Not for publication or presentation · 2018. 2. 2. · Not for publication or presentation...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA Salt Lake City, UT Wednesday, February 21, 2018, 12:15 pm – 2:15 pm

Co‐Chair: Edwin Alyea, MD, Dana Farber Cancer Ins tute Telephone: 617‐632‐3903; Email: [email protected]

Co‐Chair: Uday Popat, MD, MD Anderson Cancer Center Telephone: 713‐745‐3055; Email: [email protected]

Co‐Chair: Ronald Sobecks, MD, Cleveland Clinic Founda on Telephone: 216‐444‐4626; Email: [email protected]

Scien fic Director: Wael Saber, MD, MS, CIBMTR Sta s cal Center Telephone: 414‐805‐0677; Email: [email protected]

Sta s cal Director: Ying Liu, PhD, CIBMTR Sta s cal Center Telephone: 414‐456‐8280; Email: [email protected]

Sta s cian: Zhen‐Huan (Kenny) Hu, MPH, CIBMTR Sta s cal Center Telephone: 414‐805‐0656; Email: [email protected]

1. Introductiona. Minutes and overview plan from February 2017 meeting (Attachment 1)b. Introduction of incoming co‐chair: Bart Scott, MD; Fred Hutchinson Cancer Research Center; E‐mail:

[email protected]. Instructions for sign‐in and voting

2. Accrual summary (Attachment 2)

3. Presentations, Published or Submitted Papers

a. CK12‐02b Hill BT, Ahn KW, Hu Z‐H, Aljurf M, Beitinjaneh A, Cahn JY, Cerny J, Kharfan‐Dabaja MA, GangulyS, Ghosh N, Grunwald MR, Inamoto Y, Kindwall‐Keller T, Nishihori T, Olsson RF, Saad A, Seftel M, Seo S,Szer J, Tallman M, Ustun C, Wiernik PH, Maziarz RT, Kalaycio M, Alyea E, Popat U, Sobecks R, Saber W.Assessment of impact of human leukocyte antigen type on outcomes of allogeneic hematopoietic stemcell transplant for chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2017 Oct. In Press.

b. CK12‐01 Hu B, Lin X, Lee HC, Huang X, Slack R, Jabbour E, Verstovsek S, Ravandi F, Garcia‐Manero G,Champlin R, Hu Z‐H, Ahn KW, Lee Y, Popat U, Sobecks R, Alyea E, Kantarjian H, Cortes J, Saber W. Optimaltiming of allogeneic stem cell transplantation for chronic myeloid leukemia patients in the tyrosine kinaseinhibitor era. 59th ASH Annual Meeting and Exposition. Poster.

c. CK14‐02 Kim HT, Hu Z‐H, Ahn KW, Davids MS, Volpe VO, Alyea E, Popat U, Sobecks R, Saber W, Brown JR.Prognostic score and cytogenetic risk classification for chronic lymphocytic leukemia patients whounderwent reduced intensity conditioning allogeneic HCT: a CIBMTR report. 59th ASH Annual Meetingand Exposition. Oral.

d. CK15‐02 Chhabra S, Ahn KW, Hu Z‐H, Jain S, Stuart RK, Kalaycio M, Popat U, Sobecks R, Alyea E, Saber W.Comparison of outcomes after myeloablative versus reduced intensity conditioning allogeneic

1


hematopoietic cell transplantation for chronic myeloid leukemia. 59th ASH Annual Meeting and Exposition. Oral.

e. CK16‐02a DeFilipp Z, Ancheta R, Liu Y, Ahn KW, Hu Z‐H, Alyea E, Popat U, Sobecks R, Saber W.Contemporary role of maintenance tyrosine kinase inhibitors following allogeneic hematopoietic celltransplantation for chronic myeloid leukemia: a CIBMTR analysis. 44th Annual Meeting of the EBMT.Oral.

4. Studies in Progress (Attachment 3)

a. CK12‐01 Optimal timing of allogeneic stem cell transplantation for chronic myeloid leukemia patients in the tyrosine kinase inhibitor era. (B Hu/H Lee) Manuscript Preparation

b. CK14‐02 Prognostic score and cytogenetic risk classification for chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HCT: a CIBMTR report. (H Kim/J Brown) Manuscript Preparation

c. CK15‐02 Comparison of outcomes after myeloablative versus reduced intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia. (S Chhabra/S Jain/PK Stuart) Manuscript Preparation

d. CK16‐02a Contemporary role of maintenance tyrosine kinase inhibitors following allogeneic hematopoietic cell transplantation for chronic myeloid leukemia: a CIBMTR analysis. (Z DeFilipp/R Ancheta) Manuscript Preparation

e. CK16‐02b The benefit of donor lymphocyte infusion in the tyrosine kinase inhibitors era in chronic myeloid leukemia post allogeneic hematopoietic cell transplantation. (S Schmidt) Analysis

f. CK15‐01 Comparison of transplant vs. non‐transplant therapies for myelofibrosis. (K Ballen/RA Mesa/KL Gowin) Analysis

g. CK15‐03 Outcome of allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia with antecedent history of Philadelphia‐negative myeloproliferative neoplasm. (V Gupta) Data File Preparation

h. CK16‐01 Identification of germline predisposition mutations in young myelodysplastic syndrome patients. (L Godley) Data File Preparation

i. CK17‐01 Development of a prognostic scoring system predictive of outcomes in patients with myelofibrosis after allogeneic hematopoietic cell transplantation. (T Roni/SA Giralt/J Palmer) Protocol Development

j. CK17‐02 Reduced‐intensity conditioning transplantation in older MDS: the effect of specific conditioning regimens on transplant outcomes. (B Oran) Protocol Development

5. Introduction to TED (Transplant Essential Data) vs. CRF (Case Report Form) level databases (W Saber)

6. Future/Proposed Studies

a. PROP 1711‐02 Impact of donor age on the outcomes of allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome. (G Murthy) (Attachment 4)

b. PROP 1711‐30/PROP 1711‐72 Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with autologous or allogeneic hematopoietic stem‐cell transplantation. (Y Sawalha/B Hill) (Attachment 5) Outcomes of allogeneic stem cell transplantation in patients with Richter’s syndrome. (A Mukherjee/SR Pingali/NV Koshy) (Attachment 6)

c. PROP 1711‐42 A personalized prediction model for outcomes after allogeneic stem cell transplant in patients with myelodysplastic syndromes. (A Nazha/N Majhail) (Attachment 7)

d. PROP 1711‐61 The impact of somatic mutations on allogeneic transplant in chronic myelomonocytic leukemia. (M Mei/R Nakamura/R Pillai) (Attachment 8)

2


e. PROP 1711‐75 Outcomes of patients with myelodysplastic syndrome who relapse post allogeneic hematopoietic stem cell transplantation. (R Tamari/B Gyurkocza/B Shaffer/SA Giralt) (Attachment 9)

f. PROP 1711‐85 Allogeneic stem cell transplant outcomes for patients with atypical chronic myeloid leukemia. (B Tomlinson/M Gallogly/M de Lima) (Attachment 10)

g. PROP 1711‐111 Allogeneic stem cell transplantation for prolymphocytic leukemias. (L Gowda/F Foss/M Kalaycio/H Alkhateeb) (Attachment 11)

h. PROP 1711‐141 Allogeneic stem cell transplant outcomes in chronic myelogenous leukemia in the era of 2nd and 3rd generation TKIs for patients with recognized or unrecognized BCR ABL mutations. (LG Schachter/RT Maziarz/J Szer) (Attachment 12)

i. PROP 1711‐147 Graft failure, donor lymphocyte infusion, and second transplant after allogenic hematopoietic cell transplant for myelofibrosis. (A Kishtagari/AT Gerds) (Attachment 13)

Dropped proposed studies

a. PROP 1709‐03 JAK1/2 inhibitor prior to allogeneic stem cell transplantation in patients withmyelofibrosis. Dropped due to lack of long‐term follow‐up and few outcome events.

b. PROP 1710‐03 Impact of post‐transplant maintenance therapy with BCR‐ABL tyrosine kinase inhibitorson outcomes of chronic myeloid leukemia accelerated phase or blast crisis in the era of reduced toxicityand non‐myeloablative regimens. Dropped due to overlapping with CK16‐02a.

c. PROP 1711‐77 To understand the outcomes and predictive factors of salvage DLI or a secondhematopoietic cell transplant or both in patients with relapsed myelofibrosis after a first allo HCT.Dropped due to insufficient number of eligible cases.

d. PROP 1711‐98 Role of allogeneic stem cell transplant in ASXL1‐mutated myeloid malignancies. Droppeddue to data not collected on the forms.

e. PROP 1711‐120 Prognostic significance of response to pre‐transplant therapy on outcomes afterhematopoietic stem cell transplant in myelodysplastic syndromes. Dropped due to overlapping withCK11‐02.

3

Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA Orlando, FL Saturday, February 25, 2017, 2:45 pm – 4:45 pm

Co-Chair: Edwin Alyea, MD, Dana Farber Cancer Institute Telephone: 617-632-3903; Email: [email protected]

Co-Chair: Uday Popat, MD, MD Anderson Cancer Center Telephone: 713-745-3055; Email: [email protected]

Co-Chair: Ronald Sobecks, MD, Cleveland Clinic Foundation Telephone: 216-444-4626; Email: [email protected]

Scientific Director: Wael Saber, MD, MS, CIBMTR Statistical Center Telephone: 414-805-0677; Email: [email protected]

Statistical Director: Kwang Woo Ahn, PhD, CIBMTR Statistical Center Telephone: 414-456-7386; Email: [email protected]

Statistical Director: Ying Liu, PhD, CIBMTR Statistical Center Telephone: 414-456-8280; Email: [email protected]

Statistician: Zhen-Huan (Kenny) Hu, MPH, CIBMTR Statistical Center Telephone: 414-805-0656; Email: [email protected]

1. IntroductionThe Chronic Leukemia Working Committee (CKWC) met on Saturday, February 25, 2017 at 2:45 p.m. Thechairs, scientific director and statisticians were presented at the meeting. Attendees were asked to havetheir name badges scanned at the front gate for attendance purposes and to maintain the committeemembership roster.

As the chair of CKWC, Dr. Uday Popat welcomed the attendees on behalf of the working committee, andgave the introduction presentation, introducing the leadership members of the working committee, thegoals, expectations and limitations of the working committee, how to become and maintain themembership in the committee, the rules of authorship as well as the rules for the voting process. Dr. Popatwelcomed the EBMT Chronic Malignancies Working Party Chair, Dr. Nicolaus Kroger, to attend thecommittee meeting. Dr. Popat also emphasized that each proposal was given 5 minutes for presentation and5 minutes for discussion. Minutes from the 2016 Tandem in Honolulu were approved by the attendees.

2. Accrual summaryThe accrual summary was referenced by Dr. Uday Popat for review but not formally presented. The fullaccrual summary was available online as part of the working committee attachments.

3. Presentations, Published or Submitted PapersDr. Uday Popat listed the submitted or published studies of the working committee during 2016, as well asthose being presented at the conferences, mentioning that it was a very productive year. Due to the fullagenda, the 2016 presentations and published papers were not presented. At the moment, three studieswere published or accepted for publication, one was recently submitted and one abstract was presented.These include:

4


a. CK11-02 Shaffer BC, Ahn KW, Hu Z-H, Nishihori T, Malone A, Valcárcel D, Grunwald MR, Bacher U, Hamilton B, Kharfan-Dabaia MA, Saad A, Warlick E, Reshef R, Wirk BM, Sabloff M, Fasan O, Gerds A, Marks D, Olsson R, Wood WA, Costa LJ, Miller AM, Cortes J, Daly A, Kindwall-Keller T, Kamble R, Rizzieri D, Cahn JY, Cutler C, Gale RP, William B, Litzow M, Wiernik PT, Liesveld J, Savani BN, Vjj R, Ustun C, Copelan E, Popat U, Kalaycio M, Maziarz R, Alyea E, Sobecks R, Pavletic S, Tallman M, Saber W. Scoring system prognostic of outcomes in patients undergoing allogeneic hematopoietic cell transplantation for myelodysplastic syndrome. Journal of Clinical Oncology, 2016; 34(16): 1864-1871.

b. CK13-01 Chaudhury S, Sparapani R, Hu Z-H, Nishihori T, Abdel-Azim H, Malone A, Olsson R, Hamadani M, Daly A, Bacher U, Wirk BM, Kamble RT, Gale RP, Wood W, Hale G, Wiernik PH, Hashmi SK, Marks D, Ustun C, Munker R, Savani BN, Alyea E, Popat U, Sobecks R, Kalaycio M, Maziarz R, Hijiya N, Saber W. Outcomes of allogeneic hematopoietic cell transplantation in children and young adults with chronic myeloid leukemia: a CIBMTR cohort analysis. Biology of Blood Marrow Transplant, 2016; 22(6): 1056-1064.

c. CK13-02 Liu HD, Ahn KW, Hu Z-H, Hamadani M, Nishihori T, Wirk B, Beitinjaneh A, Rizzieri D, Grunwald MR, Sabloff M, Olsson R, Bajel A, Bredeson C, Daly A, Inamoto Y, Majhail N, Saad A, Gupta V, Gerds A, Malone A, Tallman M, Reshef R, Marks D, Copelan E, Gergis U, Savoie ML, Ustun C, Litzow MR, Cahn J-Y, Kindwall-Keller T, Akpek G, Savani BN, Aljurf M, Rowe JM, Wiernik PH, Hsu JW, Cortes J, Kalaycio M, Maziarz R, Sobecks R, Popat U, Alyea E, Saber W. Allogeneic hematopoietic cell transplant for adult chronic myelomonocytic leukemia. Biology of Blood Marrow Transplant. Accepted for publication.

d. CK12-02b Hill B, Ahn KW, Hu Z-H, Kalaycio M, Maziarz R, Cortes J, Alyea E, Popat U, Sobecks R, Saber W. Assessment of human leukocyte antigen type on outcomes of allogeneic transplant for chronic lymphocytic leukemia. Poster presentation at the 58th ASH Annual Meeting and Exposition.

e. CK14-01 Gerds A, Ahn KW, Hu Z-H, Abdel-Azim H, Akpek G, Aljurf M, Ballen K, Amer B, Bacher U, Cahn J-Y, Chhabra S, Cutler C, Daly A, DeFilipp Z, Gale RP, Gergis U, Grunwald MR, Hale G, Hamilton BK, Jagasia M, Kamble RT, Kindwall-Keller T, Nishihori T, Olsson R, Ramanathan M, Saad A, Solh M, Ustun C, Valcárcel D, Warlick E, Wirk B, Kalaycio M, Alyea E, Popat U, Sobecks R, Saber W. Outcomes after umbilical cord blood transplantation for myelodysplastic syndromes. Submitted.

4. Studies in Progress Dr. Uday Popat gave a brief update of the ongoing studies of the working committee. Due to the full agenda, studies in progress were not presented in details at the meeting. A summary of the progress of the ongoing studies was available online as part of the attachments. a. CK12-02b Assessment of human leukocyte antigen type on outcomes of allogeneic transplant for

chronic lymphocytic leukemia. (B Hill) Manuscript Preparation

b. CK12-01 A decision analysis of the optimal timing of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in the era of tyrosine kinase inhibitors. (H Lee/J Cortes/M de Lima) Analysis

c. CK14-02 Validation of DFCI prognostic score for previously treated chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HSCT. (H Kim/J Brown) Data File Preparation

d. CK15-01 Comparison of transplant vs. non-transplant therapies for myelofibrosis. (K Ballen/RA Mesa/KL Gowin) Data File Preparation

e. CK15-02 Comparison of outcomes after myeloablative and reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia. (S Chhabra/S Jain/PK Stuart) Data File Preparation

5


f. CK15-03 Outcome of allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia with antecedent history of Philadelphia-negative myeloproliferative neoplasm. (V Gupta) Data File Preparation

g. CK16-01 Identification of germline predisposition mutations in young myelodysplastic syndrome patients (L Godley) Protocol Development

h. CK16-02a Contemporary role of tyrosine kinase inhibitors post allogeneic hematopoietic stem cell transplantation for advanced phase chronic myeloid leukemia (R Ancheta/Z DeFilipp) Protocol Development

i. CK16-02b Contemporary role of tyrosine kinase inhibitors post allogeneic hematopoietic stem cell transplantation for advanced phase chronic myeloid leukemia (S Schmidt) Protocol Development

5. Future/Proposed Studies As the scientific director, Dr. Wael Saber repeated the rules for the voting process. Dr. Edwin Alyea announced the presenters for the first 4 proposals. a. PROP 1610-17 Effect of anti-thymocyte globulin on relapse in myelodysplastic syndrome. (H Murthy/N

Farhadfar/JR Wingard)

Dr. Hemant Murthy presented the proposal. Dr. Murthy started with a brief background introduction stating that ATG is often used to reduce GVHD, as well as utilized as a therapy for MDS, reported to result in hematologic improvement among certain patients. Previous studies showed conflicting data regarding the role of ATG. Dr. Murthy also mentioned the recent publication by Dr. Brian Shaffer. The hypothesis of the current proposal was that the use of ATG either as prior therapy or as a part of conditioning regimen in patients undergoing allogeneic HCT in MDS would improve RFS, which would also make RFS the primary endpoint of the proposed study, along with DFS, OS and GRFS as the secondary endpoints. As part of subset analyses, Dr. Murphy also wanted to investigate the response of trisomy 18, HLA-DR15, and lower IPSS scores to prior ATG. Dr. Murphy mentioned that the proposed study would differentiate itself from the previous study by Dr. Shaffer based on a larger sample size, as well as that the scoring system did not include ATG and prior immune-suppression therapies in the multi-variate analyses.

One of the attendees asked how many patients had prior ATG. Dr. Murthy replied that although he did not have the number at the moment; it would become available when the study went on. Dr. Kroger asked whether the dose of ATG was available. Dr. Saber confirmed that the dose of ATG was available at the time of transplant. Another question was whether the study would adjust the effect of TBI. Dr. Murthy confirmed that TBI would be included in the analyses. Dr. Kroger asked whether the study could differentiate low risk MDS vs. high risk MDS. Dr. Murthy answered the question saying there were over 500 identified cases with low risk MDS and he believed there would be enough data to generate meaningful results.

b. PROP 1611-42 Outcomes of hematopoietic stem cell transplant in elderly patients with myelodysplastic syndrome and co-existing bone marrow fibrosis. (E Peres/N Janakiraman/S Farhan)

Dr. Shatha Farhan presented the proposal on behalf of Dr. Edward Peres. Dr. Farhan started with a brief background introduction for marrow fibrosis in MDS, stating that it was found in 10-20% of patients with MDS, and the degree of marrow fibrosis is an independent prognostic factor from IPSS score, with a dismal prognosis when treated with conventional chemotherapy. Based on existing data on younger patients undergoing HCT for MDS with coexisting MF, Dr. Farhan hypothesized that the outcome in patients older than 60 years of age would have similar outcomes and survivals compared to younger

6


patients. The study population would be patients older than 60 years of age with MDS and co-existing MF who underwent HCT between 2000 and 2014. The primary end points of the proposed study would be OS, graft failure and GVHD. Dr. Farhan then showed the baseline characteristics of the eligible population of 197 patients.

The first question asked was how many cases were based on CRF vs. TED. Dr. Saber confirmed that all data presented were based on CRF. Dr. Kroger then commented that the number of severe marrow fibrosis was low in the eligible population, and Dr. Farhan agreed. Another suggestion was to widen the age range of the study population. Dr. Farhan agreed with the suggestion. One of the attendees also asked the reliability of the data of marrow fibrosis and whether they had been audited. Dr. Saber agreed to follow with the audit team for the question.

c. PROP 1611-77 Effect of conditioning regimens on graft failure in stem cell transplant in myeloproliferative neoplasms. (S Farhan/N Janakiraman/E Peres)

Dr. Farhan continued to present the second proposal, starting with a brief introduction of the background, stating that graft failure is an important barrier in allo-HCT for MPN, and it was unknown which type of conditioning leads to the least graft failure. Dr. Farhan explained that owing to the low transplant activities for MPN, it was difficult to conduct prospective studies and use of the CIBMTR data would be the only feasible approach. The hypothesis of the proposed study was that the engraftment of transplanted donor HSC is affected by different conditioning regimens, which may affect the long-term outcomes of these patients. The primary end points would be engraftment and primary graft failure, while the secondary end points would be chimerism kinetics, secondary graft failure, OS, TRM, GVHD and treatment response. The eligible population of the proposed study included 706 adult patients receiving allogeneic transplant for MPN between 2005 and 2015. Dr. Farhan then showed the baseline characteristics of the eligible population, with 359 patients using MAC, 318 using RIC and 29 using NMA conditioning regimens.

Dr. Kroger suggested the study to also include other variables such as spleen size, splenectomy and regimens. Dr. Farhan agreed and said all these variables would be available to be included in the analyses. Another suggestion was to exclude those with prior ET. Dr. Farhan agreed with the suggestion. Another question was raised asking how the study would define graft failure. Dr. Farhan said that graft failure would be defined as no engraftment after 28 days post-transplant. Dr. Kroger asked that, due to the low rate of graft failure, whether the study would have enough statistical power to identify the prognostic factors. Dr. Farhan anticipated to having enough statistical power based on previous studies with fewer cases showing significant results.

d. PROP 1611-87 Development of a prognostic scoring system predictive of outcomes in patients with myelofibrosis after allogeneic hematopoietic cell transplantation. (T Roni/AG Sergio/P Jeanne)

Dr. Roni Tamari presented the proposal. Dr. Tamari started with a brief background introduction, stating that when and how to transplant patients with MF remains a matter of debate. The hypothesis of the proposed study was that disease status, patient- and donor-characteristics and type of transplant may be used to develop a scoring system predictive of outcomes in patients with MF undergoing allogeneic HCT. The endpoints would be to identify patient-, donor-, disease- and transplant-specific factors that positively associate with survival after allogeneic HCT. Dr. Tamari then listed the potential variables of interest to be included in the analyses, and showed the baseline characteristics of the eligible cohort of 783 patients from the CIBMTR dataset, noticing the small number of cord and haplo cases. Dr. Tamari then mentioned that the proposed study could be using EBMT data as a validation cohort.

Dr. Kroger suggested including pre-transplant treatment as a covariate, also mentioning that although important, the availability of molecular data would only be for a minority. Dr. Tamari and Dr. Saber

7


agreed that molecular data were rare and only being collected in the recent years in the CIBMTR dataset. Dr. Saber then asked Dr. Kroger how soon the EBMT data would be available for the study. Dr. Kroger replied that there were more than 100 cases already being cleaned. Another question was for the low percentage of cytogenetics availability. Dr. Saber answered the question saying that there were a lot of dry taps for cytogenetics.

Dr. Ronald Sobecks announced the presenters of the next 5 proposals.

e. PROP 1611-119 Reduced-intensity conditioning transplantation in older MDS: the effect of specific conditioning regimens on transplant outcomes. (B Oran/U Popat)

Dr. Mithun Shah presented the proposal on behalf of Dr. Betul Oran. Dr. Shah started with the question of what was the optimal conditioning regimen for transplant in older MDS. Dr. Shah then gave a brief background introduction of MDS, stating that there was no consensus regarding the optimal RIC regimen for older patients with MDS. The purpose of the proposed study was to establish the optimal RIC regimen for older patients with MDS, especially whether the incorporation of busulfan or melphalan with fludarabine was associated with difference in outcomes. The study end points would be relapse, TRM, DFS, OS, engraftment and GVHD. Dr. Shah then stated the eligibility criteria and listed the variables of interest. The study design would be to compare flu/bu vs. flu/mel based on patient and disease characteristics. Dr. Shah then demonstrated the feasibility of the proposed study, showing a total number of 1,574 eligible cases with 551 using flu/bu and 300 using flu/mel.

The first question was whether all flu/bu were RIC. Dr. Shah confirmed that the flu/bu shown were all RIC. Another question was asked about the relapse timing captured by the study. Dr. Shah said that the study would capture relapse after 3 years. The third question was about the validity of the percentage of low IPSS. Dr. Saber replied that Dr. Brian Shaffer’s new score would be a more proper way to score MDS for transplant. The last question asked about the availability of post-transplant maintenance. Dr. Shah answered that it was not included and Dr. Saber said the data would not be available and before 2015 very few MDS transplants actually had maintenance.

f. PROP 1611-147 Allogeneic stem cell transplant for myelodysplastic/myeloproliferative neoplasm - unclassified. (J Galvin/B Stein)

Dr. John Galvin presented the proposal. Dr. Galvin started with a brief background introduction of MDS/MPN-unclassifiable, stating that there was no validated risk stratification scoring system for MDS/MPN-U and previous studies did not have enough power to show the impact of MDS/MPN-U on transplant outcomes compared to other MDS subtypes. The hypothesis was that patients with MDS/MPN-U would benefit from allogeneic HCT. The aim would be to analyze outcomes of allo HCT in MDS/MPN-U, to identify prognostic factors, and to describe the toxicities associated with the transplant. Dr. Galvin then stated the eligibility criteria and listed the outcomes for the proposed study. Dr. Galvin then showed the baseline characteristics of the eligible cohort of 88 patients receiving allogeneic HCT for MDS/MPN-U.

Dr. Kroger raised the question of the difficulty to identify MDS/MPS-U. Dr. Galvin replied that there would be specific criteria for diagnosing MDS/MPS-U. It was also suggested that to truly identify the benefit of transplant for MDS/MPN-U, the study needed to compare transplant vs. non-transplant cohorts. Dr. Galvin agreed and said the study would be the first step towards that direction.

g. PROP 1611-154 Allogeneic transplantation in systemic mastocytosis. (C Ustun/W Saber)

Dr. Celalettin Ustun presented the proposal. Dr. Ustun started with a brief background introduction for systemic mastocytosis, stating it was a rare disease. Dr. Ustun then introduced the types of SM and the life span of patients with the disease based on previous studies. Due to the rareness of the disease, Dr.

8


Ustun felt that there was no way to conduct prospective studies for SM and only the CIBMTR would be able to collect supplemental data for SM in good quality and combine them with the available retrospective data. Retrospectively, the study would use data of 16 patients since 2010 to 2017, and prospectively, using a uniformed survey, the study was anticipated to collecting 15 more patients from 2017 to 2022. The primary objective would be OS at year 2, with PFS at year 2 and NRM at year 1 being secondary objectives. Dr. Ustun then mentioned the study would be expensive and that Novartis was considering financially supporting the proposed study.

Dr. Kroger commented that due to heavy data reporting regulation regarding safety concerns and side effects in Europe, only retrospective studies were possible. Another comment was, due to the rareness of the disease, patient condition could be different between transplant vs non-transplant cohorts. Dr. Ustun agreed and said the study would be for transplant patients only.

h. PROP 1611-155 The impact of pre-transplant splenectomy vs. no splenectomy, on transplant outcomes in the context of myelofibrosis/myeloproliferative disorder associated splenomegaly. (M Ramanathan)

Dr. Muthalagu Ramanathan presented the proposal. Dr. Ramanathan first mentioned the studies published by the CIBMTR in 2010 showing a positive association between splenectomy and improved engraftment. Dr. Ramanathan also mentioned that a previous single center study showed splenectomy prior to the transplant improves the post-transplant mortality. The hypothesis of the proposed study was that splenomegaly sec to extramedullary hematopoiesis is associated with graft failure and delayed engraftment post allogeneic transplant, and that pre-transplant splenectomy would improve transplant outcomes such as engraftment and overall survival. Dr. Ramanathan then showed the baseline characteristics of the eligible cohort of 61 patients undergoing pre-transplant splenectomy vs. 222 others. Dr. Ramanathan then mentioned the on-going study CK15-01 saying that the data should be already available based on that.

The first question was asked whether there were data for spleen irradiation. Dr. Ramanathan confirmed that the data were available. Another comment was due to many patients receiving splenectomy not going to transplant, the result could be misleading. Another question asked the availability of the interval between splenectomy and transplant and Dr. Ramanathan confirmed the availability of the data. The last question was if spleen size was collected. Dr. Ramanathan also confirmed the availability of that information.

i. PROP 1612-03/ PROP 1611-150 JAK1/2 inhibitor prior to allogeneic stem cell transplantation in patients with myelofibrosis. (R Salit) Impact of prior ruxolitinib therapy on post-hematopoietic stem cell transplant outcomes in myelofibrosis with splenomegaly. (JJ Pu/W Rybka/S Mineishi)

Dr. Jeffrey Pu presented the combined proposal on behalf of Dr. Rachel Salit. Dr. Pu started with a brief introduction of ruxolitinib, stating that the CIBMTR started to collect information for ruxolitinib since 2012. Dr. Pu then mentioned previous small size studies showed improved outcomes of transplant in MF patients receiving ruxolitinib. The specific aims of the proposal were to determine if post-transplant outcomes in MF patients receiving pre-transplant ruxolitinib are superior to those who did not, and to determine if post-transplant outcomes in MF patients with splenomegaly receiving pre-transplant ruxolitinib are superior to those not, based on the scientific justification that ruxolitinib was thought to reduce splenomegaly and constitutional symptoms. Dr. Pu then showed the patient eligibility of the proposed study, along with the baseline characteristics of the eligible cohort of 135 patients receiving pre-transplant ruxolitinib, and 88 patients among them with splenomegaly.

The first comment was that there could be patients who failed ruxolitinib that were not included in the cohort. Another comment was that DIPSS might not always correlate with ruxolitinib since it was approved based on IPSS. Dr. Saber confirmed that the raw data were available to compute both DIPSS

9


and IPSS and the group would check the distribution and adjust the statistical model accordingly. Another question was whether there were data for post-transplant usage of ruxolitinib. Dr. Pu and Dr. Saber replied that the study was for pre-transplant ruxolitinib.

7 additional proposals were submitted to the committee but not presented as stated below:

a. PROP 1611-10 Outcomes following relapse of myelofibrosis after allogeneic stem cell transplant. Dropped due to lack of data.

b. PROP 1611-25 Comparison of transplant outcomes between de novo and therapy related MDS. Dropped due to overlapping with the already published CK11-02.

c. PROP 1611-48 Outcomes of allogeneic transplantation for relapsed chronic lymphocytic leukemia (CLL) following ibrutinib discontinuation. Dropped due to lack of data.

d. PROP 1611-59 Prognostic factors predicting allogenic stem cell transplant outcome in chronic myelomonocytic leukemia. Dropped due to overlapping with the already published CK13-02.

e. PROP 1611-60 Outcomes of allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia in the novel agent era. Dropped due to lack of data and follow-up.

f. PROP 1611-61 Understanding the differences in disease characteristics and survival outcomes following allogeneic stem cell transplant between chronic lymphocytic leukemia and small lymphocytic lymphoma. Dropped due to lack of capability to distinguish SLL/CLL on the forms.

g. PROP 1611-64 Outcomes after second allogeneic hematopoietic cell transplantation for patients with acute and chronic leukemias who relapse after a first transplant. Dropped due to no enough data.

6. Other Business

Dr. Saber encouraged the committee to contribute to the CMS study for myelofibrosis.

The meeting was adjourned at 4:23 p.m.

The committee chairs, scientific director and statisticians had a post-WC meeting afterwards. After the new proposals were presented, each attendee had the opportunity to vote the proposals using the provided voting sheets. Based on the voting results, current scientific merit and impact of the studies on the field, the following studies were decided to move forward as the committee’s research portfolio for the upcoming year:

a. PROP 1611-87 Development of a prognostic scoring system predictive of outcomes in patients with myelofibrosis after allogeneic hematopoietic cell transplantation. (T Roni/AG Sergio/P Jeanne)

b. PROP 1611-119 Reduced-intensity conditioning transplantation in older MDS: the effect of specific conditioning regimens on transplant outcomes. (B Oran/U Popat)

10


a. CK12-01 A decision analysis of the optimal timing of allogeneic hematopoietic cell transplantation in

chronic myeloid leukemia in the era of tyrosine kinase inhibitors. (H Lee/J Cortes/M de Lima) We are currently not assigning any statistical hour to the study due to unavailability of the decision analyst. We are going to review the study status by July 2017. (Total hour: 100; Allocated for the fiscal year: 0)

b. CK12-02b Assessment of human leukocyte antigen type on outcomes of allogeneic transplant for chronic lymphocytic leukemia. (B Hill) We plan to finalize and submit the manuscript for publication by July 2017. (Total hour: 20; Allocated for the fiscal year: 20)

c. CK14-02 Validation of DFCI prognostic score for previously treated chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HSCT. (H Kim/J Brown) We anticipate to finalizing the analysis by July 2017, and have the manuscript submitted by July 2018. (Total hour: 150; Allocated for the fiscal year: 150)

d. CK15-01 Comparison of transplant vs. non-transplant therapies for myelofibrosis. (K Ballen/RA Mesa/KL Gowin) We anticipate to finalizing the data file by July 2017. We are currently not assigning any statistical hour between July 2017 and July 2018 due to unavailability of the decision analyst to do the analysis. We will review the study status by July 2017. (Total hour: 200; Allocated for the fiscal year: 50)

e. CK15-02 Comparison of outcomes after myeloablative and reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia. (S Chhabra/S Jain/PK Stuart) We plan to finalize the analysis by July 2017, and have the manuscript submitted by July 2018. (Total hour: 160; Allocated for the fiscal year: 160)

f. CK15-03 Outcome of allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia with antecedent history of Philadelphia-negative myeloproliferative neoplasm. (V Gupta) We plan to finalize the analysis by July 2017, and have the manuscript submitted by July 2018. (Total hour: 170; Allocated for the fiscal year: 170)

g. CK16-01 Identification of germline predisposition mutations in young myelodysplastic syndrome patients (L Godley) We anticipate to finalizing the protocol by July 2017, and finishing the analysis by July 2018. (Total hour: 240; Allocated for the fiscal year: 170)

h. CK16-02a Contemporary role of tyrosine kinase inhibitors post allogeneic hematopoietic stem cell transplantation for advanced phase chronic myeloid leukemia (R Ancheta/Z DeFilipp) We anticipate to finalizing the protocol by July 2017, and finishing the analysis by July 2018. (Total hour: 260; Allocated for the fiscal year: 190)

i. CK16-02b Contemporary role of tyrosine kinase inhibitors post allogeneic hematopoietic stem cell transplantation for advanced phase chronic myeloid leukemia (S Schmidt) We anticipate to finalizing the protocol by July 2017, and finishing the analysis by July 2018. (Total hour: 180; Allocated for the fiscal year: 110)

j. CK17-01/PROP 1611-87 Development of a prognostic scoring system predictive of outcomes in patients with myelofibrosis after allogeneic hematopoietic cell transplantation. (T Roni/AG Sergio/P Jeanne) We anticipate the draft protocol by July 2017. (Total hour: 310; Allocated for the fiscal year: 60)

k. CK17-02/PROP 1611-119 Reduced-intensity conditioning transplantation in older MDS: the effect of specific conditioning regimens on transplant outcomes. (B Oran/U Popat) We anticipate the draft protocol by July 2017. (Total hour: 310; Allocated for the fiscal year: 60)

Working Committee Overview Plan for 2017-2018

11


Edwin Alyea CK14-02 Validation of DFCI prognostic score for previously treated chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HSCT.

CK16-01 Identification of germline predisposition mutations in young MDS patients.

CK16-02 Contemporary role of tyrosine kinase inhibitors post allogeneic hematopoietic stem cell transplantation for advanced phase chronic myeloid leukemia. (Z DeFilipp/RG Ancheta/SA Schmidt)

CK17-01/PROP 1611-87 Development of a prognostic scoring system predictive of outcomes in patients with myelofibrosis after allogeneic hematopoietic cell transplantation.

Uday Popat CK12-01 A decision analysis of the optimal timing of allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia in the era of Tyrosine Kinase Inhibitors.

CK15-01 Comparison of transplant vs. non-transplant therapies for MPN.

CK15-03 Outcome of allogeneic HCT in patients with AML with antecedent history of Philadelphia-negative myeloproliferative neoplasm.

CK17-02/PROP 1611-119 Reduced-intensity conditioning transplantation in older MDS: the effect of specific conditioning regimens on transplant outcomes.

Ronald Sobecks CK12-02b A retrospective assessment of outcomes of patients who have undergone allogeneic HCT for CLL based on HLA type.

CK15-02 Comparison of outcomes after MA vs. RIC for allogeneic HCT for CML.

Wael Saber SC11-06 Assessment of allogeneic hematopoietic stem cell transplantation in Medicare beneficiaries with myelodysplastic syndrome and related disorders.

Oversight Assignments for Working Committee Leadership (March 2017)

12


Accrual Summary for the Chronic Leukemia Working Committee

Characteristics of recipients undergoing allogeneic transplant for MDS reported to the CIBMTR between 1995 and 2017

Variable CRF / US CRF / non-US TED (excluding

CRF) / US TED (excluding CRF) / non-US

Number of patients 6689 1257 4739 4605 Number of centers 189 151 188 248 Age, median (range) 60 (<1-83) 44 (<1-77) 53 (<1-81) 50 (<1-80) Age, years

< 10 238 (4) 112 (9) 187 (4) 218 (5) 10-19 267 (4) 107 (9) 260 (5) 288 (6) 20-29 214 (3) 136 (11) 228 (5) 367 (8) 30-39 349 (5) 179 (14) 385 (8) 539 (12) 40-49 696 (10) 250 (20) 817 (17) 913 (20) 50-59 1654 (25) 297 (24) 1627 (34) 1229 (27) 60-69 2616 (39) 158 (13) 1181 (25) 972 (21) ≥ 70 655 (10) 18 (1) 49 (1) 78 (2) Missing 0 0 5 (<1) 1 (<1)

Sex Male 4118 (62) 761 (61) 2780 (59) 2770 (60) Female 2571 (38) 495 (39) 1959 (41) 1829 (40) Missing 0 1 (<1) 0 6 (<1)

Disease at diagnosis RA 722 (11) 287 (23) 534 (11) 658 (14) RAEB 2815 (42) 528 (42) 1810 (38) 1913 (42) RARS 268 (4) 36 (3) 161 (3) 113 (2) RCMD 819 (12) 88 (7) 474 (10) 485 (11) RCMD/RS 54 (<1) 1 (<1) 34 (<1) 28 (<1) 5q- syndrome 74 (1) 4 (<1) 51 (1) 35 (<1) CMML 619 (9) 125 (10) 401 (8) 395 (9) MDS unclassifiable 1054 (16) 130 (10) 1187 (25) 811 (18) Other MDS 264 (4) 58 (5) 87 (2) 167 (4)

Graft source Bone marrow 1411 (21) 405 (32) 1079 (23) 1119 (24) Peripheral blood 4763 (71) 766 (61) 3410 (72) 3280 (71) Cord blood 500 (7) 86 (7) 186 (4) 111 (2) Missing 15 (<1) 0 64 (1) 95 (2)

Donor type HLA-identical sibling 1583 (24) 559 (44) 2121 (45) 2217 (48)

13




Haplo-identical 189 (3) 6 (<1) 88 (2) 12 (<1) Unrelated donor 4112 (61) 431 (34) 1932 (41) 1972 (43) Cord blood 500 (7) 86 (7) 186 (4) 111 (2) Other/missing 305 (5) 175 (14) 412 (9) 293 (6)

Year of transplant 1995-1996 154 (2) 82 (7) 176 (4) 196 (4) 1997-1998 182 (3) 93 (7) 202 (4) 259 (6) 1999-2000 196 (3) 147 (12) 202 (4) 322 (7) 2001-2002 289 (4) 145 (12) 226 (5) 348 (8) 2003-2004 353 (5) 149 (12) 278 (6) 399 (9) 2005-2006 473 (7) 169 (13) 307 (6) 382 (8) 2007-2008 563 (8) 88 (7) 333 (7) 350 (8) 2009-2010 571 (9) 78 (6) 611 (13) 545 (12) 2011-2012 806 (12) 27 (2) 745 (16) 650 (14) 2013-2014 1235 (18) 120 (10) 639 (13) 509 (11) 2015-2016 1357 (20) 126 (10) 680 (14) 440 (10) 2017* 510 (8) 33 (3) 340 (7) 205 (4)

* New cases are continually being reported during this period.

14


Characteristics of recipients undergoing allogeneic HCT for myelofibrosis reported to the CIBMTR between 1995 and 2017



Number of patients 1193 321 1272 1095 Number of centers 122 85 125 153 Age, median (range) 58 (<1-79) 52 (2-74) 58 (<1-76) 54 (2-75) Age, years

< 10 10 (<1) 2 (<1) 14 (1) 10 (<1) 10-19 10 (<1) 7 (2) 9 (<1) 21 (2) 20-29 10 (<1) 9 (3) 17 (1) 29 (3) 30-39 41 (3) 24 (7) 49 (4) 97 (9) 40-49 178 (15) 84 (26) 201 (16) 240 (22) 50-59 468 (39) 119 (37) 480 (38) 403 (37) 60-69 412 (35) 73 (23) 464 (36) 278 (25) ≥ 70 64 (5) 3 (<1) 38 (3) 17 (2)

Sex Male 686 (58) 209 (65) 766 (60) 688 (63) Female 507 (42) 112 (35) 506 (40) 407 (37)

Disease at diagnosis PV 139 (12) 29 (9) 164 (13) 79 (7) ET 174 (15) 37 (12) 180 (14) 122 (11) Chronic myelofibrosis 880 (74) 255 (79) 928 (73) 894 (82)

Graft source Bone marrow 156 (13) 75 (23) 120 (9) 183 (17) Peripheral blood 997 (84) 239 (74) 1127 (89) 892 (81) Cord blood 39 (3) 7 (2) 17 (1) 9 (<1) Missing 1 (<1) 0 8 (<1) 11 (1)

Donor type HLA-identical sibling 329 (28) 133 (41) 578 (45) 522 (48) Haplo-identical 22 (2) 1 (<1) 23 (2) 2 (<1) Unrelated donor 741 (62) 154 (48) 576 (45) 513 (47) Cord blood 39 (3) 7 (2) 17 (1) 9 (<1) Other/missing 62 (5) 26 (8) 78 (6) 49 (4)

Year of transplant 1995-1996 15 (1) 8 (2) 11 (<1) 19 (2) 1997-1998 22 (2) 11 (3) 13 (1) 36 (3) 1999-2000 31 (3) 22 (7) 19 (1) 44 (4) 2001-2002 52 (4) 21 (7) 33 (3) 81 (7)

15




2003-2004 54 (5) 30 (9) 46 (4) 99 (9) 2005-2006 76 (6) 43 (13) 76 (6) 99 (9) 2007-2008 124 (10) 38 (12) 75 (6) 116 (11) 2009-2010 124 (10) 30 (9) 176 (14) 188 (17) 2011-2012 38 (3) 5 (2) 307 (24) 158 (14) 2013-2014 189 (16) 43 (13) 236 (19) 126 (12) 2015-2016 285 (24) 42 (13) 239 (19) 83 (8) 2017* 183 (15) 28 (9) 41 (3) 46 (4)


16


Characteristics of recipients undergoing allogeneic transplant for CML reported to the CIBMTR between 1995 and 2017



Number of patients 4039 2924 4163 8267 Number of centers 177 194 199 270 Age, median (range) 40 (1-77) 36 (1-76) 42 (<1-76) 37 (<1-75) Age, years

< 10 84 (2) 68 (2) 65 (2) 195 (2) 10-19 359 (9) 305 (10) 251 (6) 657 (8) 20-29 576 (14) 610 (21) 493 (12) 1650 (20) 30-39 1010 (25) 876 (30) 967 (23) 2466 (30) 40-49 1162 (29) 693 (24) 1258 (30) 2209 (27) 50-59 705 (17) 317 (11) 847 (20) 951 (12) 60-69 128 (3) 53 (2) 258 (6) 128 (2) ≥ 70 15 (<1) 1 (<1) 15 (<1) 4 (<1) Missing 0 1 (<1) 9 (<1) 7 (<1)

Sex Male 2355 (58) 1785 (61) 2462 (59) 4963 (60) Female 1684 (42) 1139 (39) 1694 (41) 3267 (40) Missing 0 0 7 (<1) 37 (<1)

Graft source Bone marrow 2542 (63) 1703 (58) 1956 (47) 4607 (56) Peripheral blood 1320 (33) 1142 (39) 1991 (48) 3258 (39) Cord blood 174 (4) 74 (3) 133 (3) 101 (1) Missing 3 (<1) 5 (<1) 83 (2) 301 (4)

Donor type HLA-identical sibling 868 (21) 1601 (55) 2560 (61) 5347 (65) Haplo-identical 30 (<1) 3 (<1) 54 (1) 1 (<1) Unrelated donor 2804 (69) 965 (33) 928 (22) 2292 (28) Cord blood 174 (4) 74 (3) 133 (3) 101 (1) Other/missing 163 (4) 281 (10) 488 (12) 526 (6)

Year of transplant 1995-1996 714 (18) 500 (17) 657 (16) 1342 (16) 1997-1998 755 (19) 548 (19) 723 (17) 1740 (21) 1999-2000 677 (17) 629 (22) 616 (15) 1775 (21) 2001-2002 357 (9) 392 (13) 277 (7) 1203 (15) 2003-2004 410 (10) 370 (13) 251 (6) 740 (9)

17




2005-2006 318 (8) 270 (9) 175 (4) 426 (5) 2007-2008 238 (6) 54 (2) 133 (3) 215 (3) 2009-2010 247 (6) 54 (2) 159 (4) 273 (3) 2011-2012 52 (1) 14 (<1) 389 (9) 255 (3) 2013-2014 126 (3) 44 (2) 329 (8) 156 (2) 2015-2016 115 (3) 40 (1) 323 (8) 102 (1) 2017* 30 (<1) 9 (<1) 131 (3) 40 (<1)


18


Characteristics of recipients undergoing autologous transplant for CLL reported to the CIBMTR between 1995 and 2017



Number of patients 84 41 269 243 Number of centers 42 14 66 58 Age, median (range) 52 (33-73) 50 (38-67) 53 (19-81) 52 (27-72) Age, years

10-19 0 0 1 (<1) 0 20-29 0 0 2 (<1) 4 (2) 30-39 12 (14) 3 (7) 14 (5) 12 (5) 40-49 25 (30) 18 (44) 81 (30) 76 (31) 50-59 26 (31) 18 (44) 110 (41) 113 (47) 60-69 19 (23) 2 (5) 56 (21) 37 (15) ≥ 70 2 (2) 0 5 (2) 1 (<1)

Sex Male 61 (73) 33 (80) 188 (70) 193 (79) Female 23 (27) 8 (20) 81 (30) 49 (20) Missing 0 0 0 1 (<1)

Disease at diagnosis CLL, NOS 21 (25) 24 (59) 86 (32) 48 (20) CLL, B-cell 62 (74) 17 (41) 178 (66) 194 (80) CLL, T-cell 1 (1) 0 5 (2) 1 (<1)

Graft source Bone marrow 15 (18) 1 (2) 113 (42) 5 (2) Peripheral blood 66 (79) 39 (95) 150 (56) 207 (85) Missing 3 (4) 1 (2) 6 (2) 31 (13)

Year of transplant 1995-1996 15 (18) 3 (7) 43 (16) 14 (6) 1997-1998 26 (31) 28 (68) 54 (20) 36 (15) 1999-2000 18 (21) 6 (15) 73 (27) 90 (37) 2001-2002 6 (7) 2 (5) 36 (13) 40 (16) 2003-2004 4 (5) 1 (2) 27 (10) 22 (9) 2005-2006 9 (11) 0 7 (3) 23 (9) 2007-2008 3 (4) 0 6 (2) 4 (2) 2009-2010 2 (2) 0 5 (2) 8 (3) 2011-2012 0 0 9 (3) 5 (2) 2013-2014 1 (1) 0 5 (2) 1 (<1)

19




2015-2016 0 1 (2) 3 (1) 0 2017* 0 0 1 (<1) 0


20


Characteristics of recipients undergoing allogeneic transplant for CLL reported to the CIBMTR between 1995 and 2017



Number of patients 1447 380 1853 1392 Number of centers 122 82 133 145 Age, median (range) 55 (12-75) 54 (2-71) 56 (7-80) 53 (4-74) Age, years

< 10 0 1 (<1) 2 (<1) 3 (<1) 10-19 3 (<1) 1 (<1) 2 (<1) 0 20-29 12 (<1) 1 (<1) 15 (<1) 21 (2) 30-39 65 (4) 30 (8) 80 (4) 75 (5) 40-49 334 (23) 100 (26) 349 (19) 370 (27) 50-59 625 (43) 163 (43) 808 (44) 643 (46) 60-69 377 (26) 82 (22) 552 (30) 270 (19) ≥ 70 31 (2) 2 (<1) 45 (2) 10 (<1)

Sex Male 1074 (74) 281 (74) 1346 (73) 1008 (72) Female 372 (26) 99 (26) 506 (27) 382 (27) Missing 1 (<1) 0 1 (<1) 2 (<1)

Disease at diagnosis CLL, NOS 703 (49) 123 (32) 557 (30) 586 (42) CLL, B-cell 740 (51) 257 (68) 1285 (69) 800 (57) CLL, T-cell 4 (<1) 0 11 (<1) 6 (<1)

Graft source Bone marrow 292 (20) 61 (16) 247 (13) 158 (11) Peripheral blood 1068 (74) 305 (80) 1566 (85) 1183 (85) Cord blood 85 (6) 13 (3) 33 (2) 16 (1) Missing 2 (<1) 1 (<1) 7 (<1) 35 (3)

Donor type HLA-identical sibling 405 (28) 219 (58) 957 (52) 761 (55) Haplo-identical 17 (1) 0 36 (2) 1 (<1) Unrelated donor 865 (60) 135 (36) 692 (37) 544 (39) Cord blood 85 (6) 13 (3) 33 (2) 16 (1) Other/missing 75 (5) 13 (3) 135 (7) 70 (5)

Year of transplant 1995-1996 61 (4) 29 (8) 46 (2) 34 (2) 1997-1998 57 (4) 22 (6) 63 (3) 41 (3) 1999-2000 85 (6) 36 (9) 87 (5) 101 (7)

21




2001-2002 108 (7) 44 (12) 125 (7) 163 (12) 2003-2004 179 (12) 49 (13) 121 (7) 164 (12) 2005-2006 210 (15) 55 (14) 165 (9) 183 (13) 2007-2008 258 (18) 33 (9) 182 (10) 146 (10) 2009-2010 115 (8) 24 (6) 392 (21) 184 (13) 2011-2012 56 (4) 14 (4) 426 (23) 232 (17) 2013-2014 175 (12) 48 (13) 157 (8) 100 (7) 2015-2016 96 (7) 18 (5) 57 (3) 37 (3) 2017* 47 (3) 8 (2) 32 (2) 7 (<1)


22


TO: Chronic Leukemia Working Committee Members

FROM: Wael Saber, MD, MS; Scientific Director for the Chronic Leukemia Working Committee

RE: 2017-2018 Studies in Progress Summary

CK12-01: Optimal timing of allogeneic stem cell transplantation for chronic myeloid leukemia patients in the tyrosine kinase inhibitor era (B Hu/H Lee/J Cortes/M de Lima) The objectives of the study are: 1) to estimate residual life expectancies for patients diagnosed with CML in CP based on the timing of various allo-HSCT strategies using data from both MD Anderson Cancer Center and the CIBMTR databases; 2) to calculate residual life expectancies for patients who did not undergo allo-HSCT and continued their TKI therapies. The abstract of the study has been presented at ASH and the analysis results have been circulated among the writing committee. The PIs are currently working on the draft manuscript. The goal of the study is to have the manuscript submitted by June 2018.

CK14-02: Prognostic score and cytogenetic risk classification for chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HCT: a CIBMTR report (H Kim/J Brown) The primary objective of the study is to determine patient-, disease-, and transplant-related variables associated with poor progression-free and overall survival outcomes among previously treated CLL patients undergoing reduced intensity/non-myeloablative (RIC/NMA) conditioning allo-HCT, with a particular goal of assessing the prognostic value of cytogenetics, in the context of other known prognostic markers. The secondary aim of the study is to validate or refine the prognostic score developed by the DFCI transplant group in previously treated CLL patients who underwent RIC/NMA allo-HCT using a large independent cohort. The abstract of the study has been presented at ASH and the PI is currently working on the draft manuscript. The goal of the study is to have the manuscript submitted by June 2018.

CK15-01: Comparison of transplant vs. non-transplant therapies for myelofibrosis (K Ballen/RA Mesa/KL Gowin) The primary objectives of the study are: 1) to compare survivals after HCT vs. non-transplant therapies for myelofibrosis; 2) to determine patient-, disease-, and treatment-related prognostic factors that are associated with superior survival. The collection of non-HCT data has been completed and the study protocol has been presented and circulated among the working committee members. The statisticians are currently working on analyzing the data. The goal of the study is to finalize data analysis by April 2018.

CK15-02: Comparison of outcomes after myeloablative versus reduced intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia (S Chhabra/S Jain/RK Stuart) The primary aim of the study is to compare the overall survival in patients with CML receiving allo-HCT using RIC vs. MAC between the ages of 40 and 60 years. The secondary aims of the study are: 1) to compare other outcomes after allo-HCT in CML patients receiving RIC vs. MAC; 2) to examine the GVL effect in CML patients after allo-HCT; 3) and to compare the effect of disease status at transplant, age, and HCT-CI on outcomes after RIC vs. MAC allo-HCT. The abstract of the study has been presented at ASH and the draft manuscript has been circulated among the writing committee. The goal of the study is to have the manuscript submitted by Mar 2018.

23


CK15-03: Outcome of allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia with antecedent history of Philadelphia-negative myeloproliferative neoplasm (V Gupta) The primary aims of the study are: 1) to analyze outcomes of HCT in patients with leukemic transformation from Philadelphia-negative MPN; 2) to identify patient, disease and transplant related factors associated with outcomes. The secondary aim of the study is to study the graft-versus-leukemia effect in this setting. Data file preparation is underway. The goal of the study is to finish data file preparation and start analysis by June 2018.

CK16-01: Identification of germline predisposition mutations in young myelodysplastic syndrome patients (L Godley) The primary aims of the study are: 1) to determine the frequency of germline variants in candidate genes in a cohort of paired samples derived from patients with myelodysplastic syndromes and their HLA-matched related donors; 2) to compare clinical/mobilization characteristics in related donors with a germline mutation versus related donors without germline mutations; 3) to compare engraftment parameters in MDS patients with germline deleterious mutations who underwent HLA matched related allogeneic stem cell transplant from HLA-matched related donors who shared the germline variant versus those who do not share the variant. The protocol of the study has been presented and circulated among the working committee members. The PI is currently working with the biorepository to get the DNA samples. The goal of the study is to finalize data analysis by June 2018.

CK16-02a: Contemporary role of maintenance tyrosine kinase inhibitors following allogeneic hematopoietic cell transplantation for chronic myeloid leukemia: a CIBMTR analysis (Z DeFilipp/R Ancheta) The primary aims of the study are: 1) to compare LFS of patients transplanted with CML who received maintenance TKI therapy and compare to controls (no maintenance therapy); 2) to compare the OS between these two groups. The abstract of the study has been submitted to EBMT conference. The PIs are currently working on the draft manuscript. The goal of the study is to have the final manuscript by May 2018.

CK16-02b: The benefit of donor lymphocyte infusion in the tyrosine kinase inhibitors era in chronic myeloid leukemia post allogeneic hematopoietic cell transplantation (S Schmidt) The objective of the study is to compare differences in overall survival in individuals who relapsed post HCT regardless of presence or absence of maintenance TKI therapy and went on to receive either: TKI alone or DLI (including DLI + TKI or DLI + others). The analysis is completed. The goal of the study is to have the draft manuscript circulated by April 2018.

CK17-01: Development of a prognostic scoring system predictive of outcomes in patients with myelofibrosis after allogeneic hematopoietic cell transplantation (T Roni/SA Giralt/J Palmer) The primary objective of the study is to identify patient-, disease-, and transplant-specific factors that positively associate with overall survival after allo-HCT for patients with myelofibrosis; the secondary objective is to develop a scoring system prognostic of OS post allo-HCT; the third objective is to validate the scoring system in an independent dataset. The study is currently under protocol development. The goal is to finalize the protocol and start data file preparation by June 2018.

CK17-02: Reduced-intensity conditioning transplantation in older MDS: the effect of specific conditioning regimens on transplant outcomes (B Oran) The objectives of the study are: 1) to investigate whether a certain conditioning regimen is associated with decreased incidence of disease progression in older MDS patients treated with RIC regimens; 2) to analyze transplant-related mortality, progression-free and overall survival between different treatment groups. The study is currently under protocol development. The goal is to finalize the protocol and start data file preparation by June 2018.

24


Proposal 1711-02

Title: Impact of donor age on the outcomes of allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome

Guru Subramanian Guru Murthy, MD, [email protected] , Medical College of Wisconsin, Milwaukee WI, Wael Saber MD MS, [email protected], Medical College of Wisconsin, Milwaukee, WI

Hypothesis: We postulate that survival of older patients with myelodysplastic syndrome (MDS) who undergo allogeneic stem cell transplantation (allo-SCT) from a younger matched unrelated donor is superior compared to undergoing allo-SCT from a matched sibling.

Specific aims: To compare the overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse rate, incidence of acute graft versus host disease (GVHD) and chronic GVHD in MDS patients undergoing allo-SCT from older matched related versus younger matched unrelated donor.

Scientific impact: The proposed study would provide more clear information about the impact of donor age and type on the outcomes of allo-SCT for older patients with MDS. This information would be pivotal in the donor selection process.

Scientific justification: Allo-SCT is a potentially curative treatment option for patients with MDS. With a median age at diagnosis of about 70 years, a considerable proportion of these patients are older adults. The use of a sibling donor of similar age group in this setting is associated with issues such as comorbidities and regenerative potential of stem cells and immune cells. It is currently unclear if older related donors are better than younger unrelated donors in this group of MDS patients undergoing allo-SCT. Results of prior single center and registry studies have yielded conflicting results. A large study from CIBMTR by Alousi et al included patients aged ≥ 50 years who underwent allo-SCT for leukemia/lymphoma and compared the outcomes based on donor age [matched sibling donor (MSD) ≥ 50 (n = 1415) versus matched unrelated donor (MUD) < 50 years (n = 757)] [1]. This study revealed an association between performance status and the choice of donor on transplant outcomes. For patients with performance scores of 90 or 100, the NRM, relapse and overall mortality were higher after MUD transplants. For patients with scores below 90, NRM and overall mortality were not significantly different after MUD and MSD transplants. However, only 10% of patients in this study had MDS patients. Studies by Kollman et al. have revealed improved transplant outcomes using younger MUD [2,3]. A major disadvantage of these analyses is the inclusion of patients with a variety of hematologic malignancies which limits their ability to generalize the findings to individual disease states.

A few studies have also focused exclusively on patients with MDS undergoing allo-SCT. A study by Saber et al. using the CIBMTR database included 701 adult MDS patients between 2002 and 2006 [4]. This study showed that matched related donor (MRD) recipients had similar DFS and OS compared with 8 of 8 MUD recipients and both MRD and 8 of 8 MUD had superior DFS and OS compared with 7 of 8 MUD. Due to a strong correlation between donor age and donor source, this study was not able to examine the independent association between donor age and transplant outcomes. A single center study by Reshuf et al. included 53 patients with MDS who underwent reduced intensity conditioning (RIC) allo-SCT from MRD (n = 19), MUD (n = 23) or single allele mismatched unrelated donors (n = 11) [5]. They

25


found that patients undergoing unrelated donor allo-SCT had a lower relapse risk (41% vs 63% at 2 years) and improved relapse-free survival (27% vs 11% at 2 years). OS at 2 years was comparable in both groups (32% vs 26%). Another registry study from EBMT by Kroger et al. included 719 MDS patients (age > 50) who underwent allo-SCT from either related (n = 555) or unrelated (n = 164) donors [6]. Compared with HLA-identical siblings, the 5-year OS of younger MUD (< 30 years) was higher (40% vs 33%) and lower in older MUD (> 30 years, 24% vs 33%). There was also a trend for lower risk of relapse (at 3 years) and lower NRM for patients transplanted from younger MUD in comparison with HLA-identical sibling transplantation. Hence, with the literature available currently, the impact of donor age on the outcomes of allo-SCT for MDS remains unclear. This justifies the need for further research in this population as it would be an important factor in the clinical decision-making process.

Patient eligibility population: Adult patients with age ≥ 50 years who underwent allo-SCT for MDS from HLA identical sibling (age ≥ 50 years) or well matched unrelated donor (age < 50 years) between the period 2002 to 2014 and reported to CIBMTR will be included. Patients with T-cell depleted grafts, recipients of prior autologous and allogeneic transplants, mismatched unrelated donor transplants, cord blood transplants or identical twin transplants will be excluded.

Data requirements: This retrospective study requires analysis of CIBMTR collected data related to allo-SCT from 2002-2014. This proposal does not require biologic samples.

Outcomes: Primary:

• OS at 3 years

Secondary: • DFS at 3 years • NRM at 3 years • Relapse rate at 3 years • Incidence of acute GVHD at 3 years • Incidence of chronic GVHD at 3 years

Variables: Disease-related:

• Disease: primary vs secondary/therapy related • IPSS-R score • CIBMTR MDS risk score

Patient-related: • Age • Gender • Race • CMV status • ABO status • HCT-CI • Performance status • Interval between diagnosis and transplant

26


Donor-related: • HLA match: Matched sibling vs. 8/8 matched unrelated donors • Age • Sex: male vs. female • CMV status • ABO status

Transplant-related: • Conditioning type: MA vs. RIC • Conditioning regimen: TBI based vs. non-TBI based • Source of stem cell: Bone marrow versus peripheral blood • GvHD prophylaxis • Year of transplant

Study design: This is a retrospective analysis of the CIBMTR database. The study would include patients aged ≥ 50 years with a diagnosis of MDS who underwent first allo-SCT and meet the above-mentioned study criteria. Baseline characteristics of the study population will be summarized using descriptive statistics. The cohort will be divided into two groups – related donors (≥ 50 years) and unrelated donors (< 50 years) and the outcomes will be compared between the two groups. The primary outcome will be OS at 3 years. The secondary outcomes will be relapse rate, NRM, DFS, incidence of acute GVHD and chronic GVHD. Patient related, donor related and transplant related variables summarized above will be considered as prognostic factors which determine the outcomes. A multivariate logistic regression model will be built using these variables to identify independent prognostic factors associated with the outcomes.

Definition of outcomes: OS will be defined as time from transplant to death from any cause; survivors will be censored at last contact. DFS will be defined as time to treatment failure (death or relapse). Relapse will be defined as disease recurrence as reported by the centers to the CIBMTR with NRM as competing event. NRM will be defined as death from any cause in the first 28 days post allo-SCT or death without evidence of disease recurrence beyond day 28. Acute GVHD will be graded using the International Blood & Marrow Transplant Research Severity Index [7]. Chronic GVHD will be diagnosed by standard criteria [8]. For cumulative incidence of GVHD, death without GVHD will be considered a competing event.

References: 1. Alousi AM, Le-Rademacher J, Saliba RM et al. Who is the better donor for older hematopoietic

transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood. 2013;121(13):2567-73.

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

3. Kollman C, Spellman SR, Zhang MJ et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood. 2016;127(2):260-7.

4. Saber W, Cutler CS, Nakamura R, et al. Impact of donor source on hematopoietic cell transplantation outcomes for patients with myelodysplastic syndromes (MDS). Blood. 2013;122(11):1974-82

27


5. Yam C, Crisalli L, Luger SM et al. Unrelated donors are associated with improved relapse-free survival compared to related donors in patients with myelodysplastic syndrome undergoing reduced intensity allogeneic stem cell transplantation. Am J Hematol. 2016;91(9):883-7.

6. Kröger N, Zabelina T, de Wreede L et al. Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia. 2013;27(3):604-9

7. Rowlings PA, Przepiorka D, Klein JP et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol 1997;97(4):855-864

8. Shulman HM, Sullivan KM, Weiden PL et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69(2):204-217

28


Baseline characteristics for patients undergoing allo-HCT for MDS between 2002 and 2016

Variable HLA-identical sibling

Well-matched unrelated

Number of patients 906 1628 Number of centers 140 125 Age, median (range) 61 (50-78) 65 (50-79) 50-59 374 (41) 454 (28) 60-69 457 (50) 913 (56) 70-79 75 (8) 261 (16) Gender Male 586 (65) 1047 (64) Female 320 (35) 581 (36) Karnofsky score 90-100 511 (56) 862 (53) < 90 376 (42) 718 (44) Missing 19 (2) 48 (3) Secondary disorder No 702 (77) 1258 (77) Yes 166 (18) 336 (21) Missing 38 (4) 34 (2) HCT-CI 0 168 (19) 233 (14) 1 82 (9) 163 (10) 2 82 (9) 197 (12) 3+ 414 (46) 818 (50) NA, f2400 (pre-TED) not completed 155 (17) 200 (12) Missing 5 (<1) 17 (<1) Disease status at transplant Early 298 (33) 510 (31) Advanced 541 (60) 992 (61) NOS 67 (7) 126 (8) IPSS prior to transplant Low 122 (13) 211 (13) Intermediate-1 415 (46) 761 (47) Intermediate-2 183 (20) 383 (24) High 16 (2) 30 (2) Missing 170 (19) 243 (15) IPSS karyotype category Favorable 357 (39) 645 (40) Intermediate 159 (18) 283 (17) Poor 299 (33) 566 (35)

29




TBD (needs rev.) 57 (6) 80 (5) Not tested 10 (1) 23 (1) Missing 24 (3) 31 (2) Treatment prior to conditioning No 184 (20) 228 (14) Yes 716 (79) 1394 (86) Missing 6 (<1) 6 (<1) Time from diagnosis to transplant, median (range) 7 (<1-220) 9 (<1-266) < 6 months 359 (40) 494 (30) 6-12 months 254 (28) 574 (35) ≥ 12 months 290 (32) 554 (34) Missing 3 (<1) 6 (<1) Year of transplant 2002-2003 54 (6) 34 (2) 2004-2005 63 (7) 71 (4) 2006-2007 46 (5) 110 (7) 2008-2009 94 (10) 138 (8) 2010-2011 107 (12) 175 (11) 2012-2013 201 (22) 413 (25) 2014-2015 246 (27) 460 (28) 2016 95 (10) 227 (14) Donor age at donation, median (range), yr 59 (34-82) 28 (18-62) 10-19 0 65 (4) 20-29 0 830 (51) 30-39 10 (1) 382 (23) 40-49 104 (11) 233 (14) 50-59 379 (42) 70 (4) 60-69 356 (39) 5 (<1) 70-79 53 (6) 0 ≥ 80 1 (<1) 0 Missing 3 (<1) 43 (3) Donor/recipient CMV serostatus +/+ 350 (39) 436 (27) +/- 114 (13) 162 (10) -/+ 232 (26) 506 (31) -/- 194 (21) 491 (30) Missing 16 (2) 33 (2) Donor/recipient sex match M-M 322 (36) 833 (51) M-F 149 (16) 378 (23)

30




F-M 257 (28) 211 (13) F-F 166 (18) 202 (12) Missing 12 (1) 4 (<1) Graft type Bone marrow 32 (4) 205 (13) Peripheral blood 873 (96) 1423 (87) Missing 1 (<1) 0 Conditioning regimen intensity MAC 355 (39) 549 (34) RIC 406 (45) 916 (56) NMA 88 (10) 118 (7) TBD 39 (4) 42 (3) Missing 18 (2) 3 (<1) ATG/Campath ATG alone 129 (14) 606 (37) CAMPATH alone 35 (4) 63 (4) No ATG or CAMPATH 725 (80) 957 (59) Missing 17 (2) 2 (<1) GVHD prophylaxis TAC + MMF ± other(s) (except post-CY) 147 (16) 363 (22) TAC + MTX ± other(s) (except MMF, post-CY) 377 (42) 810 (50) TAC + other(s) (except MMF, MTX, post-CY) 64 (7) 136 (8) TAC alone 30 (3) 42 (3) CSA + MMF ± other(s) (except post-CY) 115 (13) 129 (8) CSA + MTX ± other(s) (except MMF, post-CY) 108 (12) 64 (4) CSA + other(s) (except MMF, MTX, post-CY) 15 (2) 11 (<1) CSA alone 21 (2) 14 (<1) Other(s) 13 (1) 27 (2) Missing 16 (2) 32 (2)

31


Proposal: 1711-30

Title: Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with autologous or allogeneic hematopoietic stem-cell transplantation

Yazeed Sawalha, MD, [email protected], Cleveland Clinic Taussig Cancer Institute, Brian T. Hill, MD, PhD, [email protected], Cleveland Clinic Taussig Cancer Institute

Hypothesis: Outcomes of patients with Richter’s syndrome (RS) treated with chemoimmunotherapy alone are very poor. Autologous or allogeneic hematopoietic stem-cell transplantation (HSCT) have been commonly used to improve outcomes and achieve durable remissions. However, the evidence supporting this approach is limited to few small retrospective studies with short follow-up. As additional cases of RS are identified in the era of novel targeted agents for chronic lymphocytic leukemia (CLL), more data are needed to document the outcomes of HSCT in this patient population.

Specific aims: • Report the outcomes of autologous and allogeneic HSCT for patients with RS. The primary

outcome is overall-survival (OS). Other outcomes of interest include progression-free survival(PFS), relapse/progression and non-relapse mortality (NRM).

• Report outcomes of patients with RS who were previously treated with novel agents such asibrutinib, idelalisib and venetoclax for CLL.

• Identify patient-, disease- and transplant-related factors that can predict survival and/or diseaseprogression/relapse after HSCT.

Scientific justification: RS occurs in approximately 2% to 10% of all patients with CLL and represents the transformation of CLL into high-grade aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL) (1-3). DLBCL arising in this setting is clonally related to the underlying CLL in 80% of the cases and has distinct biological and clinical features that are different from de novo DLBCL (4).

RS carries a very poor prognosis with a median survival of less than 1-2 years (1, 2, 4, 5). This is driven by poor responses to chemoimmunotherapy (overall response rates of 40-60% and complete remission (CR) rates of 5-38%) and early relapses in the majority patients (3). As most patients cannot achieve durable responses with chemoimmunotherapy alone, and given the efficacy of HSCT in the treatment of other aggressive lymphomas, both autologous and allogeneic HSCT have been evaluated as post-remission and/or salvage therapies. There is little published about the outcomes of HSCT in patients with RS, yet current CIBMTR consensus guidelines recommend the use of allogeneic HSCT for patients with RS (6).

A study from MD Anderson Cancer Center (MDACC) reported the outcomes of 130 patients with RS (5). Seventeen patients underwent allogeneic HSCT (7 as post-remission therapy and 10 as salvage therapy) and 3 patients underwent autologous HSCT as salvage therapy. The 3-year OS for patients who underwent post-remission allogeneic HSCT was 75%, compared with 27% for patients who did not receive post-remission HSCT and 21% for those who received salvage therapy with autologous or allogeneic HSCT (p = 0.019). Post-remission therapy with allogeneic HSCT was independently associated with improvement in OS in multivariate analysis.

32

Not for publication or presentation Attachment 5 The largest report of patients with RS who underwent HSCT came from a retrospective analysis from the European Group for Blood and Marrow Transplantation (EBMT) that included 59 patients with RS (16 patients had transformations to other types of lymphoma, including Hodgkin’s lymphoma) who were transplanted between 1997 and 2007 (2). Twenty-five patients received allogeneic HSCT and 34 patients received autologous HSCT. A higher proportion of patients in the allogeneic HSCT group (36%) had chemoresistant disease compared with the autologous HSCT group (9%). The median follow-up duration was approximately 2.5 years. The 3-year OS was 59% for patients who underwent autologous HSCT, which was more favorable than outcomes of historical controls from the MDACC study who had chemosensitive disease and did not undergo consolidation with autologous HSCT (3-year OS of 27%). The 3-year OS for patients who underwent allogeneic HSCT was 36% (41% for patients with chemosensitive disease and 17% for patients with chemoresistant disease). In multivariate analysis, younger age at transplantation, disease status pre-transplantation and the use of reduced-intensity conditioning were significantly associated with superior relapse-free survival.

In a report by the Mayo Clinic of 120 patients with RS published as an abstract form, 13 patients received HSCT (10 autologous, 2 allogeneic and 1 autologous followed by an allogeneic HSCT) (7). Patients who received HSCT had superior OS (median of 5.2 years versus 0.7 years, p = 0.005).

Despite the marked improvement in treatment outcomes in CLL with the use of novel agents such as ibrutinib, venetoclax and idelalisib, RS still occurs and is associated with dismal outcomes (8). The biological and clinical behavior of RS in patients with prior history of CLL treated with novel agents might be different, and data regarding the efficacy of HSCT in this setting are lacking.

In conclusion, the proposed study provides a unique opportunity to generate important details about the outcomes of a relatively large cohort of patients with RS who underwent autologous and/or allogeneic HSCT at CIMBTR centers.

Study population: • Patients ≥ 18 years who have undergone autologous and/or allogeneic HSCT at a CIBMTR center

between 1990-2015. • Diagnosis of RS (DLBCL transformed from CLL/SLL).

Variables: Data captured in the Hodgkin and Non-Hodgkin Lymphoma Pre-HSCT Data Form will include Patient-related:

• Gender • Age at RS diagnosis (<60, ≥60 years) • Karnofsky performance status at RS diagnosis (<90, ≥90)

Disease-related: • Time from diagnosis to transplant • Disease stage at diagnosis (I-II, III-IV) • Extranodal involvement (yes, no) • LDH at RS diagnosis (≤ upper limit of normal ULN, > upper limit of normal ULN) • Type and number of therapies given between RS diagnosis and preparative regimen (1, ≥ 2) • Rituximab exposure before HSCT (yes, no) • Best response to therapy prior to preparative regimen (CR/CRu, PR, NR/SD, PD) • Response to therapy prior to preparative regimen (chemosensitive or chemoresistant)

33


• RS disease status at the last evaluation prior to preparative regimen (CR, primary induction failure resistant, primary induction failure sensitive, relapsed sensitive, relapsed resistant, relapsed untreated)

Transplant-related: • HSCT type • Product type • Conditioning regimen (myeloablative, reduced-intensity)

Data captured in the Chronic Lymphocytic Leukemia (CLL) Pre-HSCT Data Form will include: Disease-related:

• Rai stage at diagnosis • Cytogenetics at diagnosis including FISH • Systemic therapy for CLL (number and types of treatment including novel agents such as

ibrutinib, venetoclax and idelalisib whenever available) • Cytogenetics after diagnosis to prior to preparative regimen • Heavy chain rearrangement prior to preparative regimen • Most recent disease assessment prior to start of the preparative regimen • Time from CLL diagnosis to RS

Data captured in the Hodgkin and Non-Hodgkin Lymphoma Post HSCT Data Form as well as the Six Months to Two Years Post-HSCT Data Form and the Yearly Follow-Up for Greater than Two Years Post-HSCT Data Form will include, survival, relapse and cause of death.

Data captured in the Chronic Lymphocytic Leukemia (CLL) Post HSCT Data Form will include date of CLL relapse/progression.

Study design: Survival probabilities will be estimated by the Kaplan-Meier method. OS will be defined as time to death after transplantation. Death from any cause will be considered an event, and surviving patients will be censored at the time of last follow-up. PFS will be defined as survival without disease relapse or progression after transplantation. Relapse or progression of disease and death will be events. Relapse/progression will be defined as any new lesion after complete remission or increase in size of previously involved sites after transplantation, with NRM as a competing risk. NRM will be defined as any death within the first 28 days after transplantation or any death occurring after day 28 in the absence of disease relapse/progression. Cox proportional hazards analysis will be used to identify univariate and multivariate risk factors for treatment failure overall mortality. A variable entry criterion of P ≤ 0.10 and a variable retention criterion of P ≤ 0.05 will be used to identify multivariate risk factors. All statistical tests will be two-sided, and p≤ 0.05 will be used to indicate statistical significance.

Patient-, disease-, and HSCT-related factors will be compared between autologous and allogeneic HSCT groups by using the Chi square test for categorical variables and the Wilcoxon two-sample test for continuous variables.

References: 1. Parikh SA, Rabe KG, Call TG, Zent CS, Habermann TM, Ding W, et al. Diffuse large B-cell lymphoma

(Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. British journal of haematology. 2013;162(6):774-82.

34

Not for publication or presentation Attachment 5 2. Cwynarski K, van Biezen A, de Wreede L, Stilgenbauer S, Bunjes D, Metzner B, et al. Autologous and

allogeneic stem-cell transplantation for transformed chronic lymphocytic leukemia (Richter's syndrome): A retrospective analysis from the chronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphoma working party of the European Group for Blood and Marrow Transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(18):2211-7.

3. Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome. Blood. 2014;123(11):1647-57. 4. Rossi D, Spina V, Deambrogi C, Rasi S, Laurenti L, Stamatopoulos K, et al. The genetics of Richter

syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117(12):3391-401.

5. Tsimberidou AM, O'Brien S, Khouri I, Giles FJ, Kantarjian HM, Champlin R, et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(15):2343-51.

6. Kharfan-Dabaja MA, Kumar A, Hamadani M, Stilgenbauer S, Ghia P, Anasetti C, et al. Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2016;22(12):2117-25.

7. Sharma RG, Call TG, Habermann TM, Ding W, Leis JF, Schwager S, et al. Outcomes Of Chronic Lymphocytic Leukemia Patients With Richter Syndrome. Blood. 2013;122(21):4179-.

8. Davids MS, Huang Y, Rogers KA, Stern R, Brown JR, Thompson PA, et al. Richter's syndrome (RS) in patients with chronic lymphocytic leukemia (CLL) on novel agent therapy. Journal of Clinical Oncology. 2017;35(15_suppl):7505-.

35

Not for publication or presentation Attachment 5 Baseline characteristics for patients undergoing 1st allo/auto HCT for Richter's syndrome

Variable Allo Auto Number of patients 100 27 Number of centers 56 22 Age, median (range), by years 60 (21-73) 64 (31-79) 20-29 1 (1) 0 30-39 3 (3) 1 (4) 40-49 15 (15) 2 (7) 50-59 33 (33) 7 (26) 60-69 45 (45) 14 (52) ≥ 70 3 (3) 3 (11) Gender Male 73 (73) 19 (70) Female 27 (27) 8 (30) Karnofsky score 90-100 44 (44) 10 (37) < 90 20 (20) 0 Missing 36 (36) 17 (63) Disease status prior to transplant CR 18 (18) 10 (37) PR 44 (44) 8 (30) Stable 14 (14) 3 (11) Progressive 12 (12) 4 (15) Untreated 1 (1) 0 Nodal PR 2 (2) 2 (7) Not evaluable 4 (4) 0 Missing 5 (5) 0 Year of transplant 1994-1996 3 (3) 1 (4) 1997-1999 3 (3) 2 (7) 2000-2002 10 (10) 0 2003-2005 13 (13) 0 2006-2008 10 (10) 3 (11) 2009-2011 11 (11) 0 2012-2014 24 (24) 11 (41) 2015-2016 26 (26) 10 (37) Time from diagnosis to transplant, years 3 (<1-20) 1 (<1-14) Time from diagnosis to transplant 0-3 yrs 55 (55) 17 (63) 3-6 yrs 23 (23) 5 (19) ≥ 6 yrs 22 (22) 5 (19)

36


Variable Allo Auto Donor type Autologous 0 27 HLA-identical sibling 38 (38) 0 Other related 13 (13) 0 Well-matched unrelated 30 (30) 0 Partially-matched unrelated 7 (7) 0 Unrelated (matching TBD) 3 (3) 0 Cord blood 9 (9) 0 Graft source Bone marrow 14 (14) 1 (4) Peripheral blood 77 (77) 26 (96) Cord blood 9 (9) 0 Conditioning regimen intensity MAC 25 (25) 7 (26) RIC 37 (37) 18 (67) NMA 31 (31) 0 TBD 7 (7) 2 (7) GVHD prophylaxis Autologous 0 27 Ex-vivo T-cell depletion 1 (1) 0 CD34 selection 2 (2) 0 Post-CY + other(s) 4 (4) 0 TAC + MMF ± other(s) (except post-CY) 20 (20) 0 TAC + MTX ± other(s) (except MMF, post-CY) 28 (28) 0 TAC + other(s) (except MMF, MTX, post-CY) 11 (11) 0 TAC alone 2 (2) 0 CSA + MMF ± other(s) (except post-CY) 11 (11) 0 CSA + MTX ± other(s) (except MMF, post-CY) 12 (12) 0 CSA + other(s) (except MMF, MTX, post-CY) 1 (1) 0 CSA alone 4 (4) 0 Other(s) 1 (1) 0 Missing 3 (3) 0

37


Proposal 1711-72

Title: Outcomes of allogeneic stem cell transplantation in patients with Richter’s syndrome.

Akash Mukherjee, MD, [email protected]. Houston Methodist Hospital, Sai Ravi Pingali, MD, [email protected], Houston Methodist Hospital, Houston, TX, Nebu Varghese Koshy, MD, [email protected], Louisiana State University Health, Shreveport, LA

Hypothesis: Consolidation with allogeneic hematopoietic cell transplantation (allo-HCT) can achieve long term remission in patients with Richter’s syndrome (RS).

Specific aims: • To evaluate non-relapse mortality rate (NRM), overall survival (OS) and progression free survival

(PFS) in this patient population.• To evaluate engraftment, incidence of acute and chronic GVHD at day 100, 1, 3 and 5 years.

Scientific impact: There are no large studies either evaluating outcomes of allo-HCT in patients with RS. This study is only feasible with large data sets like CIBMTR data-base. Comparing outcomes of allo-HCT in patients with RS would be very helpful in clinical practice. This study would allow us to make clinical practice decisions as treatment for CLL and RS continues to evolve and allo-HCT being used only in very select cases.

Scientific justification: Richter’s syndrome occurs in 2% to 8% of patients with chronic lymphocytic leukemia (CLL) or Small lymphocytic lymphoma (SLL) and refers to its transformation from CLL/SLL to high grade aggressive lymphoma- mostly diffuse large B cell lymphoma (DLBCL) or Hodgkin’s lymphoma. It is associated with poor prognosis compared to de novo large cell lymphomas with median survival duration of less than a year despite use of multi-agent immunochemotherapy.1-6. A single institution retrospective study of 39 patients with RS in 1993 showed a median survival duration of only 5 months using multi-agent chemotherapy.1.Another study using Hyper CVAD in patients with RS showed a CR rate of 38% with median OS of 10 months only.2.Addition of Rituximab to Hyper CVAD alternating with methotrexate and cytarabine failed to improve outcomes and median OS remained only 9 months.3.

Several centers have used consolidation hematopoietic cell transplantation (HCT) to improve outcomes for these patients. Both autologous (auto-HCT) and allogeneic hematopoietic cell transplantation (allo-HCT) have proven role in lymphoma like- DLBCL, HL, CLL/SLL. Role of allo-HCT to improve prognosis of RS patient’s in combination with conventional chemotherapy was evaluated by Rodriguez et al. Eight patients with RS (5 were resistant relapse and 3 were sensitive or untreated relapse) underwent allo-HCT between 1991 to 1997 at MD Anderson and reported 3 out of 8 patients to be alive and in remission at 14 months, 47 months and 67 months respectively.4. Another retrospective study by Tsimberidou et al. reported outcomes of 20 patients with RS who underwent stem cell transplantation (7 patients had allo-HCT as post remission consolidation therapy and 13 patients (10 allo-HCT and 3 auto-HCT) as salvage therapy. Cumulative OS was 75% at 3 years for patients who underwent allo-HCT after a CR/PR, 27% for patients who responded to initial therapy and received no HCT and 21% for patients with relapsed/refractory RS who had allo-HCT or auto-HCT as salvage therapy (p=0.019). Further multivariate analysis showed allo-HCT as a post remission therapy to be an independent factor

38

mailto:[email protected]


for prolonged survival (p=0.002) and further reinforced place of allo-HCT in addition to conventional chemotherapy to improve outcome in patients with RS.5.

Another retrospective study to evaluate HCT outcome on RS patients using EBMT database which included 34 patients who received auto-HCT with mostly chemosensitive disease and 25 patients who had allo-HCT with 36% being chemorefractory at SCT. 72% of allo-HCT recipients got RIC. The study showed a 3-year probability of OS, relapse free survival (RFS) and the cumulative incidences of relapse and NRM were 36%, 27%, 47% and 26% for allo-HCT and 59%, 45%, 43% and 12% for auto-HCT respectively. Multivariate analysis showed chemosensitive disease and RIC to be significantly associated with better RFS after allo-HCT in RS. This paper highlighted the role of both auto and allo-HCT in RS patient’s management.6.

With this background information, we would like to study the clinical outcome of RS patients who underwent autologous and allogeneic stem cell transplantation either as post remission consolidation therapy given after multiagent induction chemotherapy or as a salvage therapy in refractory/relapsed setting using our CIBMTR database.

Patient eligibility population: All patients age equal to or more than 18 years of age with histologically proven CLL transformation to RS who underwent auto-HCT or allo-HCT from 1990 to 2016.

Data Requirements: • CIBMTR forms required to carry out this proposed study:• Richter’s transformation patients Pre-HCT Data• 100 Day Post-HCT Data• Year 1,3,5 Post-HCT Data• Post-Transplant Essential Data• Recipient Death Data

Study design: This is a retrospective study with review of CIBMTR database. Plan will be to analyze all patients with Richter’s syndrome that got an allo-HCT, from year 2002-2016.

Variables to be evaluated include the demographics (age, gender, race, etc.), disease stage at transplant, transplant characteristics (type of donor, preparative regimen, source of stem cells), outcome data including engraftment and post-transplant outcomes. We will use descriptive statistics, discuss relevant characteristics and discuss the outcomes of patients as related to the donor type.

Outcome analysis: Overall survival (OS) is defined as time from HCT to last follow-up. Similarly, non-relapse mortality (NRM) will be computed from time of HCT to last known vital sign. Time-to-progression is defined time of HCT and date of disease progression. Patients who are alive and did not experience progression of disease at the last follow-up date will be censored. The Kaplan-Meier method will be used to estimate OS and DFS and the log-rank test was used to assess differences between specific groups7. NRM and time-to-progression will be determined by the cumulative incidence function using the competing risks method. The cumulative incidence of grade II-IV acute graft vs. host disease (GVHD) and chronic GVHD (cGVHD) (limited and extensive) will also be determined using the competing risks method8. The

39


competing risks include disease progression and death, while those patients who do not experience GVHD or progression of disease and alive at the last follow-up will be censored.

References: 1. Robertson LE, Pugh W, O’Brien, et al: Richter’s syndrome: A report on 39 patients. J Clin Oncol 11:

1985-1989, 1993.2. Dabaja BS, O’Brien SM, Kantarjian HM, et al: Fractionated cyclophosphamide, vincristine, liposomal

daunorubicin (daunoxome) and dexamethasone (hyper CVAD) regimen in Richter’s syndrome. LeukLymphoma 42:329-337, 2001.

3. Tsimberidou AM, Kantarjian HM, Cortes J, et al: Fractionated cyclophosphamide, vincristine,liposomal daunorubicin and dexamethasone plus rituximab and granulocyte-macrophage-colonystimulating factor (GM-CSF) alternating with methotrexate and Cytarbine plus rituximab and GM-CSF in patients with Richter syndrome or fludarbine-refractory chronic lymphocytic leukemia.Cancer 97:1711-1720, 2003.

4. Rodriguez J, Keating M, O’Brien S, Champlin R, Khouri I. Allogeneic hematopoietic transplantation forRichter’s syndrome.Br Journal of Haem. 2000, 110, 897-899.

5. Tsimberidou AM, O’Brien S, Khouri I, et al. Clinical outcome and prognostic factors in patients withRichter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem celltransplantation. J Clin Oncol 24:2343-2351. 2006.

6. Cwynarski K, Biezen AV, Wreede LD, et al. Autologous and allogeneic stem cell transplantation fortransformed chronic lymphocytic leukemia (Richter’s syndrome): A retrospective analysis from thechronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphomaworking party of the European group for Blood and Marrow transplantation. J Clin Oncol 30:2211-2217. 2012.

7. Kaplan EL, M. P. " Nonparametric estimation for incomplete observations." J Am Stat Assoc 1958(53): 457-481.

8. Prentice RL, K. J., Peterson AV "The analysis of failure times in the presence of competing risks." Jr.Biometrics 1978(34(4)): 541-554.

40


Baseline characteristics for patients undergoing 1st allo/auto HCT for Richter's syndrome

Variable Allo Auto

Number of patients 100 27 Number of centers 56 22

Age, median (range), by years 60 (21-73) 64 (31-79) 20-29 1 (1) 0

30-39 3 (3) 1 (4) 40-49 15 (15) 2 (7) 50-59 33 (33) 7 (26)

60-69 45 (45) 14 (52) ≥ 70 3 (3) 3 (11)

Gender

Male 73 (73) 19 (70) Female 27 (27) 8 (30)

Karnofsky score

90-100 44 (44) 10 (37) < 90 20 (20) 0 Missing 36 (36) 17 (63)

Disease status prior to transplant CR 18 (18) 10 (37) PR 44 (44) 8 (30)

Stable 14 (14) 3 (11) Progressive 12 (12) 4 (15) Untreated 1 (1) 0

Nodal PR 2 (2) 2 (7) Not evaluable 4 (4) 0 Missing 5 (5) 0

Year of transplant 1994-1996 3 (3) 1 (4)

1997-1999 3 (3) 2 (7) 2000-2002 10 (10) 0 2003-2005 13 (13) 0

2006-2008 10 (10) 3 (11) 2009-2011 11 (11) 0 2012-2014 24 (24) 11 (41)

2015-2016 26 (26) 10 (37)

41


Variable Allo Auto Time from diagnosis to transplant, years 3 (<1-20) 1 (<1-14)

Time from diagnosis to transplant 0-3 yrs 55 (55) 17 (63) 3-6 yrs 23 (23) 5 (19)

≥ 6 yrs 22 (22) 5 (19) Donor type

Autologous 0 27

HLA-identical sibling 38 (38) 0 Other related 13 (13) 0 Well-matched unrelated 30 (30) 0

Partially-matched unrelated 7 (7) 0 Unrelated (matching TBD) 3 (3) 0 Cord blood 9 (9) 0

Graft source Bone marrow 14 (14) 1 (4) Peripheral blood 77 (77) 26 (96)

Cord blood 9 (9) 0 Conditioning regimen intensity

MAC 25 (25) 7 (26) RIC 37 (37) 18 (67) NMA 31 (31) 0

TBD 7 (7) 2 (7) GVHD prophylaxis

Autologous 0 27

Ex-vivo T-cell depletion 1 (1) 0 CD34 selection 2 (2) 0 Post-CY + other(s) 4 (4) 0

TAC + MMF ± other(s) (except post-CY) 20 (20) 0 TAC + MTX ± other(s) (except MMF, post-CY) 28 (28) 0 TAC + other(s) (except MMF, MTX, post-CY) 11 (11) 0

TAC alone 2 (2) 0 CSA + MMF ± other(s) (except post-CY) 11 (11) 0 CSA + MTX ± other(s) (except MMF, post-CY) 12 (12) 0

CSA + other(s) (except MMF, MTX, post-CY) 1 (1) 0 CSA alone 4 (4) 0 Other(s) 1 (1) 0

42


Variable Allo Auto Missing 3 (3) 0

43


Proposal 1711-42

Title: A personalized prediction model for outcomes after allogeneic stem cell transplant in patients with myelodysplastic syndromes

Aziz Nazha, MD, [email protected], Cleveland Clinic, Navneet Majhail, MD, Cleveland Clinic, Taussig Cancer Center, Wael Saber, MD, [email protected], Medical College of Wisconsin, Betty K. Hamilton, MD, [email protected], Cleveland Clinic

Hypothesis: We hypothesize that incorporation of genomic-clinical data using machine learning algorithms can create a personalized (precision) prediction model that can predict outcomes that include overall survival (OS), relapse-free survival (RFS), relapse and non-relapse related mortality at different time points post-allogeneic stem cell transplantation for patients with myelodysplastic syndromes (MDS).

Specific Aims: We propose a retrospective analysis of CIBMTR clinical and genomic data of 1514 patients reported in previous study (Lindsley R, et al, NEJM, 2017)1 to build a model that can incorporate clinical, cytogenetic, transplant-related data, and genomic data to precisely predict overall outcomes after transplant using state of the art multiple machine learning algorithms. We hypothesize that this approach can overcome some of the limitation of traditional statistical approaches such as cox regression, outperform current prognostic models such as IPSS, IPSS-R, HCT-CI, and can provide personalized prediction that is specific to each patient thus improving patient selection for transplant.

Scientific impact: The personalized model can provide a useful decision-making tool that can help physician in selecting the appropriate patients to receive allogeneic stem cell transplant based on their clinical and molecular features.

Scientific justification: Myelodysplastic syndromes (MDS) are a group of disorders characterized by the clonal acquisition of somatic mutations that result in profound cytopenias and the risk of acute myeloid leukemia (AML) transformation2. The outcome of patients with MDS is heterogeneous, with some patients alive years after their diagnosis, while others live only for months despite therapy. The accurate prediction of an MDS patient’s outcome is important as it helps determine expectations regarding treatment options, and of overall outcome. For the treating physician, prognostic systems aid treatment decisions and disease management.

Allogeneic stem cell transplant remains the only potentially curative option for MDS. However, majority of patients do not qualify to receive transplantation given their age and comorbidities3. Selecting appropriate patients to receive transplant is this patient population with multiple co-morbidities is clinically essential.

For the past two decades, several prognostic scoring systems have been developed and applied in clinical practice and have been used in determining clinical trial design and eligibility. These models depend mainly on clinical variables that are obtained from bone marrow biopsy results and chromosomal analysis. Several pros and cons for each model have been recognized when applying them in real time4. These limitations become more apparent when applying these models during the disease

44


course, and either prior to initiating specific therapies, or following therapy failure (particularly with hypomethylating agents (HMAs)), or in patients with secondary MDS, therapy related MDS (t-MDS), or chronic myelomonocytic leukemia (CMML)4. With the revolution of genomic sequencing technologies, several somatic mutations have also shown to impact outcome in patients with MDS and related leukemias5. While the incorporation of these genomic alterations into established prognostic models has undoubtedly improved the performance of these models6, the ideal way to take maximal advantage of this information in combination with other prognostic factors remains a work in progress.

In a retrospective analysis of 687 patients with MDS treated at the Cleveland Clinic between 1/2000 and 1/2017, significant heterogeneity was observed when comparing risk stratification per IPSS, MD Anderson Prognostic Scoring System (MDAPSS), and WHO Prognostic Scoring System (WPSS) to IPPS-R risk categories. For example, among 378 patients with lower-risk disease (Very Low / Low) per IPSS-R, 3 patients (1%) were re-classified INT-2 per IPSS, 73 (19%) as INT and 28 (7%) as high/very high per WPSS, and 11 (29%) as higher-risk per MDAPSS. Among 128 patients with intermediate risk by IPSS-R, 102 (20%) were reclassified as lower-risk per IPSS, 44 (34%) as lower-risk and 47 (37%) as higher-risk per WPSS, and 65 (50%) as lower-risk per MDAPSS. Among 181 patients with high/very high-risk by IPSS-R, 44 (25%) were reclassified as lower-risk by IPSS, 54 (30%) per WPSS, and 58 (32%) per MDAPSS. Among 523 patients with lower-risk (low / INT-1) by IPSS, 102 (20%) were reclassified as INT risk and 46 (9%) as higher-risk per IPSS-R, 113 (22%) as INT and 62 (12%) as higher-risk per WPSS, and 186 (36%) as higher risk per MDAPSS. Among 164 patients with higher-risk (INT-2/High) per IPSS, 26 (16%) were reclassified as INT per IPSS-R, 24 (15%) per WPSS, and 53 (32%) per MDAPSS. More importantly, the predicted OS per IPSS-R was overestimated when compared to the actual OS (evaluable in 429 patients) for patients in lower-risk categories. The difference between the median predicted IPSS-R OS and median actual OS was 70.6 months (m) for very low risk, 54 m for low, 9.5 m for INT, 6.7 m for high, and -2.4 m for very high risk (patients lived longer than their predicted OS). The IPSS, on the other hand, underestimated the OS, as the difference between the median predicted OS and median actual OS was -23.3 m for low risk, -16.5 m for INT1, -11.8 m for INT2, and -11.1 m for high risk. This study showed significant intra-patient (difference of outcome in the same patient based on the model used) and intra-group (difference in outcome among patients who have similar risk category by a given model) variability is observed when applying commonly used models in MDS. More importantly, IPSS-R overestimated OS for lower-risk disease and IPSS underestimated OS across all risk categories. This heterogeneity can impact survival expectations, treatment strategies such as allogeneic stem cell transplant, and clinical trial eligibility criteria based on the model used.

Based on this analysis, we have explored the incorporation of genomic-clinical data using machine learning algorithms to create a personalized (precision) prediction model that can outperform other commonly used models in MDS. We analyzed the clinical and mutational data from MDS patients diagnosed according to 2008 WHO criteria. The new model was developed in a cohort from our institution and validated in a separate cohort from other MDS Clinical Research Consortium sites. Next generation targeted deep sequencing of 60 gene mutations commonly mutated in myeloid malignancies was included. A random survival forest (RSF) algorithm was used to build the model, in which clinical and molecular variables are randomly selected for inclusion in determining survival, thereby avoiding the shortcomings of traditional Cox step-wise regression in accounting for variable interactions. Survival prediction is thus specific to each patient’s particular clinical and molecular characteristics. The accuracy of the proposed model compared to other models was assessed by concordance (c-) index. Of the 975 patients included, 527 were in the training cohort and 448 in the validation cohort. In the training cohort, the median age was 67 years (range, 19-99). Risk stratification by IPSS: 148 (28%) low, 235 (45%) intermediate-1, 106 (20%) intermediate-2, 38 (7%) high and by IPSS-R: 78 (15%) very low, 200 (38%) low,

45


95 (18%) intermediate, 98 (19%) high, and 56 (10%) very high. Cytogenetic analysis by IPSS-R criteria: 15 (3%) very good, 331 (62%) good, 87 (17%) intermediate, 37 (7%) poor, and 57 (11%) very poor. The most commonly mutated genes were: SF3B1 (14%), ASXL1 (13%), TET2 (12%), SRSF2 (11%), DNMT3A (11%), STAG2 (9%), TP53 (8%), and RUNX1 (8%). All clinical variables and mutations present in >/= 5 patients were included in the RSF algorithm. Variable importance analysis (the most important variables that contributed to the outcome) and multiple backward elimination analysis (identifying the least number of variables that can provide the least error rate) identified the following variables (ranked from the most important to the least important) that impacted OS: cytogenetics categories by IPSS-R, bone marrow blasts %, 2008 WHO criteria, platelets, WBC, hemoglobin, TP53, RUNX1, ANC, STAG2, SRSF2, NPM1, secondary vs. de novo MDS, age, PHF6, IDH1, EZH2, and SF3B1. The clinical and mutational variables can be entered into a web application that can run the trained model and provide OS and AML transformation estimates as an output, Figure 1. The C-index for the new model was 0.71 for OS and 0.76 for AML transformation. The new model outperformed all commonly used models for OS and AML transformation including IPSS (c-index 0.65, 0.72), IPSS-R (0.67, 0.73), WHO prognostic scoring system (WPSS) (0.65, 0.73) and MD Anderson prognostic model (MDAPSS) (0.65, 0.7), respectively. When applying the new model to the validation cohort, the c-index for OS and AML transformation were 0.7, 0.75, respectively. To ease the translation of this model into the clinic, a web user interface was built as shown in Figure 1.

Patient eligibility population: Our study cohort will consist of patients previously reported in the Lindsey R, et al paper in NEJM, 20171. That study included patients from the CIBMTR database with MDS for whom comprehensive report form–level data had been collected between 2005 and 2014 and had their samples sequenced for the presence of 129 genes.

Data requirements: The dataset for Lindsey R et al1 analysis will be used for this study. No further data-cleaning or data-abstraction will be required.

46


Patient, disease, and transplant variables include: Patient characteristics:

• Age at transplant• Gender• Race• Karnofsky performance score at transplant• Comorbidity index

Disease characteristics: • Cytogenetics• Molecular data of 129 genes obtained by next generation targeted deep sequencing

Transplant characteristics: • Preparative regimen• Donor relationship• Donor age• Donor-recipient gender match• Donor-recipient CMV status• Donor cell dose- bone marrow versus peripheral blood

Outcomes: • Relapse• Transplant-related mortality• Relapse-free survival• Overall survival• Cause of Death

Study design: Clinical and mutational data will be obtained from CIBMTR data. Risk models that include IPSS, IPSS-R, and HCT-CI will be calculated as described previously. OS Overall survival will be defined as the time from transplantation until death from any cause or until censoring at the time that the patient was last known to be alive. Relapse-free survival will be defined as the time from transplantation until relapse or until censoring at the time of patient last follow up. For survival analyses, random survival forest algorithm (RFS) will be used as this algorithm incorporate log-rank test for right censored data. For binary outcomes, multiple machine learning algorithms will be used that include naive bays, random forest, ensemble random forest, and boosted gradient decision trees. All the analyses will be done in R. The user interface for the web application will be built using shiny app.

References: 1. Lindsley RC, Saber W, Mar BG, et al: Prognostic Mutations in Myelodysplastic Syndrome after Stem-

Cell Transplantation. N Engl J Med 376:536-547, 20172. Sekeres MA, Cutler C: How we treat higher-risk myelodysplastic syndromes. Blood 123:829-36, 20143. Giralt SA, Horowitz M, Weisdorf D, et al: Review of stem-cell transplantation for myelodysplastic

syndromes in older patients in the context of the Decision Memo for Allogeneic Hematopoietic StemCell Transplantation for Myelodysplastic Syndrome emanating from the Centers for Medicare andMedicaid Services. J Clin Oncol 29:566-72, 2011

4. Nazha A, Sekeres MA: Improving Prognostic Modeling in Myelodysplastic Syndromes. Curr HematolMalig Rep 11:395-401, 2016

47


5. Haferlach T, Nagata Y, Grossmann V, et al: Landscape of genetic lesions in 944 patients withmyelodysplastic syndromes. Leukemia 28:241-7, 2014

6. Nazha A, Narkhede M, Radivoyevitch T, et al: Incorporation of molecular data into the RevisedInternational Prognostic Scoring System in treated patients with myelodysplastic syndromes.Leukemia 30:2214-2220, 2016

48


MDS cases of Coleman Lindsley’s study

Variable Unrelated Related Cord Blood Number of patients 1165 181 168 Number of centers 122 40 62 HLA matching out of 8 loci

1/8 0 0 1 (1) 2/8 0 0 5 (4) 3/8 1 (<1) 0 7 (6) 4/8 0 0 25 (20) 5/8 5 (<1) 0 41 (33) 6/8 9 (1) 0 22 (18) 7/8 161 (15) 0 16 (13) 8/8 863 (83) 181 (100) 6 (5) Not-high resolution typed 126 (N/A) 0 (N/A) 45 (N/A)

Cytogenetic score for IPSS score Favorable 393 (39) 37 (37) 41 (30) Intermediate 167 (16) 20 (20) 28 (21) Poor 405 (40) 38 (38) 61 (45) TBD 25 (2) 3 (3) 2 (1) Not tested 28 (3) 2 (2) 3 (2) Unknown 147 (N/A) 81 (N/A) 33 (N/A)

Cytogenetic score for IPSS-R score Very good 9 (1) 0 0 Good 453 (44) 40 (40) 49 (36) Intermediate 196 (19) 25 (25) 32 (24) Poor 206 (20) 18 (18) 41 (30) Very poor 102 (10) 12 (12) 8 (6) TBD 24 (2) 3 (3) 2 (1) Not tested 28 (3) 2 (2) 3 (2) Unknown 147 (N/A) 81 (N/A) 33 (N/A)

IPSS score Low 114 (13) 13 (14) 14 (12) Intermediate 1 459 (51) 45 (50) 55 (46) Intermediate 2 276 (31) 27 (30) 44 (37) High 46 (5) 5 (6) 6 (5) Unknown 270 (N/A) 91 (N/A) 49 (N/A)

IPSS-R score Very Low 93 (11) 8 (9) 14 (12) Low 229 (26) 21 (24) 23 (19) Intermediate 257 (29) 29 (33) 35 (29)

49


Variable Unrelated Related Cord Blood High 162 (19) 19 (21) 27 (23) Very High 131 (15) 12 (13) 20 (17) Unknown 293 (N/A) 92 (N/A) 49 (N/A)

Recipient age at transplant 0-9 years 14 (1) 2 (1) 19 (11) 10-19 years 38 (3) 1 (1) 23 (14) 20-29 years 52 (4) 5 (3) 9 (5) 30-39 years 55 (5) 8 (4) 15 (9) 40-49 years 133 (11) 15 (8) 19 (11) 50-59 years 308 (26) 48 (27) 31 (18) 60 + years 565 (48) 102 (56) 52 (31) Median (Range) 60 (0-77) 61 (4-77) 50 (1-73)

Recipient race Caucasian 1092 (94) 164 (91) 141 (84) African American 35 (3) 7 (4) 15 (9) Asian 21 (2) 6 (3) 10 (6) Pacific Islander 1 (<1) 1 (1) 1 (1) Native American 1 (<1) 1 (1) 0 Other 12 (1) 1 (1) 1 (1) Unknown 3 (N/A) 1 (N/A) 0 (N/A)

Recipient race/ethnicity Caucasian, non-Hispanic 1053 (92) 146 (82) 125 (75) African-American, non-Hispanic 32 (3) 7 (4) 15 (9) Asian, non-Hispanic 21 (2) 6 (3) 10 (6) Pacific islander, non-Hispanic 1 (<1) 1 (1) 1 (1) Native American, non-Hispanic 1 (<1) 1 (1) 0 Hispanic, Caucasian 39 (3) 18 (10) 16 (10) Hispanic, African-American 3 (<1) 0 0 Unknown 15 (N/A) 2 (N/A) 1 (N/A)

Recipient sex Male 703 (60) 111 (61) 98 (58) Female 462 (40) 70 (39) 70 (42)

Karnofsky performance score 10-80 348 (30) 34 (19) 37 (22) 90-100 636 (55) 66 (36) 115 (68) Missing 181 (16) 81 (45) 16 (10)

Disease at transplant AML 0 1 (1) 0 MDS 1165 (100) 180 (99) 168 (100)

Disease status at transplant

50


Variable Unrelated Related Cord Blood Early 472 (41) 48 (27) 56 (33) Advanced 624 (54) 68 (38) 104 (62) Other 69 (6) 65 (36) 8 (5)

Graft source BM 209 (18) 12 (7) 0 PBSC 947 (81) 167 (92) 0 UCB 0 0 168 (100) BM + PBSC 3 (<1) 0 0 PBSC + UCB 6 (1) 0 0 Others 0 2 (1) 0

Conditioning regimen intensity Myeloablative 597 (51) 108 (60) 84 (50) RIC 488 (42) 63 (35) 31 (18) Non-myeloablative 70 (6) 8 (4) 52 (31) Other 10 (1) 2 (1) 1 (1)

GvHD Prophylaxis Ex vivo T-cell depletion alone 13 (1) 1 (1) 0 Ex vivo T-cell depletion + post TX suppression 7 (1) 0 0 CD34 selection alone 15 (1) 1 (1) 0 CD34 selection + post TX suppression 16 (1) 0 0 Cyclophosphamide alone 6 (1) 0 0 Cyclophosphamide + other 9 (1) 4 (2) 0 Tacrolimus + MMF ± others 238 (20) 27 (15) 57 (34) Tacrolimus + MTX ± others (except MMF) 555 (48) 100 (55) 4 (2) Tacrolimus + others (except MTX, MMF) 84 (7) 24 (13) 10 (6) Tacrolimus alone 25 (2) 5 (3) 5 (3) CSA + MMF ± others (except Tacrolimus) 75 (6) 5 (3) 73 (43) CSA + MTX ± others (except Tacrolimus, MMF) 63 (5) 6 (3) 1 (1) CSA + others (except Tacrolimus, MTX, MMF) 6 (1) 0 4 (2) CSA alone 7 (1) 1 (1) 1 (1) Other GVHD prophylaxis 46 (4) 7 (3) 13 (7)

In vivo T-cell Depletion No 497 (43) 69 () 82 (49) Yes 431 (37) 21 () 59 (35) Unknown 237 (20) 91 () 27 (16)

D-R sex matchingMale/Male 522 (46) 46 (41) 42 (25) Male/Female 302 (26) 23 (20) 37 (22) Female/Male 171 (15) 23 (20) 56 (34) Female/Female 151 (13) 21 (19) 32 (19)

51


Variable Unrelated Related Cord Blood Unknown 19 (N/A) 68 (N/A) 1 (N/A)

D-R CMV matchingNegative/Negative 367 (32) 46 (25) 26 (15) Negative/Positive 380 (33) 38 (21) 41 (24) Positive/Negative 118 (10) 21 (12) 23 (14) Positive/Positive 275 (24) 71 (39) 33 (20) Unknown 25 (2) 5 (3) 45 (27)

Donor age at donation To Be Determined/NA 31 (3) 90 (50) 1 (1) 0-9 years 3 (<1) 1 (1) 158 (94) 10-19 years 40 (3) 0 9 (5) 20-29 years 518 (44) 12 (7) 0 30-39 years 302 (26) 8 (4) 0 40-49 years 205 (18) 22 (12) 0 50+ years 66 (6) 48 (27) 0 Median (Range) 30 (1-62) 54 (7-77) 3 (0-16)

Donor race Caucasian 934 (91) 72 (83) 124 (83) African American 27 (3) 5 (6) 9 (6) Asian 18 (2) 4 (5) 5 (3) Pacific Islander 2 (<1) 4 (5) 1 (1) Native American 8 (1) 1 (1) 0 Unknown 27 (3) 0 8 (5) Other 15 (1) 1 (1) 3 (2) Unknown 134 (N/A) 94 (N/A) 18 (N/A)

Donor race/ethnicity Caucasian, non-Hispanic 914 (91) 68 (78) 104 (73) African-American, non-Hispanic 26 (3) 5 (6) 9 (6) Asian, non-Hispanic 18 (2) 4 (5) 5 (4) Native American, non-Hispanic 8 (1) 0 0 Hispanic, Caucasian 22 (2) 8 (9) 21 (15) Hispanic, African-American 1 (<1) 0 0 Hispanic, Native American 0 1 (1) 0 Hispanic, race unknown 14 (1) 0 2 (1) Other 1 (<1) 1 (1) 1 (1) Unknown 161 (N/A) 94 (N/A) 26 (N/A)

Year of transplant 2004 - 2005 52 (4) 0 4 (2) 2006 - 2007 226 (19) 0 18 (11) 2008 - 2009 235 (20) 29 (16) 49 (29)

52


Variable Unrelated Related Cord Blood 2010 - 2011 236 (20) 54 (30) 49 (29) 2012 - 2013 368 (32) 94 (52) 44 (26) 2014 - 2015 48 (4) 4 (2) 4 (2)

Follow-up among survivors, months N Eval 471 88 67 Median (Range) 38 (6-119) 24 (3.3-72) 52 (12-101)

53


Proposal 1711-61

Title: The impact of somatic mutations on allogeneic transplant in chronic myelomonocytic leukemia

Matthew Mei, MD, [email protected], City of Hope Medical Center, Ryotaro Nakamura, MD, [email protected], City of Hope Medical Center, Raju Pillai, MD, [email protected], City of Hope Medical Center

Hypothesis: We hypothesize that somatic mutations have prognostic relevance with respect to allogeneic transplantation in chronic myelomonocytic leukemia (CMML).

Specific aims: • Determine the impact of molecular genetics on the outcome after allogeneic hematopoietic cell

transplantation (alloHCT) in patients with CMML.• Determine if the CMML specific prognostic system (CPSS)-Mol score correlates with outcomes after

alloHCT in patients with CMML.

Scientific impact: The relative rarity of CMML, the resulting scarcity of literature, and the extremely heterogeneous natural history of the disease, makes it extremely challenging to predict transplantation outcomes for patients with this disease. Given that the recurrent somatic mutations in CMML appear to occur in a well-defined and fairly restricted set of genes,1 establishing a clear prognostic role of a particular mutation or set of mutations, specifically with respect to alloHCT and independent of other clinical factors, could significantly impact transplant outcome prediction in patients with CMML.

Scientific justification: CMML is a clonal myeloid neoplasm associated with highly heterogeneous clinical behavior and median overall survival (OS) from diagnosis of less than 3 years.2 Nearly all patients with CMML have identifiable and well-defined recurrent somatic mutations, which have been shown to influence OS. The risk of leukemic transformation3 and information regarding these genetic mutations has been incorporated into many of the more recent risk stratification models in CMML.3-6 With systemic therapy having a limited effect at best on the natural history of disease, alloHCT remains the only potentially curative treatment for patients with this disease. However, the impact of genetic mutations has not been evaluated in CMML in the context of alloHCT.

The current data regarding alloHCT in CMML exist in the form of retrospective studies, none of which have incorporated molecular data in their analysis and only a few have used a validated CMML-specific prognostic model.7,8 A recent CIBMTR analysis showed that the CMML-specific prognostic scoring system (CPSS)9 correlated with overall survival (OS) post-alloHCT; but it was not predictive for relapse, disease-free survival (DFS) or non-relapse mortality (NRM), and its impact on OS was chiefly due to its effect on post-relapse survival.10 The impact of the MD Anderson prognostic score (MDAPS)11 on alloHCT outcomes has been evaluated in two smaller studies. In the first study, Kerbauy, et al. found a trend towards higher relapse with a higher MDAPS score but the association was not statistically significant, and no association was found between the MDAPS score and OS or RFS.8 Meanwhile, in another study, Eissa, et al. reported a positive correlation between MDAPS with relapse risk but not with NRM or OS.7 Therefore, neither the CPSS nor the MDAPS appears to be robustly predictive of alloHCT outcomes on their own.

54


Given these limitations and the increasing use of molecular assays, we propose a study to assess the outcomes of alloHCT with the specific goal of incorporating a mutational analysis. We hypothesize that the mutational profile is specifically correlated with outcomes after alloHCT. We also hypothesize that the CPSS-Mol model will be better correlated with alloHCT outcomes than the CPSS alone.

Patient eligibility population: Patients with CMML (either CMML-1 or CMML-2) aged 18 and above who underwent alloHCT from 2001 through 2015 will be included in the study. Patients with prior transformation to AML at any time prior to alloHCT will be excluded. Patients receiving cord blood transplants or haploidentical transplantation will be excluded. Only patients who have available biologic samples in the NMDP repository will be included.

Data requirements: Patient characteristics (age, gender, KPS, HCT-CI), disease-specific characteristics (prior treatment, marrow blasts, HCT-specific CPSS), HCT-related variables (conditioning regimen, GVHD prophylaxis, donor type, graft source, donor-recipient sex match, donor-recipient CMV status).

Outcome measures will include GVHD (acute GVHD grade 2-4, chronic GVHD at 1, 3, and 5 years post-HCT), NRM, relapse, DFS, and OS.

Sample requirements: Molecular analysis We propose to assay for recurrent somatic mutations using biologic samples from the NMDP repository, and Oncoheme mutation assay (oncoheme-mutations).

As DNA samples are collected immediately before conditioning, there is a potential concern that the malignant clone would be potentially reduced by pre-transplant therapy (presumably in the form of either hypomethylating agents or cytotoxic chemotherapy). However, the previous CIBMTR analysis of clinical outcomes found that over 50% of patients received neither cytotoxic therapy nor hypomethylating agents (HMA), and even with treatment,9 it is unlikely that the malignant clone would be eradicated given the poor complete response rate with HMA in CMML. The feasibility of detecting genetic mutations using the archived CIBMTR sample repository has been previously demonstrated in a large successful MDS study by Lindsey et al.12

Previous experience with this assay Oncoheme mutation assay was developed in the clinical molecular diagnostic laboratory at City of Hope in 2015. Since 2016, the assay has been CLIA certified and in continuous clinical use. One of the investigators (RP) is a molecular pathologist, who was involved in the assay development and has extensive experience in wet lab and data analysis components. As a clinical molecular pathologist, RP is involved in the routine sign-out of NGS results. The proposed assay has also been used in a recently published research project.13

Samples 500 ng of DNA will be requested for this assay.

Testing methodology for somatic mutations NGS libraries will be prepared from genomic DNA using the SureSelect target enrichment system (Agilent Technologies Inc.) after transposase-based fragmentation and adapter ligation. The adapter-ligated library will be PCR-amplified and quality control will be done for sizing and concentration. Capture of target regions will be performed using a custom SureSelect library (Agilent Technologies) for

55

https://www.cityofhope.org/clinical-molecular-diagnostic-laboratory/list-of-cmdl-tests/oncoheme-mutations


all coding exons plus 10 flanking bases of 72 genes. After hybridization of 750 ng of adapter-ligated library with biotin-labeled probes that are specific to target regions, the dual-index tag will be added during post-capture PCR amplification. The amplified captured libraries will be quality controlled using a high sensitivity DNA Bioanalyzer kit (Agilent Technologies Inc.) then pooled and sequenced using Miseq V2 Reagent Kit/300 cycles with 150bp paired-end sequencing. Alignment of sequence reads to the human genome (GRCh37/hg19), variant calling and annotation will be performed independently using two software applications – CLC Biomedical Workbench (CLC Bio, Aarhus, Denmark)) and NextGENE (Softgenetics, State Collage, PA). Annotated variants will be processed using previously published criteria.14,15 Synonymous variants, variants located >2bp outside protein-coding regions, polymorphisms >1% in population databases including: ExaC, Exome Variant Server and 1000 Genomes Project, andvariants with <30X coverage will be filtered. The remaining variants will be evaluated using tumorspecific databases (COSMIC, cBioportal), information retrieved from literature, sequence conservation,and in silico prediction algorithms including: SIFT, Polyphen-2, FATHMM, for clinical significance.

Study design: The study will be a retrospective analysis of patients who underwent alloHCT for CMML from 2001 through 2015. Descriptive analyses of patient-, disease- and donor-variables will be performed. Kaplan-Meier curves will be used for OS and DFS. Cumulative incidence curves will be used for NRM, relapse, and GVHD. Probabilities of OS, DFS, NRM, relapse, and GVHD at specified time points and 95% CIs will be estimated from these curves. Multivariate analyses for survival (OS, DFS), NRM, relapse, and GVHD will be performed using the Cox proportional hazards model and the proportional sub-distribution hazards model for competing risks adjusting for the effects of covariates whenever appropriate. The covariates to be evaluated will include patient-specific variables (age, gender, KPS, HCT-CI), disease-related variables (time from diagnosis to alloHCT, CPSS before transplantation, treatment before transplantation), and transplant-related variables (graft source, donor type, GVHD prophylaxis, donor-recipient sex match, donor-recipient CMV serostatus, year of transplantation). Both univariate and multivariate analyses will be conducted to examine the associations between single somatic mutations, composite mutations, and the CPSS-Mol, and alloHCT outcomes.

We estimated that about 400 patients had specimen available for mutation assay testing. With 400 samples available, we have 98% chance to detect at least one patient carrying a somatic mutation if the mutation rate is 1%. The minimum detectable hazard ratios will range from 1.44 to 1.76 for the association between a somatic mutation and OS when the mutation rate varies from 10% to 50% using a 2-sided 0.05 log-rank test with 90% power.

Mutation rate 0.1 0.2 0.3 0.4 0.5 HR* 1.76 1.55 1.48 1.45 1.44

* Assume that 15 years of enrollment and 2 additional years of follow-up,overall 1-year survival rate is 50%.

References: 1. Ball M, List AF, Padron E. When clinical heterogeneity exceeds genetic heterogeneity: thinking

outside the genomic box in chronic myelomonocytic leukemia. Blood. 2016;128(20):2381-2387.2. Solary E, Itzykson R. How I treat chronic myelomonocytic leukemia. Blood. 2017;130(2):126-136.3. Elena C, Galli A, Such E, et al. Integrating clinical features and genetic lesions in the risk assessment

of patients with chronic myelomonocytic leukemia. Blood. 2016;128(10):1408-1417.4. Itzykson R, Kosmider O, Renneville A, et al. Prognostic score including gene mutations in chronic

myelomonocytic leukemia. J Clin Oncol. 2013;31(19):2428-2436.

56


5. Patnaik MM, Padron E, LaBorde RR, et al. Mayo prognostic model for WHO-defined chronicmyelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia.2013;27(7):1504-1510.

6. Patnaik MM, Itzykson R, Lasho TL, et al. ASXL1 and SETBP1 mutations and their prognosticcontribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia.2014;28(11):2206-2212.

7. Eissa H, Gooley TA, Sorror ML, et al. Allogeneic Hematopoietic Cell Transplantation for ChronicMyelomonocytic Leukemia: Relapse-Free Survival Is Determined by Karyotype and Comorbidities.Biol Blood Marrow Transplant. 2011;17(6):908-915.

8. Kerbauy DMB, Chyou F, Gooley T, et al. Allogeneic Hematopoietic Cell Transplantation for ChronicMyelomonocytic Leukemia. Biol Blood Marrow Transplant. 2005;11(9):713-720.

9. Such E, Germing U, Malcovati L, et al. Development and validation of a prognostic scoring system forpatients with chronic myelomonocytic leukemia. Blood. 2013;121(15):3005-3015.

10. Liu HD, Ahn KW, Hu Z-H, et al. Allogeneic Hematopoietic Cell Transplantation for Adult ChronicMyelomonocytic Leukemia. Biol Blood Marrow Transplant. 2017;23(5):767-775.

11. Onida F, Kantarjian HM, Smith TL, et al. Prognostic factors and scoring systems in chronicmyelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002;99(3):840-849.

12. Lindsley RC, Saber W, Mar BG, et al. Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J Med. 2017;376(6):536-547.

13. Aldoss I, Pham A, Li SM, et al. Favorable impact of allogeneic stem cell transplantation in patientswith therapy-related myelodysplasia regardless of TP53 mutational status. Haematologica.2017;10.3324/haematol.2017.172544.

14. Li MM, Datto M, Duncavage EJ, et al. Standards and Guidelines for the Interpretation and Reportingof Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association forMolecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. JMol Diagn. 2017;19(1):4-23.

15. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics andthe Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.

57


Baseline characteristics for CMML patients undergoing HCT with available DNA derived from peripheral blood in the Biorepository

Variable TED only CRF Number of patients 95 239 Number of centers 45 72 Age at diagnosis, median (range), yrs 55 (25-69) 61 (28-76) Age at diagnosis

20-29 2 (2) 2 (<1) 30-39 9 (9) 11 (5) 40-49 19 (20) 27 (11) 50-59 35 (37) 75 (31) 60-69 30 (32) 106 (44) ≥ 70 0 17 (7) Missing 0 1 (<1)

Age at HCT, median (range), yrs 56 (25-70) 62 (28-77) Age at HCT

20-29 2 (2) 2 (<1) 30-39 8 (8) 9 (4) 40-49 15 (16) 26 (11) 50-59 33 (35) 66 (28) 60-69 37 (39) 112 (47) ≥ 70 0 24 (10)

Gender Male 52 (55) 163 (68) Female 43 (45) 76 (32)

Karnofsky score 90-100 61 (64) 141 (59) < 90 31 (33) 89 (37) Missing 3 (3) 9 (4)

Time from diagnosis to transplant, median (range) 9 (2-104) 9 (<1-112) Time from diagnosis to transplant

0-6 months 24 (25) 63 (26) 6-12 months 40 (42) 101 (42) ≥ 12 months 31 (33) 74 (31) Missing 0 1 (<1)

Year of transplant 2001-2002 0 18 (8) 2003-2004 0 18 (8) 2005-2006 0 20 (8) 2007-2008 4 (4) 25 (10)

58


Variable TED only CRF 2009-2010 23 (24) 23 (10) 2011-2012 25 (26) 30 (13) 2013-2014 26 (27) 64 (27) 2015 17 (18) 41 (17)

Graft source Bone marrow 11 (12) 45 (19) Peripheral blood 84 (88) 194 (81)

Donor type HLA-identical sibling 11 (12) 14 (6) Well-matched unrelated 70 (74) 176 (74) Partially-matched unrelated 13 (14) 43 (18) Mis-matched unrelated 0 5 (2) Multi-donor 1 (1) 0 Missing 0 1 (<1)

Donor age at donation, median (range), yr 32 (20-68) 31 (19-76) Donor age at donation

10-19 3 (3) 8 (3) 20-29 35 (37) 99 (41) 30-39 26 (27) 63 (26) 40-49 17 (18) 40 (17) 50-59 9 (9) 19 (8) 60-69 4 (4) 6 (3) ≥ 70 0 4 (2) Missing 1 (1) 0

Conditioning regimen intensity MAC 57 (60) 106 (44) RIC/NMA 37 (39) 113 (47) Missing 1 (1) 20 (8)

GVHD prophylaxis Ex-vivo T-cell depletion 1 (1) 3 (1) CD34 selection 1 (1) 5 (2) Post-CY ± other(s) 3 (3) 1 (<1) TAC + MMF ± other(s) (except post-CY) 14 (15) 34 (14) TAC + MTX ± other(s) (except MMF, post-CY) 56 (59) 125 (52) TAC + other(s) (except MMF, MTX, post-CY) 11 (12) 18 (8) TAC alone 2 (2) 8 (3) CSA + MMF ± other(s) (except post-CY) 2 (2) 15 (6) CSA + MTX ± other(s) (except MMF, post-CY) 4 (4) 25 (10) CSA + other(s) (except MMF, MTX, post-CY) 0 1 (<1) CSA alone 0 2 (<1)

59


Variable TED only CRF Other(s) 1 (1) 1 (<1) Missing 0 1 (<1)

60


Proposal 1711-75

Title: Outcomes of patients with myelodysplastic syndrome who relapse post allogeneic hematopoietic stem cell transplantation

Roni Tamari, MD, [email protected], Memorial Sloan Kettering Cancer Center, Boglarka Gyurkocza, MD, [email protected], Memorial Sloan Kettering Cancer Center, Brian Carl Shaffer, MD, [email protected], Memorial Sloan Kettering Cancer Center, Sergio Andres Giralt, MD, [email protected], Memorial Sloan Kettering Cancer Center

Hypothesis: Identifying patterns and characteristics of relapse post allo-HCT in patients with myelodysplastic can assist with guiding management.

Specific aim: The primary objective is to study outcomes of patients with myelodysplastic syndrome (MDS) who relapsed post allo-HCT.

Scientific impact: Identifying characteristics of patients who relapsed post allo-HCT and their responses to different treatments can guide future stratified intervention in this challenging patient population.

Scientific justification: Relapse after allo-HCT is the major cause of treatment failure, occurring in about 30-40% of patients with MDS and acute myelogenous leukemia (AML)1 and the prognosis of these patients is dismal. There is no defined standard approach to the management of post-transplant relapses and treatment options at time of relapse post-HCT vary between withdrawal of immune suppressive medications, donor lymphocyte infusion (DLI) with or without low/high dose chemotherapy2,3,4, second allo-HCT5,6, 7 or supportive care and hospice. The decision about type of intervention depends on patient’s overall performance status, presence of toxicities from initial treatment/transplant, presence of graft versus host disease and time from initial transplant to relapse among other variables. The current available data is mostly driven from patients with AML with low numbers of patients with MDS.

Recently, Schmid et al8 published the outcomes of 698 patients with MDS who relapsed post allo-HCT whose outcomes were reported to the European Society of Blood and Marrow Transplantation (EBMT). In this analysis they reported that shorter remission from transplant, advanced disease status, older age, unrelated donors and acute graft versus host disease were associated with worse outcomes. Considering that MDS is a heterogenous disease and distinct from de-novo AML and also with increasing numbers of transplants for this indication we believe that this analysis using data reported to the CIBMTR has the potential to affect clinical practice.

Patient eligibility population: • The study population will include all adult patients who underwent allo-HCT for MDS and MDS

that progressed to AML between 2000-2016.• All graft sources will be included: match related, match and mismatch unrelated, umbilical cord

blood units and haploidentical allo-grafts, peripheral blood stem cells (PBSC) and bone marrowgrafts (BM).

61


• Different Conditioning regimens will be included: Myeloablative, non-myeloablative, andreduced intensity conditioning.

• Different types of GVHD prophylaxis will be included: Ex-vivo T cell depletion, In vivo T celldepletion, Calcineurin inhibitors (CNI).

Data requirements: Patient-related:

• Age (at transplant): continuous• Gender: male vs. female• Karnofsky performance status (%) (at transplant and at time of relapse)• HCT-CI (at transplant and at time of relapse)• Presence of GVHD post-transplant and at time of relapse (acute/chronic/grade)

Disease-related: Disease pre-transplant: • Disease status at time of transplant- CR, vs CRi, vs MRD pos• Blasts > 10%, blasts 5-10%, blasts < 5%• Cytogenetic risk group• Presence of high risk molecular mutations (particularly TP53)• Treatment prior to transplant: none vs. hypomethylating agents vs. induction chemotherapyDisease at time of relapse:• Time from date of allo-HSCT to relapse (days): continuous• Relapsed with MRD vs excess blasts• Blasts>10%, blasts 5-10%, blasts <5%• Cytogenetic at time of relapse• Molecular abnormalities at time of relapse

Transplant-related: • TBI: no vs. yes• Conditioning regimen: ablative vs. non-myeloablative/RICGraft source:• Donor-recipient HLA match: HLA-identical sibling vs. matched or mismatched URD vs.

haploidentical vs cord blood units.• Source of stem cells: BM vs. PBSC vs. UCB

Treatment for post-transplant relapse: • Withdrawal of immunosuppressive medications• Chemotherapy: hypomethylating agents vs. induction chemo vs. other• DLI: with or without chemotherapy• Second allo-HCT• Supportive care

Study design: A retrospective study will be conducted utilizing CIBMTR data. All patients with MDS and MDS that progressed to AML reported to the CIBMTR from 2000-2016 who received an allogeneic HCT will be included. All graft sources will be included: match related, match and mismatch unrelated, umbilical cord blood units and haploidentical allo-grafts. Ablative, non-myeloablative, and reduced intensity conditioning will be included.

62


Overall survival (OS) will be measured from time of relapse to death from any cause. Cox regression will be used to assess the univariate associations between overall survival and pre-transplant characteristics as well as disease characteristics at the time of relapse. A multivariate model will be built using the factors that have significant univariate association.

Treatments for relapse will also be compared using Cox regression; these models will adjust for the clinical factors associated with both treatment selection and overall survival.

63


Baseline characteristics for patients who relapsed after undergoing allo-HCT for MDS between 2000 and 2016

Variable N (%) Number of patients 1400 Number of centers 156 Age, median (range) 62 (18-81) Age

18-29 48 (3) 30-39 57 (4) 40-49 144 (10) 50-59 348 (25) 60-69 660 (47) 70-79 142 (10) ≥ 80 1 (<1)

Gender Male 847 (61) Female 553 (40)

Karnofsky score 90-100 803 (57) < 90 554 (40) Missing 43 (3)

Secondary disorder No 1045 (75) Yes 301 (22) Missing 54 (4)

HCT-CI 0 239 (17) 1 119 (9) 2 145 (10) 3+ 610 (44) TBD, review needed for history of malignancies 2 (<1) NA, f2400 (pre-TED) not completed 271 (19) Missing 14 (1)

Disease status at transplant Early 412 (29) Advanced 878 (63) NOS 110 (8)

IPSS prior to transplant Low 138 (10) Intermediate-1 614 (44)

64


Variable N (%) Intermediate-2 356 (25) High 39 (3) Missing 253 (18)

IPSS karyotype category Favorable 423 (30) Intermediate 246 (18) Poor 581 (42) TBD (needs rev.) 74 (5) Not tested 23 (2) Missing 53 (4)

Treatment prior to conditioning No 256 (18) Yes 1136 (81) Missing 8 (<1)

Time from diagnosis to transplant, median (range) 7 (<1-173) Time from diagnosis to transplant

< 6 months 530 (38) 6-12 months 446 (32) ≥ 12 months 415 (30) Missing 9 (<1)

Year of transplant 2000-2001 48 (3) 2002-2003 51 (4) 2004-2005 87 (6) 2006-2007 100 (7) 2008-2009 169 (12) 2010-2011 144 (10) 2012-2013 318 (23) 2014-2015 360 (26) 2016 123 (9)

Donor age at donation, median (range), yr 40 (18-82) Donor age at donation

10-19 24 (2) 20-29 411 (29) 30-39 241 (17) 40-49 234 (17) 50-59 212 (15) 60-69 197 (14) 70-79 36 (3) ≥ 80 1 (<1)

65


Variable N (%) Missing 44 (3)

Donor/recipient CMV serostatus +/+ 412 (29) +/- 164 (12) -/+ 415 (30) -/- 378 (27) Missing 31 (2)

Donor/recipient sex match M-M 561 (40) M-F 299 (21) F-M 277 (20) F-F 243 (17) Missing 20 (1)

Graft type Bone marrow 198 (14) Peripheral blood 1200 (86) Missing 2 (<1)

Conditioning regimen intensity MAC 549 (39) RIC 628 (45) NMA 168 (12) TBD 39 (3) Missing 16 (1)

ATG/Campath ATG + CAMPATH 1 (<1) ATG alone 433 (31) CAMPATH alone 58 (4) No ATG or CAMPATH 891 (64) Missing 17 (1)

GVHD prophylaxis TAC + MMF ± other(s) (except post-CY) 267 (19) TAC + MTX ± other(s) (except MMF, post-CY) 603 (43) TAC + other(s) (except MMF, MTX, post-CY) 108 (8) TAC alone 38 (3) CSA + MMF ± other(s) (except post-CY) 161 (12) CSA + MTX ± other(s) (except MMF, post-CY) 122 (9) CSA + other(s) (except MMF, MTX, post-CY) 16 (1) CSA alone 21 (2) Other(s) 27 (2) No GVHD prophylaxis 33 (2)

66


Variable N (%) Missing 4 (<1)

DCI post-HCT No 1138 (81) Yes 213 (15) Missing 49 (4)

Subsequent HCT No 1268 (91) Yes 132 (9)

67


References:

1 Barrett AJ, Battiwalla M. Relapse after allogeneic stem cell transplantation. Expert Rev Hematol. 2010 Aug;3(4):429-41. doi: 10.1586/ehm.10.32.

2 Levine JE, Braun T, Penza SL,et al Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol. 2002 Jan 15;20(2):405-12.

3 Czibere A, Bruns I, Kröger N et al 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis. Bone Marrow Transplant. 2010 May;45(5):872-6.

4 Schroeder T, Czibere A, Platzbecker U et al Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia. 2013 Jun;27(6):1229-35.

5 Eapen M, Giralt SA, Horowitz MM et al Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant. 2004 Oct;34(8):721-7.

6 Shaw BE, Mufti GJ, Mackinnon S, et al Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant. 2008 Dec; 42(12):783-9.

7 Andreola G, Labopin M, Beelen D et al Long-term outcome and prognostic factors of second allogeneic hematopoietic stem cell transplant for acute leukemia in patients with a median follow-up of ⩾10 years. Bone Marrow Transplant. 2015 Dec; 50(12):1508-12.

8 Schmid C, de Wreede LC, van Biezen A, et al Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia after allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of European Society of Blood and Marrow Transplantation. Haematologica. 2017 Nov 3. [Epub ahead of print]

68

https://www.ncbi.nlm.nih.gov/pubmed/?term=Barrett%20AJ%5BAuthor%5D&cauthor=true&cauthor_uid=21083034

https://www.ncbi.nlm.nih.gov/pubmed/?term=Battiwalla%20M%5BAuthor%5D&cauthor=true&cauthor_uid=21083034

https://www.ncbi.nlm.nih.gov/pubmed/21083034

https://www.ncbi.nlm.nih.gov/pubmed/?term=Levine%20JE%5BAuthor%5D&cauthor=true&cauthor_uid=11786567

https://www.ncbi.nlm.nih.gov/pubmed/?term=Braun%20T%5BAuthor%5D&cauthor=true&cauthor_uid=11786567

https://www.ncbi.nlm.nih.gov/pubmed/?term=Penza%20SL%5BAuthor%5D&cauthor=true&cauthor_uid=11786567


https://www.ncbi.nlm.nih.gov/pubmed/?term=Czibere%20A%5BAuthor%5D&cauthor=true&cauthor_uid=19820729

https://www.ncbi.nlm.nih.gov/pubmed/?term=Bruns%20I%5BAuthor%5D&cauthor=true&cauthor_uid=19820729

https://www.ncbi.nlm.nih.gov/pubmed/?term=Kr%C3%B6ger%20N%5BAuthor%5D&cauthor=true&cauthor_uid=19820729

https://www.ncbi.nlm.nih.gov/pubmed/?term=schroder+azacitidine+and+donor+lymphocyte

https://www.ncbi.nlm.nih.gov/pubmed/?term=Schroeder%20T%5BAuthor%5D&cauthor=true&cauthor_uid=23314834

https://www.ncbi.nlm.nih.gov/pubmed/?term=Czibere%20A%5BAuthor%5D&cauthor=true&cauthor_uid=23314834

https://www.ncbi.nlm.nih.gov/pubmed/?term=Platzbecker%20U%5BAuthor%5D&cauthor=true&cauthor_uid=23314834

https://www.ncbi.nlm.nih.gov/pubmed/?term=schroder+azacitidine+and+donor+lymphocyte+infusion

https://www.ncbi.nlm.nih.gov/pubmed/?term=Eapen%20M%5BAuthor%5D&cauthor=true&cauthor_uid=15322568

https://www.ncbi.nlm.nih.gov/pubmed/?term=Giralt%20SA%5BAuthor%5D&cauthor=true&cauthor_uid=15322568

https://www.ncbi.nlm.nih.gov/pubmed/?term=Horowitz%20MM%5BAuthor%5D&cauthor=true&cauthor_uid=15322568


https://www.ncbi.nlm.nih.gov/pubmed/?term=Shaw%20BE%5BAuthor%5D&cauthor=true&cauthor_uid=18724393

https://www.ncbi.nlm.nih.gov/pubmed/?term=Mufti%20GJ%5BAuthor%5D&cauthor=true&cauthor_uid=18724393

https://www.ncbi.nlm.nih.gov/pubmed/?term=Mackinnon%20S%5BAuthor%5D&cauthor=true&cauthor_uid=18724393



https://www.ncbi.nlm.nih.gov/pubmed/?term=Andreola%20G%5BAuthor%5D&cauthor=true&cauthor_uid=26389832

https://www.ncbi.nlm.nih.gov/pubmed/?term=Labopin%20M%5BAuthor%5D&cauthor=true&cauthor_uid=26389832

https://www.ncbi.nlm.nih.gov/pubmed/?term=Beelen%20D%5BAuthor%5D&cauthor=true&cauthor_uid=26389832



https://www.ncbi.nlm.nih.gov/pubmed/?term=Schmid%20C%5BAuthor%5D&cauthor=true&cauthor_uid=29101205

https://www.ncbi.nlm.nih.gov/pubmed/?term=de%20Wreede%20LC%5BAuthor%5D&cauthor=true&cauthor_uid=29101205

https://www.ncbi.nlm.nih.gov/pubmed/?term=van%20Biezen%20A%5BAuthor%5D&cauthor=true&cauthor_uid=29101205

https://www.ncbi.nlm.nih.gov/pubmed/?term=Christoph+Schmid%2C+Liesbeth+C+de+Wreede%2C+Anja+van+Biezen%2C


Proposal 1711-85

Title: Allogeneic stem cell transplant outcomes for patients with atypical chronic myeloid leukemia

Benjamin Kent Nagy Tomlinson, MD, [email protected], University Hospitals Seidman Cancer Center, Case Comprehensive Cancer center, Molly Gallogly, MD, PhD, [email protected], Case Comprehensive Cancer center, Marcos de Lima, MD, [email protected], University Hospitals Seidman Cancer Center, Case Comprehensive Cancer center

Hypothesis: Allogeneic stem cell transplant results in long term disease control for patients with atypical chronic myeloid leukemia

Specific aims: Primary Objective:

• Describe overall survival for patients with atypical chronic myelogenous leukemia undergoingallogeneic stem cell transplant.

Secondary Objective: • Evaluate treatment outcomes including leukemia free survival, treatment related mortality, and

rates of graft versus host disease in recipients of allogeneic stem cell transplant for atypical chronicmyelogenous leukemia patients.

• Identify potential prognostic features for patients with atypical chronic myelogenous leukemiaundergoing allogeneic stem cell transplant.

Scientific justification: Atypical chronic myeloid leukemia (aCML) is a classification of myeloid malignancy that mimics the cytology and histology of BCR-ABL defined CML, but is a distinct disease and considered a myelodysplastic/myeloproliferative (MDS/MPN) overlap syndrome. It is separated from other MDS/MPN overlap disease such as chronic neutrophilic leukemia, chronic myelomonocytic leukemia, and a broader group of otherwise unclassifiable MDS/MPN (MDS/MPN-U).1 It is overall a rare disease, with the precise incidence being difficult to define, but appearing to represent less than 1% of the total cases of CML, including BCR-ABL positive disease.2 Our understanding of the disease has broadened in recent years with identification of recurring mutations, including SETBP1, JAK2 and possibly CSF3R.3,4 Rigorous reviews suggest that current WHO criteria clearly identify aCML as a distinct disease from MDS/MPN-U with a disparate prognosis and clinical course.5

The overall prognosis of aCML is poor. Estimates for median overall survival are usually between 1 and 2 years. A larger series of aCML and MDS/MPN-U patients from 7 large center found worse OS in aCML patients, with a median survival of 12.4 months comparted to 21.8 months in MDS/MPN-U patients. Transformation to acute myeloid leukemia (AML) was also higher in the aCML cohort.5 Small case series report median OS of 14 months to over 3 years.6-8 Unfavorable prognostic features appear to include advanced age, white blood cell count > 50,000/µL, presence of circulating blasts, and Hgb < 10g/dL.9. There is no accepted upfront standard of care for aCML; treatment options include hypomethylating agents, high intensity chemotherapy, interferon, and, more recently, tyrosine kinase inhibitors (in the presence of potentially targetable gene mutations).10

Allogeneic hematopoietic stem cell transplant (alloHSCT) is accepted as the only potentially curative therapy for aCML, and given the overall prognosis, many authors recommend early consideration of

69


alloHSCT.10 There is limited outcome data to establish the precise benefits of alloHSCT, with most publications being single institution reviews. An early report of 9 cases from Germany established that alloHSCT can result in long term survival, and further follow up of 21 cases found a 5-year OS of 80%.11,12 A series of 20 cases from MD Anderson suggested markedly different outcomes with an actuarial 2-year survival of 47%. Multivariate analyses could not be performed due to the statistical power of the samples. Conditioning regimens in both series were disparate, but the majority of patients received myeloablative conditioning.

Overall, there is little data to guide providers on regimen intensity, timing of allogeneic stem cell transplant, and role of preceding therapy. Available series suggest that myeloablative conditioning was the most common, but available numbers of patients receiving reduced intensity conditioning are too low establish. Data from CIBMTR may be sufficient to select a cohort of patients likely to have aCML and not related diseases in order to define outcomes for this specific population. We propose a descriptive study from the CIBMTR for cohort of patients likely to have aCML to help define OS, LFS, GVHD risk and identify potential prognostic factors for survival and success of alloHSCT.

Patient eligibility population: Inclusion criteria

• HSCT recipients with a primary diagnosis of aCML or BCR-ABL negative CML undergoing first allogeneic stem cell transplant from 2001-2015

Exclusion criteria • Diagnosis of MDS/MPN unclassifiable • Diagnosis of CMML • Diagnosis of chronic neutrophilic leukemia • Circulating monocytes at diagnosis > 10% • Documented PDGFR or FGFR rearrangement • No documentation of negative BCR-ABL testing

Data requirements: Patient data

• Age • Gender • Race

AML information • Date of aCML diagnosis • Baseline laboratory/Cytogenetics

o Must have documented negative testing for BCR-ABL o Must have < 10% circulating monocytes o Must have < 20% marrow blasts or circulating blasts o Must have leukocytes > 13e9/L

• Disease status at time of diagnosis – chronic vs accelerated phase • Disease status at time of Transplant • Therapy received prior to transplant (azanucleosides, cytotoxic chemotherapy, hydroxyurea,

radiation, interferon) • Splenectomy status

Allogeneic HSCT related data • Date of allogeneic HSCT • Preparative regimen and preparative regimen intensity

70


• Donor source• Stem cell source (bone marrow versus mobilized peripheral blood)• Engraftment dates (neutrophils, platelets)• GVHD prophylaxis• GVHD occurrences and grade• Date of relapse (if applicable)• Date of death or last known contact• Cause of death (treatment related vs disease related vs unrelated)

Study design: This will be a retrospective review of all patients meeting inclusion criteria. Patient and disease characteristics will be collected from the CIBMTR registry for patients receiving HSCT from 2001 through 2015. Patients will be grouped into those receiving cells from halpoidentical donors and 8/8 matched unrelated donors for comparison. Groups’ characteristics will defined with descriptive statistics. Overall survival and disease free survival will be described with Kaplan-Meier methods. Acute and chronic GVHD, treatment related mortality and aCML relapse will be calculated using cumulative incidence curves.

Potential patient, disease, and treatment related prognostic factors will be evaluated with multivariate analysis with Cox proportional hazards regression to study association between treatment groups and outcomes.

References: 1. Mughal TI, Cross NCP, Padron E, et al. An International MDS/MPN Working Group’s perspective and

recommendations on molecular pathogenesis, diagnosis and clinical characterization ofmyelodysplastic/myeloproliferative neoplasms. Haematologica. 2015;100(9):1117.

2. Giri S, Pathak R, Martin MG, Bhatt VR. Characteristics and survival of BCR/ABL negative chronic myeloidleukemia: a retrospective analysis of the Surveillance, Epidemiology and End Results database.Therapeutic Advances in Hematology. 2015;6(6):308-312.

3. Pardanani A, Lasho TL, Laborde RR, et al. CSF3R T618I is a highly prevalent and specific mutation inchronic neutrophilic leukemia. Leukemia. 2013;27(9):1870-1873.

4. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia andatypical CML. The New England journal of medicine. 2013;368(19):1781-1790.

5. Wang SA, Hasserjian RP, Fox PS, et al. Atypical chronic myeloid leukemia is clinically distinct fromunclassifiable myelodysplastic/myeloproliferative neoplasms. Blood. 2014;123(17):2645-2651.

6. Onida F, Ball G, Kantarjian HM, et al. Characteristics and outcome of patients with Philadelphiachromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer. 2002;95(8):1673-1684.

7. Hernandez JM, del Canizo MC, Cuneo A, et al. Clinical, hematological and cytogenetic characteristics ofatypical chronic myeloid leukemia. Annals of oncology : official journal of the European Society forMedical Oncology. 2000;11(4):441-444.

8. Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al. BCR rearrangement-negative chronic myelogenousleukemia revisited. Journal of clinical oncology : official journal of the American Society of ClinicalOncology. 2001;19(11):2915-2926.

9. Breccia M, Biondo F, Latagliata R, Carmosino I, Mandelli F, Alimena G. Identification of risk factors inatypical chronic myeloid leukemia. Haematologica. 2006;91(11):1566-1568.

10. Gotlib J. How I treat atypical chronic myeloid leukemia. Blood. 2017;129(7):838.11. Koldehoff M, Beelen DW, Trenschel R, et al. Outcome of hematopoietic stem cell transplantation in

patients with atypical chronic myeloid leukemia. Bone marrow transplantation. 2004;34(12):1047-1050.

71


12. Koldehoff M, Steckel NK, Hegerfeldt Y, Ditschkowski M, Beelen DW, Elmaagacli AH. Clinical course and molecular features in 21 patients with atypical chronic myeloid leukemia. International journal oflaboratory hematology. 2012;34(1):e3-5.

72


Baseline characteristics for patients undergoing allo-HCT for aCML between 2001 and 2016

Variable Ted only CRF Number of patients 139 49 Number of centers 95 39 Age at transplant, median (range), years 50 (7-70) 48 (9-71)

18-29 yrs. 11 (8) 8 (16) 30-39 yrs. 25 (18) 6 (12) 40-49 yrs. 25 (18) 10 (20) 50-59 yrs. 39 (28) 13 (27) 60-69 yrs. 28 (20) 9 (18) ≥ 70 yrs. 2 (1) 1 (2) Missing 9 (6) 2 (4)


Karnofsky score 90-100% 39 (28) 18 (37) < 90% 16 (12) 8 (16) Missing 84 (60) 23 (47)

Sub-disease aCML, Ph-/BCRABL- 42 (30) 36 (73) aCML, Ph-/BCRABL? 69 (50) 10 (20) aCML, Ph?/BCRABL- 7 (5) 2 (4) aCML, Ph?/BCRABL? 21 (15) 1 (2)

Time to HSCT from diagnosis, months 8 (2-358) 8 (2-155) 0-12 months 98 (71) 32 (65) 12-36 months 29 (21) 14 (29) ≥ 36 months 11 (8) 3 (6) Missing 1 (<1) 0

Year of transplant 2001-2002 51 (37) 9 (18) 2003-2004 21 (15) 10 (20) 2005-2006 16 (12) 13 (27) 2007-2008 6 (4) 6 (12) 2009-2010 7 (5) 1 (2) 2011-2012 13 (9) 1 (2) 2013-2014 15 (11) 2 (4) 2015-2016 10 (7) 7 (14)

Donor type HLA-identical sibling 76 (55) 17 (35) Other related 7 (5) 3 (6)

73


Variable Ted only CRF Well-matched unrelated 14 (10) 13 (27) Partially-matched unrelated 6 (4) 12 (24) Mis-matched unrelated 1 (<1) 1 (2) Unrelated (matching TBD) 35 (25) 3 (6) Graft type Bone marrow 43 (31) 16 (33) Peripheral blood 93 (67) 33 (67) Missing 3 (2) 0 Conditioning regimen intensity MAC 82 (59) 30 (61) RIC/NMA 48 (35) 15 (31) Missing 9 (6) 4 (8) ATG/campath ATG alone 24 (17) 11 (22) CAMPATH alone 11 (8) 2 (4) No ATG or CAMPATH 63 (45) 36 (73) Missing 41 (29) 0 GVHD prophylaxis Ex-vivo T-cell depletion 3 (2) 1 (2) CD34 selection 6 (4) 2 (4) Post-CY ± other(s) 3 (2) 3 (6) TAC + MMF ± other(s) (except post-CY) 9 (6) 0 TAC + MTX ± other(s) (except MMF, post-CY) 26 (19) 14 (29) TAC + other(s) (except MMF, MTX, post-CY) 0 4 (8) TAC alone 2 (1) 1 (2) CSA + MMF ± other(s) (except post-CY) 8 (6) 3 (6) CSA + MTX ± other(s) (except MMF, post-CY) 33 (24) 16 (33) CSA + other(s) (except MMF, MTX, post-CY) 3 (2) 2 (4) CSA alone 4 (3) 2 (4) Other(s) 4 (3) 0 Missing 38 (27) 1 (2)

74


Proposal 1711-111

Title: Allogeneic stem cell transplant for prolymphocytic leukemias

Lohith Gowda, [email protected], Yale University Scholl of Medicine, Connecticut, Francine Foss, [email protected], Yale University School of Medicine, Connecticut, Matt Kalaycio, [email protected], Cleveland Clinic Foundation, Cleveland Ohio, Hassan Alkhateeb, [email protected], Mayo Clinic Foundation, Rochester, Minnesota

Hypothesis: We hypothesize that hematopoietic cell transplant is an effective consolidative strategy for patients with prolymphocytic leukemia (PLL).

Objectives: This study will evaluate transplant outcomes of patients with PLL who underwent allogeneic HCT (allo-HCT). Our specific aims are:

Primary aim: • To determine the overall survival (OS) and progression free survival (PFS) in patients with PLL

after allo-HCT.Secondary aims:

• To determine the incidence and severity of acute and chronic graft-versus-host disease (GVHD)after allo-HCT

• To determine the incidence and frequency of non-relapsed mortality (NRM) and cumulativeincidence of relapse following transplant

• To determine causes of death post-transplant• To determine engraftment outcomes

Study justification: Pro lymphocytic leukemias, both, B and T cell lineage (B-PLL and T-PLL) are a rare group of lymphoid leukemias (<2%) that affect individuals in their 60’s and generally presents with either symptomatic splenomegaly or lymphocytosis (1). Skin lesions, pleural/peritoneal effusions and high LDH are a few other hallmark manifestations that frequently manifests in patients with PLL. Historically, survival for patients with T- PLL was low with a median OS of 7 months while using CHOP like regimens and about 30-50 months for B-PLL (1, 2). Monoclonal antibodies like Alemtuzumab, either alone or in combination with chemotherapy has shown enhanced overall response rates (ORR) compared to CHOP like chemotherapy(3). Apart from alemtuzumab, other T cell targeting agents like nelarabine, pentostatin and bendamustine are also increasingly used in management of T-PLL with encouraging response rates (ORR- 30%- 50%) (4, 5). Similarly, in B-PLL, B cell receptor inhibitors like Ibrutinib are making foray in to clinical practice and offer an effective alternative to conventional multiagent chemo-immunotherapy options used for several decades(6, 7). Collectively, these measures in small series appear to impart improved response rates to induction therapy. Despite this progress, disease relapse post induction remains the commonest cause of treatment failure in PLL. Hence, allogeneic stem cell transplant is used an effective consolidation strategy. However, to date no large study has evaluated the role of allo-SCT in modern era with better supportive care options. In addition, a recent study has questioned the conventional wisdom of performing allo-SCT for PLL patients achieving complete remission (CR) with induction (8, 9)). A prior study from CIBMTR showed the utility of HCT in select patients in CR, but was limited in numbers (10). Due to the rarity of this disorder and continued paucity of prospective data, a

75


revised large registry study may be our only option to identify predictors of survival in PLL patients opting to proceed for allo-HCT.

Study population: Inclusion Criteria:

• Patients with a diagnosis of PLL undergoing first allo-HCT between 1995-2016 • Myeloablative and reduced-intensity conditioning (MC or RIC) transplants • Bone marrow (BM), peripheral blood (PB) and umbilical cord (UC) graft sources

Data requirements: Data will be analyzed from the CIBMTR Report forms. Supplemental data if made available will be utilized.

Outcomes: • Neutrophil engraftment: Time to neutrophils (ANC) > 0.5 x109/L sustained for 3 consecutive

days. • Platelet engraftment: Time to achieve a platelet count >20 x 109/L independent of platelet

transfusions for 7 consecutive days. • Acute Graft-versus-host disease (aGVHD) severity: cumulative incidence of grades II-IV; time from

transplant to first grade 2-4 and 3-4 aGVHD. • Chronic Graft-versus-host disease (cGVHD) severity: Limited and extensive; time from transplant

to first limited chronic GVHD and time from transplant to first extensive cGVHD. • Non-relapse mortality (NRM): Cumulative incidence of NRM at day 100 and 1, 3, and 5 years.

Defined as death without preceding disease relapse/progression. Relapse/progression are competing events.

• Relapse/Progression: Cumulative incidence of disease relapse/progression at 1 and 3 years, with NRM as competing event.

• Progression-free survival (PFS): Survival without relapse/progression or death. Relapse or progression of disease and death are competing events. Those who survive without relapse/progression are censored at last follow-up.

• Overall survival (OS): Time to death. Death from any cause will be considered an event. Surviving patients will be censored at the time of last follow-up.

Variables to be studied: (Highlighted will be included in multi variate models): Patient-related:

• Gender: Male vs. Female • Age at HCT • Karnofsky performance score: >90 vs. <90 • Race: White vs. Black vs. Hispanic vs. others • Hematopoietic cell transplantation co-morbidity index (HCT-CI) (≥3 vs. <3) • CMV serostatus matching (+/-, +/+, -/-, -/+) between donor and recipient

Disease-related: • Disease status pre-transplant (CR1 or > CR1 or primary induction failure) • Time from diagnosis to transplant • Time to achieve first complete remission • Relapse post SCT (yes vs. no) • Time to relapse post SCT • Cytogenetics at Diagnosis and pre- SCT

76


• Causes of DeathTreatment-related:

• Conditioning intensity (myeloablative vs. reduced intensity vs. nonmyeloablative)• GVHD prophylaxis for allo-HCT• Donor Type: HLA-identical sibling vs unrelated donor vs haplo-identical• Graft Source: BM vs PB vs UCB• HLA matching Status

CRF data (if available): • Creatinine at diagnosis: <2 mg/dL vs. ≥2 mg/dL• LDH at diagnosis: Continuous• Beta-2-microglobulin at diagnosis: mcg/mL: continuous• Hemoglobin at diagnosis: g/dL, continuous• WBC at diagnosis: k/l, continuous• Pleuro-peritoneal effusion: yes vs. no

Study design: This is a retrospective study examining HCT outcomes for those with PLL. The analysis will be restricted to transplants performed from 1996 to 2016. Patient, disease and transplant-related factors will be compared between groups (those in CR vs not in CR) using the Chi-square test for categorical variables and the Wilcoxon two sample test for continuous variables. Kaplan-Meier product limit estimates will be used to calculate the probabilities of OS and PFS. The cumulative incidence of NRM, disease progression, and acute and chronic GVHD will be estimated accounting for competing risks. Cox proportional hazards regression will be used to compare the two groups (in CR vs not in CR at the time of transplant): NRM, relapse/progression, PFS, OS, neutrophil and platelet engraftment.

References: 1. Graham RL, Cooper B, Krause JR. T-cell prolymphocytic leukemia. Proceedings. 2013 Jan;26(1):19-21.

PubMed PMID: 23382603. Pubmed Central PMCID: 3523759.2. Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C, et al. Clinical and laboratory

features of 78 cases of T-prolymphocytic leukemia. Blood. 1991 Dec 15;78(12):3269-74. PubMedPMID: 1742486.

3. Hopfinger G, Busch R, Pflug N, Weit N, Westermann A, Fink AM, et al. Sequentialchemoimmunotherapy of fludarabine, mitoxantrone, and cyclophosphamide induction followed byalemtuzumab consolidation is effective in T-cell prolymphocytic leukemia. Cancer. 2013 Jun15;119(12):2258-67. PubMed PMID: 23512246.

4. Gandhi V, Tam C, O'Brien S, Jewell RC, Rodriguez CO, Jr., Lerner S, et al. Phase I trial of nelarabine inindolent leukemias. Journal of clinical oncology : official journal of the American Society of ClinicalOncology. 2008 Mar 01;26(7):1098-105. PubMed PMID: 18309944.

5. Ravandi F, Aribi A, O'Brien S, Faderl S, Jones D, Ferrajoli A, et al. Phase II study of alemtuzumab incombination with pentostatin in patients with T-cell neoplasms. Journal of clinical oncology : officialjournal of the American Society of Clinical Oncology. 2009 Nov 10;27(32):5425-30. PubMed PMID:19805674. Pubmed Central PMCID: 4881363.

6. Gordon MJ, Raess PW, Young K, Spurgeon SEF, Danilov AV. Ibrutinib is an effective treatment for B-cell prolymphocytic leukaemia. British journal of haematology. 2017 Nov;179(3):501-3. PubMedPMID: 27391978.

7. Dearden C. B- and T-cell prolymphocytic leukemia: antibody approaches. Hematology / the EducationProgram of the American Society of Hematology American Society of Hematology Education Program.2012;2012:645-51. PubMed PMID: 23233647.

77


8. Jain P, Aoki E, Keating M, Wierda WG, O'Brien S, Gonzalez GN, et al. Characteristics, outcomes, prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2017 Jul 01;28(7):1554-9. PubMed PMID: 28379307.

9. Guillaume T, Beguin Y, Tabrizi R, Nguyen S, Blaise D, Deconinck E, et al. Allogeneic hematopoietic stem cell transplantation for T-prolymphocytic leukemia: a report from the French society for stem cell transplantation (SFGM-TC). European journal of haematology. 2015 Mar;94(3):265-9. PubMed PMID: 25130897.

10. Kalaycio ME, Kukreja M, Woolfrey AE, Szer J, Cortes J, Maziarz RT, et al. Allogeneic hematopoietic cell transplant for prolymphocytic leukemia. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2010 Apr;16(4):543-7. PubMed PMID: 19961946. Pubmed Central PMCID: 2839005.

78


Baseline characteristics of patients undergoing 1st allo-HCT for PLL, TED vs CRF

Variable Ted only CRF Number of patients 288 61 Age, median (range), yrs 58 (24-76) 57 (34-80) Age, yrs 20-29 2 (<1) 0 30-39 11 (4) 2 (3) 40-49 49 (17) 11 (18) 50-59 125 (43) 23 (38) 60-69 83 (29) 22 (36) ≥ 70 18 (6) 3 (5) Gender Male 171 (59) 40 (66) Female 117 (41) 21 (34) Disease status at HCT CR 132 (46) 25 (41) Nodular PR 2 (<1) 0 PR 85 (30) 15 (25) No response/stable 17 (6) 3 (5) Progression 23 (8) 7 (11) Relapse 5 (2) 2 (3) Missing 24 (8) 9 (15) Time from diagnosis to transplant, median (range) 8 (<1-115) 8 (2-193) Time from diagnosis to transplant 0-3 months 10 (3) 3 (5) 3-6 months 76 (26) 15 (25) ≥ 6 months 201 (70) 43 (70) Missing 1 (<1) 0 Year of transplant 1997-1998 2 (<1) 0 1999-2000 3 (1) 1 (2) 2001-2002 4 (1) 2 (3) 2003-2004 21 (7) 4 (7) 2005-2006 19 (7) 3 (5) 2007-2008 13 (5) 15 (25) 2009-2010 51 (18) 14 (23) 2011-2012 66 (23) 0 2013-2014 56 (19) 8 (13) 2015-2016 53 (18) 14 (23) Graft source Bone marrow 24 (8) 10 (16)

79


Variable Ted only CRF Peripheral blood 257 (89) 41 (67) Cord blood 6 (2) 10 (16) Missing 1 (<1) 0

Donor type HLA-identical sibling 117 (41) 15 (25) Twin 0 1 (2) Other related 26 (9) 8 (13) Well-matched unrelated 76 (26) 19 (31) Partially-matched unrelated 22 (8) 5 (8) Unrelated (matching TBD) 40 (14) 3 (5) Cord blood 6 (2) 10 (16) Missing 1 (<1) 0

Conditioning regimen MAC 110 (38) 24 (39) RIC/NST 170 (59) 37 (61) Missing 8 (3) 0

80


Proposal 1711-141

Title: Allogeneic stem cell transplant outcomes in chronic myelogenous leukemia in the era of 2nd and 3rd generation TKIs for patients with recognized or unrecognized BCR ABL mutations

Levanto G Schachter, DO, MS, [email protected], Kaiser Permanente, Richard T Maziarz, MD, [email protected], Oregon Health Sciences University, Jeffrey Szer, MD, [email protected], Royal Melbourne Hospital

Hypothesis: Outcomes of patients with CML who undergo transplantation have evolved over the past 15 years to both include patients who have received second or third generation tyrosine kinase inhibitors (TKI) to salvage primary first-generation failures or alternatively, received second or third generation TKIs as primary therapy. These treatments will also induce resistance with specific mutations within BCR ABL. We hypothesize that outcomes of patients transplanted for CML with these advanced disease states may actually be lower than previous years due to the emergence of high-grade disease resistance.

Specific aims: • To determine the overall survival after allogeneic stem cell transplantation for patients with

CML with a history of treatment with second and third generation tyrosine kinase inhibitors.• To determine progression free survival, event free survival, relapse rate and non-relapse

mortality of patients with CML undergoing allogeneic stem cell transplantation with a history oftreatment with second and third generation tyrosine kinase inhibitors.

• To determine patient-, disease-, and transplantation- specific variables including BCR-ABLmutational analysis which influence the outcome of patients with CML undergoing allogeneicstem cell transplantation, treated with second and third generation tyrosine kinase inhibitorseither as primary or as salvage therapy.

Scientific impact: This study will provide an updated analysis of outcomes of CML patients who are treated with allogeneic transplant later in their disease course, compared to previous algorithms for management. In addition, through the evaluation of available pre-transplant BCR-ABL mutational analysis data and matching these abnormalities to the outcomes for allogeneic transplant in CML, we will be able to define a group of high risk mutations or mutation combinations that may predict better or worse outcomes with HSCT, similar to circumstances seen with acute myeloid leukemia and transplant.

Scientific justification: The use of Tyrosine kinase inhibitors (TKI) targeting the Bcr-Abl complex is the standard of care as upfront treatment for patients newly diagnosed with chronic myeloid leukemia. First and second generation tyrosine kinase inhibitors are approved, and have become standard therapy in the front line for CML.1 While the majority of patients respond to imatinib or second generation TKIs for many years, there are those patients who ultimately prove to have intolerance or resistance.

The majority of current algorithms have, in most situations, placed transplant as third line. The LeukemiaNet guidelines from 2013 recommend transplant if a patient fails any two TKIs, and considering transplant if a patient fails one second generation TKI.1 The other pathway towards allogeneic stem cell transplantation in CML include developing the T315I resistant mutation or progression to accelerated or blast phase of their malignancy.2 The current approach still includes early transplantation for those

81


presenting in blast phase or for patients who present in accelerated phase and do not have an optimal response to the first line TKI. This approach is consistent with many current institutional algorithms balancing drug therapy for CML and allogeneic transplantation.3

These are also the standards by which most developed countries are utilizing TKI and hematopoietic stem cell transplantation as therapies for their patients, with recognition that some developing countries have reported that transplantation remains a primary consideration balancing the risk: benefit of therapy with the cost of the TKIs.4 Concern remains though, that when transplantation is utilized as third line therapy (or even later) that patient outcomes will be compromised. Khoury et al noted in a previous CIBMTR analysis of 449 patient transplanted from 1999-2004 that overall and leukemia free survival were negatively impacted if the time from diagnosis to transplant was greater than one year.5 Thus, there could be a direct deleterious effect of waiting for multiple therapies to fail prior to transplantation. Alternatively, or more likely in addition, worse outcomes may be the natural expectation as only patients with advanced, multi-drug resistant disease are pursuing the transplant course.

Previously, several retrospective studies have been performed both at an institutional and at the registry level that have demonstrated that pre-transplantation exposure to imatinib do not negatively influence the transplant metrics. An investigation of the chronic leukemia committee of the CIBMTR for example, found no significant impact on overall survival, progression free survival and regimen related toxicity.6 Similarly, there have been small, single institutional reports that suggest that there are no adverse outcomes on transplantation from pre-transplantation exposure to second-generation tyrosine kinase inhibitors7 but no large scale, retrospective studies have yet been performed.

Those who fail TKIs are often found to have mutations in the BCR-ABL complex. These mutations primarily occur in the ABL kinase domain and impede the conformational binding needed.8 These mutations may confer only a moderate degree of resistance and be overcome by dose escalation or be associated with absolute resistance to imatinib.9 P-loop mutations are associated with a significantly worse survival than most other mutations10,11, although second generation TKIs such as dasatinib or nilotinib may be effective in some cases. E225K/V and Y253H mutations, for example, are highly resistant to imatinib, are partially resistant to nilotinib/dasatinib and have greater transformation potency. T3151 mutations are resistant to all current TKIs except for ponatinib and some consider the presence of this mutation at all as an indication for allogeneic stem cell transplant. Beyond T315I there is little consensus on which mutations are an indication for transplant and which confer worse outcome despite transplant. With the greater availability of BCR-ABL mutational testing and the frequent use of second generation TKIs since the previous analysis we will be able to further elucidate these questions.

Data requirements: For this study we utilize data collected from the CIBMTR database via the pre-transplant post-transplant essential data forms as well as from core research forms with detailed information obtained from the disease specific inserts for chronic myelogenous leukemia.

Patient eligibility population: This study will include patients with available data undergoing their first allogeneic transplant for CML from 2001 through 2015, an interval which will allow the capture of all patients who possibly could have had exposure to second-generation TKI's either in the first or second line. Related, matched unrelated, haploidentical, and cord blood allogeneic transplants will be included. We will pattern the study based on the previous CIBMTR analysis of all CML patients with imatinib pretreatment.

82


Patient related variables of interest will include age, sex, race, performance status.

Disease related variables of interest will include stage, imatinib response prior to transplant, type of imatinib failures, dasatinib vs nilotinib exposure and type of failure, bosutinib or ponatinib exposure and type of failure, duration of second generation TKI therapy, interval from last dose of TKI to transplant and if TKI therapy was utilized post-transplant. Capture of pretreatment comorbidities associated with TKI therapy would be advantageous.

Transplant related variables of interest will include donor: recipient sex match, related versus unrelated donor (with sub -analysis between well-managed, partially matched and mismatched unrelated donors), donor: recipient CMV status, conditioning regimen (conventional versus reduced intensity), total body irradiation (yes vs no), marrow vs peripheral blood vs cord blood, year of transplantation, GVHD prophylaxis, time from diagnosis to transplant.

Sample requirements: In the previous manifestation of this study, there was consideration for a short form for data acquisition regarding mutations of BCR ABL that would be spearheaded by the investigators. Information on mutation status may be available for more recent transplants. Based on available data, and independent sample request to further evaluate mutational status on transplant outcomes may be performed.

Study design: This study will be a retrospective study of transplantation after second-generation tyrosine kinase inhibitor use for CML patients who may have been treated with imatinib and then found to either be intolerant or resistance to primary TKI therapy or represent patients who had never seen first-generation TKI’s and only failed the broader spectrum agents. The primary endpoint will be overall survival from time of transplantation. The secondary endpoints will be progression free survival, event free survival, incidence of acute GVHD, incidence of chronic GVHD, and non- relapse mortality. Progression free survival will be defined as time to disease progression. Event free survival will be defined as time to disease progression or death from any cause. Non-relapse mortality will be defined as any death not due to disease progression. Patients will be stratified by disease status, donor type and age group.

The collected patient, disease, and treatment related variables will be compared using the chi-square statistic for categorical variables and the Wilcoxon 2-sample test for continuous variables. The probabilities of overall survival and leukemia free survival and progression free survival for all patients will be calculated using the Kaplan Meier estimator with the variance estimated by Greenwood's formula. Patients will be censored at date of last known follow-up. Cumulative incidence estimates will be determined for acute and chronic GVHD rates and relapse risk.

References: 1. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the

management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884. doi:10.1182/blood-2013-05-501569.

2. Champlin R, de Lima M, Kebriaei P, et al. Nonmyeloablative allogeneic stem cell transplantation forchronic myelogenous leukemia in the imatinib era. Clin Lymphoma Myeloma. 2009;9 Suppl 3:S261-S265. doi:10.3816/CLM.2009.s.021.

3. Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21stcentury. Blood. 2015;125(21):3230-3235. doi:10.1182/blood-2014-10-567784.

4. Ruiz-Argüelles GJ, Tarin-Arzaga LC, Gonzalez-Carrillo ML, et al. Therapeutic choices in patients with

83


Ph-positive CML living in Mexico in the tyrosine kinase inhibitor era: SCT or TKIs? Bone Marrow Transplant. 2008;42(1):23-28. doi:10.1038/bmt.2008.90.

5. Khoury HJ, Kukreja M, Goldman JM, et al. Prognostic factors for outcomes in allogeneictransplantation for CML in the imatinib era: a CIBMTR analysis. Bone Marrow Transplant.2011;47(6):810-816. doi:10.1038/bmt.2011.194.

6. Lee SJ, Kukreja M, Wang T, et al. Impact of prior imatinib mesylate on the outcome of hematopoieticcell transplantation for chronic myeloid leukemia. Blood. 2008;112(8):3500-3507.doi:10.1182/blood-2008-02-141689.

7. Jabbour E, Cortes J, Kantarjian H, et al. Novel tyrosine kinase inhibitor therapy before allogeneicstem cell transplantation in patients with chronic myeloid leukemia. Cancer. 2007;110(2):340-344.doi:10.1002/cncr.22778.

8. Kantarjian HM, Talpaz M, Giles F, O'Brien S, Cortes J. New Insights into the Pathophysiology ofChronic Myeloid Leukemia and Imatinib Resistance. Annals of Internal Medicine. 2006;145(12):913.doi:10.7326/0003-4819-145-12-200612190-00008.

9. Shah NP. Loss of response to imatinib: mechanisms and management. Hematology Am Soc HematolEduc Program. 2005;2005(1):183-187. doi:10.1182/asheducation-2005.1.183.

10. Branford S. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtuallyalways accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102(1):276-283. doi:10.1182/blood-2002-09-2896.

11. Nicolini FE, Corm S, Lê Q-H, et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the Frenchintergroup of CML (Fi(ϕ)-LMC GROUP). Leukemia. 2006;20(6):1061-1066.doi:10.1038/sj.leu.2404236.

84


Baseline characteristics for patients undergoing allo-HCT for CML with prior 2nd generation TKIs

Variable N (%) Number of patients 550 Number of centers 126 Age, median (range), yrs 46 (18-76)

18-29 yrs 78 (14) 30-39 yrs 115 (21) 40-49 yrs 148 (27) 50-59 yrs 161 (29) 60-69 yrs 42 (8) ≥ 70 yrs 6 (1)

Gender Male 316 (57) Female 234 (43)

Karnofsky score 90-100 277 (50) < 90 99 (18) Missing 174 (32)

Disease status prior to HCT Hematologic CR 136 (25) Chronic phase 277 (50) Accelerated phase 83 (15) Blast phase 54 (10)

Number of lines of previous therapies 1 120 (22) 2 129 (23) 3+ 292 (53) Missing 9 (2)

Choice of pre-transplant TKI therapy IM + DA + NI 149 (27) IM + DA 276 (50) IM + NI 47 (9) DA + NI 31 (6) DA 39 (7) NI 7 (1) Other 1 (<1)

Time from diagnosis to HCT, median (range), ms 25 (<1-296) 0-12 months 123 (22) 12-36 months 231 (42) ≥ 36 months 196 (36)

85


Variable N (%) Year of transplant

2004-2005 1 (<1) 2006-2007 63 (11) 2008-2009 203 (37) 2010-2011 88 (16) 2012-2013 46 (8) 2014-2015 111 (20) 2016 38 (7)

Donor type HLA-identical sibling 165 (30) Other related 63 (11) Well-matched unrelated 247 (45) Partially-matched unrelated 68 (12) Mis-matched unrelated 5 (<1) Multi-donor 2 (<1)

Graft source Bone marrow 128 (23) Peripheral blood 421 (77) Missing 1 (<1)

Conditioning regimen intensity MAC 439 (80) RIC 76 (14) NMA 27 (5) TBD 5 (<1) Missing 3 (<1)

GVHD prophylaxis Ex-vivo T-cell depletion 7 (1) CD34 selection 4 (<1) Post-CY + other(s) 41 (7) TAC + MMF ± other(s) (except post-CY) 84 (15) TAC + MTX ± other(s) (except MMF, post-CY) 248 (45) TAC + other(s) (except MMF, MTX, post-CY) 29 (5) TAC alone 13 (2) CSA + MMF ± other(s) (except post-CY) 33 (6) CSA + MTX ± other(s) (except MMF, post-CY) 76 (14) CSA + other(s) (except MMF, MTX, post-CY) 3 (<1) CSA alone 1 (<1) Other(s) 5 (<1) Missing 6 (1)

86


Proposal 1711-147

Title: Graft failure, donor lymphocyte infusion, and second transplant after allogenic hematopoietic cell transplant for myelofibrosis

Ashwin Kishatagari, MD, [email protected], Cleveland Clinic Taussig Cancer Institute, Aaron T. Gerds, MD, MS, [email protected], Cleveland Clinic Taussig Cancer Institute

Specific aims: Primary aim:

• Describe the rates and risk factors associated with graft failure after allogenic hematopoieticcell transplantation for primary myelofibrosis and post-essential thrombocythemia / polycy-themia vera myelofibrosis.

Secondary aims: • Describe the outcomes of donor lymphocyte infusion as a salvage treatment for graft failure

after allogenic hematopoietic cell transplantation for primary myelofibrosis and post-essentialthrombocythemia / polycythemia vera myelofibrosis.

• Describe outcomes of second transplant as a salvage treatment for graft failure after allogenichematopoietic cell transplantation for primary myelofibrosis and post-essential thrombo-cythemia / polycythemia vera myelofibrosis.

Scientific justification: Myelofibrosis is a myeloproliferative neoplasm with cardinal features of extramedullary hematopoie-sis, hepatosplenomegaly, cytopenias, and constitutional symptoms that result in decreased survival and leukemic transformation. It is predominantly a disease seen in older patients with a median age at diagnosis of 67 years [1]. Allogenic hematopoietic cell transplantation (Allo-HCT) remains the only cura-tive therapy for myelofibrosis. With the introduction of the reduced-intensity conditioning regimen, Allo-HCT has become feasible in older and medically unfit patients. The number of Allo-HCTs per-formed for myelofibrosis has been steadily increasing over the past years, even after the approval of the Janus Kinase (JAK) inhibitor, ruxolitinib. This increase may be attributed to improved patient selec-tion based on the new prognostic molecular markers, more frequent use of matched unrelated donors, and improved supportive care. Graft failure still remains an important contributor to morbidity and mortality in patients with myelofibrosis who undergo Allo-HCT and ranges from 2% to 24% [2]. Data on graft failure are not uniform and no definitive predictors for graft failure have yet been determined. The increasing use of reduced intensity conditioning (RIC), and wider applications of alternative donors in recent years have the potential to turn graft failure into an increasing problem. However, random-ized prospective data comparing different intensity of conditioning regimens are lacking for myelofi-brosis. A recent retrospective, small cohort study reported the cumulative incidence of graft failure within 60 days after allo-HCT was high (28%), and this was primarily associated with intensity of condi-tioning regimen [3]. In a large CIBMTR study published over a decade ago, the rate of graft failure was higher in those with matched unrelated donors than in those with matched sibling donors (20% Vs 9%) among 289 patients (median age was 47 years) who underwent Allo-HCT for primary myelofibrosis [4]. Majority of the patients in the study received myeloablative conditioning regimen. It is important to identify patients who are at risk of graft failure to limit the number of risk factors to prevent this severe complication occurring after allo-HCT.

87


The prognosis of patients with graft failure is poor [5], and there is no standard recommendation re-garding the treatment of these patients in general; use of donor lymphocyte infusions (DLIs) and a sec-ond allo-HCT have been suggested as therapeutic options to restore hematopoiesis. Robust data sup-porting either of these approaches in myelofibrosis are lacking. The use of DLI after allo-HCT has been already suggested as safe and effective immunoadaptive approach in hematological malignancies. In patients with graft failure without autologous reconstitution, the only available treatment is a second transplant. No large series of graft failure after allo-HCT for myelofibrosis and subsequent salvage treatment options has been published.

Our hypothesis is that graft source, conditioning intensity, and degree of marrow fibrosis will be asso-ciated with graft failure. We also hypothesize that DLI and second transplant are feasible options for restoring hematopoiesis in patients who experience graft failure, leading to long-term survival. By identifying the risk factors that lead to graft failure after allo-HCT for myelofibrosis, a high-risk popula-tion can be identified for intervention with the aim of improving post-transplant outcomes. Also, a de-scriptive study of patient who went on to DLI or second transplants can help inform treatment deci-sions in the case of graft failure. The rational of this study is that the results can inform the treatment decision making process for individual patients, and aid in and clinical trial design. Given the lower rates of graft failure, a large multicenter effort through the CIBMTR is needed.

Patient eligibility population: Inclusion criteria:

• Diagnosis of primary myelofibrosis and post-essential thrombocythemia / polycythemia veramyelofibrosis.

• Age ≥ 18 years at the time of transplant• Allogenic stem cell transplant occurred between 2000 and 2016• At least 1 year follow up forms completed

Data requirements: Forms required:

• Myelodysplasia / Myeloproliferative Disorders Pre-HSCT Data (Form 2014 MDS)• Pre-Transplant Essential Data (Form 2400 Pre-TED)• Myelodysplasia / Myeloproliferative Disorders Post-HSCT Data (Form 2114 MDS)• Post-Transplant Essential Data (Form 2450 Post-TED)

Patient-related: • Age at HCT• Race• Performance Status• HCT-CI (if available)• CMV status

Disease-related data: • Date of diagnosis• Subtype at diagnosis• Degree of bone marrow fibrosis at diagnosis• Cytogenetic results (if known)• DIPSS risk scores (if known)

88


• Pre-transplant therapy (if known)• Spleen size• Disease status prior to transplant

Transplant-related data: • Date of transplant• Conditioning regimen• Donor characteristics• Donor-recipient HLA matching• Cell dose• GVHD prophylaxis

Post-transplant course: • Date of relapse• Post-transplant therapy- DLI and Second transplant• Date of acute and chronic GVHD (if applicable)• Date of death of last known contact• Cause of death (if known)

Study design: Patient, disease, and transplant-related variables for patients receiving allogenic hematopoietic stem cell transplantation for primary myelofibrosis and post-essential thrombocythemia / polycythemia vera myelofibrosis will be described. Analyses will be stratified by conditioning regimen intensity and re-ported separately for full-intensity (myeloablative) and reduced-intensity transplants. Univariate prob-abilities of overall and disease-free survival will be calculated using the Kaplan-Meier estimator; the log-rank test will be used for univariate comparisons. Probabilities of graft failure, acute and chronic GVHD, non-relapse mortality and relapse will be calculated using cumulative incidence curves accom-modating competing risks. Assessment of potential risk factors for outcomes of interest will be evalu-ated in multivariate analyses using Cox proportional hazards regression. The proportional hazards as-sumption will be tested. If violated, it will be added as time-dependent covariate. Step-wise selection procedure will be used to select significant covariates.

References: 1. Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A: Population-based incidence and

survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: An olmstedcounty study, 1976-1995. Am J Hematol 1999, 61:10–15.

2. Kröger NM, Deeg JH, Olavarria E, Niederwieser D, Bacigalupo A, Barbui T, Rambaldi A, Mesa R,Tefferi A, Griesshammer M, et al.: Indication and management of allogeneic stem celltransplantation in primary myelofibrosis: a consensus process by an EBMT/ELN internationalworking group. Leukemia 2015, 29:2126–2133.

3. Slot S, Smits K, van de Donk NWCJ, Witte BI, Raymakers R, Janssen JJWM, Broers a EC, TeBoekhorst P a W, Zweegman S: Effect of conditioning regimens on graft failure in myelofibrosis: aretrospective analysis. Bone Marrow Transplant 2015, 50:1424–31.

4. Ballen KK, Shrestha S, Sobocinski KA, Zhang MJ, Bashey A, Bolwell BJ, Cervantes F, Devine SM, GaleRP, Gupta V, et al.: Outcome of Transplantation for Myelofibrosis. Biol Blood Marrow Transplant2010, 16:358–367.

5. Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn B-M, Mattsson J, Ringden O: Graft failure

89


in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant 2013, 48:537–543.

90


Baseline characteristics of patients undergoing allo-HCT for MF, 2000-2016

Variable Graft failure No graft failure Number of patients 128 746 Number of centers 73 159 Patient-related Age, median (range) 56 (22-72) 56 (19-76) Age

18-65 yrs. 113 (88) 641 (86) 66-75 yrs. 15 (12) 105 (14)


Karnofsky score 90-100 71 (55) 438 (59) < 90 56 (44) 281 (38) Missing 1 (<1) 27 (4)

HCT-CI 0 25 (20) 136 (18) 1 14 (11) 64 (9) 2 14 (11) 80 (11) 3+ 23 (18) 185 (25) NA, f2400 (pre-TED) not completed 51 (40) 272 (36) Missing 1 (<1) 9 (1)

Disease-related Disease at diagnosis

Myelofibrosis 113 (88) 626 (84) Polycythemia vesa 3 (2) 46 (6) Essential thrombocythemia 12 (9) 74 (10)

DIPSS prior to HCT Low 10 (8) 110 (15) Intermediate-1 53 (41) 320 (43) Intermediate-2 55 (43) 271 (36) High 3 (2) 12 (2) Missing 7 (5) 33 (4)

Cytogenetics Favorable (normal) 44 (34) 292 (39) Favorable (other) 17 (13) 105 (14) Unfavorable 17 (13) 118 (16) TBD 13 (10) 58 (8)

91


Variable Graft failure No graft failure Not tested 11 (9) 42 (6) Missing 26 (20) 131 (18)

JAK2 mutation No 14 (11) 84 (11) Yes 32 (25) 213 (29) No tested 5 (4) 20 (3) Not available before 2007 51 (40) 273 (37) Missing 26 (20) 156 (21)

Number of lines of pre-treatments 0 30 (23) 180 (24) 1 50 (39) 290 (39) 2 18 (14) 144 (19) 3+ 28 (22) 116 (16) Missing 2 (2) 16 (2)

Transplant-related Time from diagnosis to HCT 20 (3-350) 20 (<1-522) Time from diagnosis to HCT

0-3 months 12 (9) 115 (15) 3-6 months 28 (22) 171 (23) ≥ 6 months 88 (69) 456 (61) Missing 0 4 (<1)

Year of transplant 2000-2001 14 (11) 50 (7) 2002-2003 9 (7) 69 (9) 2004-2005 13 (10) 83 (11) 2006-2007 16 (13) 76 (10) 2008-2009 26 (20) 115 (15) 2010-2011 7 (5) 33 (4) 2012-2013 8 (6) 40 (5) 2014-2015 28 (22) 186 (25) 2016 7 (5) 94 (13)

Use of TBI No 92 (72) 607 (81) Yes 36 (28) 138 (18) Missing 0 1 (<1)

Conditioning regimen intensity MAC 54 (42) 388 (52) RIC 58 (45) 305 (41)

92


Variable Graft failure No graft failure NMA 15 (12) 44 (6) TBD 1 (<1) 7 (<1) Missing 0 2 (<1)

Donor type HLA-identical sibling 31 (24) 256 (34) Other related 5 (4) 29 (4) Well-matched unrelated 62 (48) 320 (43) Partially-matched unrelated 13 (10) 93 (12) Mis-matched unrelated 4 (3) 20 (3) Multi-donor 2 (2) 2 (<1) Unrelated (matching TBD) 3 (2) 11 (1) Cord blood 8 (6) 15 (2)

Donor-recipient CMV status +/+ 35 (27) 219 (29) +/- 11 (9) 101 (14) -/+ 30 (23) 169 (23) -/- 39 (30) 220 (29) CB - recipient + 5 (4) 10 (1) CB - recipient - 3 (2) 5 (<1) Missing 5 (4) 22 (3)

Graft source Bone marrow 22 (17) 92 (12) Peripheral blood 98 (77) 639 (86) Cord blood 8 (6) 15 (2)

GVHD prophylaxis Ex-vivo T-cell depletion 1 (<1) 6 (<1) CD34 selection 4 (3) 11 (1) Post-CY + other(s) 4 (3) 22 (3) TAC + MMF ± other(s) (except post-CY) 27 (21) 87 (12) TAC + MTX ± other(s) (except MMF, post-CY) 40 (31) 315 (42) TAC + other(s) (except MMF, MTX, post-CY) 4 (3) 34 (5) TAC alone 1 (<1) 16 (2) CSA + MMF ± other(s) (except post-CY) 16 (13) 77 (10) CSA + MTX ± other(s) (except MMF, post-CY) 23 (18) 145 (19) CSA + other(s) (except MMF, MTX, post-CY) 2 (2) 9 (1) CSA alone 3 (2) 13 (2) Other(s) 1 (<1) 10 (1) Missing 2 (2) 1 (<1)

93


Variable Graft failure No graft failure

Subsequent HCT

No 80 (63) 715 (96)

Yes 48 (38) 31 (4)

DCI

No 110 (86) 672 (90)

Yes 18 (14) 35 (5)

Missing 0 39 (5)

94

Not for publication or presentation · 2018. 2. 2. · Not for publication or presentation...

Documents

Transcript of Not for publication or presentation · 2018. 2. 2. · Not for publication or presentation...