not for publication or presentation · not for publication or presentation ... qayed m, salit r,...

Not for publication or presentation

A G E N D A 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. Introduction

a. Minutes and Overview Plan from February 2016 meeting (Attachment 1)

2. Accrual summary (Attachment 2)

3. Presentations, published or submitted papers

a. 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, Askar M, 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 transplantation for acute leukemia: An analysis of risk factors and effect on outcomes. Bone Marrow Transplant. 2016 Dec; [Epub ahead of print].

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.

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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.

4. Future/proposed studies

a. PROP 1611-04 Risk stratification by time to onset of acute GVHD. (H Choe/ S Lee) (Attachment 3)

b. PROP 1611-05 Analysis of the risk factors for hepatic acute GVHD after allogeneic stem cell transplantation (Y Arai) (Attachment 4)

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)

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)

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)

f. PROP 1608-01 Evaluate the relationship between clostridium difficile colitis and subsequent gastrointenstinal graft versus host disease in recipients of allogeneic stem cell transplantation (D Bhutani/ A Deol) (Attachment 8)

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)

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)

Dropped proposed studies

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.

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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 calcineruin 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.

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) 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

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M I N U T E S CIBMTR WORKING COMMITTEE FOR GRAFT-VERSUS-HOST DISEASE Honolulu, HI Saturday, February 20, 2016, 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 Directors:

Mukta Arora, MD, MS, University of Minnesota Medical Center, Minneapolis, MN; Telephone: 612-626-4105; E-mail: [email protected] Stephen Spellman, MBS, CIBMTR Statistical Center, Minneapolis, MN; Telephone: 612-617-8334; E-mail: [email protected]

Statistical Director:

Tao Wang, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-4339; 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 2015 meeting

Dr. Dan Couriel began meeting at 12:15pm by introducing the GVWC leadership and thegoals and limitations of the GVWC.

2. Accrual summary

Repository summary

Steve Spellman presented a summary on the repository, saying there’s been an interest in thistopic for GVHD purposes. Mr. Spellman referenced that the accrual repository tables can befound in Attachment 2 of the Immunobiology Working Committee (IBWC)’s Tandem materials.

3. Presentations, published or submitted papers

a. GV11-03 Inamoto Y, Flowers ME, Wang T, Urbano-Ispizua A, Hemmer MT, Cutler CS,Couriel DR, Alousi AM, Antin JH, Gale RP, Gupta V, Hamilton BK, Kharfan-Dabaja MA,Marks DI, Ringden OT, Socie G, Solh MM, Akpek G, Cairo MS, Chao NJ, Hayashi RJ,Nishihori T, Reshef R, Saad A, Shah A, Teshima T, Tallman MS, Wirk B, Spellman SR, AroraM, Martin PJ. Tacrolimus versus cyclosporine after hematopoietic cell transplantation foracquired aplastic anemia. Biology Blood Marrow Transplant. 2015 Oct; 21(10):1776-82.

Not for publication or presentation Attachement 1

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b. 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, YuL, Bitan M, Cairo MS, Qayed M, Salit R, Gale PR, Martino R, Jaglowski S, Bajel A, Savani B,Frangoul H, Lewis I, Storek J, Askar M, Kharfan-Dabaja MA, Aljurf M, Ringden O, Reshef R,Olsson R, Hashmi SK, MacMillan M, Lazaryan A, Spellman SR, Arora M, Cutler CS. Acuteand chronic GVHD after umbilical cord blood transplantation for acute leukemia: Ananalysis of risk factors and effect on outcomes. Submitted.

c. 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 Highlypersonalized treatment recommendations from cohort and registry data using Q-learning.Submitted.

d. GV12-01 Khoury, HJ, Wang T, Arora M, Hemmer MT, Spellman SR, Cutler CS, Couriel DR,Alousi AM, Pidala J. Outcomes of grades II-IV acute graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation: How much progress was achieved?Presentation at ASH meeting in Orlando, FL, December 2015.

e. GV12-02 Nikiforow S, Wang T, Hemmer MT, Spellman SR, Alousi AM, Couriel DR, Pidala J,Arora M, Cutler CS. Upper gastrointestinal acute graft-versus-host disease adds minimalprognostic value when present in isolation or in addition to grade I or other grade II-defining GvHD manifestations. Presentation at ASH meeting in Orlando, FL, December2015.

Dr. Amin Alousi explained that the GVWC, like all WCs, are judged by publications andpresentations and 2015 was another good year of progress. Dr. Alousi briefly touched oneach of the above studies’ and emphasized that the 2 studies from 2012 have a highpriority of being submitted for publication by the end of this academic 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 1502-01 Allogeneic transplant in the presence of haplotype alleles associated withceliac disease associates with increased risk of stage II-IV GI acute GVHD or chronic GIGVHD. (R Strair)(Attachment3)

Dr. Roger Strair presented the proposal. Dr. Strair alleged that there is a symptomaticoverlap in the gastrointestinal (GI) involvement between celiac disease and GVHD, andthat patients with celiac disease can be identified by patients with specific HLA markers.Dr. Strair hypothesizes that transplant recipients with these HLA markers that associatewith celiac disease will have increased GI-involved GVHD. When asked about ifmismatched donor-recipient HLA types would be pursued, Dr. Strair conceded that itwould not be feasible in this population. It was also mentioned that Hispanicdonors/recipients with celiac disease do not carry the DQ2/8 phenotype. Furthermore,the CIBMTR data collection forms do not collect information on whether the recipient hadceliac disease prior to transplant. A comment from the GVWC was that GI-based cGVHD


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is difficult to diagnose. Another concern from the GVWC was if the results from an analysis were negative, the manuscript would not be interesting. When asked if there were animal models where this hypothesis could be explored prior to pursuing a study in the CIBMTR cohort, Dr. Strair explained the animal models described in literature.

b. PROP 1511-03 Mycophenolate mofetil-based regimen for GVHD prophylaxis in childrenwill be associated with higher incidence of acute gastrointestinal GVHD and decreaseddisease-free and overall survival. (A Levinson/ P Satwani) (Attachment 4)

Dr. Anya Levinson presented on behalf of her fellow investigator. Dr. Levinson first provided a background on the topic of her proposal. MMF was implemented for faster neutrophil engraftment and as an alternative to methotrexate in GVHD prophylaxis. However, MMF may be leading to an over diagnosis of gastrointestinal (GI)-related aGVHD. Dr. Levinson cited several studies that MMF use has led to more severe aGVHD or a non-improved level of GVHD-free, relapse-free survival (GRFS).

While discussing the eligible population selected from the CIBMTR registry, Dr. Levinson conceded that the number of patients receiving a calcineruin inhibitor (Tacrolimus or Cyclosporine; CNI) + MMF was low, relative to the patients who received CNI + MTX. Dr. Levinson mentioned she had received a suggestion to restrict to patients receiving myeloablative conditioning intensity. In an effort to increase the power of the proposed study, Dr. Levinson suggested that she could add up to 140 patients who received CNI + MMF in GVHD prophylaxis from her own center, and perhaps add patients from other individual centers (overlapping patients already included in the registry would have to be excluded).

The first question from the GVWC was to consider merging this proposal with a current ongoing study within the GVWC (GV14-01). While Dr. Levinson noted that her proposal wanted to compare outcomes in patients receiving CNI + MMF versus CNI + MTX in the pediatric setting and GV14-01 posed the same question but in adults, she was open to the idea of merging her proposal with the ongoing study, as long as both questions could be addressed. The second question asked about the logistics of adding patients from different individual centers (as a result of Dr. Levinson saying her center has 140 patients to possibly add to study) and the answer to that was it takes some time for centers to fill out data forms before those patients’ information becomes available in the CIBMTR registry. There also could be an overlap between the 140 patients and those currently being described in the proposed population. A member of the GVWC offered that there would be up to 124 cases from Columbia, but their data would have been submitted at the TED level. The third question asked Dr. Levinson why she wanted to restrict the population to pediatric patients. Dr. Levinson responded that the incidence of GVHD varies by age and it would make the study more straightforward to analyze pediatric recipients. The fourth question asked how the analysis will be able to tell a patient who is experiencing GI inflammation and whether that was caused by aGVHD or MMF toxicity. This analysis would not include biopsy data, so that would not be possible to determine cause of GI inflammation.

c. PROP 1511-07 GVHD-free relapse-free survival (GRFS) in alternative donor hematopoieticcell transplantation. (R Mehta/ S Holtan/ D Weisdorf) (Attachment 5)


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Dr. Rohtesh Mehta presented the proposal, on behalf of his fellow investigators. The goal of this proposal is evaluate GRFS among alternative donors (non-matched related or non-matched unrelated donor) in an effort to determine the preferential donor choice. The alternative donors considered in the study are UCB graft sources, haploidentical donor using either BM or PB graft sources, 1-antigen mismatched PB graft and 1-antigen mismatched BM graft.

The first question asked was if Dr. Mehta planned to separate the patients undergoing transplant with a haploidentical donor into those who received post-transplant cyclophosphamide and T-cell depletion. Dr. Mehta responded that the GVHD prophylaxis had a lot of variability and the plan was to adjust for this factor in the analysis. The second question suggested to consider leukemia-free survival (LFS) as the primary endpoint in the analysis, instead of GRFS, because GRFS gives equal weight to lethal and non-lethal outcomes (GVHD, relapse). Dr. Mehta stated the proposal’s hypothesis is that GRFS will be similar across the donor cohorts, even while the component outcomes (aGVHD, cGVHD, relapse, death) will likely vary across the cohorts, which is why GRFS is the primary outcome. The third point of discussion was a suggestion that this proposal would be more appropriate in the Graft Sources Working Committee, as the main effect of comparison comprised of different graft sources. The GVWC leadership responded that the GVWC recently completed an analysis where GRFS was the primary endpoint and learned valuable insight into the complications in analyzing this outcome. And after having discussed this proposal months prior to Tandem with the Graft Sources leadership, it was agreed that Dr. Mehta’s proposal would be more effectively served to be presented before the GVWC. A third question asked whether Dr. Mehta would consider adding HLA-matched unrelated donors to the study population (currently only included those with 1-HLA antigen mismatch). Dr. Mehta agreed as matched URD would serve as a baseline and provide clarity on behalf of those recipients considering undergoing transplant with a 1-HLA antigen mismatch donor. A fourth question asked about the impact of graft failure in regards to the GRFS endpoint and whether patients who experienced graft failure would be evaluated. Dr. Mehta answered that these patients were not planned to be evaluated in the proposed analysis but this could be considered.

d. PROP 1511-54/1511-67 Risk factors for GVHD and outcomes after haplo-identicaltransplant using post-transplant cyclophosphamide (A Im/ B Hamilton/ N Majhail/ SPavletic) (Attachment 6)

Dr. Annie Im presented this proposal, on behalf of her fellow investigators. The main aims of the proposed study are to describe the incidence of GVHD after transplant from haploidentical donor and receiving post-transplant cyclophosphamide. The hypothesis from the investigators is that haploidentical transplant with post-transplant cyclophosphamide will have a low incidence of both aGVHD and cGVHD. Dr. Im said the plan for analysis was to analyze the population separately by conditioning intensity and graft source.

The first question asked why all haploidentical donor transplants weren’t being considered for the proposal (and only those who received post-transplant cyclophosphamide). Dr. Im stated the main focus behind the proposal was to focus on those patients who underwent both treatments (haploidentical donor and post-transplant


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cyclophosphamide in GVHD prophylaxis), but conceded that there may be an issue with sample size. The GVWC leadership further stated that the relevant sample size concerns would arise when evaluating the number of events occurring in the primary outcome (GVHD) within this population, which will only further reinforce the sample size concerns. A second question was asked as to why pediatric patients were not included, to which Dr. Im said there were very few pediatric patients who fit their selection criteria. A concern was raised about the low level of follow-up among surviving patients (median of 13 months) and that changing the primary endpoint to aGVHD could ensure more patients are evaluated by the time of the analysis. Dr. Im stated the follow-up should increase by the time the analysis is performed. Dr. Im also explained that the latest outcome analyzed in this study would be cGVHD, which typically occurs in patients within the first year post-transplant. A third question asked if it would be possible to investigate whether a single or double dose of cyclophosphamide was given post-transplant. The GVWC leadership answered that dose information on GVHD prophylaxis drugs is not currently collected on the CIBMTR forms. A fourth question asked to clarify how haploidentical donors were identified, to which the GVWC leadership responded that they are identified as related donors with at least a 2-antigen mismatch. A suggestion from the GVWC was to consider adding TED-level patients to the study to increase the number of patients involved in the study. Further discussion was that while an analysis in aGVHD in TED-level patients would be impossible, since date of onset of aGVHD is not currently collected, a subset analysis of CRF-level patients could be done to analyze aGVHD. Meanwhile, cGVHD could be evaluated in the entire TED-level population.

e. PROP 1511-81 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/ LLamb) (Attachment 7)

Dr. Ayman Saad presented the proposal, on behalf of his fellow investigators. The aim of this proposed study is to identify a correlation between T cell doses (specifically, CD3+, CD4+ and CD8+) in T-cell replete HLA-matched PBSC transplant and the risk of advanced GVHD (aGVHD grade III-IV or extensive/severe cGVHD). Secondly, the goal of the study is to identify a T cell dose cutoff that influences DFS. Dr. Saad stated there are currently conflicting data on a possible correlation between graft T cell dose and post-allogeneic transplant outcomes. The possible impact of this study could be a change in GVHD prophylaxis regimens and graft engineering to target a specific T cell dose range.

The first question asked if the investigators would examine the impact of CD34 dose, and its influence on CD3 dose. Dr. Saad responded that in the past, he had experience analyzing 600 patients and found that CD3 and CD34 dose were not correlated. A second question asked for clarification on what patients will be included in the proposed study. Dr. Saad stated that the population will consist of patients undergoing their first allogeneic transplant with a T-cell replete PBSC graft for a hematological malignancy. A third question, after alluding to the discovery of the impact that donor age had on outcomes, asked what donor characteristics would be included in the analysis. Dr. Saad responded that donor age will be important to include. Another concern expressed was that the sample size for a similar topic proposed last year was very low. It was clarified


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that the proposal from 2015 had been restricted to RIC patients, which limited the sample size.

f. PROP 1511-34 Comparison of GVHD prophylaxis regimens with tacrolimus/methotrexateversus tacrolimus/sirolimus-based regimens for mismatched unrelated donorhematopoietic stem cell transplantation (Z Gul/ G Hilderbrandt/ M Khan) (Attachment 8)

Dr. Gerhard Hilderbrandt presented the proposal on behalf of his fellow investigators. The proposed hypothesis is that sirolimus-based GVHD prophylaxis regimens result in decreased GVHD in patients undergoing mismatched transplant, compared to patients receiving MTX GVHD prophylaxis regimens. Dr. Hilderbrandt demonstrated that a majority of research evaluating GVHD prophylaxis drugs have focused on matched related or matched unrelated donors, although a substantial portion of the population undergoing transplant will likely use a mismatched donor. Dr. Hilderbrandt admitted that one limitation of the study is there are comparably much less patients who received sirolimus, making an analysis potentially difficult.

The first comment from the GVWC was that of concern over small sample size if the investigators attempted to sort out GVHD prophylaxis into too many particular categories, especially in the Tac + Siro +/- other cohort. Dr. Hilderbrandt conceded that the investigators would be limited to their categories for analysis by the size of the population. A question asked how mismatched unrelated donors were defined. The GVWC leadership responded that these patients had to have at least 1-antigen mismatch among the A-, B-, C-, and DRB1-loci, and the matching level on the DQB1 locus is likely known but not considered in determining ‘mismatch.’

Dr. Pidala announced that was the end of the proposals for potential future GVWC studies. Dr. Pidala also announced that the GVWC leadership will be circulating an email in the near future identifying areas of priority on which future GVWC studies should focus and encourage prospective investigators to propose a study in these areas. Dr. Pidala also encouraged members to send in proposals or concept sheets throughout the year and the GVWC leadership will work with those investigators to develop the proposal.

Dropped proposed studies

Dr. Mukta Arora introduced this next section of the meeting, to address those proposals that were dropped before presenting to the GVWC.

g. PROP 1511-02 A study of clinical outcomes among patients receiving calcineurin inhibitorsvs. calcineurin inhibitors +methotrexate for acute graft versus host disease prophylaxisfollowing matched sibling allogeneic bone marrow transplantation for acutelymphoblastic leukemia.Dropped due to small sample size.

h. PROP 1511-04 Bone marrow grafts will result in improved GVHD-free, relapse-freesurvival when compared to peripheral blood grafts in children with Leukemia ReceivingAllogeneic Hematopoietic Cell Transplantation From Matched Sibling donors and fullymatched unrelated donors- extension of GV15-02 study


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Topic already addressed in prior study from University of Minnesota (“Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation.” Holtan SG, et. al.)

Dr. Arora noted that these investigators would be invited to participate in the GRFS proposal that had been presented (PROP 1511-07), if that proposal is selected to proceed as a GVWC study.

i. PROP 1511-20 The impact of rabbit antithymocyte globulin on the outcome ofmismatched hematopoietic cell transplantDropped due to limitations with ATG data collection.

j. PROP 1511-22 High dose cytoxan versus standard GVHD prophylaxis in patients over theage of 60Dropped due to small sample size

k. PROP 1511-28 Comparison of calcineurin inhibitors (Cyclosporine/Tacrolimus)+methotrexate with post-transplant cyclophosphamide alone as GVHD prophylaxis inpatients undergoing allogeneic hematopoietic cell transplant.Dropped due to small sample size in post-transplant Cyclophosphamide alone cohort.

l. PROP 1511-88 Comparison of GVHD incidence after donor lymphocyte infusion in HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic celltransplantation.Dropped due to small sample size and difficulty in interpreting and reliability of data onGVHD occurring after a post-HCT DLI.

m. PROP 1511-93 Factors associated with survival in patients with severe acute GVHD.Dropped due to overlap with current study, GV12-01.

Form Revisions – Acute/Chronic GVHD

Dr. Arora presented a summary of the forms revisions made to the GVHD sections of theCIBMTR data collection forms. These revised forms will begin collecting data in Fall 2016.Though the current studies will not be able to use these data, this provides insight into whatadditional data will be collected for potential future studies.

The additions made to the aGVHD section of forms were:

Added total dose and type of ATG

Added cyclophosphamide to list of GVHD prophylaxis drugs

Added overall grade and stage of each organ at diagnosis of aGVHD

Added date of maximum overall grade of aGVHDo Dr. Arora noted that on the past and current CIBMTR forms, the date of

diagnosis of aGVHD is the only date requested

Added Pentostatin and PUVA to aGVHD therapy drugs

Removed Methotrexate and Ursodiol from aGVHD therapy drugs

The additions made to the cGVHD section of forms were:

Added the following question “Were signs of aGVHD present at the time of cGVHDdiagnosis (overlap syndrome)?”

Added organ involvement with NIH scoring at diagnosis of cGVHD

Added platelets and bilirubin at diagnosis of cGVHD

Separated topical GI corticosteroids from systemic therapy questions

Added following drugs to cGVHD treatment options:


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o ATG (dose/type)o Aldesleukin (interleukin-2, IL-2)o Bortezomibo Interleukin inhibitorso PUVAo UVBo Rituximabo TKIs

Removed following drugs from cGVHD treatment options:o Etretinateo Ursodiolo Lamprene

Added questions to capture discontinuation of systemic steroids and otherimmunosuppressive agents

A comment from the GVWC leadership was that the GVWC will need to monitor the data being submitted for cGVHD, to make sure these new details are not solely coming from large-volume centers or centers with an interest in CGVHD. A question from the GVWC asked if there are certain time points when physicians should target to fill in the data collection forms, and the response was the typical CIBMTR post-transplant time points (100-day, 6-month, 1-year, 2-year). Another question asked if a simple PDF checklist could be used to fill out the NIH scoring criteria for cGVHD organ involvement. The GVWC leadership will be working on something similar to aid in data collections, noting that there are limitations based on electronic medical records. A question was asked which form will be collecting the cGVHD scoring data, which is only at the time of diagnosis and not each subsequent follow-up form. CIBMTR audits do not include the NIH scoring, as of this time (as it is not currently collected). The source documentation could be problematic, which will need to be considered as the audit rules develop.

5. Studies in progress (Attachment 9)a. GV12-01 Outcomes of grades II-IV acute GVHD post-allogeneic HCT: How much progress

was achieved? (HJ Khoury) Manuscript Preparationb. GV12-02 Upper gastrointestinal acute GVHD adds minimal prognostic value when present in

isolation or in addition to grade I or other grade II-defining GVHD manifestations (SNikiforow/ C Cutler) Manuscript Preparation

c. GV15-02 Do bone marrow grafts result in improved GVHD-free, relapse-free survival whencompared to peripheral blood grafts in adults receiving allogeneic HCT from unrelateddonors? (A Alousi/ S Holtan/ D Weisdorf) Manuscript Preparation

d. GV13-01 Impact of donor sex, parity and sibling/unrelated status on outcomes of allogeneicHCT (A Kumar/ A Loren) Data File Preparation

e. GV14-01 Comparison of mycophenolate versus methotrexate in combination with acalcineurin inhibitor for GVHD prophylaxis in allogeneic HCT (B Hamilton/ S Chhabra/ NMajhail/ L Costa/ R Stuart/ D Kim/ O Ringden) Data File Preparation

f. GV14-02 Influence of recipient age on risk for acute and chronic GVHD in children receivingHLA-identical bone marrow transplantation (M Qayed/ J Horan) Data File Preparation

g. GV15-01 Impact of donor obesity and inflammation on acute and chronic GVHD among HCTrecipients (L Turcotte/ M Verneris) Data File Preparation


11

Dr. Arora presented brief updates on each of the above GVWC studies currently in progress.

Dr. Amin Alousi presented an update on GV15-02. Dr. Alousi explained that he had intended to submit the analysis to ASH, but problems arose when there was a violation of the hazard proportionality assumption.

The first question asked about the validity of GRFS, since it gives equal weight to each of its component outcomes (aGVHD III-IV, cGVHD, relapse, death). Dr. Alousi brought up the concept of ‘current GRFS’, which would update patients who experienced a non-lethal outcome and later recovered.

Another question was that since the survival curves appeared to intersect at 1-year post-transplant, would GRFS be a valid endpoint to evaluate the population at 1 year? Dr. Alousi agreed that GRFS suggests that BM is a better graft source than PB at 1 year, but illustrated that OS is superior for PB 1 year post-transplant, which reiterates Dr. Alousi’s concern about GRFS. While GRFS may be the goal of transplant, Dr. Alousi stated that not all of the components of GRFS are equal (it’s more important to be alive with cGVHD than have died with no GVHD or relapse present). A question was asked of the statisticians that with a violation of the proportional hazard models, is the Cox model still the best model to use in the analysis. The response from the GVWC Statistical Director was that the Cox model is still appropriate, so long as the violations are found and separate models are generated based on the time periods. Another question asked was why we chose to answer this question within a CIBMTR analysis rather than simply analyzing the results of BMTCTN randomized BM versus PB trial to capture GRFS. Dr. Alousi responded that while the CTN trial was a relatively large (550 patients) trial, the cohort size of the registry is much larger and in fact allowed us to see differences in OS which likely would be missed in the smaller dataset from the CTN trial.

6. Other Business

Hearing no other business to discuss, Dr. Couriel ended the meeting at 2:15pm.


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Working Committee Overview Plan for 2016 - 2017

a. GV12-01 Outcomes of grades 2-4 acute GVHD post-allogeneic HCT: How much progress was achieved? (HJKhoury)

This study will determine the prognostic factors influencing changes in overall survival, disease-freesurvival and treatment-related mortality in patients who develop grade 2-4 aGVHD.A revised draft of the manuscript will be received by March 2016. The manuscript will then be revisedand submitted by June 2016.

b. GV12-02 Prognostic implications of acute upper gastrointestinal GVHD in patients undergoingmyeloablative HCT (S Nikiforow / C Cutler)

This study will evaluate the impact of isolated acute upper gastrointestinal (UGI) graft-versus-hostdisease in outcomes of overall survival, treatment-related mortality, disease-free survival and incidenceof cGVHD, compared to patients with no aGVHD or aGVHD without UGI involvement.The initial draft of the manuscript will be received by April 2016. The manuscript will then be revisedand submitted by June 2016.

c. GV13-01 Impact of donor parity and donor type on outcomes of allogeneic HCT (A Kumar / A Loren)

This study will evaluate the outcomes of overall survival, acute and chronic GVHD in transplantswhere a multiparous female HLA-identical sibling donor compared to a matched unrelated maledonor in a myeloablative setting for AML and ALL.The data file will be finalized by April 2016 and the analysis will be completed by June 2016. Weanticipate that an abstract for ASH will be submitted by August 2016. We further anticipatethat the initial draft of the manuscript will be received by September 2016 and will besubmitted by December 2016.

d. GV14-01 Comparison of MMF vs. MTX in combination with a CNI for GVHD prophylaxis in allogeneic HCT (BHamilton / 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 prophylaxisregimen 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 andhematopoietic recovery will also be evaluated.We anticipate having the data file prepared for analysis by September 2016 and the analysis to be completedby December 2016. We further anticipate receiving the initial draft of the manuscript by March 2017.


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e. GV14-02 Influence of age on risk for GVHD in children receiving HLA-identical bone marrowtransplantation (M Qayed / J Horan)

This study aims to examine the impact of age on the risk of aGVHD and cGVHD in children with acute leukemia receiving bone marrow grafts from HLA-identical sibling donors. The data file will be finalized by April 2016 and the analysis will be completed by June 2016. We anticipate that an abstract for ASH will be submitted by August 2016. We further anticipate that the initial draft of the manuscript will be received by October 2016 and a revised version will be submitted by February 2017.

f. GV15-01 Impact of donor obesity and inflammation on acute and chronic GVHD among HCT recipients (LTurcotte / M Verneris)

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. We anticipate having the data file prepared for analysis by July 2016 and the analysis to be completed by September 2016. We further anticipate submitting an abstract for Tandem by October 2016 and receiving the initial draft of the manuscript by December 2016.

g. GV15-02 Do BM grafts result in improved GRFS when compared to PB grafts in adults receiving allogeneicHCT from matched-unrelated donors? (A Alousi / S Holtan / D Weisdorf)

This study will compare the endpoint of GVHD-free, relapse-free survival (GRFS) in BM versus PB adult recipients undergoing allogeneic HCT for AML, ALL, CML, MDS from an 8/8- or 7/8-matched unrelated donor. The initial draft of the manuscript will be received by March 2016. The manuscript will then be revised and submitted by June 2016.

h. 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 hematologicalmalignancies who underwent HCT in one of the following “alternative donor” categories – (a) UCBtransplant (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 thedistribution of contributing events of GRFS at 1- and 2-years post-transplant. The study will also analyzeOS and DFS at 1- and 2-years post-transplant.We anticipate receiving the draft protocol by July 2016. We further anticipate finalizing the protocol byNovember 2016 and preparing the data file for analysis by February 2017.


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i. GV16-02 The impact of the graft T cell dose on the outcome of allogeneic HLA-matched peripheral bloodstem 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 PBSCtransplantation. The study will also test the correlation of those graft doses with OS and DFS amongallogeneic PBSC transplants.We anticipate receiving the draft protocol by July 2016. We further anticipate finalizing the protocol byMarch 2017.

The top two 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.


15

Joseph Pidala GV12-01: Outcomes of grades 2-4 acute GVHD post-allogeneic HCT: How much progress was achieved? GV16-02: The impact of the graft T cell dose on the outcome of allogeneic HLA-matched peripheral blood stem cell transplantation

Daniel Couriel GV14-02: Influence of donor and recipient age on risk for GVHD in

children receiving HLA-identical bone marrow transplantation GV15-01: Impact of donor obesity and inflammation on acute and chronic GVHD among HCT recipients GV12-02: Prognostic implications of acute upper gastrointestinal GVHD in patients undergoing myeloablative HCT

Amin Alousi GV13-01: Impact of donor parity and donor type on outcomes of allogeneic HCT GV14-01 Comparison of MMF vs. MTX in combination with a CNI for GVHD prophylaxis in allogeneic HCT GV15-02: Do BM grafts result in improved GRFS when compared to PB grafts in adults receiving allogeneic HCT from matched-unrelated donors? GV16-01: GRFS in alternative donor HCT

Oversight Assignment for Working Committee Leadership (March 2015)


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Not for publication or presentation Attachment 2

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

Characteristics of leukemia patients receiving allogeneic HCT between 1990-2016

Characteristics of patients: HLA-identical

sibling Other

related Unrelated

donor

Cord

blood

Number of patients 26624 5598 32006 6204

Number of centers 433 371 377 244

Age at transplant, years, median (range) 38 (<1-78) 37 (<1-82) 40 (<1-83) 18 (<1-83)

Disease

AML 10432 (39) 2359 (42) 12447 (39) 2818 (45)

ALL 5171 (19) 1157 (21) 6193 (19) 2057 (33)

Other leukemia 1185 (4) 342 (6) 1644 (5) 263 (4)

MDS 6249 (23) 911 (16) 5836 (18) 274 (4)

CML 3587 (13) 829 (15) 5886 (18) 792 (13)

Sex

Male 15546 (58) 3306 (59) 18748 (59) 3452 (56)

Female 11076 (42) 2291 (41) 13255 (41) 2752 (44)

Missing 2 (<1) 1 (<1) 3 (<1) 0

Graft source

Bone marrow 14633 (55) 2019 (36) 16480 (51) -

Peripheral blood 11721 (44) 2862 (51) 15077 (47) -

Missing 270 (1) 717 (13) 449 (1) -

GVHD prophylaxis

None 1046 (4) 960 (17) 728 (2) 121 (2)

Ex-vivo T-cell depletion 1592 (6) 719 (13) 2915 (9) 32 (<1)

CD34 selection 393 (1) 278 (5) 537 (2) 174 (3)

Post-transplant Cy + others 136 (<1) 664 (12) 277 (<1) 4 (<1)

Tac + MTX alone 2858 (11) 297 (5) 7256 (23) 217 (3)

Tac + MTX + others 602 (2) 50 (<1) 2670 (8) 78 (1)

Tac + MMF alone 532 (2) 329 (6) 1467 (5) 912 (15)

Tac + MMF + others 145 (<1) 71 (1) 566 (2) 205 (3)

Tac alone 382 (1) 75 (1) 859 (3) 194 (3)

Tac + others 342 (1) 42 (<1) 767 (2) 235 (4)

CsA + MTX alone 13120 (49) 984 (18) 8749 (27) 251 (4)

CsA + MTX + others 498 (2) 63 (1) 1572 (5) 89 (1)

CsA + MMF alone 794 (3) 93 (2) 1326 (4) 2005 (32)

CsA + MMF + others 47 (<1) 13 (<1) 221 (<1) 144 (2)

CsA alone 3277 (12) 293 (5) 882 (3) 1185 (19)

CsA + others 246 (<1) 32 (<1) 348 (1) 241 (4)

Others 550 (2) 86 (2) 338 (1) 97 (2)

Missing 64 (<1) 549 (10) 528 (2) 20 (<1)

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sibling Other

related Unrelated

donor

Cord

blood


Conditioning regimen intensity

Myeloablative 22650 (85) 392 (41) 23564 (74) 4608 (74)

RIC 2207 (8) 127 (13) 5461 (17) 570 (9)

NMA 981 (4) 391 (41) 1412 (4) 896 (14)

Missing 786 (3) 37 (4) 1569 (5) 130 (2)

Grade of aGVHD

None 12801 (48) 395 (42) 11025 (34) 2599 (42)

Grade I 4086 (15) 148 (16) 4878 (15) 894 (14)

Grade II 3450 (13) 232 (24) 6491 (20) 1186 (19)

Grade III 3224 (12) 70 (7) 4794 (15) 765 (12)

Grade IV 1199 (5) 38 (4) 2571 (8) 338 (5)

Missing 1864 (7) 64 (7) 2247 (7) 422 (7)

Organ involvement of aGVHD

Skin 4921 (41) 802 (43) 7213 (39) 1313 (41)

Skin + Liver 1204 (10) 119 (6) 1462 (8) 102 (3)

Skin + Liver + UGI 68 (<1) 8 (<1) 203 (1) 22 (<1)

Skin + Liver + LGI 1814 (15) 240 (13) 2540 (14) 237 (7)

Skin + Liver + UGI + LGI 243 (2) 50 (3) 634 (3) 92 (3)

Skin + UGI 291 (2) 64 (3) 901 (5) 159 (5)

Skin + LGI 1462 (12) 263 (14) 2516 (13) 468 (15)

Liver 241 (2) 28 (1) 216 (1) 39 (1)

Liver + UGI 34 (<1) 7 (<1) 43 (<1) 11 (<1)

Liver + LGI 291 (2) 22 (1) 297 (2) 57 (2)

Liver + UGI + LGI 74 (<1) 14 (<1) 125 (<1) 35 (1)

UGI 239 (2) 46 (2) 589 (3) 133 (4)

LGI 611 (5) 81 (4) 855 (5) 194 (6)

UGI + LGI 206 (2) 51 (3) 401 (2) 131 (4)

Missing 260 (2) 75 (4) 739 (4) 190 (6)

Incidence of cGVHD

No 17251 (65) 4059 (73) 19004 (59) 4654 (75)

Yes 9371 (35) 1506 (27) 12956 (40) 1541 (25)

Missing 2 (<1) 0 46 (<1) 9 (<1)

Maximum grade of cGVHD

Limited 3068 (33) 352 (23) 2817 (22) 597 (39)

Extensive 5897 (63) 708 (47) 9547 (74) 882 (57)

Missing 406 (4) 446 (30) 592 (5) 62 (4)

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sibling Other

related Unrelated

donor

Cord

blood


Overall severity of cGVHD

Mild 3910 (42) 502 (33) 4414 (34) 878 (57)

Moderate 3210 (34) 349 (23) 3618 (28) 358 (23)

Severe 1786 (19) 205 (14) 2314 (18) 222 (14)

Missing 465 (5) 450 (30) 2610 (20) 83 (5)

Year of transplant

1990-1995 9702 (36) 975 (17) 4139 (13) 89 (1)

1996-2000 6300 (24) 1049 (19) 6600 (21) 479 (8)

2001-2005 4777 (18) 1245 (22) 8373 (26) 1032 (17)

2006-2010 3257 (12) 826 (15) 7504 (23) 2447 (39)

2011-2016 2588 (10) 1503 (27) 5390 (17) 2157 (35)

Follow-up of survivors, months, median (range)

76 (<1-316) 25 (<1-292) 72 (<1-314) 52 (<1-245)

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.

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Characteristics of non-leukemia patients receiving allogeneic HCT between 1990-2016


sibling Other

related Unrelated

donor

Cord

blood


Number of centers 412 336 307 207

Age at transplant, years, median (range) 26 (<1-82) 22 (<1-77) 28 (<1-75) 5 (<1-73)

Disease

NHL 3000 (25) 703 (23) 2840 (34) 467 (16)

HD 360 (3) 154 (5) 633 (8) 131 (4)

SAA 3182 (27) 435 (14) 1537 (18) 199 (7)

MM 1528 (13) 402 (13) 654 (8) 44 (1)

Inherited abnormalities of erythrocyte diff-or function

2518 (21) 401 (13) 792 (9) 503 (17)

SCID & other immune system disorders

558 (5) 625 (20) 831 (10) 682 (23)

Inherited abnormality of platelets

22 (<1) 8 (<1) 37 (<1) 38 (1)

Histiocytic disorders 113 (<1) 64 (2) 355 (4) 224 (7)

Others 657 (6) 268 (9) 752 (9) 724 (24)

Sex

Male 7136 (60) 1825 (60) 5281 (63) 1821 (60)

Female 4802 (40) 1235 (40) 3150 (37) 1191 (40)

GVHD prophylaxis

None 472 (4) 629 (21) 155 (2) 93 (3)

Ex-vivo T-cell depletion 570 (5) 478 (16) 868 (10) 16 (<1)

CD34 selection 227 (2) 190 (6) 308 (4) 42 (1)

Post-transplant Cy + others 296 (2) 215 (7) 57 (<1) 2 (<1)

Tac + MTX alone 850 (7) 95 (3) 1431 (17) 101 (3)

Tac + MTX + others 221 (2) 22 (<1) 619 (7) 16 (<1)

Tac + MMF alone 271 (2) 117 (4) 482 (6) 325 (11)

Tac + MMF + others 89 (<1) 27 (<1) 163 (2) 96 (3)

Tac alone 160 (1) 42 (1) 288 (3) 109 (4)

Tac + others 112 (<1) 12 (<1) 183 (2) 112 (4)

CsA + MTX alone 5297 (44) 426 (14) 1775 (21) 163 (5)

CsA + MTX + others 267 (2) 41 (1) 295 (3) 32 (1)

CsA + MMF alone 660 (6) 104 (3) 651 (8) 816 (27)

CsA + MMF + others 42 (<1) 9 (<1) 87 (1) 66 (2)

CsA alone 1931 (16) 261 (9) 520 (6) 844 (28)

CsA + others 277 (2) 27 (<1) 183 (2) 125 (4)

Others 173 (1) 55 (2) 139 (2) 44 (1)

Missing 23 (<1) 310 (10) 227 (3) 10 (<1)

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sibling Other

related Unrelated

donor

Cord

blood


Graft source

Bone marrow 7461 (62) 1313 (43) 4692 (56) -

Peripheral blood 4399 (37) 1435 (47) 3584 (43) -

Missing 78 (<1) 312 (10) 155 (2) -


Myeloablative 8359 (70) 1539 (50) 4017 (48) 1941 (64)

RIC 1228 (10) 293 (10) 2244 (27) 446 (15)

NMA 1510 (13) 520 (17) 1424 (17) 538 (18)

Missing 841 (7) 708 (23) 746 (9) 87 (3)

Grade of aGVHD

None 6938 (58) 1703 (56) 3664 (43) 1480 (49)

Grade I 1559 (13) 260 (8) 1139 (14) 447 (15)

Grade II 1289 (11) 248 (8) 1343 (16) 476 (16)

Grade III 1135 (10) 197 (6) 1054 (13) 279 (9)

Grade IV 402 (3) 75 (2) 598 (7) 134 (4)

Missing 615 (5) 577 (19) 633 (8) 196 (7)

Organ involvement of aGVHD

Skin 1983 (45) 369 (47) 1679 (41) 673 (50)

Skin + Liver 410 (9) 51 (7) 241 (6) 44 (3)

Skin + Liver + UGI 26 (<1) 0 33 (<1) 6 (<1)

Skin + Liver + LGI 537 (12) 92 (12) 489 (12) 84 (6)

Skin + Liver + UGI + LGI 72 (2) 14 (2) 116 (3) 32 (2)

Skin + UGI 79 (2) 9 (1) 173 (4) 50 (4)

Skin + LGI 631 (14) 112 (14) 631 (15) 196 (15)

Liver 79 (2) 12 (2) 44 (1) 6 (<1)

Liver + UGI 10 (<1) 0 10 (<1) 1 (<1)

Liver + LGI 107 (2) 11 (1) 94 (2) 29 (2)

Liver + UGI + LGI 13 (<1) 6 (<1) 34 (<1) 7 (<1)

UGI 69 (2) 17 (2) 114 (3) 29 (2)

LGI 245 (6) 39 (5) 256 (6) 76 (6)

UGI + LGI 45 (1) 24 (3) 73 (2) 39 (3)

Missing 79 (2) 24 (3) 147 (4) 64 (5)

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sibling Other

related Unrelated

donor

Cord

blood


Incidence of cGVHD

No 9037 (76) 2417 (79) 5458 (65) 2318 (77)

Yes 2896 (24) 558 (18) 2955 (35) 690 (23)

Missing 5 (<1) 85 (3) 18 (<1) 4 (<1)


Limited 1071 (37) 161 (29) 717 (24) 327 (47)

Extensive 1701 (59) 223 (40) 2058 (70) 339 (49)

Missing 124 (4) 174 (31) 180 (6) 24 (3)

Overall severity of cGVHD

Mild 1328 (46) 195 (35) 1072 (36) 392 (57)

Moderate 930 (32) 121 (22) 821 (28) 166 (24)

Severe 499 (17) 67 (12) 583 (20) 101 (15)

Missing 139 (5) 175 (31) 479 (16) 31 (4)

Year of transplant

1990-1995 3392 (28) 489 (16) 761 (9) 43 (1)

1996-2000 3056 (26) 589 (19) 1386 (16) 239 (8)

2001-2005 3056 (26) 780 (25) 2703 (32) 658 (22)

2006-2010 1418 (12) 495 (16) 2211 (26) 1091 (36)

2011-2016 1016 (9) 707 (23) 1370 (16) 981 (33)

Follow-up of alive patients, months, median (range)

77 (<1-316) 46 (<1-141) 72 (<1-295) 60 (<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.

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Proposal 1611-04 Title: Risk stratification by time to onset of acute GVHD Hannah Kyung Choe, MD, [email protected], Weill Cornell Medical College Stephanie 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 approach and design of future clinical trials. Specific aims: 1. 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 engraftment + 56 days (excluding <10 days), and later acute GVHD defined as engraftment + >56 days (excluding the prior two categories and up to day 100). 2. To identify risk factors associated with the development of each time to onset category. To identify 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, graft type, 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 days of transplant regardless of engraftment3 or by timing or response to steroids4 or by 28 days post-transplant5. These cutoffs were ascribed 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 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 cohort4. 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 2005 NIH consensus criteria had double the risk of chronic GVHD compared to classic GVHD that started

23


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 days5. Time to onset of acute GVHD 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 or cord blood (single or double unit) or haploidentical or haplo-cord 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 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. 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

Treated with steroids: yes or no

Date of chronic GVHD diagnosis Study design: Observational, retrospective cohort

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References: 1. Sullivan KM, Deeg HJ, Sanders J, Klosterman A, Amos D, Shulman H, Sale G, Martin P, Witherspoon

R, Appelbaum F. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood. 1986;67(4):1172–1175.

2. Kim DH, Sohn SK, Kim JG, Suh JS, Lee KS, Lee KB. Clinical impact of hyperacute graft-versus-host disease on results of allogeneic stem cell transplantation. Bone Marrow Transplantation. 2004;33(10):1025–1030.

3. Saliba RM, de Lima M, Giralt S, Andersson B, Khouri IF, Hosing C, Ghosh S, Neumann J, Hsu Y, De Jesus J, et al. Hyperacute GVHD: risk factors, outcomes, and clinical implications. Blood. 2007;109(7):2751–2758.

4. Mielcarek M, Burroughs L, Leisenring W, Diaconescu R, Martin PJ, Sandmaier BM, Maloney DG, Maris MB, Chauncey TR, Shizuru JA, et al. Prognostic relevance of “early-onset” graft-versus-host disease following non-myeloablative haematopoietic cell transplantation. British Journal of Haematology. 2005;129(3):381–391.

5. Moon JH, Kim SN, Kang BW, Chae YS, Kim JG, Ahn JS, Kim YK, Yang DH, Lee JJ, Kim HJ, et al. Early onset of acute GVHD indicates worse outcome in terms of severity of chronic GVHD compared with late onset. Bone Marrow Transplantation. 2010;45(10):1540–1545.

6. Mielcarek M, Martin PJ, Leisenring W, Flowers MED, Maloney DG, Sandmaier BM, Maris MB, Storb R. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102(2):756–762.

7. Omer AK, Weisdorf DJ, Lazaryan A, Shanley R, Blazar BR, MacMillan ML, Brunstein C, Bejanyan N, Arora M. Late Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2016;22(5):879–883.

25


Characteristics of patients undergoing first allogeneic transplant for hematological malignancy between 2008-2015, as reported to the CIBMTR.

Variable

Early aGVHD

(10 days pre-

/post-ANC)

Classic aGVHD

(11-56 days

post-ANC)

Late aGVHD

(57-100 days

post-ANC)

Number of patients 1850 2986 610

Number of centers 182 195 131

Patient age, years, median (range) 49 (<1-76) 54 (<1-83) 56 (2-78)

Patient age

< 10 107 (6) 71 (2) 16 (3)

10-17 96 (5) 99 (3) 8 (1)

18-29 198 (11) 275 (9) 40 (7)

30-39 194 (10) 278 (9) 49 (8)

40-49 358 (19) 458 (15) 91 (15)

50-59 471 (25) 863 (29) 185 (30)

60-69 374 (20) 813 (27) 189 (31)

70+ 52 (3) 129 (4) 32 (5)

Disease

AML 760 (41) 1194 (40) 253 (41)

ALL 304 (16) 329 (11) 52 (9)

CML 90 (5) 165 (6) 21 (3)

MDS 371 (20) 633 (21) 132 (22)

MPS 102 (6) 196 (7) 37 (6)

Other acute leukemia 17 (<1) 21 (<1) 7 (1)

Other leukemia 60 (3) 149 (5) 42 (7)

NHL 131 (7) 269 (9) 58 (10)

HD 15 (<1) 30 (1) 8 (1)

Graft type

BM 332 (18) 455 (15) 72 (12)

PB 1443 (78) 2467 (83) 531 (87)

CB 72 (4) 59 (2) 7 (1)

Missing 3 (<1) 5 (<1) 0

Donor type

HLA-identical sibling 493 (27) 961 (32) 264 (43)

Haploidentical 53 (3) 100 (3) 22 (4)

URD 8/8 958 (52) 1532 (51) 256 (42)

URD 7/8 346 (19) 393 (13) 68 (11)

26


Characteristics (continued):

Early aGVHD

(10 days pre-

/post-ANC)

Classic aGVHD

(11-56 days

post-ANC)

Late aGVHD

(57-100 days

post-ANC)


GVHD prophylaxis

Tac + MTX + others (not Cy, MMF) 318 (17) 628 (21) 139 (23)

CsA + MTX + others (not Cy, Tac, MMF) 156 (8) 182 (6) 40 (7)

Tac + MMF + others (not Cy) 14 (<1) 74 (2) 21 (3)

Tac + others (not Cy, MMF, MTX) 173 (9) 269 (9) 54 (9)

Tac 17 (<1) 27 (<1) 4 (<1)

CsA + MMF + others (not Cy, Tac) 32 (2) 33 (1) 3 (<1)

CsA + others (not Cy, Tac, MMF, MTX) 21 (1) 40 (1) 10 (2)

CsA 921 (50) 1498 (50) 293 (48)

Others (not Cy, Tac, CsA) 195 (11) 217 (7) 42 (7)

Missing 3 (<1) 18 (<1) 4 (<1)


Myeloablative 1323 (72) 1788 (60) 295 (48)

RIC 377 (20) 780 (26) 206 (34)

NMA 34 (2) 163 (5) 33 (5)

TBD (drugs but unknown intensity) 114 (6) 251 (8) 76 (12)

Unknown 2 (<1) 4 (<1) 0

Year of transplant

2008 430 (23) 526 (18) 99 (16)

2009 354 (19) 556 (19) 96 (16)

2010 258 (14) 336 (11) 48 (8)

2011 117 (6) 221 (7) 45 (7)

2012 123 (7) 235 (8) 49 (8)

2013 238 (13) 467 (16) 105 (17)

2014 202 (11) 362 (12) 96 (16)

2015 128 (7) 283 (9) 72 (12)

Days from engraftment to aGVHD onset, median

(range)

4 (<1-10) 22 (10-56) 74 (56-100)

Acute GVHD grade

I 418 (23) 844 (28) 194 (32)

II 745 (40) 1265 (42) 235 (39)

III 441 (24) 568 (19) 128 (21)

IV 246 (13) 309 (10) 53 (9)

Follow-up of surviving patients, months, median

(range)

59 (2-99) 48 (1-102) 37 (3-97)

27


Proposal 1611-05 Title: Analysis of the risk factors for hepatic acute GVHD after allogeneic stem cell transplantation Yasuyuki Arai, MD, PhD, [email protected], National Institutes of Health Hypothesis: Certain pre-transplant liver conditions, such as hepatitis viral infection, liver dysfunction, and severe iron overload are related to higher incidence of hepatic aGVHD. Scientific impact:

The updated incidence of hepatic aGVHD after allogenic transplantation will be the baseline information to future studies dealing with hepatic aGVHD.

Hepatic aGVHD is difficult to control in general and fatal in severe cases; therefore, the modification of clinical practices in transplantation should be suggested (such as intensified GVHD prophylaxis) in patients harboring such risk factors which are found in this study.

Specific aims:

To determine the precise incidence of hepatic aGVHD (both pathologically-proven and clinically-diagnosed).

To confirm specific risk factors for hepatic aGVHD and to propose new strategies for its reduction

Scientific justification: Pathogenic mechanisms of hepatic aGVHD may be different from those in other organs (skin and gut) [1], suggesting the existence of organ-specific risk factors (especially for the liver lesion) in addition to general factors such as HLA mismatches. However, almost all the previous studies analyzing risk factors have treated aGVHD as a whole, and thus risk factors specific for hepatic aGVHD may have been overlooked in these analyses, because the incidence of hepatic aGVHD is far lower compared to skin and gut lesions. Our group focused on this topic last year using the transplant database in Japan, and found that hepatitis C virus infection and pre-transplant liver dysfunction were related to significantly higher incidence of hepatic aGVHD [2]. We suppose, however, this study was not sufficient to meet the specific aims shown above, because there was a lot of missing information in this study such as details related to hepatitis virus infection (serological status and viral loads), diagnostic procedures of hepatic aGVHD (pathologically-proven or not), and the clinical course after therapeutic interventions for aGVHD. Re-analysis using the CIBMTR database with the larger number of patients and more detailed information is essential to validate our preceding report and to find out novel risk factors for hepatic aGVHD. If specific risk factors for hepatic aGVHD are confirmed, new strategies including modified donor selection and/or GVHD prophylaxis can be proposed to decrease the incidence. Hepatic aGVHD often results in non-relapse mortality because of poor response to conventional treatment [3, 4]; thus, these strategies depending on this new study may eventually improve the overall prognosis after allogeneic stem cell transplantation. Study population: Adult patients (18 years or older at transplantation) who underwent first allogeneic stem cell transplantation (any donor sources) for any diseases in the year 2000 or after.

28


Data requirements: The following data is necessary from each data collection form. We will include all the transplant cases during the period. Recipient Baseline Data (2000; Rev 1.0) Recipient Demographics (#5Gender, #8Date of Birth), Primary Disease for HSCT (#9primary disease), Clinical Status of Recipient Prior to the Preparative Regimen (#20ABO, #21KS, #61coexisting disease, #119-125Liver disease), Organ Function Prior to the Preparative Regimen (#141-149AST/Bil/LDH), Infection (#175-181), Pre-HSCT Preparative Regimen (#184-371), and HSCT history (#372) Hepatitis Serology Pre-HSCT Data (2047; Rev 2.0) All recipient data HSCT Infusion (2006; Rev 1.0) HSCT type, Product type, Pre-Collection Therapy (#1), and Product Processing/Manipulation (#44-91) Confirmation of HLA Typing (2005; Rev 2.0) Tested person (#1), and HLA Typing by DNA Technology (#5-9) 100 Days Post-HSCT Data (2100; Rev 2.0) Vital Status (#1Date, #5Subsequent HSCT), Acute GVHD (#198-227therapy, #228-275GVHD report), Organ Function (#464-486Liver), and Subsequent HSCT (#566) Six Months to Two Years Post-HSCT Data (2200; Rev 2.0) Vital Status (#1Date, #2Subsequent HSCT), Acute GVHD (#169-216GVHD report), Organ Function (#404-426Liver), and Subsequent HSCT (#507) Yearly Follow-Up for Greater Than Two Years Post-HSCT Data (2300; Rev 2.0) Vital Status (#2Date, #3Subsequent HSCT), Acute GVHD (#11-58GVHD report), and Subsequent HSCT (#216) Selective Post-Transplant Essential Data (2455; Rev 2.0) Survival (#44-56) Recipient Death Data (2900; Rev 1.0) #1-4 Study design: The probability of developing hepatic aGVHD will be estimated on the basis of cumulative incidence curves, considering early death and relapse as competitive risks [5, 6]. Each pre-transplant factor is subject to univariate analysis of cumulative incidence of hepatic aGVHD using Gray’s method [7]. Factors with significance or borderline significance (p < 0.1) and those related to pre-transplant liver conditions (hepatitis virus infection and any liver injuries) will be subject to a multivariate analysis using Fine-Gray proportional hazards models [8]. Analyses mentioned above will determine the risk factors for hepatic aGVHD. The same procedures will be performed for skin and gut aGVHD, respectively. Risk factors for each organ are compared, and if some of them are especially related to hepatic aGVHD (not to skin or gut aGVHD), then they are considered as potentially specific risk factors of hepatic aGVHD. In patients harboring such specific risk factors, transplantation strategies to avoid other modifiable risk factors will be recommended. References: 1. Norton J, al-Saffar N, Sloane JP. Adhesion molecule expression in human hepatic graft-versus-host

disease. Bone Marrow Transplant. 1992;10:153-156. 2. Arai Y, Kanda J, Nakasone H, et al. Risk factors and prognosis of hepatic acute GvHD after allogeneic

hematopoietic cell transplantation. Bone Marrow Transplant. 2016;51:96-102. 3. Akpek G, Boitnott JK, Lee LA, et al. Hepatitic variant of graft-versus-host disease after donor

lymphocyte infusion. Blood. 2002;100:3903-3907.

29


4. Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012;18:1851-1860.

5. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695-706.

6. Iacobelli S, Committee ES. Suggestions on the use of statistical methodologies in studies of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2013;48 Suppl 1:S1-37.

7. Gray RJ. A Class of k-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk. Ann Stat. 1988;16:1141-1154.

8. Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. J Am Stat Assoc. 1999;94:496-509.

30


Characteristics of patients undergoing first allogeneic transplant for hematological malignancy between 2000-2015, as reported to the CIBMTR.

Variable N (%)

Number of patients 34668

Number of centers 345

Patient age, years, median (range) 49 (18-83)

Patient age

18-29 5494 (16)

30-39 5139 (15)

40-49 7168 (21)

50-59 9383 (27)

60-69 6586 (19)

70+ 898 (3)

Disease

AML 13798 (40)

ALL 4454 (13)

CML 3205 (9)

MDS 4237 (12)

MPS 2311 (7)

Other acute leukemia 248 (<1)

Other leukemia 1578 (5)

NHL 4118 (12)

HD 719 (2)

Donor type

HLA-identical sibling 10963 (32)

Twin 204 (<1)

Haploidentical 926 (3)

URD 8/8 11004 (32)

URD 7/8 3336 (10)

URD <6/8 2454 (7)

URD well-matched 2328 (7)

URD partially-matched 1269 (4)

URD mismatched 1004 (3)

Missing 1180 (3)

Graft type

BM 7416 (21)

PB 24254 (70)

CB 2997 (9)

Missing 1 (<1)

31


Characteristics (continued): N (%)



Myeloablative 20402 (59)

RIC 8220 (24)

NMA 2700 (8)

TBD (drugs but unknown intensity) 2977 (9)

Unknown 369 (1)

Year of transplant

2000-2004 11047 (32)

2005-2009 12737 (37)

2010-2015 10884 (31)

GVHD prophylaxis

Ex-vivo T-cell depletion 958 (3)

CD34 selection 865 (2)

Cyclophosphamide 109 (<1)

Cyclophosphamide + others 759 (2)

Tac + MMF +/- others (not Cy) 4907 (14)

Tac + MTX +/- others (not Cy, MMF) 11359 (33)

Tac + others (not Cy, MMF, MTX) 1424 (4)

Tac alone 837 (2)

CsA + MMF +/- others (not Cy, Tac) 3879 (11)

CsA + MTX +/- others (not Cy, Tac, MMF) 6930 (20)

CsA + others (not Cy, Tac, MMF, MTX) 721 (2)

CsA alone 902 (3)

Others (not Cy, Tac, CsA) 375 (1)

Missing 643 (2)

Hepatic aGVHD

No aGVHD 14694 (42)

Hepatic aGVHD 3845 (11)

Liver only 275 (7)

Liver + Skin 868 (23)

Liver + Gut 582 (15)

Liver + Skin + Gut 2120 (55)

Non-hepatic aGVHD 14596 (42)

Missing 1533 (4)

Follow-up of alive patients, months, median (range) 51 (<1-199)

32


Proposal 1611-108 Title: The cumulative incidence and risk factors for Renal GVHD after Allogeneic Hematopoietic Cell Transplantation (AHCT) Amin Alousi, MD, [email protected], The University of Texas MD Anderson Cancer Center Ala Abudayyeh, MD, [email protected], The University of Texas MD Anderson Cancer Center Rima M Saliba, PHD, [email protected], The Universitydd of Texas MD Anderson Cancer Center Hypothesis: Renal chronic GVHD is associated with increased morbidity and/or mortality following allogeneic stem cell transplantation. Scientific impact: Renal GVHD is a recognized manifestation of chronic GVHD which has been poorly characterized. Establishing risk factors and impact of this disease is needed. Specific aims: Primary Objective Determine outcomes of renal chronic GVHD following allogeneic stem cell transplantation. Primary outcomes of interest include: overall survival, non-relapse mortality, and the need for kidney dialysis after development of renal cGVHD. Secondary Objective Determine risk factors associated with the development of renal-chronic GVHD. Background: Despite limited published data, renal GVHD is a recognized manifestation of chronic GVHD and has been associated with nephrotic syndrome and renal insufficiency. There are no large studies investigating the role of renal GVHD in development of renal insufficiency post-AHCT. However, it has been demonstrated that renal insufficiency post-AHCT is independently associated with increased mortality (HR 4.26; 95% CI, 3.69-4.91)(1). Renal GVHD is a rare entity and has been reported to occur 0.4 to 6.0% (2, 3) . Identifying and treating renal GVHD would preserve renal function and has been reported to achieve 63.5% remission rate when treated (4). Therefore, truly assessing the incidence of renal GVHD would be of importance for improved SCT survival outcomes. In a recently published meta-analysis there were only one hundred sixteen cases of post-HSCT nephrotic syndrome published between 1988 and 2015. The study indicated that median onset of NS was 20.5 months’ post SCT with presentations of membranous nephropathy (MGN), minimal change disease (MCD). The study describes the good response to treatment; however, does not further elaborate on renal function except that 49.3% had renal insufficiency and the outcome was reported in 26 cases only. As far as risk factors for renal GVHD were conflicting in the literature and a univariate analysis failed to identify a single predictive factor of response to therapy.(4). In single center study of 583 allo-SCT patients the prevalence of renal GVHD was 1.03% (6 patients)(3). Interestingly, all patients had normal renal function at baseline and at renal GVHD diagnosis. The available data is limited to draw any conclusions about the risks, renal, and survival outcomes associated with renal GVHD.

33


Scientific justification: Renal GVHD is a rare (but significant) occurrence which has been poorly reported upon in the literature. The majority of retrospective reports have been single center reviews with no determination of risk factors which may help us understand why some patients may be predisposed to this rare form of GVHD. Further, a nested-control design such as we are proposing would require a large database (such as the CIBMTR) in order to pool cases and then adequately match controls. Study population: All patients who underwent a first AHCT for a hematologic malignancy between the years 2000-2015 will be reviewed. Patients receiving a AHCT for a non-malignant disease, second transplants, and ex vivo T-cell depleted transplants will be excluded. Study design: The cumulative incidence of renal chronic GVHD will be determined in the overall study population considering death or disease progression before renal chronic GVHD as competing risks. Only patients who are alive on day 70 will be eligible for this analysis. Descriptive statistics will be used to describe the median time to onset and characteristics of renal chronic GVHD. Given that renal chronic GVHD is a rare event, a nested case-control study will be performed to determine outcomes and risk factors for the development of renal GVHD. Cases will constitute all patients who were diagnosed with renal GVHD during the study period. Two control groups will be identified for the underlying patient population. The first control group will include all patients who developed non-renal chronic GVHD; the second control group will constitute all patients who did not develop chronic GVHD. Cases and controls will be matched on survival time from the date of transplant to the date of diagnosis of renal chronic GVHD. The optimal case/control matching ratio and the matching time window will be selected to maximize the power of the study. Landmark analysis will be performed to determine overall survival, NRM, and the need for dialysis since the date of diagnosis of renal chronic GVHD for the cases, and since the matching survival time for the controls. Actuarial overall survival will be determined using the Kaplan-Meier method, and the cumulative incidence of NRM and dialysis will be determined accounting for competing risks. The independent impact of renal chronic GVHD on OS, NRM, and need for dialysis will be evaluated in univariate and multivariate analysis using Cox regression analysis for OS, and competing risks regression analysis for NRM and need for dialysis. Potential confounding factors that will be considered in multivariate analysis include: patient age at the time of transplant, HCT-CI (overall and specific for diabetes and hypertension) at the time of transplant, intensity of conditioning regimen (ablative vs non-myeloablative, and TBI vs non-TBI), type of GVHD prophylaxis, donor type, and stem cell source, and disease status at transplant. Interaction effects will be tested and accounted for as indicated. Risk factors for the development of renal-chronic GVHD will be determined in logistic regression analysis. Two different risk factors analyses will be performed each including the cases and one of the control groups defined above. A combined analysis may be performed if indicated by the results of the separate analyses. Risk factors considered will include: patient age at the time of transplant, HCT-CI (overall and specific for diabetes and hypertension) at the time of transplant, intensity of conditioning regimen (ablative vs non-myeloablative, and TBI vs non-TBI), type of GVHD prophylaxis, donor type, and stem cell source, and disease status at transplant. Interaction effects will be tested and accounted for as indicated.

34


Demographics: 1. Patient Factors:

Age

Sex

Weight and Height

Race/ethnicity

Disease

Remission Status

Baseline Creatinine (GFR)

Co-Morbidity Index: Hypertension, Diabetes

KPS 2. Transplant Factors:

Date of Transplant

Conditioning Type (Ablative / NMA)

Use of TBI

GVHD prophylaxis

Use of T-cell Antibodies 3. Donor/ Graft Factors:

Sibling/ Unrelated

HLA-matching

Graft Type (BM, PB or Umbilical Cord)

Sex Match/Mismatch

CMV Status (patient/donor)

ABO match Outcomes:

Engraftment Data

Date of Maximum Grade of Acute GVHD

Date of Chronic GVHD

Date of renal GVHD

Treatment for chronic GVHD

Relapse (and date)

Date of Discontinuation of Immunosuppressive Therapy

Date Death and Cause of Death Renal outcomes:

Baseline creatinine and mean change in creatinine at time points available.

If Dialysis was needed and time point of initiation (Questions 399, 400 and 401) CIBMTR data source: Data collection forms; 2000, 2006, 2450 References: 1. Abudayyeh A, Hamdi A, Lin H, Abdelrahim M, Rondon G, Andersson BS, et al. Symptomatic BK Virus

Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients. Am J Transplant. 2016;16(5):1492-502.

35


2. Luo XD, Liu QF, Zhang Y, Sun J, Wang GB, Fan ZP, et al. Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation: etiology and pathogenesis. Blood Cells Mol Dis. 2011;46(2):182-7.

3. Fraile P, Vazquez L, Caballero D, Garcia-Cosmes P, Lopez L, San Miguel J, et al. Chronic graft-versus-host disease of the kidney in patients with allogenic hematopoietic stem cell transplant. Eur J Haematol. 2013;91(2):129-34.

4. Beyar-Katz O, Davila EK, Zuckerman T, Fineman R, Haddad N, Okasha D, et al. Adult Nephrotic Syndrome after Hematopoietic Stem Cell Transplantation: Renal Pathology is the Best Predictor of Response to Therapy. Biol Blood Marrow Transplant. 2016;22(6):975-81.

36


Characteristics of patients undergoing first allogeneic transplant for T-cell replete hematological malignancy between 2000-2015, as reported to the CIBMTR.

Variable

Renal

cGVHD

Non-renal

cGVHD No cGVHD



Patient age, years, median (range) 51 (14-75) 44 (<1-79) 40 (<1-83)

Patient age

< 10 0 1126 (6) 3607 (11)

10-17 1 (1) 1293 (7) 2971 (9)

18-29 13 (14) 2938 (15) 4638 (15)

30-39 16 (17) 3192 (16) 4451 (14)

40-49 16 (17) 4062 (20) 5536 (17)

50-59 21 (22) 4311 (22) 6037 (19)

60-69 25 (26) 2613 (13) 3951 (12)

70+ 3 (3) 301 (2) 587 (2)

Missing 0 0 1 (<1)

Disease

AML 25 (26) 7040 (35) 11915 (37)

ALL 14 (15) 3206 (16) 6242 (20)

CML 8 (8) 3054 (15) 3878 (12)

MDS 13 (14) 1993 (10) 2863 (9)

MPS 10 (11) 1193 (6) 2011 (6)

Other acute leukemia 4 (4) 181 (<1) 257 (<1)

Other leukemia 6 (6) 890 (4) 928 (3)

NHL 13 (14) 1932 (10) 3172 (10)

HD 2 (2) 347 (2) 513 (2)

Graft type

BM 16 (17) 6284 (32) 12353 (39)

PB 70 (74) 12024 (61) 15009 (47)

Single CB 4 (4) 790 (4) 2440 (8)

Double CB 5 (5) 675 (3) 1702 (5)

Missing 0 63 (<1) 275 (<1)

37



Renal

cGVHD

Non-renal

cGVHD No cGVHD


Donor type

HLA-identical sibling 23 (24) 6862 (35) 11379 (36)

Twin 0 22 (<1) 350 (1)

Haploidentical (mismatched other related) 1 (1) 277 (1) 658 (2)

Other related (HLA matching unknown) 0 420 (2) 974 (3)

8/8 URD 41 (43) 6022 (30) 6541 (21)

7/8 URD 12 (13) 1757 (9) 2220 (7)

<6/8 URD 1 (1) 428 (2) 866 (3)

Well matched URD 5 (5) 1261 (6) 2120 (7)

Partially matched URD 1 (1) 957 (5) 1701 (5)

Mismatched URD 1 (1) 325 (2) 712 (2)

6/6 UCB 1 (1) 120 (<1) 279 (<1)

5/6 UCB 4 (4) 483 (2) 1208 (4)

<4/6 UCB 4 (4) 499 (3) 1240 (4)

Well matched UCB 0 17 (<1) 68 (<1)

Partially matched UCB 0 42 (<1) 188 (<1)

Mismatched UCB 0 180 (<1) 788 (2)

Missing 1 (1) 164 (<1) 487 (2)


Myeloablative 52 (55) 13976 (70) 22661 (71)

RIC 26 (27) 3499 (18) 4997 (16)

NMA 5 (5) 953 (5) 1804 (6)

TBD (drugs but unknown intensity) 12 (13) 1356 (7) 1882 (6)

Unknown 0 52 (<1) 435 (1)

Year of transplant

2000-2004 21 (22) 8661 (44) 15874 (50)

2005-2009 46 (48) 6438 (32) 8309 (26)

2010-2015 28 (29) 4737 (24) 7596 (24)

GVHD prophylaxis

None 1 (1) 141 (<1) 732 (2)

CD34 selection 1 (1) 340 (2) 824 (3)

Cyclophosphamide 0 27 (<1) 98 (<1)

Cyclophosphamide + others 0 225 (1) 610 (2)

38



Renal

cGVHD

Non-renal

cGVHD No cGVHD

Tac + MMF + others (not Cy) 15 (16) 2281 (11) 3059 (10)

Tac + MTX + others (not Cy, MMF) 37 (39) 6222 (31) 7000 (22)

Tac + others (not Cy, MMF, MTX) 7 (7) 845 (4) 952 (3)

Tac alone 2 (2) 349 (2) 601 (2)

CsA + MMF + others (not Cy, Tac) 12 (13) 1767 (9) 3119 (10)

CsA + MTX + others (not Cy, Tac, MMF) 18 (19) 6360 (32) 11323 (36)

CsA + others (not Cy, Tac, MMF, MTX) 1 (1) 590 (3) 1788 (6)

CsA alone 1 (1) 527 (3) 1215 (4)

Others (not Cy, Tac, CsA) 0 154 (<1) 380 (1)

Missing 0 8 (<1) 78 (<1)

Serum creatinine valid value available

Yes 94 (99) 19645 (99) 31392 (99)

Missing 1 (1) 191 (<1) 387 (1)

Post-tx renal failure severe enough to warrant dialysis

No 54 (57) 10892 (55) 10663 (34)

Yes 27 (28) 1428 (7) 3756 (12)

Missing 14 (15) 7516 (38) 17360 (55)

Did patient receive dialysis?

Number evaluable 27 1428 3756

No 6 (22) 463 (32) 1108 (29)

Yes 20 (74) 767 (54) 2155 (57)

Missing 1 (4) 198 (14) 493 (13)

Was renal GVHD diagnosis based on biopsy?

Yes 37 (39) 0 0

No 58 (61) 19836 31779

Follow-up of survivors, months, median (range) 72 (4-216) 72 (3-251) 52 (<1-251)

39


Proposal 1611-109 Title: Impact of Baseline Renal Sufficiency on the Rate of Acute Graft-versus-Host Disease (GVHD) following Allogeneic Hematopoietic Cell Transplantation (AHCT) and a Determination of Risk Factors on and the impact for Decline in Glomerular Filtration Rate (GFR) post-AHCT Amin Alousi, MD, [email protected], The University of Texas MD Anderson Cancer Center Ala Abudayyeh, MD, [email protected], The University of Texas MD Anderson Cancer Center Rima M Saliba, PHD, [email protected], The University of Texas MD Anderson Cancer Center Hypothesis: 1. Patients with impaired baseline renal function (GFR <60 cc/minute) are at higher risk for acute

GVHD and worse treatment-related mortality (TRM) as a result of intolerance of GVHD prophylaxis.

2. Decline in GFR is common post-AHCT and risk factors, including type of GVHD prophylaxis, for GFR decline can be identified.

Scientific impact: Baseline renal impairment in patients undergoing AHCT is becoming increasingly common as a result of an increase in patient age (and associated co-morbidities) in patients who are being referred for this therapy. In addition, AHCT results in a decline in kidney function as a result of toxicity related to conditioning, supportive care medications and (most commonly) the use of GVHD prophylaxis agents (Cyclosporine and Tacrolimus). Determining the impact of renal insufficiency (commonly defined as a GFR of < 60 cc/min) has on the incidence of acute GVHD and non-relapse mortality will inform decisions with respect to GVHD prophylaxis in this population. Further, identifying the incidence of a decline in GFR (which we will define as a decrease in GFR of 25% or greater), risk factors for it and impact on outcomes would inform treatment decisions with regard to the transplant procedure such as identifying populations who may best be suited for reduced-intensity or more kidney-sparing GVHD prophylaxis strategies (which this study may help to define).

Specific aims: This proposal has two primary objectives: A) To determine whether patients with renal insufficiency at baseline are at a higher risk for acute GVHD 2-4 and 3-4. B) To determine how AHCT impacts Day 100 GFR and the impact of decline in renal function on long-term outcomes. Scientific justification: A systematic review and meta-analysis of published literature found that approximately 16.6% of HSCT patients developed renal insufficiency, although its definition varied greatly among different reports(1). However, most studies included a limited number of patients and / or occurred in an outdated time period (when condition, HLA-typing and patient age greatly differed). (The largest study covered the time period 1991-2002 and the second largest study had only 301 patients). In these studies, factors reported to be associated with kidney function decline were age, acute and chronic GVHD, the use of total body irradiation and nephrotoxic therapies such as calcineurin inhibitors and antimicrobials((1, 2). In a systematic review of chronic kidney disease (CKD) in HCT recipients, the rate of CKD was reported to be 27.8%, and the prevailing risk factors were female

40


sex, advanced age, total body irradiation, prolonged use of cyclosporine, acute renal failure, and acute and chronic GVHD(10). In a recent published study from our center (2477 patients), advanced age and female sex were independently correlated with renal insufficiency in HCT patients. Variables associated with more intensive therapy such as an underlying diagnosis of ALL, myeloablative conditioning regimen, cord blood transplantation, active disease status at the time of transplantation, mismatched unrelated donor transplant, acute and chronic GVHD, and lower ALC were also found to be associated with an increased risk of renal insufficiency. Interestingly, patients with mixed donor chimerism were less likely to develop permanent decline in their kidney function (3). Study population: All patients who underwent a first AHCT for a hematologic malignancy between the years 2000-2015 will be reviewed. Patients receiving a AHCT for a non-malignant disease, second transplants and ex vivo T-cell Depleted transplants will be excluded. Study design: Baseline GFR will be calculated (using the CKD epi formula which consists of age, gender, rare and creatinine) for the above study population. Patients who have a baseline GFR of <60cc/min will be considered as having renal insufficiency. Demographics of this population will be collected including baseline factors: co-morbidities (including hypertension and diabetes), age, disease / disease status; transplant variables (donor type / HLA-match, graft, conditioning (ablative, reduced intensity, non-myeloablative / Use of TBI); GVHD prophylaxis type and T-cell antibodies) and compared to patients without baseline renal impairment. The cumulative incidence of grade 2-4 acute GVHD and maximum acute GVHD grade will be analyzed to determine whether acute GVHD rates are influenced by baseline renal impairment. A second analysis will be performed to determine the change in GFR between baseline and day 100 post-HCT. Descriptive statistics will be used to determine the mean change and the 25% quartiles. Risk factors for the greatest decline (>75th percentile) will be determined using regression analysis. The risk factors considered with include the above cited variables along with preceding acute GVHD and grade to determine risk factors for those patients with the greatest decline. The impact of GFR decline on Non-relapse mortality, Relapse, Chronic GVHD rates and Overall survival will be determined. Landmark analyses or time-dependent regression analyses will be used to determine the impact of the GFR greatest decline on long-term outcomes. Demographics: 1. Patient Factors:

Age

Sex

Weight and Height

Race/ethnicity

Disease

Remission Status

Baseline Creatinine (GFR)

Co-Morbidities: Hypertension, Diabetes

KPS 2. Transplant Factors:

Date of Transplant

Conditioning Type (Ablative, Reduced-Intensity, NMA)

41


Use of TBI

GVHD prophylaxis

Use of T-cell Antibodies 3. Donor/ Graft Factors:

Sibling/ Unrelated

HLA-matching

Graft Type (BM,PB or Umbilical Cord)

Sex Match/Mismatch

CMV Status (patient/donor)

ABO match Outcomes:

Engraftment Data

GFR on day 100 (and later time points based on what is collected in CIBMTR data fields).

Date of Maximum Grade of Acute GVHD

Date of Chronic GVHD

Date and Need for Hemodialysis

Date of Discontinuation of Immunosuppressive Therapy, Date of Relapse, Date Death and Cause of Death

CIBMTR Data Source: Data collection forms; 2000, 2006, 2450 References: 1. Ellis MJ, Parikh CR, Inrig JK, Kanbay M, Patel UD. Chronic kidney disease after hematopoietic cell

transplantation: a systematic review. Am J Transplant. 2008;8(11):2378-90. 2. Hingorani S. Chronic kidney disease after pediatric hematopoietic cell transplant. Biol Blood Marrow

Transplant. 2008;14(1 Suppl 1):84-7. 3. Abudayyeh A, Hamdi A, Lin H, Abdelrahim M, Rondon G, Andersson BS, et al. Symptomatic BK Virus

Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients. Am J Transplant. 2016;16(5):1492-502.

4. Luo XD, Liu QF, Zhang Y, Sun J, Wang GB, Fan ZP, et al. Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation: etiology and pathogenesis. Blood Cells Mol Dis. 2011;46(2):182-7.

5. Fraile P, Vazquez L, Caballero D, Garcia-Cosmes P, Lopez L, San Miguel J, et al. Chronic graft-versus-host disease of the kidney in patients with allogenic hematopoietic stem cell transplant. Eur J Haematol. 2013;91(2):129-34.

6. Beyar-Katz O, Davila EK, Zuckerman T, Fineman R, Haddad N, Okasha D, et al. Adult Nephrotic Syndrome after Hematopoietic Stem Cell Transplantation: Renal Pathology is the Best Predictor of Response to Therapy. Biol Blood Marrow Transplant. 2016;22(6):975-81.

42


Characteristics of pediatric patients undergoing first allogeneic transplant for hematological malignancy between 2000-2015, as reported to the CIBMTR.

Variable N (%)



Serum creatinine, pre-transplant, median (range) 0.5 (0-43)

Serum creatinine, pre-transplant

< 0.3 2162 (24)

0.31 - 0.6 4580 (52)

0.61 - 0.9 1613 (18)

0.91 - 1.20 237 (3)

> 1.2 88 (<1)

Unknown 84 (<1)

Missing 76 (<1)

Estimated GFR, median (range) 164 (<1-4,879)

Estimated GFR

< 15 32 (<1)

15-29 7 (<1)

30-59 15 (<1)

60-89 94 (1)

> 90 8608 (97)

Missing 84 (<1)

Patient age, years, median (range) 10 (<1-18)

Patient age

< 10 4659 (53)

10-17 4181 (47)

Patient race

Caucasian 6647 (75)

African-American 637 (7)

Asian 736 (8)

Pacific islander 34 (<1)

Native American 65 (<1)

Other 277 (3)

Unknown 444 (5)

43




Patient gender

Male 5256 (59)

Female 3584 (41)

Disease

AML 2981 (34)

ALL 3900 (44)

CML 596 (7)

MDS 347 (4)

MPS 481 (5)

Other acute leukemia 159 (2)

Other leukemia 10 (<1)

NHL 309 (3)

HD 57 (<1)

Graft type

BM 4899 (55)

PB 1216 (14)

Single CB 2358 (27)

Double CB 342 (4)

Missing 25 (<1)

Donor type


Twin 52 (<1)

Haploidentical (mismatched other related) 55 (<1)

Other related (HLA matching unknown) 323 (4)

8/8 URD 1081 (12)

7/8 URD 534 (6)

< 6/8 URD 287 (3)

Well matched URD 521 (6)

Partially matched URD 477 (5)

Mismatched URD 234 (3)

6/6 UCB 253 (3)

5/6 UCB 787 (9)

< 4/6 UCB 468 (5)

Well matched UCB 63 (<1)

Partially matched UCB 180 (2)

Mismatched UCB 645 (7)

Missing 240 (3)

44






RIC 230 (3)

NMA 54 (<1)


Unknown 62 (<1)

Year of transplant

2000-2004 5013 (57)

2005-2009 2305 (26)

2010-2015 1522 (17)

GVHD prophylaxis

None 129 (1)

Cyclophosphamide alone 14 (<1)

Cyclophosphamide + others 44 (<1)

Tac + MMF + others (not Cy) 427 (5)

Tac + MTX + others (not Cy, MMF) 1086 (12)


Tac alone 64 (<1)

CsA + MMF + others (not Cy, Tac) 965 (11)

CsA + MTX + others (not Cy, Tac, MMF) 4095 (46)


CsA alone 554 (6)


Missing 10 (<1)

Follow-up of alive patients, months, median (range) 73 (1-247)

45


Characteristics of adult patients undergoing first allogeneic transplant for hematological malignancy between 2000-2015, as reported to the CIBMTR.

Variable N (%)



Serum creatinine, pre-transplant, median (range) 0.8 (0-203)

Serum creatinine, pre-transplant

< 0.3 177 (<1)

0.31 - 0.6 6196 (15)

0.61 - 0.9 21339 (51)

0.91 - 1.20 10777 (26)

> 1.2 2612 (6)

Unknown 294 (<1)

Missing 309 (<1)

Estimated GFR, median (range) 98 (<1-2047)

Estimated GFR

< 15 49 (<1)

15-29 60 (<1)

30-59 2294 (6)

60-89 12408 (30)

> 90 26286 (63)

Missing 607 (1)

Patient age, years, median (range) 47 (18-83)

Patient age

18-29 7426 (18)

30-39 7502 (18)

40-49 9402 (23)

50-59 10098 (24)

60-69 6411 (15)

70+ 865 (2)

Patient race

Caucasian 34797 (83)

African-American 1987 (5)

Asian 3141 (8)

Pacific islander 93 (<1)

Native American 126 (<1)

Other 448 (1)

Unknown 1112 (3)

46


(continued): N (%)


Patient gender

Male 24342 (58)

Female 17358 (42)

Missing 4 (<1)

Disease

AML 15488 (37)

ALL 5383 (13)

CML 6252 (15)

MDS 4401 (11)

MPS 2653 (6)

Other acute leukemia 271 (<1)

Other leukemia 1780 (4)

NHL 4695 (11)

HD 781 (2)

Graft type

BM 13711 (33)

PB 24998 (60)

Single CB 858 (2)

Double CB 2026 (5)

Missing 111 (<1)

Donor type


Twin 318 (<1)

Haploidentical (mismatched other related) 793 (2)

Other related (HLA matching unknown) 911 (2)

8/8 URD 11267 (27)

7/8 URD 3367 (8)

< 6/8 URD 977 (2)

Well matched URD 2823 (7)

Partially matched URD 2158 (5)

Mismatched URD 797 (2)

6/6 UCB 145 (<1)

5/6 UCB 899 (2)

< 4/6 UCB 1260 (3)

Well matched UCB 22 (<1)

Partially matched UCB 50 (<1)

Mismatched UCB 320 (<1)

Missing 339 (<1)

47


(continued): N (%)




RIC 8086 (19)

NMA 2681 (6)


Unknown 416 (<1)

Year of transplant

2000-2004 18974 (45)

2005-2009 12179 (29)

2010-2015 10551 (25)

GVHD prophylaxis

None 745 (2)

Cyclophosphamide 111 (<1)

Cyclophosphamide + others 791 (2)

Tac + MMF + others (not Cy) 4928 (12)

Tac + MTX + others (not Cy, MMF) 12173 (29)


Tac 888 (2)

CsA + MMF + others (not Cy, Tac) 3933 (9)

CsA + MTX + others (not Cy, Tac, MMF) 13606 (33)


CsA 1189 (3)


Missing 76 (<1)

Follow-up of alive patients, months, median (range) 61 (<1-251)

48


Proposal 1611-113 Title: Investigating antibiotic exposure and risk of acute graft versus host disease in children undergoing hematopoietic stem cell transplantation for acute leukemia. Caitlin W. Elgarten, MD; [email protected], The Children’s Hospital of Philadelphia Brian T. Fisher, DO, MPH, MSCE; [email protected], Perelman School of Medicine at the University of Pennsylvania Richard Aplenc, MD, PhD, MSCE; [email protected], Perelman School of Medicine at the University of Pennsylvania Hypothesis: Among pediatric patients who undergo hematopoietic stem cell transplantation (HSCT) for acute leukemia, exposure to antibiotics with activity against anaerobic commensal microorganisms, during the pre- and peri-transplant periods is associated with an increased risk of acute graft versus host disease (aGVHD). Scientific impact: Allogeneic HSCT is a potentially curative treatment for children with high-risk hematologic malignancies. GVHD, however, continues to be a major cause of morbidity and mortality after transplantation. An emerging role in the development of GVHD has been attributed to human microbiota – the microorganisms living in association with the human body – and the dysbiosis that occurs secondary to transplant-related procedures1. The use of antibiotics in patients undergoing HSCT is pervasive; the most common indication for initiation of empiric antibiotics is neutropenic fever. The current pediatric fever and neutropenia guidelines support a variety of anti-pseudomonal beta-lactam or carbapenem agents as first-line empiric therapy. Although these antibiotics are considered similar in their effectiveness for managing fever and neutropenia, they vary considerably in their activity against anaerobic commensal organisms and therefore in their potential to alter the gut microbiota. It is thus reasonable to hypothesize that certain antibiotic exposures in the immediate post-HSCT or pre-HSCT period may portend an increased risk for development of GVHD. This proposal aims to investigate whether the risk of aGVHD varies across different antibiotics commonly used in this patient population. Identification of risk variation across these agents would impact antibiotic choice in patients who undergo – or will undergo – HSCT. Specific aims:

To determine the independent association of antibiotics commonly administered for neutropenic fever with subsequent development of aGVHD in pediatric leukemia patients undergoing HSCT.

To determine the differential impact of antibiotic exposures in the pre-transplant period with subsequent development of aGVHD in pediatric leukemia patients undergoing HSCT.

Scientific justification: The microbiota of the human gut play an important role in the inhibition of potentially pathogenic microbes and stimulation of the gut immune system. The process of HSCT and the related supportive care measures – specifically exposure to broad-spectrum antibiotics – can force the gut microbiota to shift from a mutualistic health-promoting configuration to a low diversity, disease-associated layout2-5. Accumulating data are associating low diversity microbiota with subsequent modulation of host local

49


and systemic immunity. This impact of the microbiota on an evolving immune system is particularly important in the post-HSCT period. Recent evidence has begun to link microbiota changes that occur during the transplant course with decreased overall survival and increased transplant related mortality3,6. Among a cohort of patients undergoing HSCT for malignant diseases, those with the lowest intestinal diversity at the time of engraftment had significantly decreased overall survival compared to those with high diversity2. Notably, this increase in mortality was most pronounced in the assessment of transplant-related mortality and not relapse, suggesting that the effect was mediated through negative consequences of the transplant itself such as infection or GVHD. There is also growing evidence that relates the alteration in gut microbiota with the development of GVHD. Murine models have demonstrated that specific microbiota profiles after HSCT such as decreased diversity, reduction in obligate anaerobic bacteria (i.e. clostridiales) and expansion of specific bacteria (i.e. enterococcus, enterbacteriales), are associated with the development of GVHD4,7. In human subjects, patients who sustain more pronounced microbiota injury – decreased diversity, bacterial shifts from clostridiales to lactobacillales or enterbacteriales, or colonization with drug resistant bacteria – are more likely to develop clinically significant GVHD2,5,6. Exposure to antibiotics during the transplant course is ubiquitous. Frequent antibiotic exposures – especially those that target anaerobic commensal microorganisms – lead to a loss of microbiota diversity3,5. In a recent study, Shono et al. demonstrated that the use of antibiotics with activity against anaerobic commensal organisms (imipenem/cilastin and pipercilin/tazobactam) for the treatment of neutropenic fever was associated with increased GVHD and GVHD-related mortality, whereas exposure to broad-spectrum antibiotics without anti-anaerobic activity (cefepime and aztreonam) did not have the same association8. However, this study was limited in that the cohort included only adult patients who received T-replete allografts at a single site. Moreover, this analysis failed to control for additional exposures that may confound the association between antibiotic exposure and GVHD risk. More research is needed to assess the differential impact of antibiotic choice on the development of aGVHD in pediatric patients and to clarify the impact of specific classes of antibiotics on post-transplant outcomes. Understanding if certain antibiotics are more or less likely to be associated with GVHD would inform clinical decision-making with regard to antibiotic choice in this vulnerable population. It follows that antibiotic exposure even prior to the immediate transplant period may also affect the microbiota and thereby influence GVHD-risk post-HSCT. This is important, as patients receiving bone marrow transplants for malignant conditions are likely to have additional antibiotic exposures prior to the start of transplant. In small studies, clinically significant aGVHD has been associated with specific gut microbiota signatures prior to transplant including colonization with MDR bacteria, lower diversity and a less abundance of specific bacteroides species4,9. The variation in these signatures, even prior to transplant, may result from prior antibiotic exposures. That said, it has also been reported that the gut microbiota recovers its layout prior to transplant, in spite of antibiotics received by these patients3. Given this conflicting data, more work must be done to understand how the clinical course prior to transplant influences post-transplant outcomes. No single database exists that contains extensive information on transplantation outcomes as well as healthcare resource and pharmacy utilization. The Pediatric Health Information System (PHIS) database is a comparative pediatric database that includes clinical and resource utilization data for inpatient, emergency department and observation unit patient encounters for over 45 freestanding pediatric hospitals across the United States, including 19 transplant centers. Data elements in the PHIS database include demographics, dates of admission and discharge, discharge diagnosis and procedures codes, length of stay and adjusted hospital charges. The PHIS data also contain billing data corresponding to specific resources utilized including inpatient pharmaceutical agents with medication name and route of administration. Our group has extensive experience with the PHIS database and has applied this data to

50


explore resource utilization and infectious complications in pediatric oncology patients10-17. The group has also successfully merged this data with other databases18-21, including recently with data from Center for International Blood and Marrow Transplant Research (CIBMTR), the most comprehensive database of clinical information on transplanted patients (HS14-01). The use of PHIS and CIBMTR in tandem – pharmacy utilization data from PHIS and clinical outcome data from CIBMTR - can be leveraged to assess the association antibiotic utilization and subsequent risk for aGVHD. Study population: This cohort will include patients 0-21 years who received an allogeneic HSCT for treatment of acute leukemia (ALL or AML) from 2000 – 2012. Data requirements: We propose to use data elements from the following forms in the CIBMTR database:

Recipient Baseline and 100-day follow-up data (2000, 2100)

AML pre- and post-transplant forms (2010, 2110)

ALL pre- and post-transplant forms (2011, 2111) Data elements from these forms will be used to compile outcome data including:

Presence or absence of aGVHD, including type of GVHD (e.g skin, gut, liver), maximum grade of aGVHD, date of aGVHD onset and date of maximum GVHD grade

Relapse including date of relapse

Mortality including cause and date of death We will also collect the following covariates for potential inclusion in a multivariable regression model:

Demographic information: Age at transplant and sex

Diagnostic information: Indication for transplant and date of diagnosis

Transplant-related variables: Date of transplant, conditioning regimen, donor source, stem-cell manipulation, GVHD-prophylaxis, and date of neutrophil engraftment (used to define exposure window in aim 1)

Study design: This will be a retrospective analysis of pediatric leukemia patients undergoing HSCT at centers that contribute to both CIBMTR and PHIS databases. This cohort will be established in a manner similar to protocol HS14-01, using a probabilistic merge strategy based on institutional codes, date of birth and date of transplant. Exposure: The primary exposure of interest is antibiotics commonly used for fever and neutropenia. Specifically, we will capture exposure to three classes of antibiotics:

Carbapenems: meropenem, imipenem/cilastin

Third and fourth generation cephalosporins: cefepime, ceftazidine

Piperacillin/tazobactam, ticarcillin-clavulanate This exposure variable will be indexed to the person-days in the relevant exposure window. For aim 1, the exposure window will be from the start of conditioning through neutrophil engraftment. For aim 2, the exposure window will be from six months prior to transplant to the start of conditioning.

51


Covariates: Demographic, diagnostic and transplant-related covariates will be captured from the CIBMTR database, as above. Additional covariates will be abstracted from PHIS for inclusion in the multivariable model including:

Exposure to antibiotics not considered in the primary exposure definition. This will include antibiotics commonly used for prophylaxis and gut decontamination

Exposure to any antibiotics outside the primary exposure window of interest. This will include antibiotics after engraftment but prior to the development of aGVHD

Burden of antibiotic utilization at each hospital to be included in the multivariable model to account for clustering by center

Outcomes: The primary outcome will be time to development of clinically significant aGVHD (grade II-IV) within 100 days post transplant as reported to CIBMTR. We will perform a sub-analysis specially evaluating acute gut GVHD. Secondary outcomes will include all cause mortality, non-relapse mortality, relapse and graft failure. Statistical Considerations: 1. Univariate analysis will be performed to assess the association between each covariate and acute

GVHD using χ2 tests and logistic regression as appropriate. The cumulative incidence curves for acute GVHD according to exposure will be compared using log-rank tests.

Transplant-related variables will be evaluated for their association to the exposure and the outcome. Those that are not associated with both exposure and outcome will not be included in the model.

2. We will construct a multivariable regression model that incorporates our primary exposure data and aforementioned covariates to assess time to development of aGVHD using the Fine and Gray proportional sub-hazards model with death and relapse included as competing risks.

For aim 2, a similar model will be constructed that includes pre-transplant antibiotic exposures as the exposure of interest.

In addition, for aim 2, an sensitivity analysis will be performed to assess the impact of antibiotic exposures in alternative clinically-relevant windows prior to transplant.

3. To address bias due to reverse causality (i.e. if GVHD symptoms exist before the GVHD diagnosis subjects might receive antibiotics as treatment for symptoms arising from as-yet undiagnosed GVHD), we will perform a sensitivity analysis in which antibiotics administered in 14 days prior to aGVHD development are not considered in the analysis.

Based on prior experience with the CIBMTR and PHIS databases within our group, we estimate that approximately 800 patients will be included in the final cohort. With this sample size we will be able to detect a hazard ratio of 1.66 if we assume a type one error rate of 5% and a power of 80%. Non-CIBMTR data source: Our group has previously worked with CIBMTR to develop a cohort of children undergoing HSCT for acute leukemia based on data merged from PHIS and CIBMTR (HS14-01). The data were merged based on date of birth, date of transplant and location of transplant to create a single, robust dataset. There are 797 subjects with comprehensive CIBMTR data in the merged dataset. Performing a similar merge allows us to supplement the clinical information available through CIBMTR with granular data regarding antibiotic administration available in PHIS to answer questions about the impact of antibiotic exposure on post-transplant GVHD onset.

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References: 1. Zama D, Biagi E, Masetti R, et al. Gut microbiota and hematopoietic stem cell transplantation: where

do we stand? Bone marrow transplantation. 2016. 2. Taur Y, Jenq RR, Perales MA, et al. The effects of intestinal tract bacterial diversity on mortality

following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174-1182. 3. Biagi E, Zama D, Nastasi C, et al. Gut microbiota trajectory in pediatric patients undergoing

hematopoietic SCT. Bone marrow transplantation. 2015;50(7):992-998. 4. Bilinski J, Robak K, Peric Z, et al. Impact of Gut Colonization by Antibiotic-Resistant Bacteria on the

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective, Single-Center Study. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2016;22(6):1087-1093.

5. Taur Y, Jenq RR, Ubeda C, van den Brink M, Pamer EG. Role of intestinal microbiota in transplantation outcomes. Best Pract Res Clin Haematol. 2015;28(2-3):155-161.

6. Shono Y, Docampo MD, Peled JU, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Science Translational Medicine. 2016;8(339):339ra371-339ra371.

7. Jenq RR, Taur Y, Devlin SM, et al. Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2015;21(8):1373-1383.

8. Shono Y, Docampo MD, Peled JU, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8(339):339ra371.

9. Bilinski J, Grzesiowski P, Muszynski J, et al. Fecal Microbiota Transplantation Inhibits Multidrug-Resistant Gut Pathogens: Preliminary Report Performed in an Immunocompromised Host. Arch Immunol Ther Exp (Warsz). 2016;64(3):255-258.

10. Lothstein K, Fisher B, Li Y, et al. Zoonotic infections in pediatric patients with acute leukemia. Pediatric blood & cancer. 2013;60(12):E160-162.

11. Fisher BT, Aplenc R, Localio R, Leckerman KH, Zaoutis TE. Cefepime and mortality in pediatric acute myelogenous leukemia: a retrospective cohort study. The Pediatric infectious disease journal. 2009;28(11):971-975.

12. Fisher BT, Gerber JS, Leckerman KH, et al. Variation in hospital antibiotic prescribing practices for children with acute lymphoblastic leukemia. Leukemia & lymphoma. 2013;54(8):1633-1639.

13. de Blank P, Zaoutis T, Fisher B, Troxel A, Kim J, Aplenc R. Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer. The Journal of pediatrics. 2013;163(3):699-705.e691.

14. Kavcic M, Fisher BT, Li Y, et al. Induction mortality and resource utilization in children treated for acute myeloid leukemia at free-standing pediatric hospitals in the United States. Cancer. 2013;119(10):1916-1923.

15. Kavcic M, Fisher BT, Seif AE, et al. Leveraging administrative data to monitor rituximab use in 2875 patients at 42 freestanding children's hospitals across the United States. The Journal of pediatrics. 2013;162(6):1252-1258, 1258.e1251.

16. Fisher BT, Singh S, Huang YS, et al. Induction mortality, ATRA administration, and resource utilization in a nationally representative cohort of children with acute promyelocytic leukemia in the United States from 1999 to 2009. Pediatric blood & cancer. 2014;61(1):68-73.

17. Walker DM, Fisher BT, Seif AE, et al. Dexrazoxane use in pediatric patients with acute lymphoblastic or myeloid leukemia from 1999 and 2009: analysis of a national cohort of patients in the Pediatric Health Information Systems database. Pediatric blood & cancer. 2013;60(4):616-620.

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18. Li Y, Hall M, Fisher BT, et al. Merging Children's Oncology Group Data with an External Administrative Database Using Indirect Patient Identifiers: A Report from the Children's Oncology Group. PLoS One. 2015;10(11):e0143480.

19. Miller TP, Troxel AB, Li Y, et al. Comparison of administrative/billing data to expected protocol-mandated chemotherapy exposure in children with acute myeloid leukemia: A report from the Children's Oncology Group. Pediatric blood & cancer. 2015;62(7):1184-1189.

20. Miller TP, Li Y, Kavcic M, et al. Accuracy of Adverse Event Ascertainment in Clinical Trials for Pediatric Acute Myeloid Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(13):1537-1543.

21. Aplenc R, Fisher BT, Huang YS, et al. Merging of the National Cancer Institute-funded cooperative oncology group data with an administrative data source to develop a more effective platform for clinical trial analysis and comparative effectiveness research: a report from the Children's Oncology Group. Pharmacoepidemiology and drug safety. 2012;21 Suppl 2:37-43.

54


Characteristics of patients 21 years or younger undergoing first allogeneic HCT for AML and ALL between 2004-2011, as reported to the CIBMTR.

Variable

Single

Cord

Double

Cord Sib BM Well URD Part URD

Number of patients 264 65 102 243 119

Number of centers 35 22 24 32 31

Patient age at transplant, median (range) 6 (<1-21) 14 (1-20) 9 (<1-20) 11 (<1-21) 11 (1-21)

Patient age at transplant

<1-9 194 (73) 18 (28) 56 (55) 104 (43) 43 (36)

10-21 70 (27) 47 (72) 46 (45) 139 (57) 76 (64)

Disease

AML 116 (44) 26 (40) 60 (59) 125 (51) 39 (33)

ALL 148 (56) 39 (60) 42 (41) 118 (49) 80 (67)

Disease status

Early 88 (33) 17 (26) 67 (66) 94 (39) 38 (32)

Intermediate 140 (53) 41 (63) 30 (29) 112 (46) 71 (60)

Advanced 35 (13) 7 (11) 3 (3) 37 (15) 10 (8)

Missing 1 (<1) 0 2 (2) 0 0

Graft source

BM 0 0 102 195 (80) 91 (76)

PB 0 0 0 48 (20) 28 (24)

UCB 264 65 0 0 0

Year of transplant

2004-2007 114 (43) 5 (8) 59 (58) 174 (72) 96 (81)

2008-2011 150 (57) 60 (92) 43 (42) 69 (28) 23 (19)

Follow-up of survivors, months, median (range) 60 (4-121) 41 (22-74) 62 (4-124) 69 (22-124) 73 (10-120)

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Proposal 1608-01 Title: Evaluate the relationship between clostridium defficile colitis and subsequent gastrointenstinal graft versus host disease in recipients of allogeneic stem cell transplantation Divaya Bhutani, MD, [email protected], Karmanos Cancer Institute Abhinav Deol, MD, [email protected], Karmanos Cancer Institute Hypothesis: Clostridium difficile colitis (CDC) increases the risk of subsequent development of gastrointestinal acute graft versus host disease (GI GVHD). Specific aims: Compare the incidence of subsequent development of acute GI GVHD in patients with and without preceding CDC after undergoing allogeneic stem cell transplantation. Scientific justification: Rationale for the study: Clostridium Difficile Colitis (CDC) remains a common infection in patient undergoing Allogeneic Stem cell transplantation (allo-SCT) with reported incidence ranging from 9-24% in the first 100 days post transplantation (1-4). Common risk factors for development of GI GVHD are HLA-mismatch, older age, high disease risk index (5). Prior studies have evaluated the risk of clostridium difficile colitis (CDC) in this patient population and have shown increased incidence of development of subsequent GI GVHD in patients who develop CDC post transplantation. Alonso et al (1) reported a statistically significant increase in the rates of GI GVHD (25% at 1 year follow-up) in patients with preceding CDC as compared to a rate of 4.6% in controls. Similarly chakrabarty et al (6) also showed a statistically significant increase in incidence of severe (grade 3-4) GVHD in patients with preceding CDC along with an increased risk of non-relapse mortality in patients with CDC. Importance of the Intended study: Given that both CDC and GI GVHD are common complication of allogeneic stem cell transplantation, understanding their relationship will be vital to help reduce the incidence of GI GVHD. CDC is easily preventable infection with high sensitivity to oral anti-microbials such as oral Vancomycin. If our hypothesis is proven a prospective examination of prophylaxis against CDC could be easily done to help reduce the incidence of GI GVHD which carries significant morbidity and mortality. Study population:

Any patient who underwent Allogeneic stem cell transplantation over a ten year period from 2000-2010.

Donor type including (Related, Unrelated, Cord blood and Haploidentical).

Any transplant regimen including full intensity, RIC or NMA.

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Data requirements: We will need data collection forms for infections. No supplemental data is required Desired outcome variables: 1. Patient Related:

Age

gender

Race

performance status 2. Disease Related:

Underlying Diagnosis

CMV status 3. Transplant Related:

Disease Status at the time of transplant

Type of Transplant (Matched related, unrelated, cord blood, hapoidentical)

Incidence of Clostridium Difficile colitis

Conditioning regimen (Full intensity, RIC, NMA)

Non-relapse Mortality

Incidence of Acute GVHD (grade 1-2 and grade 3-4)

Incidence of GI GVHD

Incidence of Chronic GVHD

Progression free Survival Study design:

• Compare the incidence of subsequent GI GVHD in patients who develop preceding CDC as compared to the patients without history of preceding CDC.

• Compare other outcomes (OS, PFS, NRM, Chronic GVHD) among the two groups. • Statistical methodology: Kaplan Meyer analysis to compare the outcomes.

References: 1. Alonso CD, Treadway SB, Hanna DB, Huff CA, Neofytos D, Carroll KC, Marr KA.Epidemiology and

outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2012 Apr;54(8):1053-63.

2. Chopra T, Chandrasekar P, Salimnia H, Heilbrun LK, Smith D, Alangaden GJ. Recent epidemiology of Clostridium difficile infection during hematopoietic stem cell transplantation. Clin Transplant. 2011 Jan-Feb;25(1):E82-7.

3. Hosokawa K, Takami A, Tsuji M. Relative incidences and outcomes of Clostridium difficile infection following transplantation of unrelated cord blood, unrelated bone marrow, and related peripheral blood in adult patients: a single institute study. Transpl Infect Dis. 2014 Jun;16(3):412-20.

4. Zacharioudakis IM, Ziakas PD, Mylonakis E. Clostridium difficile infection in the hematopoietic unit: a meta-analysis of published studies. Biol Blood Marrow Transplant. 2014 Oct;20(10):1650-4.

5. Solh M, Zhang X, Connor K. Factors Predicting Graft-versus-Host Disease-Free, Relapse-Free Survival after Allogeneic Hematopoietic Cell Transplantation: Multivariable Analysis from a Single Center. Biol Blood Marrow Transplant. 2016 Apr 14. pii: S1083-8791(16)30025-8.

6. Chakrabarti S, Lees A, Jones SG, Milligan DW. Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality. Bone Marrow Transplant. 2000 Oct;26(8):871-6.

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http://www.ncbi.nlm.nih.gov/pubmed/?term=Alonso%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

http://www.ncbi.nlm.nih.gov/pubmed/?term=Treadway%20SB%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

http://www.ncbi.nlm.nih.gov/pubmed/?term=Hanna%20DB%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

http://www.ncbi.nlm.nih.gov/pubmed/?term=Huff%20CA%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

http://www.ncbi.nlm.nih.gov/pubmed/?term=Neofytos%20D%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

http://www.ncbi.nlm.nih.gov/pubmed/?term=Carroll%20KC%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

http://www.ncbi.nlm.nih.gov/pubmed/?term=Marr%20KA%5BAuthor%5D&cauthor=true&cauthor_uid=22412059

http://www.ncbi.nlm.nih.gov/pubmed/22412059


http://www.ncbi.nlm.nih.gov/pubmed/?term=Chopra%20T%5BAuthor%5D&cauthor=true&cauthor_uid=20973823

http://www.ncbi.nlm.nih.gov/pubmed/?term=Chandrasekar%20P%5BAuthor%5D&cauthor=true&cauthor_uid=20973823

http://www.ncbi.nlm.nih.gov/pubmed/?term=Salimnia%20H%5BAuthor%5D&cauthor=true&cauthor_uid=20973823

http://www.ncbi.nlm.nih.gov/pubmed/?term=Heilbrun%20LK%5BAuthor%5D&cauthor=true&cauthor_uid=20973823

http://www.ncbi.nlm.nih.gov/pubmed/?term=Smith%20D%5BAuthor%5D&cauthor=true&cauthor_uid=20973823

http://www.ncbi.nlm.nih.gov/pubmed/?term=Alangaden%20GJ%5BAuthor%5D&cauthor=true&cauthor_uid=20973823


http://www.ncbi.nlm.nih.gov/pubmed/?term=Hosokawa%20K%5BAuthor%5D&cauthor=true&cauthor_uid=24810244

http://www.ncbi.nlm.nih.gov/pubmed/?term=Takami%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24810244

http://www.ncbi.nlm.nih.gov/pubmed/?term=Tsuji%20M%5BAuthor%5D&cauthor=true&cauthor_uid=24810244

http://www.ncbi.nlm.nih.gov/pubmed/?term=Transpl+Infect+Dis+2014%3A+16%3A+412%E2%80%93420

http://www.ncbi.nlm.nih.gov/pubmed/?term=Zacharioudakis%20IM%5BAuthor%5D&cauthor=true&cauthor_uid=24914822

http://www.ncbi.nlm.nih.gov/pubmed/?term=Ziakas%20PD%5BAuthor%5D&cauthor=true&cauthor_uid=24914822

http://www.ncbi.nlm.nih.gov/pubmed/?term=Mylonakis%20E%5BAuthor%5D&cauthor=true&cauthor_uid=24914822

http://www.ncbi.nlm.nih.gov/pubmed/?term=Ioannis+M.+Clostridium+Difficile+Infection+in+the+Hematopoietic+Unit

http://www.ncbi.nlm.nih.gov/pubmed/?term=Solh%20M%5BAuthor%5D&cauthor=true&cauthor_uid=27095692

http://www.ncbi.nlm.nih.gov/pubmed/?term=Zhang%20X%5BAuthor%5D&cauthor=true&cauthor_uid=27095692

http://www.ncbi.nlm.nih.gov/pubmed/?term=Connor%20K%5BAuthor%5D&cauthor=true&cauthor_uid=27095692


http://www.ncbi.nlm.nih.gov/pubmed/?term=Chakrabarti%20S%5BAuthor%5D&cauthor=true&cauthor_uid=11081387

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lees%20A%5BAuthor%5D&cauthor=true&cauthor_uid=11081387

http://www.ncbi.nlm.nih.gov/pubmed/?term=Jones%20SG%5BAuthor%5D&cauthor=true&cauthor_uid=11081387

http://www.ncbi.nlm.nih.gov/pubmed/?term=Milligan%20DW%5BAuthor%5D&cauthor=true&cauthor_uid=11081387

http://www.ncbi.nlm.nih.gov/pubmed/?term=Bone+Marrow+Transplantation+(2000)+26%2C+871%E2%80%93876


Characteristics of patients receiving their first allogeneic transplant between 2000-2010, as reported to the CIBMTR.

Variable CDC

Other bacterial

infection

No bacterial

infection



Patient age 43 (<1-73) 48 (<1-74) 42 (<1-83)

Age at transplant

< 10 69 (10) 11 (8) 2330 (9)

10 - 17 60 (9) 15 (11) 2119 (8)

18 - 29 87 (12) 13 (9) 3715 (15)

30 - 39 104 (15) 14 (10) 3582 (14)

40 - 49 129 (18) 21 (15) 5053 (20)

50 - 59 157 (22) 37 (27) 5874 (23)

60 - 69 95 (13) 23 (17) 2645 (10)

70+ 3 (<1) 4 (3) 156 (<1)

Missing 0 0 1 (<1)

Disease

AML 317 (45) 54 (39) 9177 (36)

ALL 147 (21) 20 (14) 4512 (18)

CML 37 (5) 7 (5) 2842 (11)

MDS 53 (8) 12 (9) 1499 (6)

MPS 27 (4) 14 (10) 1827 (7)

Other acute leukemia 17 (2) 6 (4) 1042 (4)

Other leukemia 13 (2) 2 (1) 278 (1)

NHL 69 (10) 17 (12) 2900 (11)

HD 8 (1) 1 (<1) 560 (2)

MM 16 (2) 5 (4) 838 (3)

Type of donor

Cord blood 94 (13) 15 (11) 2197 (9)

HLA identical sibling 267 (38) 55 (40) 7306 (29)

Twin 8 (1) 2 (1) 194 (<1)

Haploidentical 16 (2) 4 (3) 147 (<1)

Other relatives 22 (3) 2 (1) 862 (3)

Well-matched unrelated 214 (30) 45 (33) 9351 (37)

Partially-matched unrelated 72 (10) 8 (6) 3914 (15)

Mismatched unrelated 10 (1) 5 (4) 1362 (5)

Unrelated (HLA matching unknown) 1 (<1) 2 (1) 136 (<1)

Missing 0 0 6 (<1)

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Characteristics (continued): CDC

Other bacterial

infection

No bacterial

infection


Graft type

BM 157 (22) 39 (28) 7992 (31)

PBSC 453 (64) 84 (61) 15250 (60)

UCB 94 (13) 15 (11) 2197 (9)

Missing 0 0 36 (<1)


Myeloablative 497 (71) 79 (57) 16503 (65)

RIC 111 (16) 31 (22) 4213 (17)

NMA 31 (4) 10 (7) 1343 (5)

TBD 56 (8) 17 (12) 2415 (9)

Missing 9 (1) 1 (<1) 1001 (4)

Year of transplant

2000 - 2003 53 (8) 23 (17) 10791 (42)

2004 - 2007 289 (41) 50 (36) 10350 (41)

2008 - 2010 362 (51) 65 (47) 4334 (17)

Time from transplant to bacterial infection, days 9 (1-100) 11 (1-97) N/A

Site of bacterial infection

No bacterial infection 0 0 25475

Feces-stool 671 (95) 81 (59) 0

Small intestine 1 (<1) 3 (2) 0

Large intestine 10 (1) 35 (25) 0

GI tract, not specified 22 (3) 19 (14) 0

Follow-up of alive patients, months, median

(range)

72 (1-171) 73 (3-163) 76 (<1-195)

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Proposals: 1610-08 and 1611-24 Title: Risk Factors of Acute and Chronic Graft-versus-Host Disease in T-Replete HLA-Haploidentical Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide Betty Ky Hamilton, MD, [email protected], Cleveland Clinic Navneet Majhail, MD, [email protected], Cleveland Clinic Steven Pavletic, MD, MS, [email protected], National Cancer Institute Annie Im, MD, [email protected], University of Pittsburgh Cancer Institute Armin Rashidi, MD, PhD, [email protected], University of Minnesota Daniel Weisdorf, MD, [email protected], University of Minnesota Hypothesis: We hypothesize that haploidentical transplantation using post-transplant cyclophosphamide (PT-Cy) has a low incidence of both acute and chronic graft-versus-host disease (GVHD) and that through the CIBMTR database, we will be able to identify risk factors for GVHD in the haploidentical setting. Specficially, we further hypothesize that:

The incidence of acute GVHD is similar after myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC)

Peripheral blood (PB) grafts are associated with a higher incidence of chronic GVHD compared to bone marrow (BM) grafts.

Scientific impact: The identification of risk factors for acute and chronic GVHD in patients undergoing PT-Cy-based T-replete haploHCT is critical to improving risk stratification and GVHD outcomes for patients undergoing HCT.

Specific aims: The primary aim of this study is to describe the incidence, characteristics, and risk factors for acute and chronic GVHD in patient undergoing PT-Cy-based T-replete haploidentical HCT (haploHCT). GVHD characteristics will be described separately for myeloablative BM and PB stem cells and reduced intensity BM and PB. The role of conditioning intensity (MAC versus RIC) and stem cell source (BM vs. PB) will be evaluated as risk factors for acute and chronic GVHD. Secondary aims are to evaluate the incidence of CMV viremia, hematopoietic recovery, relapse, transplant-related mortality, GVHD-free survival and overall survival. Scientific justification: For adults with advanced hematologic malignancies needing allogeneic HCT, an HLA-matched sibling donor is generally considered the optimal donor source [1]. When such donor is not available, a well matched unrelated donor (MUD) is considered the best alternative [1, 2]. However, for many patients, especially non-Caucasian, there is limited availability of fully matched unrelated donors [3]. For these patients, alternative donor sources such as haploidentical donors can be the only available donor sources, and is particularly attractive because it promises nearly universal donor availability. However, historically it has been associated with high transplant-related mortality [4]. Recently with the advent of PT-Cy GVHD prophylaxis, outcomes have improved significantly [5, 6], approaching those in the matched setting [7, 8]. Despite its now widespread use, however, there is little data, describing acute and chronic GVHD outcomes after haploHCT, as well as potential risk factors for developing GVHD, such as donor-

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mailto:[email protected]

mailto:[email protected]


recipient sex, haplo-source (maternal/paternal/sibling), and specifically, conditioning intensity (MAC/RIC) and stem cell source (BM/PB). We thus propose to study and describe the incidence, characteristics, and risk factors for acute and chronic GVHD in patients undergoing haploHCT. We further propose to evaluate the role of conditioning and source of stem cells source on the incidence of both acute and chronic GVHD. Several analyses have now evaluated the combination of conditioning intensity and stem cells source in haploHCT. These results are summarized in Table 1. Table 1. Rates of acute and chronic GVHD after haploHCT

Study N (haplo)

Graft source

Conditioning Acute GVHD (II-IV)

Chronic GVHD

Comments

Brunstein 20117 50 BM RIC/NMA 32% at day 100

13% at 1 year

Di Stasi 20145 32 BM RIC/NMA 29% at day 100

19% at 3 years

McCurdy 20158 372 BM RIC/NMA 32% at day 180

13% at 2 years

Kasamon 20159 271 BM RIC/NMA 33% at day 180

10% at 1 year

Age 50-75 years

Raiola 201410 92 BM RIC/NMA and MA

14% 15%

Bashey 20134

53 BM and PB

RIC/NMA and MA

30% at 6 months

38% at 2 years

cGVHD lower compared to MRD and MUD

Ciurea 20156 192 BM and PB

RIC/NMA and MA

16-19% at day 90

30-34% at 3 years

Castagna 201411 69 BM and PB

RIC/NMA 25-33% 13% No difference BM or PB

Blaise 201612 31 BM and PB

RIC/NMA 23% 0% at 2 years

Age >55 years; Mostly PB

Gaballa 201613 60 BM RIC 28% at day 100

24% at 1 year

Ghosh 201614 180 BM RIC 27% at day 100

12% at 1 year

cGVHD lower compared to MSD (lymphomas)

Rashidi 201615 52 PB RIC and MA 40% at day 180

10% at 1.5 years

GVHD rates comparable to MUDs

Kanate 201616 185 BM and PB

RIC/NMA 27% at day 100

13% at 1 year

Mostly BM; GVHD rates better than MUD +/-ATG

61


Bashey 201617 116 BM and PB

RIC and MA 41% at 6 months

31% at 2 years (25% for PB only)

O’Donnell 201618 86 BM vs. PB

RIC 33% BM vs. 40% PB at day 100

21% BM vs. 14% PB at 1 year

Comparison of haplo BM versus PB

In a recent CIBMTR study by Ciurea et al., an analysis was performed to compare haploHCT with PT-Cy versus MUD HCT for 2974 patients with AML transplanted between 2008-2012 [9]. Patients were evaluated separately by conditioning intensity. For both groups, the incidence of chronic GVHD was significantly lower after haploHCT compared to MUD HCT (MAC: 30% vs 53% at 3 years, RIC/NMA: 34% vs 52% at 3 years). However, given that PB grafts are known to confer a higher risk of chronic GVHD, and 90% of the patients who underwent MUD HCT received PB grafts (compared to the 90% of patients who underwent Haplo-HCT), a separate analysis was performed to evaluate only those who received BM grafts. In this analysis, there was no difference in 3-year rates of chronic GVHD between haploHCT and MUD HCT for either conditioning regimen (range, 30-36%). These findings suggest that the graft source may have a role the apparently lower chronic GVHD rates with haploHCT. In contrast, two analyses of patients who underwent PT-Cy-based haploHCT with RIC/NMA conditioning compared PB and BM graft sources and showed a similar incidence of chronic GVHD; however, the groups were small [10, 11]. MAC has been recognized as a risk factor for acute GVHD in matched donor HCT due to the detrimental effect of high-dose therapy on gut barrier integrity [12]. However, whether MAC is a risk factor for acute GVHD in haploHCT has not been adequately studied. Only one study from Europe investigated this question, with no significant difference between MAC and RIC transplants [13]. However, GVHD prophylaxis in this study was PT-Cy-based only in 25-30% of patients, limiting the generalizability of the results to the now popular PT-Cy-based approach. By depleting alloreactive T cells, PT-Cy may offset the effect of conditioning-induced gut barrier damage on donor T-cell alloreactivity and acute GVHD risk. The goal of the proposed study is thus to identify the risk factors of acute and chronic GHVD after PT-Cy-based T-replete haploHCT using the CIBMTR database. Among the various potential risk factors that will be investigated, a particular focus will be on graft source (BM vs. PB) as a risk factor for chronic GHVD and conditioning intensity (MAC vs. RIC) as a risk factor for acute GVHD. Study population: Inclusion criteria

Patients with a hematologic malignancy

Age ≥ 18 years

First T-replete haploHCT using PT-Cy between 2007 and 2015. HaploHCT is defined as 2 or more antigen-level mismatches among HLA-A, -B, -C, and -DRB1

Exclusion Criteria Ex-vivo T-cell depletion

Use of ATG or alemtuzumab in conditioning

PT-Cy as single GVHD prophylaxis

Combined Haplo-Cord transplants

Data requirements: TED and CRF forms using CIBMTR database

62


Outcomes:

Cumulative incidence, severity, and organ involvement of acute GVHD until Day +180

Cumulative incidence, type, and severity of chronic GVHD

Time to hematopoietic recovery (platelets and neutrophil)

Primary graft failure

Secondary graft failure

Cumulative incidence of chronic GVHD (limited and extensive) at 1 year

CMV viremia

Non-relapse mortality

Cumulative incidence of relapse

Disease-free survival

Overall survival

GVHD-free relapse-free survival (GRFS)

Causes of death Variables: Patient characteristics:

Patient age at HCT

Gender

Karnofsky performance score: ≥90 vs. <90

HCT-CI: 0 vs. 1-2 vs. ≥3

Race: White vs. African American vs. Hispanics vs. others Disease Characteristics:

Disease diagnosis

Disease type: myeloid vs. lymphoid vs. other Time from diagnosis to HCT: 0-6 vs. 6-12 vs. ≥ 12 months

Disease Risk Index (DRI)

Cytogenetics Transplant characteristics:

MAC vs. RIC according to CIBMTR definition [14]

TBI-based MAC vs. chemo-based MAC

CD34 cell dose in the graft

CD3 cell dose in the graft

Graft type: BM vs. PB

Donor relationship

GVHD prophylaxis in addition to PT-Cy: Tac + MMF (+/- others) vs. others

Donor/Recipient gender: F/F vs. M/M vs. F/M vs. M/F

Donor/Recipient CMV status: -/+ vs. +/- vs. +/+ vs. -/- Study design: This is a retrospective CIBMTR-based study describing incidence, characteristics, and risk factors of GVHD in T-replete PT-Cy-based haploHCT. The primary outcomes are the cumulative incidence of grade 2-4 and grade 3-4 acute GVHD, organ involvement, and type and severity of chronic GVHD. Secondary outcomes include hematopoietic recovery, CMV viremia, transplant-related mortality, relapse, GVHD-free survival, GVHD-free relapse-free survival, and overall survival. Patient, disease, and transplant-related variables will be described. Survival will be calculated using the Kaplan-Meier estimator. For

63


neutrophil and platelet recovery, acute GVHD (grade II-IV and III-IV) and chronic GVHD, death without the event will be the competing event. For non-relapse mortality, relapse/progression will be the competing event. For relapse rate, non-relapse mortality will be the competing event. Data on patients without an event will be censored at last follow up. Univariate analysis with Gray test and log-rank test will be used for cumulative incidence and survival respectively. The proportional hazards Cox model will be conducted. Backward elimination will be used to select significant covariates. Conditioning intensity and graft source will be included in all steps of model building regardless of level of significance. Results will be expressed as hazard ratio with 95% confidence intervals. Possible interactions within the treatment groups and significant variables will be tested. All models will be tested regarding proportional hazard of assumptions. If the assumption is violated, time dependent covariates will be constructed. References: 1. Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched unrelated

donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood 2012;119:3908-3916.

2. Appelbaum FR. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia when a matched related donor is not available. Am Soc Hematol Educ Program 2008;412-417.

3. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 2014;371:339-348.

4. Ciceri F, Labopim M, Aversa F, et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission. Blood 2008;112:3574-3581.

5. Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood 2001;98:3456-3464.

6. O’Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using From www.bloodjournal.org by guest on November 5, 2015. For personal use only. 25 posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2002;8:377-386.

7. Rashidi A, DiPersio JF, Westervelt P, et al. Comparison of Outcomes after Peripheral Blood Haploidentical versus Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Review. Biol Blood Marrow Transplant 2016;22:1696-701.

8. Bashey A, Zhang X, Jackson K, et al. Comparison of Outcomes of Hematopoietic Cell Transplants from T-Replete Haploidentical Donors Using Post-Transplantation Cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 Allele-Matched Unrelated Donors and HLA-Identical Sibling Donors: A Multivariable Analysis Including Disease Risk Index. Biol Blood Marrow Transplant 2016;22:125-33.

9. Ciurea SO, Zhang MJ, Bacigalupo AA, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood 2015;126:1033-40.

10. Castagna L, Crocchiolo R, Furst S, et al. Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide. Biol Blood Marrow Transplant 2014;20:724-9.

11. O'Donnell PV, Eapen M, Horowitz MM, et al. Comparable outcomes with marrow or peripheral blood as stem cell sources for hematopoietic cell transplantation from haploidentical

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donors after non-ablativeconditioning: a matched-pair analysis. Bone Marrow Transplant 2016;51:1599-1601.

12. Hill GR, Crawford JM, Cooke KJ, et al. Total body irradiation and acute graft versus host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 1997;90:3204.

13. Rubio MT, Savani BN, Labopin M, et al. Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT. J Hematol Oncol 2016 (in press).

14. Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009;15:1628-33.

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Characteristics of adult patients undergoing first allogeneic BM/PB HCT from a haploidentical donor receiving post-transplant Cyclophosphamide between 2007-2015, as reported to the CIBMTR

Variable MA RIC/NMA

Number of patients 135 330

Number of centers 27 51


Myeloablative 135 0

RIC/NMA 0 308 (93)

Unknown 0 22 (7)

Patient age at transplant, years, median (range) 47 (18-71) 59 (18-78)

Graft type

BM 43 (32) 215 (65)

PB 92 (68) 115 (35)

Patient gender

Male 73 (54) 207 (63)

Female 62 (46) 123 (37)

Karnofsky performance score

< 90 71 (53) 113 (34)

90 - 100 60 (44) 211 (64)

Missing 4 (3) 6 (2)

Disease

Myeloid 92 (68) 214 (65)

Lymphoid 41 (30) 102 (31)

Other malignancy 2 (2) 14 (4)

GVHD prophylaxis

Cy + Tac + MMF + others 122 (90) 312 (95)

Other 13 (10) 18 (5)

Follow-up of survivors, months, median (range) 12 (3-51) 13 (2-97)

66


Proposal 1611-15/1611-131 Title: Alterations in the characteristics and outcomes of acute and chronic GVHD following post-transplant high dose Cytoxan (Cy) prophylaxis for haploidentical transplantation and in patients over 60 at high risk for GVHD Rima M. Saliba, PhD, [email protected], The University of Texas MD Anderson Cancer Center Stefan O. Ciurea, MD, [email protected], The University of Texas MD Anderson Cancer Center Jeff Schriber, MD, [email protected], Cancer Transplant Institute Scottsdale Arizona Background Haploidentical related donor transplant has been facilitated by the use of high dose Cy post-transplant. This regimen appears to change the epidemiology of GVHD in patients undergoing haploidentical related donor versus matched unrelated donor allogeneic stem cell transplantation with standard GVHD prophylaxis. Post- transplant Cy regimen has also been adapted for use in patients at higher risk for GVHD including patients over the age of 60. Hypothesis: The rate of non-relapse mortality (NRM) and chronic GVHD (cGVHD) following acute GVHD (aGVHD) is lower with the use of post-transplant Cy prophylaxis; and this difference may be most pronounced in patients over the age of 60. Specific aims:

Compare the incidence, organ distribution, and outcome of maximum grade 1, grade 2, and grade 3-4 aGVHD in recipients of haploidentical related donor transplant with post transplant Cy (+other) prophylaxis versus matched unrelated donor transplant with standard GVHD prophylaxis. Outcomes of interest include NRM, overall survival (OS), and cGVHD.

Compare the overall incidence, type of onset (de novo vs progressive vs quiescent), severity (extensive vs limited), organ involvement, and outcome of cGVHD in recipients of haploidentical related donor transplant with post-transplant Cy (+other) prophylaxis versus matched unrelated donor transplant with standard GVHD prophylaxis. Outcomes of interest include NRM, OS, and relapse or progression of malignancy.

Compare the incidence of aGVHD and cGVHD, as well as the rates of NRM and relapse, disease-free survival and OS, between patients treated with post-transplant Cy versus standard GVHD prophylaxis regimens (irrespective of donor type) in patients over the age of 60.

Scientific justification: The incidence of GVHD following related haploidentical transplantation in patients receiving post- transplant Cy has been consistently reported to be low in several patient populations1-6. In a recently published CIBMTR study5, the 3-months incidence of grade II-IV acute GVHD was reported to be significantly lower in recipients of haploidentical transplantation with post-transplant Cy compared with recipients of matched unrelated donor transplantation using standard GVHD prophylaxis. This reduction in the incidence of aGVHD did not however translate into lower rate of NRM, superior OS, or lower incidence of cGVHD (at least not in recipients of bone marrow grafts). On the other hand, the cause of death data reported in the study suggest a lower mortality rate for patients with GVHD after haploidentical related versus matched unrelated donor. These findings raise the question on whether, in addition to the overall incidence, outcomes of acute and/or chronic GVHD are different following

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haploidentical with post-transplant Cy compared with matched unrelated donor transplantation with standard GVHD prophylaxis. More detailed understanding of the epidemiology of GVHD and its contribution to outcomes following haploidentical transplantation with post-transplant Cy is needed for a more complete assessment of the ultimate benefit of this type of transplantation. Such comparison may also guide future studies testing novel GVHD therapies and shed light on the pathophysiology of the disease. The use of less intensive transplant regimens has allowed allogeneic transplant to increasingly be used safely in patients over the age of 60, thus extending the effective age limit for transplant closer to the median age of diagnosis for AML and MDS. Despite such improvements, acute and chronic GVHD remain major causes of morbidity and mortality especially in the older patient cohorts. The advent of post-transplant Cytoxan is increasingly being used in patients at higher risk for GVHD, including patients who have mismatches and are older. Although the incidence of GVHD may be lower the concern is that the lack of a GVL effect may result in an increase in relapse rates. We (Schriber J, Fauble V, Simpson E et al, BBMT Vol 22, issue 3, S412-S413) recently reviewed the experience of the Cancer Transplant Institute, Scottsdale in treating patients over the age of 60 and noted very high rates and mortality directly attributable of GVHD using conventional GVHD prophylaxis regimens. This caused a shift in our standard practice and we now include post-transplant Cy for all patients over the age of 60. Our own comparison with small numbers suggests a significant decrease in the incidence and mortality of acute GVHD in patients receiving post-transplant Cy. The data are too early to determine if this will affect relapse rates, DFS or OS. There are currently several CTN trials that are attempting to define the role of post-transplant Cy versus other more standard methods of GVHD prophylaxis. CTN 1301 is a phase 3 trial comparing different GVHD prevention strategies including post-transplant Cy, CD 34 cell selected graft, versus standard Tacrolimus/MTX. The trial is limited to BM grafts and the age max is 66. This limits the ability to define a role in patients over the age of 60. The proposed trial if positive would likely result in a new trial or an amended version that could focus on an older patient group. CTN 1203 is a randomized phase 2 comparing three novel regimens including post-transplant Cy with a contemporary control using standard therapy. This trial will have 90 patients in each arm, but does allow a maximum age of 75. Although these trials will look at post-transplant Cy, it is likely that there will be limited information on patients over the age of 60. Study population:

All adult (age 18-70 years) patients who received their first T-cell replete allogeneic stem cell transplantation from a haploidentical (mismatched at least two or more HLA- loci to donors) related or a matched (matched at the allele-level at HLA-A, -B, -C, and - DRB1) unrelated donor between 2008 and 2015.

All hematologic malignancies Myeloablative, reduced intensity, or non-myeloablative conditioning regimens Bone marrow or peripheral blood stem cells graft GVHD prophylaxis: Cyclophosphamide + others; Tac + MMF +/- others (not Cy); Tac + MTX +/-

others (not Cy, MMF); CsA + MMF +/- others (not Cy, Tac); CsA + MTX +/- others (not Cy, Tac, MMF).

Data requirements: Patient-related

Age

Gender

CMV serostatus

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Donor related

Age

Gender

CMV serostatus Disease-related

Disease

Disease status at transplant Transplant-related

Source of Stem Cells

GVHD Prophylaxis Regimen

Treatment Regimen

Conditioning intensity Post-transplant-related

Maximum grade of aGVHD


Acute and chronic GVHD organ involvement

TRM

Cause of Death (GVHD vs other)

DFS

OS Study design: The cumulative incidence method accounting for competing risks will be used to estimate the incidence of GVHD, disease progression and NRM. Actuarial OS and PFS will be estimated using the Kaplan-Meier method. GVHD organ distribution will be summarized using descriptive statistics. Outcomes following GVHD will be estimated in landmark analysis starting on the day of onset of GVHD. Outcomes of interest following acute GVHD include OS, NRM, and chronic GVHD. Outcomes of interest following chronic GVHD include OS, NRM, progression, and PFS. The independent effect of transplant type (Haploidentical with post-transplant Cy vs matched unrelated donor with standard GVHD prophylaxis) on the incidence of GVHD and outcomes following GVHD will be evaluated on univariate and multivariate analyses using competing risks regression analysis. Interaction effects according to stem cell source (BM vs PB), conditioning intensity, and type of standard GVHD prophylaxis in non-Cy group will be evaluated and accounted for when indicated. Subset analyses including only patients older than 60 will be performed to compare OS, NRM, progression of malignancy and PFS in recipients of high dose Cytoxan versus standard GVHD prophylaxis regimens. Interaction effects by donor type, stem cell source will be evaluated and accounted for when indicated. References 1. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone

marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14(6): 641-650. doi: 10.1016/j.bbmt.2008.03.005

2. Di Bartolomeo P, Santarone S, De Angelis G, Picardi A, Cudillo L, Cerretti R et al. Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation for patients with high-risk hematologic malignancies. Blood 2013; 121(5): 849-857. doi: 10.1182/blood-2012-08- 453399

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3. Wang Y, Liu DH, Liu KY, Xu LP, Zhang XH, Han W et al. Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center. Cancer 2013; 119(5): 978-985. doi: 10.1002/cncr.27761

4. Bacigalupo A, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F et al. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update. Bone Marrow Transplant 2015; 50 Suppl 2: S37-39. doi: 10.1038/bmt.2015.93

5. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood 2015; 126(8): 1033-1040. doi: 10.1182/blood- 2015-04-639831

6. Ruggeri A, Sun Y, Labopin M, Bacigalupo A, Lorentino F, Arcese W et al. Post-transplant cyclophosphamide versus antithymocyte-globulin as graft versus host disease prophylaxis in haploidentical transplant. Haematologica 2016. doi: 10.3324/haematol.2016.151779

7. Kasamon Y et al. Outcomes of Nonmyeloablative HLA-Haploidentical Blood or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide in Older Adults. J Clin Oncol 33: 3152-3161, 2015

8. Rashidi A, Ebadi M, Colditz GA, DiPersio JF, Outcomes of allogeneic stem cell transplantation in elderly patients with acute myeloid leukemia: a systematic review and meta- analysis, Biology of Blood and Marrow Transplantation (2015), doi: 10.1016/j.bbmt.2015.10.019.

9. Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA - Journal of the American Medical Association. 2011;306:1874- 1883.

10. Ustun C, Lazarus HM, Weisdorf D. To transplant or not: a dilemma for treatment of elderly AML patients in the twenty-first century. Bone marrow transplantation. 2013;48: 1497-1505.

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Characteristics of patients undergoing first allogeneic HCT for hematological malignancy with haploidentical or 8/8-matched unrelated donor between 2008-2015, as reported to the CIBMTR.

Variable Haploidentical URD 8/8

Number of patients 887 5780

Number of centers 91 178

Patient age, years, median (range) 55 (18-82) 57 (18-83)

Patient age

18-29 120 (14) 528 (9)

30-39 93 (10) 540 (9)

40-49 120 (14) 866 (15)

50-59 209 (24) 1565 (27)

60-69 275 (31) 1883 (33)

70+ 70 (8) 398 (7)

Disease

AML 376 (42) 2329 (40)

ALL 117 (13) 525 (9)

CML 36 (4) 224 (4)

MDS 182 (21) 1840 (32)

MPS 3 (<1) 0

Other acute leukemia 12 (1) 33 (<1)

Other leukemia 24 (3) 286 (5)

NHL 114 (13) 469 (8)

HD 23 (3) 74 (1)

Graft type

BM 379 (43) 879 (15)

PB 508 (57) 4901 (85)


Myeloablative 312 (35) 2987 (52)

RIC 99 (11) 2077 (36)

NMA 429 (48) 197 (3)

TBD (drugs but unknown intensity) 46 (5) 506 (9)

Unknown 1 (<1) 13 (<1)

Year of transplant

2008-2011 219 (25) 2641 (46)

2012-2015 668 (75) 3139 (54)

GVHD prophylaxis

None 12 (1) 111 (2)

Ex-vivo T-cell depletion 62 (7) 10 (<1)

CD34 selection 44 (5) 49 (<1)

Cyclophosphamide 0 24 (<1)

Cyclophosphamide + others 461 (52) 94 (2)

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Variable Haploidentical URD 8/8

Tac + MMF +/- others (not Cy) 204 (23) 1017 (18)

Tac + MTX +/- others (not Cy, MMF) 46 (5) 3136 (54)

Tac + others (not Cy, MMF, MTX) 6 (<1) 410 (7)

Tac 18 (2) 147 (3)

CsA + MMF +/- others (not Cy, Tac) 11 (1) 359 (6)

CsA + MTX +/- others (not Cy, Tac, MMF) 14 (2) 266 (5)

CsA + others (not Cy, Tac, MMF, MTX) 2 (<1) 36 (<1)

CsA 3 (<1) 43 (<1)

Others (not Cy, Tac, CsA) 4 (<1) 75 (1)

Missing 0 3 (<1)

Follow-up of survivors, months, median (range) 13 (2-97) 25 (1-102)

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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

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) This study will compare GVHD-free, relapse-free survival (GRFS) post-allogeneic HCT with malignant disease between BM and PB graft sources among patients undergoing transplant with 8/8- and 7/8-matched unrelated donors. The analysis was completed in November 2015 and the results were presented by Dr. Alousi at the GVWC 2016 Tandem meeting. Comments were solicited from the study leadership and revisions to the manuscript were made in October 2016. The manuscript was circulated to the Writing Committee for feedback in February 2017 and the goal is to submit the manuscript to JAMA by March 2017. GV13-01: Unrelated male donors versus parous sibling female donors: Impact on transplant-related outcomes (AJ Kumar / A Loren) This study will evaluate the outcomes of overall survival, acute and chronic GVHD in transplants where a multiparous female HLA-identical sibling donor compared to a matched unrelated male donor in a myeloablative setting for AML and ALL. The analysis was completed and presented at the CIBMTR Statistical Meeting in July 2016. After minor revisions, the analysis was finalized with the conclusion that matched unrelated male donors led to a higher risk of grade II-IV acute and chronic GVHD compared to HLA-identical parous female sibling donors. Donor type did not significantly affect OS, relapse, TRM or DFS. These findings were presented as an ASH oral presentation in December 2016. Manuscript preparation is underway and the goal of the study is to submit the manuscript to Blood by June 2017. 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 data file is being prepared and the goal is to have the analysis completed by March 2017. An initial draft of the manuscript will then be expected by May 2017. GV14-02: Influence of donor and recipient age on risk for acute and chronic GVHD in children receiving HLA-identical bone marrow transplantation (M Qayed / JT Horan) This study will examine the impact of age on the risk of aGVHD and cGVHD in children with acute leukemia receiving bone marrow grafts from HLA-identical sibling donors. A review of the data

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collection forms was completed and the dataset was finalized in April 2016. The analysis was completed and presented at the CIBMTR Statistical Meeting in July 2016. After minor revisions, the analysis was finalized with the conclusion that children between the ages of 2-<13 have a lower risk for acute and chronic GVHD than those children 13 years and older (children younger than 2 years of age appeared to show a reduced risk for chronic GVHD, but an analysis in a larger sample would be necessary to properly evaluate). These findings were presented as an ASH poster presentation in December 2016. Manuscript preparation is underway and the goal of the study is to submit the manuscript to Blood by March 2017. GV15-01: Impact of donor obesity and inflammation on acute and chronic GvHD among HCT recipients (L Turcotte / M Verneris) 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 analysis was completed and presented at the CIBMTR Statistical Meeting in July 2016. After revisions and review of sample analysis data, the analysis was finalized in October 2016. The manuscript is in preparation and the goal is to submit the manuscript by June 2017. GV16-01: GVHD-free relapse-free survival in alternative donor hematopoietic cell transplantation (R Mehta / S Holtan / D Weisdorf) This study aims to compare GVHD-free relapse-free survival (GRFS) and chronic GVHD-free relapse-free survival (CRFS) among patients with hematological malignancies who underwent transplant with alternative donors (umbilical cord blood, haploidentical donor, 7/8-matched unrelated donor). The initial protocol was received in June 2016. After revisions and changes, the protocol was presented at the CIBMTR Statistical Meeting in October 2016. The protocol is undergoing further revisions and it is the goal of the study to have a finalized protocol by February 2017, then complete data file preparation by May 2017. 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 initial protocol was discussed in December 2016 and planned to be brought to the CIBMTR Statistical Meeting in January 2017. Pending approval to proceed, the protocol will be forwarded to form a Writing Committee and the protocol will be finalized by March 2017.

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