have used the term “hyperacute” to refer to GVHD symptoms pre-engraftment2, others have defined it as onset of aGVHD within 14-28 days of transplant regardless of engraftment3,4 or by timing or response to steroids5. These cutoffs were defined due to convenience of sample collection or arbitrarily chosen, therefore there is no evidence from which to draw a consensus on the definitions of hyperacute or early onset acute GVHD. Given that the pathophysiology of acute GVHD is linked to the donor T cell engraftment, we propose, similar to Sullivan et al. in their original description of hyperacute GVHD, that the time of onset of acute GVHD be categorized in relation to engraftment date. The onset of acute GVHD has also been shown to vary by conditioning intensity with later onset after non-myeloablative conditioning compared to myeloablative6.

Early onset acute or hyperacute GVHD has been described as having higher NRM and a lower response rate to first-line therapy compared to later onset GVHD in HLA-mismatched and unrelated donor transplants but not related donors.3 Conversely, when grouping patients by timing of steroid initiation into early (<23 days after transplant), intermediate (23-41 days), or late (>41 days), a multi-institutional study of 395 patients, demonstrated increased NRM and worse survival in the early onset cohort5. The time to onset of acute GVHD may also be associated with the risk of chronic GVHD development, although data are conflicting. In MUD transplants, patients with “late onset” acute GVHD according to

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2005 NIH consensus criteria had double the risk of chronic GVHD compared to classic GVHD that started before day 1007. In a single institution study, early onset acute GVHD classified as within 28 days post-transplant was associated with decreased survival and increased risk of chronic GVHD compared to GVHD developing beyond 28 days4. In a recently published GITMO study of early intervention for acute GVHD, Bacigalupo et al. observed a significantly higher NRM in patients with early onset acute GVHD within 20 days of transplant, (31% vs 18%, p=0.0006) and lower 4-year overall survival (33% vs 60%, p=001). Notably, early intervention of steroids in grade 1 GVHD for this early onset group did not reduce progression to grade 2-4 GVHD. These results imply that steroid therapy may be particularly ineffective in early onset acute GVHD while also corroborating reports that early onset acute GVHD is associated with higher risk8. Early onset of acute GVHD may be an indication for clinical trial-directed therapy given steroid futility. To the best of our knowledge, time to onset of acute GVHD and response to steroids has never been systematically studied in the CIBMTR database. Study population: Adult alloSCT recipients of an HLA-matched (unrelated or related) or 1 allele mismatched (7/8) donor who received either myeloablative or nonmyeloablative conditioning for hematologic malignancies are eligible. The study will include first allogeneic transplant recipients only. Prior autologous SCT may be included. Data from transplants between 2008-2015 will be included. No ex-vivo T-cell depleted, ATG, alemtuzumab, or post-transplant Cy will be included. GVHD prophylaxis with Tacrolimus/Methotrexate and Cyclosporine/Methotrexate only will be included. Data requirements: We will examine transplant outcomes for allogeneic HCT with HLA-matched sibling donors and HLA-matched unrelated donors, HLA-mismatched donors, cords (single unit, double unit), and haploidentical transplants. Because we need the data of acute GVHD diagnosis, only CRF data will be used. Specific variables are listed below. Patient-related

• Age • Gender: male or female • Karnofsky performance score at SCT: ≥90 or <90 • Race: White vs. Black vs. Asian/Pacific Islander vs. Hispanics vs Others

Disease-related • Disease type: AML, MDS, ALL, MPD, CML, CLL, NHL, HL • Disease status

Transplant-related • Donor: related or unrelated or cord • Graft type: bone marrow or peripheral blood • Donor/recipient sex match • HLA match • Conditioning regimens groups: myeloablative vs. non-myeloablative • ATG: yes or no • Alemtuzumab: yes or no • GVHD prophylaxis: Tac/MTX or CSA/MTX

Post-transplant variables of interest • Date of engraftment • Date of acute GVHD diagnosis • Organ involvement of acute GVHD

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• Treated with steroids: yes or no • Specific therapy: steroids or other • Acute GVHD still present • Date of chronic GVHD diagnosis

Sample Requirements

• No samples required. Study Design:

• Observational, retrospective cohort Non-CIBMTR Data Source:

• No other data sources References:

1. Sullivan, K. M. et al. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood. 1986;67;1172–1175.

2. Kim, D. H. et al. Clinical impact of hyperacute graft-versus-host disease on results of allogeneic stem cell transplantation. Bone Marrow Transplant. 2004;33:1025–1030.

3. Saliba, R. M. et al. Hyperacute GVHD: risk factors, outcomes, and clinical implications. Blood. 2007;109:2751–2758.

4. Mielcarek, M. et al. Prognostic relevance of ‘early-onset’ graft-versus-host disease following non-myeloablative haematopoietic cell transplantation. Br. J. Haematol. 2005;129:381–391.

5. Moon, J. H. et al. Early onset of acute GVHD indicates worse outcome in terms of severity of chronic GVHD compared with late onset. Bone Marrow Transplant. 2010;45:1540–1545.

6. Mielcarek, M. et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102:756–762.

7. Omer, A. K. et al. Late Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Biol. Blood Marrow Transplant. 2016;22:879–883.

8. Bacigalupo, A. et al. Steroid treatment of acute graft versus host disease grade I: a randomized trial. Haematologica. 2017;102(12):2125-2133.

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Characteristics of patients undergoing first allogeneic transplant for hematological malignancy with a T-cell replete graft between 2008-2015, as reported to the CIBMTR.

Variable

Early aGVHD Within 10 days of engraftment

Intermediate aGVHD

11-56 days post-ANC

Late aGVHD >57 days post-

ANC Number of patients 1635 2197 862 Number of centers 165 171 132 Age at transplant, years Median (range) 47 (<1-76) 53 (<1-79) 55 (1-78) <10 145 (9) 71 (3) 29 (3) 10-17 90 (6) 77 (4) 22 (3) 18-29 197 (12) 201 (9) 64 (7) 30-39 193 (12) 226 (10) 84 (10) 40-49 294 (18) 342 (16) 115 (13) 50-59 393 (24) 599 (27) 229 (27) 60-70 276 (17) 563 (26) 265 (31) 70+ 47 (3) 118 (5) 54 (6) Disease AML 656 (40) 845 (38) 356 (41) ALL 336 (21) 292 (13) 100 (12) CML 66 (4) 117 (5) 20 (2) MDS 256 (16) 415 (19) 192 (22) MPS 88 (5) 149 (7) 61 (7) Other acute leukemia 27 (2) 29 (1) 12 (1) Other leukemia 46 (3) 99 (5) 37 (4) NHL 115 (7) 193 (9) 58 (7) HD 13 (<1) 24 (1) 9 (1) PCD/MM 32 (2) 34 (2) 17 (2) Type of donor Cord blood 463 (28) 409 (19) 108 (13) HLA identical sibling 339 (21) 645 (29) 374 (43) Haploidentical (>1-antigen mm) 46 (2) 64 (2) 19 (2) 8/8-matched unrelated 615 (38) 913 (42) 305 (35) 7/8-matched unrelated 163 (10) 165 (8) 55 (6) <6/8-matched unrelated 13 (<1) 1 (<1) 1 (<1) Graft type Bone marrow 190 (12) 241 (11) 89 (10) Peripheral blood stem cells 982 (60) 1547 (70) 665 (77) Cord blood 463 (28) 409 (19) 108 (13)

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Variable

Early aGVHD Within 10 days of engraftment

Intermediate aGVHD

11-56 days post-ANC

Late aGVHD >57 days post-

ANC Number of patients 1635 2197 862 Conditioning regimen intensity Myeloablative 1186 (73) 1278 (58) 423 (49) RIC 266 (16) 542 (25) 284 (33) NMA 122 (7) 307 (14) 124 (14) TBD 60 (4) 67 (3) 31 (4) Missing 1 (<1) 3 (<1) 0 GVHD prophylaxis TAC + MMF + other(s) (except PT-Cy) 364 (22) 504 (23) 175 (20) TAC + MTX + other(s) (except MMF, PT-Cy) 745 (46) 1082 (49) 503 (58) CSA + MMF + other(s) (except PT-Cy) 409 (25) 463 (21) 128 (15) CSA + MTX + other(s) (except MMF, PT-Cy) 117 (7) 148 (7) 56 (6) Year of transplant 2008-2010 760 (46) 799 (36) 305 (35) 2011-2013 384 (23) 546 (25) 221 (26) 2014-2016 491 (30) 852 (39) 336 (39) Time from neutrophil engraftment to aGVHD onset Median (range), days 3 (-10-10) 22 (11-56) 104 (57-2407) No engraftment 0 0 0 < 10 days before neutrophil recovery 600 (37) 0 0 < 10 days after neutrophil recovery 1035 (63) 0 0 11-56 days after neutrophil recovery 0 2197 0 57-100 days after neutrophil recovery 0 0 418 (48) 101-180 days after neutrophil recovery 0 0 236 (27) > 180 days after neutrophil recovery 0 0 208 (24) Maximum acute GVHD grade II 838 (51) 1365 (62) 467 (54) III 492 (30) 564 (26) 292 (34) IV 304 (19) 267 (12) 103 (12) Follow-up of survivors, months, median (range) 47 (2-102) 36 (1-102) 35 (3-103) Abbreviations: AML=Acute myelogenous leukemia, ALL=Acute lymphoblastic leukemia, CML=Chronic myelogenous leukemia, MDS=Myelodysplastic-myeloproliferative diseases, NHL=Non-Hodgkin lymphoma, HL=Hodgkin Lymphoma, PCD/MM=Plasma cell disorders/multiple myeloma, RIC = Reduced intensity, NMA = Non-myeloablative, TBD = To be determined, TAC = Tacrolimus, MMF = Mycophenolate mofetil, PT-Cy = Post-transplant Cyclophosphamide, MTX = Methotrexate, CSA = Cyclosporine.

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Proposal 1711-163

Title: Comparison of antibacterial prophylaxis strategies and outcomes in allogeneic stem cell transplantation patients with acute graft vs host disease

Whitney Wallis, PharmD, [email protected], Monroe Carell Jr. Children’s Hospital Amin Alousi, MD, [email protected], M.D. Anderson Cancer Center Alison Gulbis, PharmD, [email protected], M.D. Anderson Cancer Center

Specific aims: Primary objectives:

• To determine the cumulative incidence of bacterial blood stream infections in patients withacute GVHD (aGVHD) grade II-IV.

• To compare the cumulative incidence of bacterial bloodstream infections by day 100 in theabove patients at centers that systematically give antibiotics for antibacterial prophylaxis vs.patients at center that do not give antibacterial prophylaxis.

Secondary objectives: • To compare the outcomes listed below among stem cell transplant recipients with aGVHD who

received antibacterial prophylaxis to those that did not receive antibacterial prophylaxis• Incidence of bacterial bloodstream infections by day 100 among patients with lower

gastrointestinal (GI) aGVHDo Incidence of clostridium difficile infections by day 100o 6-month non-relapse mortalityo 6-month overall survival

Scientific justification: Infectious complications after allogeneic stem cell transplant (Allo-SCT) remain a significant cause of morbidity and mortality. aGVHD is a known risk factor for infection, a risk that is potentially heightened with the use of corticosteroids.1;2 (Tomblyn, et al. BMT. 2009, Miller, et al. BBMT. 2017.) Specifically, in patients with acute gastrointestinal GVHD (GI GVHD), density of post-engraftment enteric bacterial bloodstream infection (EB-BSI), Enterococci and gram negative rods (Klebsiella, Enterobacter), is considerably higher relative to patients without GVHD (2.44 vs 1.58, p=0.05).3 (Levinson et al. CID. 2015) Furthermore, TRM at one year in patients who develop an EB-BSI subsequent to GI GVHD is significantly higher compared to patients without GVHD (33.4% vs 15.3%; p=0.004).4 (Satwani et al. BBMT. 2017) Various prophylactic antibiotics have been implemented to mitigate the infection risk associated with corticosteroid treatment. However, data surrounding this approach is lacking and while the Infectious Diseases Society of America recommends bacterial prophylaxis for patients with chronic GVHD (targeting encapsulated organisms); there are no formal recommendations with regard to bacterial prophylaxis in patients receiving systemic therapy for acute GVHD. Use of prophylaxis strategies, notably fluoroquinolones, during neutropenia have increased worldwide and consequently, antibiotic resistance and unexpected pathogens have emerged5;6 (Sepkowitz. BMT.2002, Averbuch, et al. Clin Infect Dis. 2016) Among neutropenic patients prescribed routine antibiotic prophylaxis, the incidence of bacterial bloodstream infections (BSI) has been found to be approximately 30%. Etiology of infections is diverse; however, increased rates of Enterobacter bacteremia’s have been observed in patients receiving a regimen that consisted of a third generation cephalosporin7 (Yemm, et al. J Antimicrob Chemother. 2017). Recently, data suggest a correlation with the gut microbiome and clinical outcomes, including aGVHD8 (Jenq, et al. BBMT. 2015) and bacterial BSI.

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The risk of gram-negative bacteremia was 5-fold greater in patients with Proteobacteria gut domination, which was significantly higher in patients who received fluoroquinolones9 (Taur, et al. Clin Infect Dis. 2012). Prophylaxis strategies identified via a preliminary multicenter survey among Allo-SCT centers in May 2016 were heterogeneous and included centers which did not routinely administer prophylaxis and those that systematically gave a specified antibiotic class (penicillin, fluoroquinolones, and macrolides) to all patients on steroids for acute GVHD (or less commonly a specific subset, namely those with lower GI GVHD). Additional information will be obtained after a formal survey is conducted. Because the CIBMTR does not record the use of prophylaxis in this setting, this proposal will include a formal survey to characterize the different prophylaxis strategies utilized by stem cell transplant centers, provide epidemiologic data on infections identified in patients receiving treatment for aGVHD, and compare the relative benefit of different prophylaxis strategies. Additionally, this study will provide hypothesis-generating data that can serve as the basis of future prospective studies evaluating antibacterial prophylaxis in patients with aGVHD. Study population: We propose to perform a retrospective analysis of patients who received systemic corticosteroids for treatment of grade II-IV aGVHD who underwent allogeneic stem cell transplantation from 2010-2016 to determine the cumulative incidence of BSI by day 100. A separate, subset analysis will be performed in patients who received a transplant at a center that had a formal policy with respect to antibacterial prophylaxis to compare rates of BSI based on the top three identified strategies (including centers who do not administer antibiotics). Factors included in this analysis will be captured by the existing CIBMTR data collection forms and survey responses. Outcomes: Primary Outcome:

• Bacterial bloodstream infection: development of microbiologically proven bacterial bloodstream infection by day 100. This event will be summarized by the cumulative incidence estimate.

Secondary Outcomes: • Bacterial bloodstream infection among patients with lower gastrointestinal • GVHD: development of microbiologically proven bacterial bloodstream infection by day 100 in

patients with lower gastrointestinal GVHD. This event will be summarized by the cumulative incidence estimate.

• Etiology of bacterial bloodstream infection: identification of the bacterial pathogen responsible for bloodstream infection. This event will be summarized by cumulative incidence of pathogen specific bloodstream infection among various antibacterial prophylaxis regimens.

• Clostridium difficile infection: development of microbiologically or radiologically proven Clostridium difficile by day 100. The event will be summarized by cumulative incidence estimate of infection among each antibacterial prophylaxis regimen.

• Non-relapse mortality at 180 days: death without evidence of disease recurrence. This event is summarized by the cumulative incidence estimate with relapse as the competing risk.

• Overall survival at 180 days: time to death from any cause. Event will be summarized by a survival curve.

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Variables to be analyzed: • Disease-related:

Lower GI aGVHD vs non-GI aGVHD • Treatment-related:

Prophylaxis regimen: fluoroquinolone vs cephalosporin vs penicillin vs other vs none (three most commonly identified strategies will be studied (more based on numbers)).

• Bacterial Infection Related: Pathogen identified

Study design: This is a retrospective analysis of data obtained by CIBMTR data collection forms and formal survey results, obtained via a stem cell transplant clinical pharmacist e-mail based server. Patients who were treated with corticosteroids for aGVHD at a major stem cell transplant center identified in the aforementioned survey will be analyzed. Descriptive statistics will be used to summarize patient characteristics. Bacterial bloodstream infection will be determined using cumulative incidence. Overall survival will be estimated using the Kaplan-Meier method. References:

1. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic stem cell transplant recipients: a global perspective. BMT 2009. 44; 453-55.

2. Miller HK, Braun TM, Stillwell T, et al. Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease. BBMT 2017. 23; 522-28.

3. Levinson A, Pinkney K, Jin Z, et al. Acute Gastrointestinal Graft-vs-Host Disease Is Associated with Enteric Bacterial Bloodstream Infection Density in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients. Clin Infect Dis 2015. 61;350-7.

4. Satwani P, Freedman J, Chaudhury S, et al. A Multicenter Study of Bacterial Blood Stream Infections in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients: The Role of Acute Gastrointestinal Graft-vs-Host Disease. BBMT 2017. 23; 642-47.

5. Sepkowitz KA. Antibiotic prophylaxis in patients receiving hematopoietic stem cell transplant. BMT 2002. 29; 367-71.

6. Averbuch D, Tridello G, Mikulska M, et al. Antimicrobial resistance in Gram-negative rods causing bacteremia in hematopoietic stem cell transplant patients: intercontinental prospective study of Infectious Disease Working party of the European Bone Marrow Transplantation group. Clin Infect Dis. 2017. Doi: 10.1093/cid/cix646.

7. Yemm KE, Barreto JN, Mara KC, et al. A comparison of levofloxacin and oral third-generation cephalosporins as antibacterial prophylaxis in acute leukemia patients during chemotherapy-induced neutropenia. J Antimicrob 2017. Doi: 10.1093/jac/dkx338.

8. Jenq RR. Taur Y, Devlin M, et al. Intestinal Blautia is Associated with Reduced Death for Graft-versus-Host Disease. BBMT 2015. 21; 1373-83.

9. Taur Y, Xavier JB, Lipuma L, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic stem cell transplantation. Clin Infect Dis 2012. 55; 905-14.

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Characteristics of patients who underwent first allogeneic transplant with aGVHD grade II-IV and treated with systemic corticosteroids, from 2010 to 2016, as reported to the CIBMTR.

Variable N (%) Number of patients 5765 Number of centers 216 Gender

Male 3409 (59) Female 2356 (41)

Age at transplant, years Median (range) 51 (<1 - 82) <10 653 (11) 11-20 475 ( 8) 21-30 490 ( 8) 31-40 518 ( 9) 41-50 657 (11) 51-60 1239 (21) >60 1733 (30)

Disease AML 2007 (35) ALL 830 (14) Other leukemia 186 ( 3) CML 169 ( 3) MDS 1602 (28) Other acute leukemia 62 ( 1) NHL 277 ( 5) HL 17 (<1) Plasma cell disorder/Multiple Myeloma 8 (<1) Other Malignancies 3 (<1) Severe aplastic anemia 139 ( 2) Inherited abnormalities erythrocyte differentiation of function

184 ( 3)

SCID and other immune system disorders 159 ( 3) Inherited abnormalities of platelets 6 (<1) Inherited disorders of metabolism 65 ( 1) Histiocytic disorders 44 (<1) Autoimmune Diseases 2 (<1) Other, specify 5 (<1)

Graft type Bone Marrow 956 (17) Peripheral blood 3581 (62) Cord blood 1228 (21)

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Variable N (%) Number of patients 5765 Donor/recipient HLA match

Cord blood 1228 (21) HLA-identical siblings 1331 (23) matched related 53 (<1) Mismatched related, 1 mismatch 7 (<1) Mismatched related,>2 mismatch 165 ( 3) Mismatched related, mismatch unknown 155 ( 3) 8/8 unrelated 2136 (37) 7/8 unrelated 444 ( 8) <6/8 unrelated 15 (<1) Unrelated (HLA match information missing) 231 ( 4)

Year of transplant 2010 673 (12) 2011 475 ( 8) 2012 479 ( 8) 2013 968 (17) 2014 1163 (20) 2015 1141 (20) 2016 866 (15)

Bacterial BSI by 100 day post-transplant No 3950 (69) Yes 1814 (31) Missing 1 (<1)

Median follow-up of survivors, months 35 (1 - 84) Abbreviations: AML=Acute myelogenous leukemia, ALL=Acute lymphoblastic leukemia, CML=Chronic myelogenous leukemia, MDS=Myelodysplastic-myeloproliferative diseases, NHL=Non-Hodgkin lymphoma, HL=Hodgkin Lymphoma, SCID=Severe combined immunodeficiency, BSI = Blood stream infection.

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Proposal 1710-10

Title: Evaluating different ATG dosing of anti-thymocyte globulin in conditioning regimens for matched related and unrelated donor transplants.

Leland Metheny, MD, [email protected], University Hospitals Case Medical Center, Cleveland, OH Marcos de Lima, MD, [email protected], University Hospitals Case Medical Center, Cleveland, OH

Hypothesis: We hypothesized that a lower ATG dose could effectively reduce chronic GVHD incidences without increasing infection and relapses rates.

Scientific impact: Allogeneic hematopoietic stem cell transplant (HSCT) is a major consolidative therapy in patients with high risk hematologic malignancies and errors of hematopoiesis. Anti-thymocyte globulin (ATG) is often added to HSCT conditioning regimens to prevent graft rejection and reduce graft-versus-host-disease (GVHD). Doses used in retrospective and prospective clinical trials have ranged from 2.5 to 20mg/kg with rates of grade II-IV acute GVHD and chronic GVHD up to 40% and 60%, respectively(1-4). There is evidence that ATG can reduce the incidence of chronic GVHD (cGVHD)(5), and acute GVHD(6; 7), however the optimum dosing of ATG is unknown and is complicated by two formulations of rabbit ATG (Thymoglobulin or Grafalon), each with different dosing recommendations(8).

Our study aims to compare outcomes of patients undergoing matched related donor (MRD) or matched unrelated donor (MUD) transplant who had varying ATG dosages (or none) to elucidate the optimum dosage of ATG in conditioning regimens.

Specific aims: Primary Objective:

• To investigate the difference in overall survival or OS in patients who underwent MRD or MUDtransplant with myeloablative or reduced intensity conditioning with varying doses of ATG.

Secondary Objectives: • To investigate the differences in non-relapse mortality (NRM), treatment-related mortality

(TRM), relapse incidence (RI) and leukemia-free survival (LFS) among patients who underwentMRD or MUD transplant with conditioning with varying doses of ATG.

• To investigate the differences in incidence of acute and chronic graft-versus-host-disease(GVHD) patients who underwent MRD or MUD transplant with conditioning with varying dosesof ATG.

Scientific justification: Graft-versus-host disease (GVHD) is a frequent complication of allogeneic hematopoietic stem cell transplantation (HSCT). Human leukocyte antigen (HLA) matched related donors (MRD) are available for only 20-40% of patients in need of HSCT and many subjects must undergo transplant using a matched unrelated donor (MUD) graft; this graft source is associated with a greater likelihood of acute and chronic GVHD. Molecular level typing and allele matching have improved MUD transplant outcomes, with reported cumulative incidences of grade II-IV acute and chronic GVHD of 30-50% and 40-70%,

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mailto:[email protected]



respectively. Anti-thymocyte globulin (ATG), which induces tolerance by broad depletion of T cells, including alloreactive T-cells(4), has been extensively investigated as part of the preparative regimen to prevent GVHD and possibly improve engraftment. ATG can reduce the cumulative incidence of both acute and chronic GVHD in the MUD setting(7; 9). Initial ATG studies, however, did not suggest improved overall outcome as treatment related mortality (TRM) was greater due to increased risk of relapse and infections, particularly when higher doses of ATG were used(9). Although different ATG preparations are available, there is no consensus that one formulation is more effective than another and no consensus of which dosage is the optimum. Investigators have proposed that lower doses of ATG would retain the efficacy preventing GVHD while preserving the GVL effect, and reducing the cumulative incidence of severe infections(5). A small (n = 20) Bayesian randomized study compared rabbit ATG 4.5 mg/kg versus 7.5 mg/kg as part of the conditioning regimen for MUD HSCT, and suggested that the lower dose was superior using a composite endpoint of GVHD, early survival, and primary disease remission(2). Therefore, we hypothesized that a lower ATG dose could effectively reduce chronic GVHD incidences without increasing infection and relapses rates. Study population: All patients >18 years of age, with hematologic malignancy who underwent a MUD and MRD HSCT (with myeloablative conditioning and receiving BM or PB) between 2008 and 2015. Data requirements: Patient data

• Patient age • Gender • Race • Date of malignancy diagnosis

Disease data • Disease risk status (standard-risk versus high-risk) including cytogenetics • HCT-CI or DRI • Disease status at transplant (first complete remission or CR1/second CR or CR2/active disease) • Minimal residual disease status (when available)

Transplant-related data • Date of transplant • Conditioning/Preparative regimen (regimen and intensity) including use of ATG and DLI as part

of planned regimen • Donor type (MUD, MRD) • Stem-cell source (bone marrow versus peripheral blood stem-cells) • GVHD prophylaxis strategy • Incidence and grade of acute and chronic GVHD • CMV donor-recipient serostatus • CMV reactivation with end-organ involvement (if present) • Dates of relapse (if applicable), death or censor (date of last contact) • Cause of death • Transplant center name

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Study design: The design of our study is a retrospective cohort analysis comparing the outcomes of OS, NRM, RI, TRM, LFS, and GVHD incidence between adult patients undergoing MUD, MRD allogeneic HSCT from 2008-2015 who had varying ATG dosages (or none) to elucidate the optimum dosage of ATG in conditioning regimens. Retrospectively detailed information on each patient’s clinical characteristics and outcome will be tabulated and compared utilizing the CIBMTR registry. Statistical analysis: χ2 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. Multivariable analysis for overall survival, non-relapse mortality, and relapse incidence will be performed on all patients in the cohort as well as pre-specified sub-group analysis for high-risk and standard risk patients. Center effect will be adjusted in the final multivariable models References: 1. Remberger M, Svahn BM, Hentschke P, Lofgren C, Ringden O. 1999. Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation. Bone Marrow Transplant 24:823-30 2. Bashir Q, Munsell MF, Giralt S, de Padua Silva L, Sharma M, et al. 2012. Randomized phase II trial comparing two dose levels of thymoglobulin in patients undergoing unrelated donor hematopoietic cell transplant. Leukemia & lymphoma 53:915-9 3. Duggan P, Booth K, Chaudhry A, Stewart D, Ruether JD, et al. 2002. Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis. Bone marrow transplantation 30:681-6 4. Hamadani M, Blum W, Phillips G, Elder P, Andritsos L, et al. 2009. Improved nonrelapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced-intensity conditioning allogeneic transplantation for hematologic malignancies. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 15:1422-30 5. Kroger N, Solano C, Wolschke C, Bandini G, Patriarca F, et al. 2016. Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. The New England journal of medicine 374:43-53 6. Bacigalupo A. 2005. Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bone marrow transplantation 35:225-31 7. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, et al. 2009. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. The Lancet. Oncology 10:855-64 8. Ruutu T, Gratwohl A, de Witte T, Afanasyev B, Apperley J, et al. 2014. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone marrow transplantation 49:168-73 9. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, et al. 2001. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood 98:2942-7

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Characteristics of adult patients undergoing first allogeneic myeloablative transplant for

hematological malignancy from a matched donor between 2008-2015, as reported to the CIBMTR.

Variable No Yes Number of patients 4090 1046 Number of centers 170 118 Age at transplant, years Median (range) 49 (18-81) 51 (18-74) 18-29 572 (14) 156 (15) 30-39 601 (15) 129 (12) 40-49 970 (24) 180 (17) 50-59 1349 (33) 333 (32) 60+ 598 (15) 248 (24) ATG source Not applicable 4090 - Horse - 86 (8) Rabbit - 888 (85) ATG given for GVHD prophylaxis – dose not collected - 69 (7) Missing - 3 (<1) ATG dose used in regimen, mg/kg, Horse source Median (range) - 45 (<1-149) <10 - 13 (15) 10-29 - 9 (10) 30-39 - 15 (17) 40-49 - 9 (10) 50-69 - 25 (29) 70-99 - 14 (16) 100+ - 1 (1) ATG dose used in regimen, mg/kg, Rabbit source Median (range) - 4 (<1-85) <1 - 24 (3) 1-2.9 - 131 (15) 3-3.9 - 177 (20) 4-4.9 - 264 (30) 5-6.9 - 197 (22) 7-9.9 - 50 (6) 10+ - 42 (5) Missing - 3 (<1)

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Variable No Yes Number of patients 4090 1046 Disease AML 1915 (47) 474 (45) ALL 628 (15) 128 (12) CML 264 (6) 52 (5) MDS 661 (16) 237 (23) MPNs 239 (6) 70 (7) Other acute leukemia 41 (1) 11 (1) Other leukemia 57 (1) 13 (1) NHL 220 (5) 44 (4) HD 18 (<1) 7 (<1) MM 47 (1) 10 (<1) Graft type Bone Marrow 601 (15) 164 (16) Peripheral Blood 3489 (85) 882 (84) Type of donor HLA identical sibling 2312 (57) 183 (17) 8/8-matched unrelated 1778 (43) 863 (83) GVHD prophylaxis No GVHD prophylaxis 45 (1) 13 (1) Ex-vivo T-cell depletion 14 (<1) 13 (1) CD34 selection 11 (<1) 53 (5) Post-CY + other(s) 77 (2) 4 (<1) TAC + MMF +- other(s) (except PT-Cy) 435 (11) 193 (18) TAC + MTX +- other(s) (except MMF, PT-Cy) 2459 (60) 583 (56) TAC + other(s) (except MMF, MTX, PT-Cy) 342 (8) 41 (4) TAC alone 82 (2) 8 (<1) CSA + MMF +- other(s) (except PT-Cy) 115 (3) 28 (3) CSA + MTX +- other(s) (except MMF, PT-Cy) 456 (11) 85 (8) CSA + other(s) (except MMF, MTX, PT-Cy) 9 (<1) 7 (<1) CSA alone 24 (<1) 10 (<1) Other(s) 20 (<1) 8 (<1) Missing 1 (<1) 0 Year of transplant 2008 749 (18) 186 (18) 2009 777 (19) 202 (19) 2010 676 (17) 120 (11) 2011 319 (8) 91 (9) 2012 259 (6) 95 (9) 2013 464 (11) 148 (14)

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Variable No Yes 2014 497 (12) 137 (13) 2015 349 (9) 67 (6) Follow-up of survivors, months, median (range) 60 (1-107) 62 (3-102)

Abbreviations: AML = Acute myelogenous leukemia, ALL = Acute lymphoblastic leukemia, CML = Chronic myelogenous leukemia, MDS = Myelodysplastic syndrome, MPNs = Myeloproliferative diseases, NHL = Non-Hodgkin lymphoma, HD = Hodgkin disease, MM = Multiple Myeloma, PT-Cy = Post-transplant Cyclophosphamide, TAC = Tacrolimus, MMF = Mycophenolate mofetil, MTX = Methotrexate, CSA = Cyclosporine.

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Proposal 1709-04

Title: Impact of chronic graft-versus-host disease on non-relapse mortality and disease relapse in transplant recipients

Vijaya Bhatt, MBBS, [email protected], University of Nebraska Medical Center Stephanie Lee, MD, MPH, [email protected], Fred Hutchinson Cancer Research Center

Hypothesis: Transplant recipients, who develop chronic graft-versus-host disease (GVHD), have significantly higher non-relapse mortality compared to patients without chronic GVHD. This adverse effect of chronic GVHD may be more pronounced in older patients.

Scientific impact: The use of allogeneic HCT has increased significantly in recent years, particularly among older patients, however, long-term health status of older transplant recipients is poorly studied. Older patients may experience a higher degree of morbidity and mortality from chronic GVHD. The development of chronic GVHD may have significant impact on non-relapse mortality and disease relapse, particularly in older patients. Understanding the impact of chronic GVHD on non-relapse mortality and disease relapse could guide therapeutic strategies and provide useful prognostic information.

Specific Aims: • To compare the non-relapse mortality of older (≥60 years at the time of HCT) and younger

patients (40-59 years) with versus without chronic GVHD• To contrast the risk of disease relapse in older and younger patients with versus without chronic

GVHD• To compare the overall survival of older and younger patients with versus without chronic GVHD

Exploratory aims: • To determine the impact of HCT CI and graft source on the incidence of chronic GVHD• To analyze the interaction between chronic GVHD, HCT CI and disease risk index on OS• To study the impact of chronic GVHD on non-relapse mortality and the risk of disease relapse in

patients >70 years old• To identify the cause of mortality in patients with chronic GVHD.• To evaluate the practice patterns of first-line therapy for chronic GVHD in older versus younger

patients

Scientific justification: Chronic GVHD is a major late complication of HCT. The syndrome is associated with major transplant-related morbidity, mortality, infectious complications, prolonged duration of immune suppression, and impaired patient-reported quality of life (1-4). Thus, it represents a major obstacle to recovery and survival following HCT. An increasing number of patients, particularly in their 60s and 70s have undergone HCT in recent years (5), however, long-term health status of older transplant recipients is poorly studied. The incidence of chronic GVHD may increase with age (6). The development of chronic GVHD and the use of

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immunosuppressive therapy may lead to a higher degree of non-relapse mortality in older patients with chronic GVHD. Additionally, the effect of chronic GVHD on the risk of relapse has not been specifically studied in older patients. In a prior study from the Chronic GVHD Consortium (7), older patients (≥60 years) with moderate or severe chronic GVHD were found to have comparable non-relapse mortality and overall survival when compared to younger patients. In this study, the number of older patients was modest (n=128), and the outcomes of patients with versus without chronic GVHD was not studied. In this context, the objectives of this proposed study are to understand the consequences of chronic GVHD in both younger and older transplant recipients using the larger CIBMTR database to understand the potential gains of better prevention and treatment of chronic GVHD in this population. Study population: Adult patients above the age of 40 years who have received first allogeneic stem cell transplant for hematologic malignancies during the years 2000-2013. Variables and outcomes: Patient-related variables:

• Age: 40-59, 60-69, 70 years or older • Gender: male or female • Karnofsky performance score at SCT: ≥90 or <90 • Race: White vs. Black vs. Asian/Pacific Islander vs. Hispanics vs Others • Transplant comorbidity index: 0, 1-2, 3 or higher

Disease-related variables: • Disease type: AML, MDS, ALL, MPD, CML, CLL, NHL, HL • Disease status at transplant • Disease risk index

Transplant-related variables: • Donor: related or unrelated • Graft type: bone marrow or peripheral blood • Donor/recipient sex match • HLA match • Conditioning regimens groups: myeloablative vs. non-myeloablative • ATG: yes or no • Alemtuzumab: yes or no • GVHD prophylaxis: Tac/MTX or CSA/MTX • Prior autologous transplant

GVHD-related variables: • Date of acute GVHD diagnosis • Organ involvement of acute GVHD • Treated with steroids: yes or no • Date of chronic GVHD diagnosis • Severity of chronic GVHD • Initial treatment of chronic GVHD • Response of chronic GVHD to initial treatment

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Outcome variables:

• Relapse at last follow-up: Yes or no • Non-relapse mortality at last follow up: yes or no • Overall survival • Cause of death, if available

Study design: The cumulative incidence of chronic GVHD in older (≥60 years at the time of HCT) and younger patients (40-59 years) will be determined as the proportion with 95% confidence interval. After adjusting for other baseline co-variates, we will determine the impact of HCT CI and graft source on the incidence of chronic GVHD in older and younger patients using multivariate logistic regression. A time-varying covariate analysis will be performed to determine the risk of non-relapse mortality, relapse and overall survival in patients who develop chronic GVHD, compared to those without chronic GVHD. Kaplan Meier or cumulative incidence curves will be plotted for various outcomes with appropriate adjustment for competing risks. A subset analysis will be performed in patients aged 70 years and older. We will also study the interaction between chronic GVHD, baseline HCT CI and disease risk index on OS. If information is available, descriptive statistics will be used to evaluate the practice patterns of first-line therapy for chronic GVHD. We will also compare various causes of mortality (relapse versus non-relapse mortality, and if available specific groups of non-relapse mortality) in groups with versus without chronic GVHD. The CIBMTR statistician will be consulted for final statistical plan. References:

1. Lee SJ, Flowers ME. Recognizing and managing chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2008:134-41.

2. Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 2002 Jul 15;100(2):406-14.

3. Fraser CJ, Bhatia S, Ness K, Carter A, Francisco L, Arora M, et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood. 2006 Oct 15;108(8):2867-73.

4. Pidala J, Anasetti C, Jim H. Quality of life after allogeneic hematopoietic cell transplantation. Blood. 2009 Jul 2;114(1):7-19.

5. Muffly L, Pasquini MC, Martens M, Brazauskas R, Zhu X, Adekola K, et al. Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States. Blood. 2017 Aug 31;130(9):1156-64.

6. Remberger M, Kumlien G, Aschan J, Barkholt L, Hentschke P, Ljungman P, 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):674-82.

7. El-Jawahri A, Pidala J, Inamoto Y, Chai X, Khera N, Wood WA, et al. Impact of age on quality of life, functional status, and survival in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2014 Sep;20(9):1341-8.

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Characteristics of patients undergoing first allogeneic transplant for hematological malignancy for patients 40 years of age or older between 2000-2013, as reported to the CIBMTR.

Variable 40-49 50-59 60+ Number of patients 6272 7960 4855 Number of centers 245 249 203 Age of recipient at transplant, years Median (range) 46 (40-50) 55 (50-60) 64 (60-82) 40-49 6272 0 0 50-59 0 7960 0 60-69 0 0 4436 (91) 70+ 0 0 419 (9) Disease AML 2378 (38) 3008 (38) 1886 (39) ALL 681 (11) 460 (6) 129 (3) CML 755 (12) 512 (6) 119 (2) MDS 398 (6) 904 (11) 1128 (23) MPN 393 (6) 691 (9) 461 (9) Other acute leukemia 34 (<1) 29 (<1) 16 (<1) Other leukemia 275 (4) 588 (7) 361 (7) NHL 882 (14) 1171 (15) 568 (12) HD 85 (1) 48 (<1) 9 (<1) PCD/MM 347 (6) 483 (6) 160 (3) Other malignancies 44 (<1) 66 (<1) 18 (<1) Type of donor HLA identical sibling 2601 (41) 3240 (41) 1471 (30) Twin 59 (<1) 77 (<1) 57 (1) Haploidentical (>1-antigen mm) 69 (1) 101 (1) 150 (3) Other relatives 106 (2) 149 (2) 90 (2) 8/8-matched unrelated 2253 (36) 3162 (40) 2404 (50) 7/8-matched unrelated 928 (15) 992 (12) 581 (12) <6/8-matched unrelated 242 (4) 226 (3) 87 (2) Unrelated (matching cannot be determined) 13 (<1) 12 (<1) 14 (<1) Missing 1 (<1) 1 (<1) 1 (<1) Graft type Bone marrow 1572 (25) 1437 (18) 579 (12) Peripheral blood 4700 (75) 6523 (82) 4276 (88)

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Variable 40-49 50-59 60+ Number of patients 6272 7960 4855 Conditioning regimen intensity Myeloablative 4413 (70) 4071 (51) 1137 (23) Reduced Intensity 1002 (16) 2162 (27) 2282 (47) Non-myeloablative 507 (8) 1196 (15) 1081 (22) TBD 255 (4) 402 (5) 299 (6) Missing 95 (2) 129 (2) 56 (1) GVHD prophylaxis No GVHD prophylaxis 114 (2) 126 (2) 109 (2) Ex-vivo T-cell depletion 210 (3) 249 (3) 96 (2) CD34 selection 124 (2) 189 (2) 135 (3) Post-CY + other(s) 71 (1) 91 (1) 110 (2) TAC + MMF +- other(s) (except PT-Cy) 654 (10) 1137 (14) 859 (18) TAC + MTX +- other(s) (except MMF, PT-Cy) 2089 (33) 2727 (34) 1610 (33) TAC + other(s) (except MMF, MTX, PT-Cy) 218 (3) 290 (4) 213 (4) TAC alone 129 (2) 191 (2) 172 (4) CSA + MMF +- other(s) (except PT-Cy) 479 (8) 944 (12) 827 (17) CSA + MTX +- other(s) (except MMF, PT-Cy) 1735 (28) 1430 (18) 341 (7) CSA + other(s) (except MMF, MTX, PT-Cy) 162 (3) 188 (2) 122 (3) CSA alone 207 (3) 284 (4) 158 (3) Other(s) 50 (<1) 74 (<1) 76 (2) Missing 30 (<1) 40 (<1) 27 (<1) Year of transplant 2000-2003 2289 (36) 2171 (27) 697 (14) 2004-2007 2346 (37) 3063 (38) 1643 (34) 2008-2013 1637 (26) 2726 (34) 2515 (52) Follow-up of survivors, months, median (range) 84 (<1-199) 74 (<1-197) 61 (<1-192) Abbreviations: AML = Acute myelogenous leukemia, ALL = Acute lymphoblastic leukemia, CML = Chronic myelogenous leukemia, MDS = Myelodysplastic syndrome, MPN = Myeloproliferative diseases, NHL = Non-Hodgkin lymphoma, HD = Hodgkin disease, PCD/MM = Plasma Cell Disorders/Multiple Myeloma, TBD = To be determined, TAC = Tacrolimus, MMF = Mycophenolate mofetil, PT-Cy = Post-transplant Cyclophosphamide, MTX = Methotrexate, CSA = Cyclosporine.

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Proposal 1711-162

Title: Comparison of Late Effects Among Allogeneic Hematopoietic Cell Transplantation Survivors with and Without Chronic Graft-Versus-Host Disease (GVHD)

Catherine Joy Lee, MD, [email protected], Huntsman Cancer Institute, University of Utah Daniel Ricardo Couriel, MD, MS, [email protected], Huntsman Cancer Institute, University of Utah

Hypothesis: The cumulative incidence and incidence rate of late effects is greater in allogeneic hematopoietic cell transplantation (alloHCT) survivors with any chronic GVHD compared to those without any chronic GVHD but differs among survivors with chronic GVHD depending on its onset, severity, and organ involvement following alloHCT.

Specific aims: • To compare the cumulative incidence of late effects between one-year survivors of alloHCT

diagnosed with chronic GVHD versus those without chronic GHVD.• To compare the individual late effects and their incidence rates between one-year survivors of

allogeneic HCT diagnosed with chronic GVHD versus those without chronic GHVD.• To evaluate the effects of the onset, severity, and organ involvement of chronic GVHD on the

development of late effects.

Scientific Impact: These results would be the first to assess the specific impact of chronic GVHD and its onset, severity and organ involvement following allogeneic HCT on the incidence and rate of development of late effects. We will further categorize this association by grouping late effects into malignant versus non-malignant and then evaluate individual late effects. This data would provide rationale to examine treatment algorithms, alternative screening, primary, and secondary prevention practices for select late effects in allogeneic transplant survivors with chronic GVHD, with the goal of improving morbidity, quality of life, and mortality among these patients.

Scientific Justification: Advances in allogeneic HCT practices over the past two decades have resulted in improved transplant-related mortality.[1] Despite improvement in transplant practices and supportive care, the incidence of chronic GVHD at one year has increased from 28% in the mid-late 1990s to 37% in the early 21st century.[2] While in most recent years non-relapse mortality in patients with chronic GVHD at 1 and 3 years has decreased significantly, five-year overall survival remains at 45% (95% CI 45-47), mostly due to disease relapse.[2] Therefore, a considerable number of transplant survivors live with chronic GVHD and its associated immunodeficiency. It is well accepted that transplant survivors are at considerable risk for malignant and non-malignant late effects and experience higher late mortality rates compared to the general population.[1,3-8] Chronic GVHD is a risk factor for certain late effects, such as squamous cell cancers[9], cardiovascular disease[5], bronchiolitis obliterans syndrome[10] and chronic obstructive pulmonary disease, hypothyroidism and diabetes[11]. However, the correlation and actual risk to specific late effects varies between studies. To our knowledge, there has not been any registry or other clinical study that has focused on determining the cumulative incidence and incidence rate of late effects specifically following a diagnosis of chronic

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GVHD, compared to those who never developed it. Furthermore, it is unknown how the onset, severity, and organ involvement of chronic GVHD affect the development of late effects. Our objective is to use a large and representative cohort of HCT survivors with and without chronic GHVD to better characterize and compare late effects between these groups. The knowledge gathered from this study has the potential to improve screening and prevention strategies specific to this cohort of survivors, hopefully leading to a positive impact on morbidity, mortality, and quality of life. Study population: Inclusion Criteria:

• All patients with any hematologic malignancy who underwent hematopoietic allogeneic transplantation with any donor, graft source, or conditioning regimen who are alive at one year and disease free after their transplant.

• Patients who had their first allogeneic transplant between 2000-2010, with or without donor cell infusions at any time.

Exclusion Criteria: • Patients who have received more than one allogeneic transplant

Data requirements:

• Transplant Essential Data (TED) Forms • Comprehensive Report Forms (CRF)

Sample requirements:

• NA Variables:

• Age at transplant: ≥ 18 years old • Patient gender: Male vs. Female • Obesity at transplant: BMI < 30 vs. ≥ 30 • Donor/Recipient gender: F/F vs. M/M vs. F/M vs. M/F • Disease: Myeloid vs. Lymphoid • Karnofsky score ≥ 90 vs < 90 • Sorror Co-morbidity index: 0 vs. 1-2 vs. ≥ 3 • Disease Risk Index: low vs. intermediate vs. high/very high • Donor Type: MRD vs. MUD vs. mmUD vs. Cord vs. Haplo • Graft Type: BM vs. PBSC • Conditioning regimen intensity: MAC vs. RIC according to CIBMTR definition[12] • Total TBI Dose: < 12 Gy / ≥ 12 Gy • GVHD Prophylaxis: CNI+MTX vs. CNI+MMF vs. CNI+sirolimus vs. other vs. unknown or missing • In vivo or ex-vivo TCD: no vs. yes vs. unknown or missing • Chronic GVHD: no vs. yes • Maximum grade of chronic GVHD: Limited vs. Extensive vs. Unknown or missing • Onset of cGHVD: ≤ 1 year after alloHCT vs. > 1 year after alloHCT • Organ involvement of cGVHD: mucocutaneous vs. visceral involvement • Specific Systemic Therapy for cGVHD: steroid alone vs. steroid + other agent vs. CNI +/- other

agent (not steroid) vs. Sirolimus +/- other agent (not steroid) vs. TKI vs. other vs. unknown or missing

• DLI: no vs. yes vs. unknown or missing

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• Donor/Recipient CMV status: -/+ vs. +/- vs. +/+ vs. -/- Outcomes:

Primary: • Cumulative incidence of late effects at 2, 5 and 10 years for the whole group, and for patients

with chronic GVHD versus patients without chronic GVHD* • Cumulative incidence and rates of individual late effects at 2, 5 and 10 years for the whole

group, and for patients with chronic GVHD versus patients without chronic GVHD* o neurological (strokes/seizures) o cardiovascular (CHF/MI) o endocrine (diabetes, hypothyroidism, growth hormone deficiency, gonadal

dysfunction/infertility) o renal (renal failure warranting hemodialysis) o gastrointestinal/hepatic (pancreatitis/cirrhosis) o musculoskeletal (avascular necrosis) o special sensory (cataracts) o subsequent neoplasms (lymphoid, including PTLD vs MDS/AML vs solid tumors) o other (COPD, pulmonary fibrosis or other restrictive airway disease)

Secondary: • Cumulative incidence of OS and NRM for the whole group, and for patients with chronic GVHD

versus patients without chronic GVHD* • Cause of death: GVHD vs. late effects vs. relapse vs. others (i.e. other causes that are not GVHD,

late effects or relapse), for the whole group, and for patients with chronic GVHD vs. patients without chronic GVHD* *Chronic GVHD will be assessed in 3 subgroups: “All chronic GVHD”, “chronic GVHD diagnosed during the first-year post transplant or early chronic GVHD” and “late chronic GVHD”. Furthermore, each group with be analyzed by chronic GVHD severity (limited vs. extensive) and organ involvement (mucocutaneous vs. visceral).

Study design: A retrospective multicenter study will be performed using the CIBMTR dataset. Patients will be classified according to the presence or absence of chronic GVHD. Patients with chronic GVHD will be further categorized into those with a diagnosis of chronic GVHD within the first-year post transplant (i.e. early chronic GVHD), and those with a later diagnosis (i.e. late chronic GVHD). The objective of this analysis is to compare the cumulative incidence of late effects between these two populations. Late effects will be analyzed in malignant versus non-malignant categories, and then individually. Descriptive statistics, including Chi-square, Student T-test or Wilcoxon statistic will be used to compare the distribution of demographic and other patient and GVHD-related characteristics. The incidence and rate of late effects in patients with and without chronic GVHD will be analyzed with the cumulative incidence method, accounting for death and relapse as competing risks. The impact of chronic GVHD on late effects will be assessed using the Cox Proportional Hazards Method. The impact of chronic GVHD and late effects on survival outcomes (i.e. NRM and OS) will be analyzed using competing risk regression. Relapse and death will be the competing risks for cumulative incidence of OS and NRM. Cumulative incidence of late effects and survival outcomes will be estimated at 2, 5 and 10 years after HCT, and estimates will be provided with 95% confidence intervals.

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Non-CIBMTR Data Source:

• NA References: [1] Majhail NS, Rizzo JD. Surviving the cure: long term followup of hematopoietic cell transplant recipients. Bone Marrow Transplant 2013;48(9):1145-51. [2] Arai S, Arora M, Wang T, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2015;21(2):266-74. [3] Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 2011;29(16):2230-9. [4] Sun CL, Francisco L, Kawashima T, et al. Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood 2010;116(17):3129-39; quiz 3377. [5] DeFilipp Z, Duarte RF, Snowden JA, et al. Metabolic Syndrome and Cardiovascular Disease after Hematopoietic Cell Transplantation: Screening and Preventive Practice Recommendations from the CIBMTR and EBMT. Biol Blood Marrow Transplant 2016;22(8):1493-503. [6] Savani BN, Griffith ML, Jagasia S, Lee SJ. How I treat late effects in adults after allogeneic stem cell transplantation. Blood 2011;117(11):3002-9. [7] Clark CA, Savani M, Mohty M, Savani BN. What do we need to know about allogeneic hematopoietic stem cell transplant survivors? Bone Marrow Transplant 2016;51(8):1025-31. [8] Battiwalla M, Tichelli A, Majhail NS. Long Term Survivorship after Hematopoietic Cell Transplantation: Roadmap for Research and Care. Biol Blood Marrow Transplant 2016. [9] Majhail NS. Secondary cancers following allogeneic haematopoietic cell transplantation in adults. Br J Haematol 2011;154(3):301-10. [10] Sengsayadeth SM, Srivastava S, Jagasia M, Savani BN. Time to explore preventive and novel therapies for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012;18(10):1479-87. [11] Socie G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003;101(9):3373-85. [12] Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009;15(12):1628-33.

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Characteristics of patients undergoing first allogeneic transplant for hematological malignancy between 2000-2016, and are alive and disease-free 1-year post-transplant, as reported to the CIBMTR.

Variable N (%) Number of patients 17610 Number of centers 336 Age at transplant, years Median (range) 44 (<1-83) < 18 3161 (18) 18-29 2358 (13) 30-39 2261 (13) 40-49 3187 (18) 50-59 6086 (35) 60-69 303 (2) 70+ 254 (1) Disease AML 6295 (36) ALL 3078 (17) CML 1645 (9) MDS 1808 (10) MPS 1057 (6) Other acute leukemia 212 (1) Other leukemia 686 (4) NHL 1994 (11) HD 346 (2) MM 458 (3) Other malignancies 31 (<1) Type of donor Cord blood 2073 (12) HLA identical sibling 6266 (36) Twin 180 (1) Haploidentical (1-antigen mm) 56 (<1) Haploidentical (>2-antigen mm) 390 (2) Matched other relative 13 (<1) Mismatched other relative (unknown mm) 327 (2) Other relative 22 (<1) 8/8-matched unrelated 5958 (34) 7/8-matched unrelated 1825 (10) <6/8-matched unrelated 355 (2) Unrelated (matching cannot be determined) 54 (<1) Missing 91 (<1)

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Variable N (%) Number of patients 17610 Conditioning regimen intensity Myeloablative 12910 (64) RIC 3990 (20) NMA 2212 (11) TBD 719 (4) Missing 263 (1) GVHD prophylaxis No GVHD prophylaxis 326 (2) Ex-vivo T-cell depletion 511 (3) CD34 selection 420 (2) Post-CY + other(s) 450 (2) Post-CY alone 1 (<1) TAC + MMF +- other(s) (except PT-Cy) 2409 (12) TAC + MTX +- other(s) (except MMF, PT-Cy) 6209 (31) TAC + other(s) (except MMF, MTX, PT-Cy) 805 (4) TAC alone 397 (2) CSA + MMF +- other(s) (except PT-Cy) 2331 (12) CSA + MTX +- other(s) (except MMF, PT-Cy) 4643 (23) CSA + other(s) (except MMF, MTX, PT-Cy) 779 (4) CSA alone 531 (3) Other(s) 194 (<1) Missing 88 (<1)

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Variable N (%) Number of patients 17610 Year of transplant 2000 1153 (6) 2001 1132 (6) 2002 1226 (6) 2003 1293 (6) 2004 1577 (8) 2005 1708 (9) 2006 1706 (8) 2007 1536 (8) 2008 1622 (8) 2009 1500 (7) 2010 1067 (5) 2011 747 (4) 2012 759 (4) 2013 1208 (6) 2014 994 (5) 2015 664 (3) 2016 202 (1) Chronic GVHD achieved within 1 year post-transplant Yes 9135 (52) No 7975 (45) Missing 500 (3) Follow-up of survivors, months, median (range) 73 (12-199) Abbreviations: AML = Acute myelogenous leukemia, ALL = Acute lymphoblastic leukemia, CML = Chronic myelogenous leukemia, MDS = Myelodysplastic syndrome, MPN = Myeloproliferative diseases, NHL = Non-Hodgkin lymphoma, HD = Hodgkin disease, PCD/MM = Plasma Cell Disorders/Multiple Myeloma, RIC = Reduced intensity conditioning, NMA = Non-myeloablative, TBD = To be determined, PT-Cy = Post-transplant Cyclophosphamide, TAC = Tacrolimus, MMF = Mycophenolate mofetil, MTX = Methotrexate, CSA = Cyclosporine.

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TO: Graft-Versus-Host Disease Working Committee Members

FROM: Mukta Arora, MD, MS and Stephen Spellman, MBS; Scientific Directors for GVWC

RE: Studies in Progress Summary

GV14-01: Comparison of mycophenolate versus methotrexate in combination with a calcineurin inhibitor for GVHD prophylaxis in allogeneic hematopoietic cell transplantation (BK Hamilton / S Chhabra / N Majhail / L Costa / RK Stuart / D Kim / O Ringden) This study will compare the incidence of grade II-IV aGVHD between patients receiving a GVHD prophylaxis regimen of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) with mycophenolate mofetil (MMF) versus methotrexate (MTX). Incidence of grade III-IV aGVHD, cGVHD and rates of relapse, TRM, DFS, OS and hematopoietic recovery will also be evaluated. The analysis was completed and presented at the CIBMTR Statistical Meeting in September 2017. After minor revisions, the analysis was finalized with the conclusion that, among myeloabltive intensity, CSA+MMF recipients experienced significantly worse GVHD and survival than recipients of Tac+MTX, and among reduced intensity, CSA+MMF was an inferior GVHD prophylaxis regimen to prevent aGVHD . These findings will be presented as two Tandem poster presentations, separately among the patients receiving myeloablative and reduced intensity conditioning, in February 2018. Manuscript preparation is underway and the goal of the study is to submit the manuscript by June 2018.

GV15-01b: Pro-inflammatory cytokine and adipokine levels in adult unrelated marrow donors are not associated with HCT outcomes (L Turcotte / M Verneris / J Knight) This study aims to evaluate the impact of donor weight status and donor inflammatory status as a function of donor weight or donor serum inflammatory cytokine concentration on the development of GVHD in patients undergoing allogeneic HCT for AML, ALL, CML, MDS from an 8/8-matched unrelated donor. The manuscript was circulated to the study’s Writing Committee in July 2017, and a revised manuscript was submitted to BMT in August 2017. In January 2018, at the journal’s recommendation, the manuscript was reformatted and submitted as a letter for publication.

GV16-02: The impact of the graft T cell dose on the outcome of allogeneic HLA-matched peripheral blood stem cell transplantation (A Saad / S Hashmi / M Sharma / L Lamb) This study aims to correlate the graft dose of CD3+, CD4+ and CD8+ T cells with the incidence and grade of acute and chronic GVHD, and other outcomes, following PBSC HCT. The protocol was forwarded to the GVWC for feedback and to form a Writing Committee in May 2017, with the protocol being finalized in July 2017. After an extensive cleaning of the data file, the analysis results were presented at the CIBMTR Statistical Meeting in January 2018. The plan for the study is to then circulate the results to the study’s Writing Committee and receive an initial draft of the manuscript by April 2018.

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GV17-01: Investigating antibiotic exposure and risk of acute GVHD in children undergoing HCT for acute leukemia (C Elgarten/ B Fisher/ R Aplenc) This study aims to determine the association and impact of pre-transplant antibiotic exposures with subsequent development of aGVHD in pediatric leukemia patients. The hypothesis is that exposure to antibiotics with activity against anaerobic commensal microorganisms during the pre- and peri-transplant time periods will be associated with an increased risk of aGVHD. The draft protocol was received in June 2017 and revised in December 2017. The plan for the study is to finalize the protocol in February 2018 and prepare the data file for analysis by July 2018. GV17-02: Risk factors of GVHD in T-replete haploidentical HCT using post-transplant Cy (A Im/ B Hamilton/ A Rashidi/ N Majhail/ S Pavletic/ D Weisdorf) This study aims to describe the incidence and characteristics of patients undergoing post-transplant Cyclophosphamide (PT-Cy) -based T-replete haploidentical HCT, and evaluate their risk factors for acute and chronic GVHD. Specifically, the impact of conditioning intensity and graft source on GVHD will be evaluated. The draft protocol was received in June 2017 and was revised in December 2017. The protocol was then presented at the CIBMTR Statistical Meeting in January 2018, and forwarded to the GVWC in February 2018. GV17-03: Alterations in the characteristics and outcomes of GVHD following post-transplant Cy for haploidentical HCT and in patients over 60 at high risk for GVHD (R Saliba/ S Ciurea/ J Schriber) This study aims to compare outcomes between recipients of PT-Cy-based haploidentical HCT versus 8/8-matched unrelated donor with standard GVHD prophylaxis. In addition, a subset analysis will be performed comparing PT-Cy-based versus standard GVHD prophylaxis (irrespective of donor type). The draft protocol was received in June 2017 and was revised in January 2018. The protocol was then presented at the CIBMTR Statistical Meeting in February 2018. The plan for the study is to incorporate any feedback from the Statistical Meeting and then circulate the protocol to the GVWC to form a Writing Committee for the study in March 2018.

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a g e n d a cibmtr working committee for ......2018/02/23 · loren aw. graft versus host disease...

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