2015 Chronic Leukemia Agenda

Not for publication or presentation

AGENDA CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA San Diego, CA Wednesday, February 11, 2015, 2:45 pm - 4:45 pm

Co-Chair: Matt Kalaycio, MD, Cleveland Clinic Telephone: 216-444-3705; Fax: 216-445-7444; Email: [email protected] 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] Statisticians: Zhen-Huan (Kenny) Hu, MPH, CIBMTR Statistical Center Telephone: 414-805-0656; Fax: 414-805-0714; Email: [email protected] Kwang Woo Ahn, PhD, CIBMTR Statistical Center Telephone: 414-456-7386; Fax: 414-456-6530; Email: [email protected] Scientific Director: Wael Saber, MD, MS, CIBMTR Statistical Center Telephone: 414-805-0677; Fax: 414-805-0714; Email: [email protected]

1. Introduction

a. Minutes and overview plan from Feb. 2014 meeting (Attachment 1) b. Introduction of incoming co-chair: Ronald Sobecks, MD; Cleveland Clinic; Cleveland, OH; E-mail:

[email protected] c. Instructions for sign-in and voting

2. Accrual Summary (Attachment 2)

3. Presentations, Published or Submitted Papers

a. CK06-03/CK07-01b Sobecks RM, Leis JF, Gale RP, Ahn KW, Zhu X, Sabloff M, de Lima M, Brown JR, Inamoto Y, Hale GA, Aljurf MD, Kamble RT, Hsu JW, Pavletic SZ, Wirk B, Seftel MD, Lewis ID, Alyea EP, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Outcomes of HLA-matched sibling donor hematopoietic cell transplantation in chronic lymphocytic leukemia: myeloablative vs. reduced-intensity conditioning regimens. Biol Blood Marrow Transplant. 2014 Sep;20(9):1390-8. Published.

b. CK12-03 Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, Maziarz RT, Antin JH, Soiffer RJ, Weisdorf DJ, Rizzo JD, Horowitz MM, Saber W. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014 Jun 5;123(23):3664-71. Published.

c. CK02-01b Copelan EA, Avalos B, Ahn KW, Zhu X, Gale RP, Grunwald MR, Hamadani M, Hamilton BK, Hale GA, Marks DI, Waller EK, Savani BN, Costa LJ, Ramanathan M, Cahn JY, Khoury HJ, Weisdorf DJ, Inamoto Y, Kamble RT, Schouten HC, Wirk B, Litzow MR, Aljurf MD, van Besien KW, Ustun C, Bolwell BJ, Bredesonc CN, Fasan O, Ghosh N, Horowitz MM, Arora M, Szer J, Loren AW, Alyea EP, Cortes J, Maziarz RT, Kalaycio MT, Saber W. Comparison of outcomes of allogeneic transplantation for chronic myeloid leukemia with cyclophosphamide in combination with intravenous busulfan, oral busulfan or total body irradiation. BBMT. In Press.

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d. CK13-01 Chaudhury S, Hijiya N, Hu ZH, Sparapani R, Kalaycio ME, Alyea EP, Popat UR, Saber W. Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Children and Young Adults with Chronic Myeloid Leukemia: A CIBMTR Cohort Analysis. 56th ASH Annual Meeting and Exposition. Poster.

e. CK13-02 Duong HK, Akhtari M, Ahn KW, Hu ZH, Popat UR, Alyea EP, Maziarz R, Kalaycio ME, Saber W. Allogeneic hematopoietic cell transplantation for adult chronic myelomonocytic leukemia. 2015 BMT Tandem Meetings. Oral.

4. Studies in Progress (Attachment 3)

a. CK11-02 Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome after allogeneic hematopoietic cell transplantation. (B Shaffer)

Manuscript Prep

b. CK13-01 Outcomes of allogeneic hematopoietic cell transplantation in children and young adults with chronic myeloid leukemia: a CIBMTR cohort analysis. (S Chaudhury, N Hijiya)

Manuscript Prep

c. CK13-02 Allogeneic hematopoietic cell transplantation for adult chronic myelomonocytic leukemia. (H Duong, M Akhtari)

Manuscript Prep

d. CK13-03 Hematopoietic stem cell transplantation vs. chemotherapy for low and intermediate IPSS risks MDS. (W Saber)

Data File Prep

e. CK10-02 The impact of treatment with second-generation tyrosine kinase inhibitors on the outcomes of hematopoietic cell transplantation for patients with chronic myeloid leukemia. (R Maziarz, J Szer)

Protocol Develop

f. 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)

Protocol Develop

g. CK12-02b A retrospective assessment of outcomes of patients who have undergone allogeneic hematopoietic cell transplant for chronic lymphocytic leukemia based on histocompatibility leukocyte antigen type. (B Hill)

Protocol Develop

h. CK14-01 Outcomes of umbilical cord transplantation for myelodysplastic syndrome. (M Kalaycio, A Gerds)

Protocol Develop

i. 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)

Protocol Develop

5. Future/Proposed Studies

a. PROP 1411-12 Comparison of transplant vs. non-transplant therapies for myelofibrosis. (Ballen KK, Mesa RA, Gowin KL) (Attachment 4)

b. PROP 1411-54 Optimum donor lymphocyte infusion strategy for CML in post-TKI era. (Battiwalla M) (Attachment 5)

c. PROP 1412-10 Comparison of outcomes after myeloablative vs. reduced intensity conditioning for allogeneic hematopoietic stem cell transplant for chronic myeloid leukemia. (Chhabra S, Jain S, Stuart RK) (Attachment 6)

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d. PROP 1412-19 Outcome of allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia with antecedent history of Philadelphia-negative myeloproliferative neoplasm. (Gupta V) (Attachment 7)

6. Presentations

a. CK11-02 Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome after allogeneic hematopoietic cell transplantation. (B Shaffer)

b. CK14-01 Outcomes of umbilical cord transplantation for myelodysplastic syndrome. (A Gerds)

c. National MDS Study

7. Other Business

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Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA Grapevine, TX Wednesday, February 26, 2014, 2:45 pm - 4:45 pm

Co-Chair: Edwin Alyea, MD, Dana Farber Cancer Institute

Telephone: 617-632-3903; Email: [email protected]

Co-Chair: Matt Kalaycio, MD, Cleveland Clinic Foundation

Telephone: 216-444-3705; Fax: 216-445-7444; Email: [email protected]

Co-Chair: Richard Maziarz, MD, Oregon Health and Science University


Statisticians: Zhen-Huan (Kenny) Hu, MPH, CIBMTR Statistical Center


Kwang Ahn, PhD, CIBMTR Statistical Center


Rodney Sparapani, PhD, CIBMTR Statistical Center

Telephone: 414-955-8786; Email: [email protected]

Scientific Director: Wael Saber, MD, MS, CIBMTR Statistical Center


a. Introduction

The CIBMTR Chronic Leukemia Working Committee (CKWC) met on Wednesday, Feb 26, 2014 at 2:45 pm. The chairs, scientific directors and statisticians were presented. Attendees were asked to have their name badges scanned for attendance purposes and to maintain the committee membership roster.

Dr. Richard Maziarz welcomed and introduced the newly appointed CKWC chair, Dr. Uday Popat, from MD Anderson Cancer Center. Richard also introduced the CIBMTR guidelines for voting on proposals, based on a scale from 1 to 9; 1 = high scientific impact, 9 = low scientific impact. Minutes from the 2013 Tandem in Salt Lake City were approved by the committee.

b. Accrual Summary

The accrual tables were referenced for review but not formally presented. The full accrual summary was available as part of the working committee attachments. Attendees showed interest in the number of CML patients who underwent an autologous transplant.

c. Presentations, Published or Submitted Papers

Due to the full agenda, the 2013 presentations and published papers were mentioned but not presented. 4 papers were published; one submitted to BBMT. These include:

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1. CK02-01a Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson CN, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following Cyclophosphamide in combination with Busulfan compared to TBI. Blood. 2013 Dec 5;122(24):3863-70. doi: 10.1182/blood-2013-07-514448. Epub 2013 Sep 24. Published.

2. CK09-01 Gupta V, Malone AK, Hari PN, Ahn KW, Hu ZH, Gale RP, Ballen KK, Hamadani M, Olavarria E, Gerds AT, Waller EK, Costa LJ, Antin JH, Kamble RT, van Besien KM, Savani BN, Schouten HC, Szer J, Cahn JY, de Lima MJ, Wirk B, Aljurf MD, Popat U, Bejanyan N, Litzow MR, Norkin M, Lewis ID, Hale GA, Woolfrey AE, Miller AM, Ustun C, Jagasia MH, Lill M, Maziarz RT, Cortes J, Kalaycio ME, Saber W. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant;20(1):89-97. Published.

3. CK12-04 Saber W, Cutler CS, Nakamura R, Zhang MJ, Atallah E, Rizzo JD, Maziarz RT, Cortes J, Kalaycio ME, Horowitz MM. Impact of donor source on hematopoietic cell transplantation outcomes for patients with MDS. Blood;122(11):1974-82. Published.

4. CK06-03/07-01a Sabloff M. Impact of radiation-based versus chemotherapy-based myeloablative conditioning in hematopoietic progenitor cell transplantation of CLL: a report from the Center for International Blood & Marrow Transplant Research. Published.

5. CK06-03/07-01b Sobecks R. Outcomes of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia: impact of myeloablative versus reduced-intensity conditioning regimens. Submitted to BBMT.

d. Studies in Progress

Due to the full agenda, only the selected 2 studies in progress were presented. A summary of the progress of the ongoing studies was provided as an attachment to the committee members. These include:

1. CK02-01b Comparison of results using Busulfan/Cyclophosphamide compared to total body irradiation/Cyclophosphamide as preparation for allogeneic transplantation in chronic myeloid leukemia (Copelan E)

The statisticians are addressing additional comments from the journal.

2. CK06-04 Decision analysis of allogeneic HCT for myelofibrosis: comparison of allogeneic HCT and non-transplantation therapies for myelofibrosis. (Ballen K)

The study is currently at the stage of data file preparation. The committee is still waiting for the data from Mayo Clinic.

3. CK11-02 Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome after allogeneic HCT. (Shaffer B)

The PI and statistician are finalizing the protocol. We plan to present it at the stats meeting.

4. 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.(Lee H, Cortes J, Champlin R, de Lima M)

New data from MD Anderson Cancer Center have been received. The study is in protocol development stage. New analysis plan has been drafted after discussion with the PI.

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5. CK12-02b A retrospective assessment of outcomes of patients who have undergone allogeneic hematopoietic cell transplant for chronic lymphocytic leukemia based on histocompatibility leukocyte antigen type. (Hill B)

The study is currently under protocol development.

6. CK12-03 A disease risk index for patients undergoing allogeneic hematopoietic cell transplantation. (Armand P)

The manuscript was submitted to journal “Blood.”

7. CK13-01 Long-term outcome of allogeneic hematopoietic cell transplantation in children with chronic myeloid leukemia in chronic phase. (Chaudhury S)

The study is in the stage of data file preparation. CRC is helping check the outcome data.

8. CK13-02 Allogeneic hematopoietic cell transplantation for adult chronic myelomonocytic leukemia. (Duong H)

The study is in the stage of data file preparation. CRC is contacting centers for additional data verification.

e. Future/Proposed Studies

Dr. Matt Kalaycio led this section.

1. Proposal 1303-01 Therapy prior to stem cell transplant in patients with int-2 and high risk myelodysplastic syndrome and effect on post-transplant outcome. Proposal 1311-15 Impact of pre-transplantation therapy on outcomes of hematopoietic cell transplantation for myelodysplastic syndrome (Farhan S, Janakiraman N, Peres E, Wirk B)

Dr. Shatha Farhan presented the proposal. The purpose of the study is to examine the role of hypo-methylating agent (HMA) and chemo induction (IC) pre-HCT with respect to the risk of post-HCT relapse, and to determine how many cycles of HMA is most effective. The number of retrospective studies investigating this issue is currently very limited. Eligible patients for the study would be MDS with blasts < 20% in bone marrow or peripheral blood at diagnosis, age >= 18 and year of transplant >= 2000. The outcomes would be relapse, overall survival, GVHD and engraftment. In the baseline table, Dr. Farhan showed that there were 335 patients receiving HMA alone, 91 IC alone, 31 HMA & IC and 434 with neither of the 2 therapies. The main concerns raised were: 1) accuracy of data collected in the registry regarding HMA cycles and duration; and 2) not having the correct denominator (we don’t know how many received these therapies and never went on to HCT)

2. Proposal 1309-03 The role of DCI in the treatment of CLL after allogeneic stem cell transplantation: analysis of the CIBMTR. Proposal 1311-86 Evaluation of DCI for relapsed CLL after allogeneic hematopoietic cell transplantation. (Kenderian SS, Nishihori T, Hamadani M, Kharfan-Dabaja MA)

Dr. Saad Kenderian presented the proposal. The role of DLI after transplant is not well known. The published retrospective studies have only small number of patients. So the primary objective of the study is to describe outcomes among CLL patients receiving DLI or 2nd HSCT. The secondary objective is to investigate the incidence and severity of GVHD following DCI. Patients >= 18 years old, receiving DCI after 1st HCT for CLL will be included in the study. Patients receiving DLI followed by 2nd HCT will also be included in the study population as a separate group. Patients with secondary hematological malignancy, or who received DCI for treatment of infections, or PTLD (other than relapse) will be excluded. Although the number of patients available is limited, it is still larger than any of the populations ever published.

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3. Proposal 1310-08 Outcomes after umbilical cord transplantation for myelodysplastic syndrome. (Gerds AT, Kalaycio M)

Dr. Aaron T. Gerds presented the proposal. Currently there is lack of published data for UCBT specifically for MDS. The primary objective is to describe the current use of UCBT for MDS. The secondary objective is to describe patient and disease characteristics for patients with MDS who underwent an UCBT, and to describe transplant outcomes of patients with MDS who underwent an UCBT. As a cohort analysis, the study population will be stratified by conditioning regimen intensity. Patient, disease and transplant-related variables will be included in the analysis. Dr. Gerds showed that currently we have 53 eligible patients with MA and 108 with RIC.

4. Proposal 1311-28 Validation of DFCI prognostic score for previously treated chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HSCT. (Brown J, Kim HT)

Dr. Jennifer R. Brown presented the proposal. The primary objective of the study is to use the CIBMTR data to assess the prognostic value of cytogenetics and other known factors after allogeneic HCT in patients with CLL, and to validate and refine the score system previously developed by the DFCI. The previous study was published in 2013 in Leukemia. In the previous DFCI study, cytogenetics were not significantly associated with outcome but the data were incomplete and the cohort was small. The score system was built upon disease status at HCT, lymphocyte count, LDH, BM involvement and comorbidity score. Dr. Brown then showed how the actual risk score is calculated based on the listed factors, and the outcomes of groups with different scores. The proposed study will be analyzed in a larger cohort to refine the prognostic model. The available patient population for those with CLL who underwent transplant between 2000 and 2012 includes 638 patients from 134 centers (27% MA, 45% RIC, and 21% NMA), which is about 3 times of the size of the prior data set. Regarding data capture, there are 45% missing in lymphocyte count prior to transplant but it should be easy to verify that with the centers.

5. Proposal 1311-87 Evaluation of donor lymphocyte infusion after allogeneic hematopoietic cell transplantation for myelofibrosis. (Nishihori T, Kharfan-Dabaja MA)

Dr. Taiga Nishihori presented the proposal. Available publications regarding the role of DLI for myelofibrosis patients are fairly limited, and prior reports are insufficient to inform therapeutic decisions on indication and timing of DLI or appropriate cell dose for patients with myelofibrosis. The primary objective is to examine the efficacy of DLI for myelofibrosis and the incidence and severity of GVHD following DLI. Patients with myelofibrosis, age >= 18 that underwent a HCT from a sibling or unrelated donors, between 2000 and 2012, will be included. Cord blood will be excluded. Dr. Taiga then showed that there are 28 eligible patients in the CIBMTR database. Although the number is limited, it is still the largest cohort in comparison to previous publications.

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

1. Proposal 1309-06 Outcomes of hematopoietic transplantation for T-cell prolymphocytic lymphocytic leukemia (T-PLL): A comparative CIBMTR analysis. (Kamble RT, Hari P):

It overlaps with one of the studies that has been published in 2010: Kalaycio ME, Kukreja M, Woolfrey AE, Szer J, Cortes J, Maziarz RT, Bolwell BJ, Buser A, Copelan E, Gale RP, Gupta V, Maharaj D, Marks DI, Pavletic SZ, Horowitz MM, Arora M. Allogeneic hematopoietic cell transplant for prolymphocytic leukemia. Biol Blood Marrow Transplant;16(4):543-7

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2. Proposal 1311-10 Timing of allogeneic stem cell transplantation in patients with chronic lymphocytic leukemia: an analysis of the CIBMTR database. (Murthy GSG, Mahta P, Hari P) The study was dropped because of lack of a proper control group, and there are only 37 patients in the CRF dataset that meet the inclusion criteria.

3. Proposal 1311-49 Allogeneic transplantation for chronic myelomonocytic leukemia. (El-Jawahri A, Chen YB) It overlaps with CK13-02 “Allogeneic hematopoietic stem cell transplant for adult chronic myelomonocytic leukemia”

4. Proposal 1311-54 Outcomes after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis in the JAK inhibitors area. (Tamari R, Rampal R, Castro-Malaspina H) The study was dropped due to insufficient number of cases receiving JAK inhibitor in the CIBMTR database. Among the 367 eligible patients with myelofibrosis, only 3 cases received JAK inhibitor.

f. Presentations of Ongoing Studies

Dr. Richard Maziarz led this section.

1. CK11-02 Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome after allogeneic HCT. (Shaffer B)

This study was not presented at the meeting.

2. 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. (Lee H, Cortes J, Champlin R, de Lima M)

Dr. Wael Saber presented the study. MD Anderson Cancer Center (MDACC) had provided the number of their patients last year, so the study was brought to the committee to evaluate its study design. The primary objective of the study is to examine the optimal timing of allogeneic transplantation in patients that progress through TKI therapy, and the ideal window of opportunity to transplant patients while still in CP. Markov decision model will be constructed to estimate life expectancy of the cohort of CML patients in CP at initial diagnosis based on different transplantation strategies. Dr. Saber then showed the number of patients from MDACC that underwent different TKI use strategies and the baseline demographics for each group. Dr. Saber then asked the committee whether stratifying the cohort by TKI use is the most useful way to answer the question. Attendees commented that the study overall is important to the field but could be limited if information regarding the dose and duration of the actual drug is not known.

3. CK13-01 Long-term outcome of allogeneic hematopoietic cell transplantation in children with chronic myeloid leukemia in chronic phase. (Chaudhury S)

Dr. Sonali Chaudhury presented this study. The primary objective of the study is to investigate the outcomes of pediatric patients with CML who underwent an allogeneic transplant. The study population was divided into 3 cohorts: year of HCT before 2001, year of HCT after 2001 with TKI usage and year of HCT after 2001 without TKI usage. Young adults aged 18-25 were also included to compare with pediatric patients aged < 18 years. As for the inclusion criteria, Dr. Chaudhury wanted to include the 53 RIC/NMA patients who had been excluded from the study population. Dr. Chaudhury then showed the baseline demographic table for pediatric CML patients. Notably, the numbers of patients receiving transplant after 2001 using TKI and not using TKI are equally distributed. The follow-up for the entire cohort is quite good. Based on the results of univariate analyses, both pediatric patients and young adults using TKI have a better OS than those not using TKI respectively. Dr. Chaudhury also mentioned that the study patients could be compared with patients using only TKI but receiving no transplant.

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g. Other Business

The meeting was adjourned at 4:05 pm.

The committee chairs, scientific director and statisticians had a post-WC meeting at 4:15 pm. 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:

1. Proposal 1310-08 Outcomes after umbilical cord transplantation for myelodysplastic syndrome. (Gerds AT, Kalaycio M)

2. Proposal 1311-28 Validation of DFCI prognostic score for previously treated chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HSCT. (Brown J, Kim HT)

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Working Committee Overview Plan for 2014-2015

1. CK02-01b Comparison of results using Busulfan/Cyclophosphamide compared to total body irradiation/Cyclophosphamide as preparation for allogeneic transplantation in CML. We are currently addressing additional comments from the journal. We plan to publish the study by June 2014.

2. CK06-03/CK07-01b Outcomes of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia: impact of myeloablative versus reduced-intensity conditioning regimens. We plan to publish the study by June 2014.

3. CK06-04 Decision analysis of allogeneic HCT for myelofibrosis: comparison of allogeneic HCT and non-transplantation therapies for myelofibrosis. We are still waiting for the data from Mayo Clinic. No statistician hour has currently been allocated to the study.

4. CK10-02 Impact of 2nd generation TKIs on HCT outcomes for CML. The study is currently being deferred, but Dr. Richard Maziarz is working with Novartis on the funding of the study. No statistician hour has currently been allocated to the study in the coming year.

5. CK11-02 Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome after allogeneic HCT. We plan to submit the study by June 2014.

6. 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. We plan to finalize the protocol and finish analysis by June 2014.

7. CK12-02b A retrospective assessment of outcomes of patients who have undergone allogeneic stem cell transplant for Chronic Lymphocytic Leukemia based on histocompatibility leukocyte antigen type. We plan to start protocol development in March 2014 and finalize the protocol by June 2014.

8. CK12-03 A disease risk index for patients undergoing allogeneic stem cell transplantation. We plan to publish the study by June 2014.

9. CK13-01 Long-term outcome of allogeneic hematopoietic stem cell transplantation in children with chronic myeloid leukemia in chronic phase. We anticipate finalizing the protocol and finishing data file preparation by June 2014.

10. CK13-02 Allogeneic hematopoietic stem cell transplant for adult chronic myelomonocytic leukemia. We anticipate finalizing the protocol by June 2014.

11. SC11-06 PART I of an assessment of allogeneic hematopoietic stem cell transplantation in Medicare beneficiaries with myelodysplastic syndrome and related disorders. We plan to finish the analysis and start preparing manuscript by June 2014.

12. CK14-01 (PROP1310-08) Outcomes of umbilical cord transplantation for myelodysplastic syndrome. The draft protocol is expected to be received by June 2014. We anticipate finalizing the protocol by June 2015.

13. CK14-02 (PROP1311-29) Validation of DFCI prognostic score for previously treated chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HSCT. We plan to start protocol development after June 2014. We anticipate finalizing the protocol by June 2015.

14. CK14-03 HCT vs. chemo for low and intermediate IPSS risk MDS. The protocol is under development. We anticipate finalizing protocol development by June 2014.

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Oversight Assignment for Working Committee Leadership (March 2014)

Edwin Alyea CK13-01: Long-term outcome of allogeneic HCT in children with CML in CP.

CK11-02: Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome after allogeneic HCT.

CK14-02 (PROP1311-29): Validation of DFCI prognostic score for previously treated chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allogeneic HSCT.

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

CK13-02: Allogeneic hematopoietic stem cell transplant for adult CMML.

CK14-01 (PROP1310-08): Outcomes of umbilical cord transplantation for MDS.

Uday Popat CK12-01: A decision analysis of the optimal timing of allogeneic HCT in CML in the era of TKI.

Wael Saber CK06-03/07-01b: Outcomes of allogeneic hematopoietic cell transplantation in CLL: impact of myeloablative versus reduced-intensity conditioning regimens.

CK02-01b: Comparison of results using Busulfan/Cyclophosphamide compared to TBI/Cyclophosphamide as preparation for allogeneic transplantation in CML and AML.

SC11-06: The outcome of Hematopoietic Cell Transplantation (HCT) for Medicare Beneficiaries >65 years with Myelodysplastic Syndrome.

CK12-03: Validation and refining the disease risk index.

CK14-03: HCT vs. chemo for low and intermediate IPSS risk MDS.

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Accrual Summary for the Chronic Leukemia Working Committee

Characteristics of recipients undergoing autologous transplant for MDS reported to the CIBMTR between 1995 and 20141

Variable Registration only Research

Number of patients 89 53

Number of centers 57 36

Age, median (range) 52 (4-70) 48 (9-68)

Age, years

< 10 1 (1) 1 (2)

10-19 4 (4) 2 (4)

20-29 7 (8) 2 (4)

30-39 10 (11) 10 (19)

40-49 16 (18) 13 (25)

50-59 36 (40) 19 (36)

≥ 60 15 (17) 6 (11)

Sex

Male 47 (53) 27 (51)

Female 42 (47) 26 (49)

Graft source

Bone marrow 8 (9) 3 (6)

Peripheral blood 47 (53) 17 (32)

Missing 34 (38) 33 (62)

Sub-disease

MDS, NOS 25 (28) 11 (21)

RA 10 (11) 14 (26)

RAEB 41 (46) 21 (40)

CMML 6 (7) 2 (4)

RARS 1 (1) 1 (2)

Others 6 (7) 4 (8)

Year of transplant

1995-1996 13 (15) 6 (11)

1997-1998 14 (16) 10 (19)

1999-2000 24 (27) 9 (17)

2001-2002 11 (12) 12 (23)

2003-2004 20 (22) 10 (19)

2005-2006 4 (4) 4 (8)

2007-2008 0 2 (4)

2009-2010 3 (3) 0

1 There is no autologous transplant for MDS reported to the CIBMTR after 2010.

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Characteristics of recipients undergoing allogeneic transplant for MDS reported to the CIBMTR between 1995 and 2014




Age, median (range) 50 (<1-81) 53 (<1-79)

Age, years

< 10 330 (6) 323 (7)

10-19 404 (7) 318 (7)

20-29 410 (7) 303 (6)

30-39 682 (12) 429 (9)

40-49 1186 (20) 783 (16)

50-59 1761 (30) 1326 (27)

≥ 60 1124 (19) 1397 (29)

Missing 6 (<1) 0

Sex

Male 3490 (59) 2951 (60)

Female 2408 (41) 1926 (39)

Not answered 5 (<1) 1 (<1)

Missing 0 1 (<1)

Graft source

Bone marrow 1685 (29) 1462 (30)


Cord blood 200 (3) 393 (8)

Missing 136 (2) 3 (<1)

Donor type

HLA-identical sibling 3162 (54) 1413 (29)

Twin 32 (<1) 19 (<1)

Other relative 418 (7) 202 (4)

Unrelated donor 2190 (37) 3218 (66)

Other / missing 101 (2) 27 (<1)

Sub-disease

MDS, NOS 1358 (23) 646 (13)

RA 986 (17) 881 (18)

RAEB 2209 (37) 1982 (41)

CMML 508 (9) 434 (9)

RARS 181 (3) 188 (4)

RCMD 382 (6) 347 (7)

RCMD / RS 41 (<1) 54 (1)

5q-syndrome 22 (<1) 30 (<1)

Others 216 (4) 317 (6)

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Year of transplant

1995-1996 367 (6) 230 (5)

1997-1998 459 (8) 267 (5)

1999-2000 518 (9) 336 (7)

2001-2002 530 (9) 431 (9)

2003-2004 624 (11) 495 (10)

2005-2006 593 (10) 620 (13)

2007-2008 480 (8) 638 (13)

2009-2010 894 (15) 610 (13)

2011-2012 1118 (19) 778 (16)

2013-20142 320 (5) 474 (10)

2 New cases continue to be reported in this interval.

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Characteristics of recipients undergoing allogeneic HCT for myelofibrosis reported to the CIBMTR between 1995 and 2014




Age, median (range) 54 (<1-75) 53 (<1-79)

Age, years

< 10 13 (1) 6 (<1)

10-19 16 (1) 10 (1)

20-29 24 (2) 18 (2)

30-39 90 (8) 51 (7)

40-49 267 (23) 179 (24)

50-59 437 (37) 308 (42)

>= 60 330 (28) 159 (22)

Sex

Male 720 (61) 422 (58)

Female 457 (39) 309 (42)

Graft type

Bone marrow 185 (16) 182 (25)


Cord blood 12 (1) 20 (3)

Missing 12 (1) 0

Donor type


Twin 4 (<1) 8 (1)



Other / missing 8 (<1) 3 (<1)

Sub-disease

Polycythemia vera 150 (13) 79 (11)

Essential or primary thrombocythemia 187 (16) 93 (13)

Myelofibrosis with myeloid metaplasia 363 (31) 339 (46)

Chronic idiopathic myelofibrosis 477 (41) 220 (30)

Year of transplant

1995-1996 28 (2) 23 (3)

1997-1998 49 (4) 34 (5)

1999-2000 52 (4) 55 (8)

2001-2002 90 (8) 71 (10)

2003-2004 117 (10) 81 (11)

2005-2006 115 (10) 117 (16)

2007-2008 86 (7) 147 (20)

15


2009-2010 221 (19) 137 (19)

2011-2012 318 (27) 36 (5)

2013-20143 101 (9) 30 (4)


16


Characteristics of recipients undergoing autologous transplant for CML reported to the CIBMTR between 1995 and 2014




Age, median (range) 48 (3-70) 47 (17-65)

Age, years

< 10 3 (<1) 0

10-19 9 (3) 2 (2)

20-29 37 (10) 12 (9)

30-39 56 (16) 23 (18)

40-49 89 (25) 42 (33)

50-59 120 (33) 40 (31)

≥ 60 42 (12) 9 (7)

Missing 3 (<1) 0

Sex

Male 203 (57) 91 (71)

Female 156 (43) 37 (29)

Graft source

Bone marrow 70 (19) 33 (26)


Cord blood 1 (<1) 0

Missing 47 (13) 11 (9)

Year of transplant

1995-1996 84 (23) 51 (40)

1997-1998 108 (30) 42 (33)

1999-2000 118 (33) 25 (20)

2001-2002 35 (10) 4 (3)

2003-2004 9 (3) 5 (4)

2005-2006 4 (1) 1 (<1)

2011-2012 1 (<1) 0

17


Characteristics of recipients undergoing allogeneic transplant for CML reported to the CIBMTR between 1995 and 2014




Age, median (range) 38 (<1-72) 38 (1-77)

Age, years

< 10 225 (2) 148 (2)

10-19 810 (7) 625 (9)

20-29 1941 (18) 1140 (17)

30-39 3141 (29) 1808 (27)

40-49 3109 (28) 1787 (27)

50-59 1453 (13) 965 (15)

≥ 60 266 (2) 149 (2)

Missing 14 (<1) 1 (<1)

Sex

Male 6528 (60) 3910 (59)

Female 4390 (40) 2713 (41)

Unknown 1 (<1) 0

Not answered 40 (<1) 0

Graft source

Bone marrow 6181 (56) 4133 (62)


Cord blood 200 (2) 219 (3)

Missing 365 (3) 6 (<1)

Donor type


Twin 74 (<1) 26 (<1)



Other / missing 279 (3) 36 (<1)

Year of transplant

1995-1996 2009 (18) 1204 (18)

1997-1998 2481 (23) 1297 (20)

1999-2000 2375 (22) 1303 (20)

2001-2002 1408 (13) 749 (11)

2003-2004 876 (8) 778 (12)

2005-2006 504 (5) 595 (9)

2007-2008 247 (2) 292 (4)

2009-2010 320 (3) 299 (5)

2011-2012 553 (5) 64 (<1)

18


2013-20144 186 (2) 42 (<1)


19


Characteristics of recipients undergoing autologous transplant for CLL reported to the CIBMTR between 1995 and 2014




Age, median (range) 53 (19-76) 51 (33-73)

Age, years

10-19 1 (<1) 0

20-29 6 (1) 0

30-39 24 (5) 15 (12)

40-49 143 (32) 43 (34)

50-59 201 (44) 45 (36)

≥ 60 77 (17) 22 (18)

Sex

Male 335 (74) 93 (74)

Female 117 (26) 32 (26)

Graft source

Bone marrow 115 (25) 16 (13)


Missing 27 (6) 5 (4)

Sub-disease

CLL, NOS 109 (24) 46 (37)

CLL, B-cell 343 (75) 79 (63)

CLL, T-cell 5 (1) 1 (<1)

Year of transplant

1995-1996 51 (11) 18 (14)

1997-1998 80 (18) 55 (44)

1999-2000 158 (35) 23 (18)

2001-2002 69 (15) 8 (6)

2003-2004 44 (10) 5 (4)

2005-2006 21 (5) 9 (7)

2007-2008 5 (1) 4 (3)

2009-2010 10 (2) 2 (2)

2011-2012 11 (2) 0

2013-20145 3 (<1) 1 (<1)


20


Characteristics of recipients undergoing allogeneic transplant for CLL reported to the CIBMTR between 1995 and 2014




Age, median (range) 55 (4-80) 54 (2-75)

Age, years

< 10 5 (<1) 1 (<1)

10-19 2 (<1) 3 (<1)

20-29 27 (1) 12 (<1)

30-39 130 (5) 89 (6)

40-49 588 (23) 375 (25)

50-59 1133 (44) 644 (43)

≥ 60 681 (27) 363 (24)

Sex

Male 1865 (73) 1097 (74)

Female 699 (27) 390 (26)

Not answered 2 (<1) 0

Graft source

Bone marrow 343 (13) 323 (22)


Cord blood 44 (2) 85 (6)

Missing 38 (1) 3 (<1)

Donor type


Twin 9 (<1) 14 (<1)



Other / missing 37 (1) 9 (<1)

Sub-disease

CLL, NOS 852 (33) 742 (50)

CLL, B-cell 1714 (66) 745 (50)

CLL, T-cell 16 (<1) 5 (<1)

Year of transplant

1995-1996 81 (3) 87 (6)

1997-1998 103 (4) 77 (5)

1999-2000 188 (7) 123 (8)

2001-2002 254 (10) 146 (10)

2003-2004 245 (10) 220 (15)

2005-2006 281 (11) 258 (17)

2007-2008 253 (10) 291 (20)

21


2009-2010 483 (19) 124 (8)

2011-2012 573 (22) 66 (4)

2013-20146 105 (4) 95 (6)


22


TO: Chronic Leukemia Working Committee Members FROM: Wael Saber, MD, MS; Scientific Director for the Chronic Leukemia Working Committee RE: 2014-2015 Studies in Progress Summary

CK10-02: The impact of treatment with second-generation tyrosine kinase inhibitors (TKI) on the outcomes of hematopoietic cell transplantation for patients with chronic myeloid leukemia (CML) (Maziarz R, Szer J) The aims are: 1) to determine the overall survival after allogeneic stem cell transplantation for patients with CML with a history of treatment with second-generation TKIs; 2) 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 of treatment with second-generation TKIs; 3) to determine patient-, disease-, and transplantation- specific variables which influence the outcome of patients with CML undergoing allogeneic stem cell transplantation, treated with second generation TKIs either as primary or as salvage therapy. Protocol development is underway. CK11-02: Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HCT) (Shaffer B) The aims are: 1) to identify patient, disease, and transplant specific factors that positively associate with relapse after allo-HCT and to develop a prognostic scoring system from these factors; 2) to assess the association of the variables identified within this scoring system with overall survival after relapse. Manuscript preparation is underway.

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 (Lee H/Cortes J/de Lima M) The objectives of the study are: 1) to construct Markov decision model to simulate clinical course of a hypothetical patient in chronic phase CML at initial diagnosis using data from preexisting MD Anderson Cancer Center (MDACC) and the CIBMTR databases; 2) to use Markov decision analysis to estimate life expectancy for patients with CP CML at initial diagnosis based on the timing of various allogeneic stem cell transplantation strategies. Protocol development is underway.

CK12-02b: A retrospective assessment of outcomes of patients who have undergone allogeneic hematopoietic cell transplant for chronic lymphocytic leukemia (CLL) based on histocompatibility leukocyte antigen type (Hill B) The aim of the study is to compare progression free survival and overall survival of patients with CLL who have undergone allo-HCT based on patient HLA allele type. Based on previous reports, the hypothesis is that certain HLA combinations (HLA-A1+, HLA-A2- and HLA-B44-) confer superior progression free survival after allo-HCT. Protocol development is underway.

CK13-01: Outcomes of allogeneic hematopoietic cell transplantation in children and young adults with chronic myeloid leukemia: a CIBMTR cohort analysis (Chaudhury S/Hijiya N) The objectives of the study are: 1) to study the outcomes of children with CML who received a myeloablative allo-HCT; 2) to compare the survival of children (age < 18 yrs.) with CML who received a transplant to young adults (age

23


18-29 yrs.); 3) to evaluate the role of TKIs given prior to allo-HCT among pediatric patients. Manuscript preparation is underway.

CK13-02: Allogeneic hematopoietic cell transplantation for adult chronic myelomonocytic leukemia (CMML) (Duong H) The objective of the study is to determine the prognostic impact of patient-, disease-, and HCT-related variables on outcomes of adult CMML patients undergoing HCT between 2001 and 2012. Manuscript preparation is underway.

CK13-03: Hematopoietic stem cell transplantation vs. chemotherapy for low and intermediate IPSS risks myelodysplastic syndrome (Saber W) Data file preparation is underway.

CK14-01: Outcomes of umbilical cord transplantation for myelodysplastic syndrome (Kim H/Brown J) The primary aim of the study is to describe the current use of umbilical cord blood transplantation for MDS. The secondary aims of the study are: 1) to describe patient and disease characteristics of patients with MDS who underwent umbilical cord blood transplantations and reported to the CIBMTR; 2) to describe transplant outcomes of such patients. Protocol development is underway.

CK14-02: Validation of DFCI prognostic score for previously treated chronic lymphocytic leukemia patients who underwent reduced intensity conditioning allo-HCT (Kim H/Brown J) The primary aim 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. Protocol development is underway.

24


Study Proposal 1411-12

Study Title: Comparison of Transplant vs non Transplant Therapies for Myelofibrosis

Karen K. Ballen, MD, Massachusetts General Hospital, MA, [email protected] Ruben A. Mesa, MD, Mayo Clinic, Arizona, [email protected] Krisstina L. Gowin, DO, Mayo Clinic, Arizona, [email protected]

Hypothesis: Survival advantage conferred by allogeneic hematopoietic cell transplantation (HCT) compared to non-transplant based interventions in patients with myelofibrosis (primary myelofibrosis or post ET/PV myelofibrosis) is dependent on disease stage as defined by the dynamic international prognostic scoring system (DIPSS).

More specifically: 1) We hypothesize that survival post HCT is superior to non-transplant based interventions in patients with intermediate-2 and high risk disease. 2) We hypothesize that among myelofibrosis patients with low risk and intermediate-1 disease that survival with non-transplant based interventions is superior to that achieved with HCT.

Specific Aims: Project #1 (cohort study) 1. To compare survival after HCT versus non-transplantation therapies for myelofibrosis. 2. To determine patient-, disease-, and treatment-related prognostic factors that are associated with

superior survival.

Project #2 (decision analysis) 1. To define the optimal therapeutic strategy that leads to maximum quality adjusted life years (QALY),

using decision analysis. More specifically, determine the optimal role and timing of transplantation for myelofibrosis patients. Four strategies will be evaluated: (1) transplant at diagnosis; (2) transplant at progression to a higher DIPSS risk group; (3) transplant at a fixed time interval after diagnosis; and (4) only contemporary medical therapy and no transplantation

Scientific Justification: Allogeneic hematopoietic stem cell transplantation (HCT) is a curative, but risky, therapy for myelofibrosis. The appropriate timing and patient selection for HCT is unknown. The Dynamic International Prognostic Scoring System (DIPSS) utilizes age older than 65 years, hemoglobin level lower than 10g/dl, white blood cell count > 25 x109/L, peripheral blood blasts >1%, and constitutional symptoms to assess patients at any time during the course of their disease. (1) The DIPSS has been further modified to the DIPSS plus which also incorporates the need for red blood cell transfusions, platelet count < 100 × 109/L, and unfavorable karyotype. (2) Low risk disease is defined as the presence of no adverse factors, and has a median survival of 15 years. Intermediate-1 risk is the presence of 1 risk factor and has a median survival of 7 years. Patients with intermediate-2 disease have 2 or 3 risk factors and a median survival of 2.9 years. Finally, high-risk patients have 4 or more adverse factors with a median survival of only 1.3 years. In 2006, a consensus group published International Working Group criteria for treatment response in patients with myelofibrosis. (3) The European LeukemiaNet recently updated management recommendations, including allogeneic HCT for patients not expected to have survival greater than 5 years. (4)

25


Most strategies for treatment of myelofibrosis are supportive, including blood transfusions, hydroxyurea, thalidomide, lenalidomide and androgens. (5) The Jak2 kinase inhibitor, ruxolitinib, has been shown to improve constitutional symptoms and is associated with a small survival advantage for long term use. (6, 7)

Allogeneic HCT is the only known treatment modality with curative potential. Reported three year probabilities of survival have ranged from 38% to 56 %. The CIMBTR analyzed the outcome in 289 patients undergoing allogeneic HCT for myelofibrosis. (8) Overall survival at five years was 37% for HLA identical sibling donor transplants, 40% for transplants from an alternative related donor, and 30% for patients receiving unrelated donor grafts. Younger patients with a good performance status and no circulating blasts did better. However, this study did not address how to select appropriate patients or how to decide the appropriate timing for transplant. Lussana and colleagues reported a 55% three year survival for patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis. (9)Reduced intensity or non-myeloablative conditioning regimens may be best suited to the older population of patients with myelofibrosis. Kroger and colleagues treated 103 patients with primary myelofibrosis or myelofibrosis post polycythemia vera or essential thrombocythemia.(10) Patients received a busulfan and fludarabine based conditioning regimen. Ninety-eight percent of patients engrafted, and acute GVHD Grades II-IV occurred in 27% of patients. The 5 year event-free survival was 51% and as expected, younger patients and those with a matched donor did better. Gupta and colleagues for the CIBMTR studied outcomes of 233 patients receiving a reduced intensity regimen; 5 year survival was 47%. (11) Transplant has not been compared to non transplant therapies in these studies.

The CIBMTR has analyzed outcomes for transplantation and non-transplant therapies in another disease group, myelodysplastic syndromes. (12) In that study, a Markov decision analysis was used to determine the optimal timing of HCT. Delayed transplantation maximized survival in low risk patients, but reduced the number of life years in patients with more advanced disease. The study proposed here seeks to establish similar guidelines for patients with myelofibrosis, which could provide guidance to transplant physicians, non-transplant hematologists, payer groups, and health care policy advocates.

The CIBMTR has reviewed its own data on over 700 patients who received allogeneic HCT for myelofibrosis. The data has been “cleaned” and is ready to be compared to non transplant patients. This study was accepted by the Working Committee and the CIBMTR data prepared, with the plan to collaborate with Mayo Clinic-Minnesota on the non transplant data base. Unfortunately, this collaboration did not come to fruition. Therefore, we have established new collaborators through the help of Dr. Ruben Mesa and the Myeloproliferative Neoplasm Consortium. Several emails and conference calls have been held and we estimate 1558 eligible non transplant patients would be available for analysis. The investigators have reviewed the data fields and indicated they would be able to provide data in 2015, if the project is reaccepted. The breakdown of patients and collaborators is as follows:

Duke (Arcasoy)- 248 Mass General Hospital (Ballen and Hobbs)-80 Mayo Arizona (Gowin and Mesa)-252 MD Anderson (Verstovsek)-918 Vanderbilt (Mohay)-60

The transplant patients will be matched for age, risk group, and year of diagnosis with non-transplant patients under the age of 70 years from the databases of the collaborating centers. Consecutive patients treated or transplanted between the years 2000 to 2012 are included in this study. Now that new collaborations have been formed, we hope the Working Committee will be able to reapprove this study.

26


The study seeks to answer the important clinical questions of Who should be transplanted for myelofibrosis? and When should a patient be transplanted for myelofibrosis?

Patient Eligibility Population: The study population includes all patients with myelofibrosis (either primary or post polycythemia vera or essential thrombocythemia) reported to the CIBMTR from 2000-2012 who received an allogeneic HCT. Patients receiving HCT from a sibling, other related or unrelated donors after an ablative, non-myeloablative, or reduced intensity conditioning will be included. Patients who received umbilical cord blood, syngeneic transplants or patients who have transformed to acute myelogenous leukemia will be excluded. This represents the database already analyzed for other CIBMTR myelofibrosis studies, but with the addition of patients transplanted in through 2012. These transplant patients will be matched for age, risk group, and year of diagnosis with non-transplant patients under the age of 70 years from the databases of the collaborating centers above.

Data Requirements: No supplemental data is required from the CIBMTR.

Variables to be analyzed: Patient-related:

Age (at transplant/at referral to collaborating center): continuous

Gender: male vs. female

Race: Caucasian vs. African-American vs. Asian vs. Hispanic vs. Native American vs. others

Karnofsky Performance status (%) (at transplant/at referral to collaborating center) Disease-related:

Time from date of diagnosis to intervention (HCT/Referral to collaborating center), days: continuous

Disease: primary vs. post- polycythemia vera vs. post-essential thrombocythemia

DIPSS risk group at intervention (HCT/referral to collaborating center): (low vs. intermediate-1 vs. intermediate-2 vs. high

DIPSS plus risk group at intervention (HCT/Referral to collaborating center): low vs. intermediate-1 vs. intermediate-2 vs. high

Circulating blasts percentage at intervention (HCT/referral to collaborating center): continuous

Hb at intervention (HCT/at referral to collaborating center), g/dL: continuous

WBC at intervention (at HCT/at referral to collaborating center), × 109/L: continuous

Platelet count at intervention (at HCT/at referral to collaborating center), × 109/L: continuous

Ongoing need for RBC transfusion (at HCT/ referral to collaborating center): no vs. yes

Constitutional symptoms(at HCT/ referral to collaborating center): no vs. yes

LDH (at HCT/ referral to collaborating center), international units/L: continuous

Cytogenetics—unfavorable (complex [≥3], +8, -7, -5, i(17)q, 12p-, inv(3), 11q23 abnl) vs. all others-include cytogenetic report

JAK 2 mutation: no vs. yes vs not tested

Calreticulin mutation: no vs yes vs not tested

Spleen status: normal vs. splenomegaly vs. splenectomy

Number of lines of therapies between diagnosis and intervention (HCT/referral to collaborating center): continuous

Treatment-related: Transplant

27


Donor-recipient HLA match: HLA-identical sibling vs. other related vs. matched URD vs. partially match URD vs. mismatched URD

Source of stem cells: BM vs. PBSC vs. cord

Conditioning Regimen: ablative vs. non-myeloablative/RIC

TBI: no vs. yes

Year of HCT Non transplant therapies

Hydroxyurea: no vs. yes

Androgens: no vs. yes

Corticosteroids (e.g. prednisone): no vs. yes

Danazol: no vs. yes

Thalidomide: no vs. yes

Lenalidomide: no vs. yes

Erythropoietin: no vs. yes

Darbepoetin alpha: no vs. yes

Supportive care only: no vs. yes

Splenic irradiation: no vs. yes

Irradiation other sites: no vs. yes

Ruxolitinib: no vs. yes

Other medical therapies: no vs. yes

Name of medical therapy

Transplant therapy: no vs. yes

Time from referral to collaborating center to HCT, days: continuous

Post-intervention (HCT/referral to collaborating center) outcomes:

AML transformation: no vs. yes

Time form HCT/referral to AML transformation, days: continuous

Cause of death

Sample Requirements: No biologic samples are required.

Study Design: Two studies are being planned: The first project is a cohort study comparing outcomes after HCT to non-HCT therapies; the second project will be a decision analysis comparing QALY after four treatment strategies - HCT at diagnosis versus HCT at progression to a higher DIPSS risk group versus HCT at a fixed time interval after diagnosis versus a no HCT strategy. For the first project, since the CIBMTR database only includes patients who have undergone HCT, it captures only patients who survived long enough to undergo HCT, creating a data registry population that is left truncated. Thus, a left-truncated version of the Cox proportional hazards model with patient and disease-related covariates will be used. The stepwise selection procedure will be used to select significant covariates. Interaction between the main effect and significant covariates will be checked. If the proportional hazard assumption is violated, time-dependent variables will be considered. A subgroup analysis for each treatment group will be performed via a regular Cox proportional hazards model to examine treatment-related variables. For the second project, an analysis similar to that by Cutler et al, which studied treatment strategies for patients with MDS, will be performed. A Markov decision model will be constructed. Dr. Cutler has agreed to assist with this analysis.

28


References: 1. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in

primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703-1708.

1. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol.2011; 29: 392-97.

2. Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006;108(5):1497-1503.

3. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet J Clinical Oncology 2011; 29 (6): 761-770.

4. Marchetti M, Barosi G, Balestri F, et al. Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II trial. J Clin Oncol. 2004;22(3):424-431.

5. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis. New England Journal of Medicine. 2010;363(12):1117-1127.

6. Cervantes F: How I treat myelofibrosis. Blood 2014; 124 (17): 2635-42. 7. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of Transplantation for Myelofibrosis. Biology

blood marrow transplant 2010;16(3):358-367. 8. Lussana F, Rambaldi A, Finazzi MC, et al: Allogeneic hematopoietic stem cell transplantation in

patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia. Hematologica 2014; 99 (5): 916-21.

9. Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2009;114(26):5264-5270.

10. Gupta V, Malone AK, Hari PN, et al: Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the CIBMTR. Biol Blood Marrow Transplant 2014; 20: 89-97.

11. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104(2):579-585.

29


Characteristics of patients undergoing allo-HCT for myelofibrosis, 2000-2012

Variable CIBMTR

Number of patients 530

Number of centers 134

Patient-related

Age, median (range) 54 (1-79)

Age

≤ 65 491 (93)

> 65 39 (7)

Gender

Male 319 (60)

Female 211 (40)

Race

Caucasian 481 (91)

African-American 19 (4)

Asian 16 (3)

Pacific islander 2 (<1)

Other 4 (<1)

Unknown 8 (2)

Karnofsky score

90-100% 322 (61)

< 90% 185 (35)

Missing 23 (4)

Disease-related

Time from diagnosis to HCT 17 (1-357)

Time from diagnosis to HCT

0-3 months 78 (15)

3-6 months 134 (25)

≥ 6 months 315 (59)

Missing 3 (<1)

Disease at diagnosis

Primary myelofibrosis 441 (83)

Post polycythemia vesa 33 (6)

Post essential thrombocythemia 56 (11)

DIPSS prior to HCT

Low 79 (15)

Intermediate-1 236 (45)

Intermediate-2 182 (34)

High 4 (<1)

Missing 29 (5)

Blast in peripheral blood prior to HCT, % 0 (0-36)

30


Variable CIBMTR

Blast in peripheral blood prior to HCT

≤ 1% 291 (55)

> 1% 158 (30)

Missing 81 (15)

Hemoglobin prior to HCT, g/L 90 (6-9090)

Hemoglobin prior to HCT

< 100 g/L 353 (67)

≥ 100 g/L 172 (32)

Missing 5 (<1)

WBC prior to HCT, 109/L 6 (<1-431)

WBC prior to HCT

≤ 25 × 109/L 458 (86)

> 25 × 109/L 70 (13)

Missing 2 (<1)

Platelet count prior to HCT, 109/L 122 (<1-5830)

Platelet count prior to HCT

≥ 100 × 109/L 303 (57)

50-100 × 109/L 81 (15)

< 50 × 109/L 143 (27)

Missing 3 (<1)

Hemoglobin transfusion prior to HCT

No 313 (59)

Yes 170 (32)

Missing 47 (9)

System symptoms prior to HCT

No 400 (75)

Yes 91 (17)

Missing 39 (7)

Cytogenetics

Favorable (normal) 173 (33)

Favorable (other) 85 (16)

Unfavorable 79 (15)

TBD 14 (3)

Not tested 57 (11)

Missing 122 (23)

JAK2 mutation

No 83 (16)

Yes 68 (13)

No tested 20 (4)

Not available before 2007 336 (63)

31


Variable CIBMTR

Missing 23 (4)

Spleen status

Normal 113 (21)

Splenomegaly 388 (73)

Unknown 29 (5)

Treatment-related: transplant

Type of donor

HLA-identical sibling 202 (38)

Other relatives 11 (2)

Well-matched unrelated 196 (37)

Partially-matched unrelated 72 (14)

Mis-matched unrelated 22 (4)

Unrelated (matching indeterminable) 27 (5)

Donor-recipient CMV status

+/+ 168 (32)

+/- 67 (13)

-/+ 116 (22)

-/- 162 (31)

Missing 17 (3)

Donor-recipient sex match

M-M 208 (39)

M-F 120 (23)

F-M 111 (21)

F-F 91 (17)

Graft source

Bone marrow 100 (19)

Peripheral blood 430 (81)

Conditioning regimen intensity

Myeloablative 277 (52)

RIC 193 (36)

NMA 39 (7)

TBD 13 (2)

Missing 8 (2)

Use of TBI

No 390 (74)

Yes 132 (25)

Missing 8 (2)

Year of transplant

2000-2001 63 (12)

2002-2003 83 (16)

32


Variable CIBMTR

2004-2005 101 (19)

2006-2007 95 (18)

2008-2009 140 (26)

2010-2011 41 (8)

2012 7 (1)

ATG/Campath

ATG alone 195 (37)

CAMPATH alone 16 (3)

No ATG or CAMPATH 304 (57)

Missing 15 (3)

GVHD prophylaxis

Ex-vivo T-cell depletion 6 (1)

CD34 selection 14 (3)

Cyclophosphamide 1 (<1)

FK506 + MMF ± other(s) 53 (10)

FK506 + MTX ± other(s) 181 (34)

FK506 + other(s) 15 (3)

FK506 alone 8 (2)

CSA + MMF ± other(s) 68 (13)

CSA + MTX ± other(s) 147 (28)

CSA + other(s) 12 (2)

CSA alone 16 (3)

Other(s) 6 (1)

Missing 3 (<1)

Treatment-related: non-transplant

Prior therapy

No 154 (29)

Yes 365 (69)

Missing 11 (2)

Number of lines of prior therapies

0 154 (29)

1 159 (30)

2 93 (18)

3 54 (10)

4+ 42 (8)

Missing 28 (5)

Hydroxyurea (Droxia, Hydrea)

No 394 (74)

Yes 125 (24)

Missing 11 (2)

33


Variable CIBMTR

Androgens

No 510 (96)

Yes 9 (2)

Missing 11 (2)

Anagrelide

No 486 (92)

Yes 33 (6)

Missing 11 (2)

Corticosteroids

No 465 (88)

Yes 54 (10)

Missing 11 (2)

Danazol

No 515 (97)

Yes 4 (<1)

Missing 11 (2)

Thalidomide (Thalomid)

No 471 (89)

Yes 48 (9)

Missing 11 (2)

Lenalidomide (Revlimid)

No 496 (94)

Yes 23 (4)

Missing 11 (2)

Erythropoietin

No 476 (90)

Yes 43 (8)

Missing 11 (2)

Darbepoetin alpha

No 508 (96)

Yes 11 (2)

Missing 11 (2)

Ruxolitinib

No 517 (98)

Yes 2 (<1)

Missing 11 (2)

Splenic radiation

No 514 (97)

Yes 5 (<1)

Missing 11 (2)

34


Variable CIBMTR

Splenectomy

No 501 (95)

Yes 18 (3)

Missing 11 (2)

Median follow-up of survivors (range), months 63 (<1-146)

Selection exclusion table

The below selection criteria was applied # excluded N

1st allo-HCT for myelofibrosis 785

Year of HCT: 2000-2012 228 557

Donor type: matched sibling, other relative and URD (excluding twin = 6) 6 551

Graft source: BM and PBSC (excluding cord blood = 15) 15 536

EXCLUSION:

Missing 100-d follow-up form 6 530

Completeness index of follow-up

Time (N = 530) %

Set date: 12/31/13 74

1-year 97

2-year 94

3-year 92

5-year 86

35



Study Title: Optimum Donor Lymphocyte Infusion Strategy for CML in the post-TKI era

Minoo Battiwalla, MD, MS, NHLBI, NIH, [email protected]

Hypothesis: DLIs remain effective in CML patients who are Tyrosine Kinase Inhibitor (TKI) resistant, but the optimal strategy for disease control and preventing GVHD needs to be re-defined.

Specific Aims: 1. Determine the frequency of molecular, cytogenetic and hematologic relapse in the post-TKI era 2. After administration of DLI, describe overall survival (OS), relapse-free survival (RFS), and failure +

GVHD-free survival (FGFS, “pure GVL”) with relation to the type of relapse (Molec+Cytogen Vs Hematologic)

3. Describe the dose of DLI and usage of TKI/IFN, with respect to GVHD-free survival to determine the optimal dose-escalation strategy for each relapse situation

Scientific Justification: While the introductions of TKIs have changed the initial management of CML, allotransplant remains an option for select patients. In 2003, the number of HCTs reported was 223; 44% were performed in CP1 and 77% of patients received Imatinib prior to transplantation. The introduction of Imatinib therapy has had a profound impact on the use of allogeneic transplantation for CML, with a marked decrease in the number of transplants for CML and an accompanying decrease in the proportion done in CP1. (Giralt, et al.) The impact of allogeneic transplant in the post-TKI era has been described in registry studies. (Khoury, et al.) However, the impact of DLIs on CML relapse in the current era is not well understood. (Chalandon, et al)

Patient Eligibility Population: All subjects receiving allogeneic transplantation for CML starting in the year 2004 and beyond. [This is a somewhat arbitrary cutoff to define widespread adoption of Imatinib as frontline therapy]. May confine to NA and EU to reflect slow adoption of TKIs based on geography and relative cost. Consider limiting to CML-CP1 at transplant, but numbers will suffer.

Supplemental Data Requirements: NONE

Sample Requirements: NONE

Study Design: Consider stratification by Hematologic relapse versus Molecular/Cytogenetic relapse. Aim 1: Descriptive statistics of molecular, cytogenetic and hematologic relapse. Aim 2: After administration of DLI, describe OS, RFS, and FGFS with relation to the type of relapse (Molec+Cytogen vs. Hematologic). Multivariable analyses for the factors influencing RFS and FGFS. Aim 3: Describe the dose of DLI and usage of TKI/IFN, with respect to GVHD-free survival to determine the optimal dose-escalation strategy for each relapse situation. Multivariable analyses for the factors influencing RFS and FGFS and forcing variables for initial DLI dose and use of TKI or IFN into the model.

36


References: 1. Khoury, et al. Prognostic factors for outcomes in allogeneic transplantation for CML in the imatinib

era: a CIBMTR analysis. BMT 2012. 2. Giralt, et al. Impact of imatinib therapy on the use of allogeneic haematopoietic progenitor cell

transplantation for the treatment of chronic myeloid leukaemia. BJH 2007 3. Chalandon, el al. Outcome of patients developing GVHD after DLI to treat CML relapse: a study by

the Chronic Leukemia Working Party of the EBMT. BMT. 2010.

37


Baseline characteristics of patients undergoing first allogeneic transplant for CML with post-transplant

treatment of DLI or TKI in North America and Europe between 2004 and 2012

Variable DLI ± TKI TKI only



Age at transplant

Median (range) 37 (4-66) 43 (2-77)

0-10 4 (3) 12 (5)

11-20 22 (18) 21 (9)

20-30 22 (18) 30 (13)

30-40 19 (15) 31 (14)

40-50 22 (18) 64 (28)

> 50 35 (28) 71 (31)

Gender

Male 71 (57) 137 (60)

Female 53 (43) 92 (40)

Karnofsky score, %

≥ 90 87 (70) 163 (71)

< 90 27 (22) 52 (23)

Missing 10 (8) 14 (6)

Donor type


Twin 1 (<1) 1 (<1)

Other relative 2 (2) 1 (<1)

Unrelated 60 (48) 143 (62)

Not Applicable 4 (3) 17 (7)

Graft type

Bone marrow 38 (31) 56 (24)


Umbilical cord blood 0 38 (16)

DCI related

First DCI indication

Treatment for relapse 61 (49) --

Planned as part of initial HCT protocol 4 (3) --

Stable, mixed chimerism 7 (6) --

Loss of/decreasing donor T-cell chimerism 4 (3) --

Treatment for GVHD 2 (2) --

Other 17 (13) --

Not answered/Inconsistent 29 (23) --

Relapse before first DCI

Yes 84 (68) --

38


Variable DLI ± TKI TKI only

No 40 (32) --

Time from transplant to DLI

< 2 months 14 (11) --

2-4 months 21 (17) --

4-6 months 19 (15) --

> 6 months 70 (56) --

Disease related

TKI treatment post-transplant

No TKI 59 (48) 0

Planned only 14 (11) 96 (42)

Treatment for relapse (include planned TKI) 51 (41) 133 (58)

Disease status CP1 at transplant 48 (39) 64 (28)

Year of transplant

2004 22 (18) 24 (10)

2005 29 (23) 17 (7)

2006 19 (15) 29 (13)

2007 6 (5) 31 (14)

2008 19 (15) 27 (12)

2009 14 (11) 45 (20)

2010 8 (6) 39 (17)

2011 3 (2) 12 (5)

2012 4 (3) 5 (2)

Median follow-up of survivors (range), months 66 (4-122) 61 (3-120)

Selection Table

The below selection criteria was applied # of excluded N

1st allo HCT for CML between 2004-2012 1751

North America and Europe only 359 1392

Form received and at least 100 day follow up 34 1358

Patient consent to research purpose 18 1340

TKI or DLI treatment after CML transplant 1024 316

39



Study Title: Comparison of outcomes after myeloablative versus reduced intensity conditioning for allogeneic hematopoietic stem cell transplant for chronic myeloid leukemia

Saurabh Chhabra, MD, Medical University of South Carolina, [email protected] Sandeep Jain, MB, BS, Medical University of South Carolina, [email protected] Robert K. Stuart, MD, Medical University of South Carolina, [email protected]

Hypothesis: Outcomes after reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation are not inferior to those after myeloablative (MA) allogeneic hematopoietic stem cell transplantation (HCT) in patients with chronic myeloid leukemia (CML) in chronic or accelerated phase at the time of transplant.

Specific Aims: Primary aim: 1. To compare the overall survival (OS) after HCT in CML patients receiving allogeneic HCT using RIC

versus MA conditioning regimen in patients between the ages of40 and 60 years.

Secondary aims: 1. To compare the leukemia-free survival (LFS) after HCT in CML patients receiving RIC vs. MA allo-HCT. 2. To compare the relapse rate after HCT in CML patients receiving RIC vs. MA conditioning. 3. To compare the time to relapse or progression after HCT in CML patients receiving RIC vs. MA

conditioning. 4. To compare the non-relapse mortality after HCT in RIC vs. MA conditioning in this population. 5. To compare the incidence of acute and chronic graft-versus-host disease (aGVHD and cGVHD) after

HCT in RIC vs. MA conditioning in this population. 6. To elucidate the graft-versus-leukemia (GVL) effect in CML patients after allo-HCT based on

a. The rate of remission using DLI in both the groups (RIC and MA) in the event of relapse; b. The rate and duration of remission in patients with chronic GVHD in the two groups; c. The rate and duration of remission in patients receiving MURD vs. MRD allo-HCT in the two

groups; d. The rate of relapse in patients receiving T-cell depletion in the two groups.

7. To compare the effect of disease status on outcomes (OS, PFS and NRM) after RIC vs. MA allo-HCT for CML

8. To compare the effect of age on outcomes (OS and NRM) after RIC vs. MA allo-HCT

Scientific Justification: Despite reduction in numbers of allogeneic hematopoietic stem cell transplant (HCT) performed for CML in the tyrosine kinase (TKI) era, HCT remains potentially curative therapy for CML patients who have become refractory or intolerant to TKIs, or who present in accelerated phase or blast crisis. Relative susceptibility of CML to donor lymphocyte infusion (DLI) after HCT suggest significant graft-versus-leukemia (GVL) effect in CML. CML is also unique in having differentiated leukemia derived antigen-presenting cells that can directly stimulate the donor immune system. The major drawback of myeloablative conditioning (MA) is transplant-related morbidity which leads to unacceptable non-relapse mortality (NRM) rates mainly among patients with comorbid conditions or advanced age. It is

40


expected RIC allogeneic HCT will be as effective as MA conditioning HCT in CML patients, given the presence of strong GVL, with regards to achieving and maintaining remission after allo-HCT.

In 2005, a retrospective study from EBMT reported the outcomes after RIC allogeneic HCT in 186 patients with CML. The median age was 50 years, and 64% were in first chronic phase (CP1), 13% in CP2, 17% in accelerated phase, and 6% in blast crisis. The overall survival (OS) and progression-free survival (PFS) at 3 years were 58% and 37%, respectively. This study demonstrated the feasibility of RIC allo-grafting in CML patients in first or second CP [1].

The outcomes after allo-HCT in CML using RIC and MA conditioning have been reported in a small single-center study. In this retrospective case-matched study, 28 CML patients who received RIC conditioning were matched to 56 patients who received MA conditioning [2]. The study reported higher transplant related mortality (14 % vs. 7%) in MA versus RIC groups. Despite higher rate of relapse and progression in the RIC group, the 5-year and 10-year OS was similar in the two groups.

Warlick et al analyzed post-HCT outcomes of 306 CML patients reported to the Center for International Blood and Marrow Transplant Research aged 40 years and older undergoing RIC/NMA allo-HCT from 2001 to 2007[3]. Of these, 117 (38%) aged 40 to 49 years, 119 (39%) 50 to 59 years, and 70 (23%) 60 years or older. The study showed that 3-year overall survival (54%, 52%, and 41%), day +100 grade II-IV acute GVHD (26%, 32%, and 32%), chronic GVHD (58%, 51%, and 43%), and 1-year treatment-related mortality (18%, 20%, and 13%) were similar across ages. These outcomes were comparable to historical outcomes of CML patients undergoing MA conditioning before sibling or URD transplant. For CP1 patients, relapse and disease-free survival were similar across age cohorts. RIC allo-HCT for older CML patient can control relapse with acceptable toxicity and survival, especially if still in CP1.

MA allo-HCTs are performed up to the age of 60 in most centers for patients requiring allo-HCT. However, RIC may be used in patients in this age group because of the investigator’s choice or presence of comorbidities. It would be ideal to compare the post-transplant outcomes in CML patients between the ages of 40 to 60, as MA transplants are rarely performed after the age of 60 and most physicians prefer myeloablative over reduced-intensity conditioning for allo-HCT for patients under 40 years of age. Currently, it is not clear if RIC (vis-à-vis MA) can lead to similar or better outcomes in younger CML patients who may be eligible for MA transplant, but would likely be able to avoid the increased risk of NRM associated with MA conditioning, i.e., preparative-regimen related toxicity, increased incidence of acute and chronic GVHD and infections. A large comparative retrospective CIBMTR study of RIC versus MA conditioning will be able to better define OS, EFS, GVHD incidence, NRM in patients who undergo allo-HCT for CML.

Patient Eligibility Population:

Patients between the ages of 40-60 at the time of transplant

Patients with CML who received a first allogeneic HCT from 2003-2013

Patients with chronic phase (CP) or accelerate phase (AP) at the time of transplant will be included

Patients with CNS involvement will be excluded

Patients with blast phase at the time of transplant will be excluded

Patients with an 8/8 HLA-matched sibling or unrelated donor

Patients receiving haploidentical or cord blood transplant will be excluded

Patients who received MA or RIC conditioning before transplant as defined by CIBMTR

T cell depletion of the graft will be included in the study

NMA conditioning will be excluded

Patients who received peripheral blood or bone marrow graft for transplant

41


Data Requirements: Data to be analyzed will be from data collected in the CIBMTR Report Forms. No additional data will be

needed. Patient, disease and transplant variables include:

Patient characteristics:

Age at transplant

Gender

Karnofsky performance score at transplant= Disease characteristics:

Disease diagnosis

Time from diagnosis to transplant

Disease status at transplant- chronic or accelerated phase

Pre-transplant therapy- TKI, IFN or cytotoxic chemotherapy

Use and duration of TKI before transplant

Cytogenetics

WBC/Blast count Transplant characteristics:

Preparative regimen

Donor relationship

Donor age

Donor-recipient gender match


Donor cell source- bone marrow versus peripheral blood

Outcomes:

Time to hematopoietic recovery

Incidence of grade 2-4 and grade 3-4 acute GVHD

Incidence of chronic GVHD

CMV viremia

Transplant-related mortality

Relapse

Leukemia-free survival

GVHD-free survival

Overall survival

Cause of death

Use of DLI

Study Design: This is a retrospective comparative cohort study comparing outcomes after RIC versus MA conditioning prior to allo-HCT using HLA well-matched related and unrelated donors for patients with CML in CP or AP. The outcomes studied will be OS, LFS, relapse rate, incidence of acute and chronic GVHD, hematopoietic recovery, CMV viremia, and transplant-related mortality. Categorical variables will be summarized as frequency counts and percentages and compared between the RIC vs. MA groups using the Chi-Square test. Continuous variables are summarized as the mean, standard deviation, median, minimum, and maximum and compared using the Mann-Whitney test. Time to hematopoietic recovery will be defined as the first of three consecutive days for neutrophils (ANC) > 0.5 × 109/L and first of three consecutive days for platelets ≥ 20 × 109/L without prior platelet transfusion. Transplant-related

42


mortality (TRM) will be defined as death from any cause in the first 100 days post-transplant irrespective of relapse status. Death beyond day +100 will only be considered transplant related if the disease is in remission. This event will be summarized as cumulative incidence estimate with relapse/progression as the competing risk. Relapse will be summarized by cumulative incidence estimates with TRM as the competing risk. Leukemia-free survival (LFS) will be defined as time to relapse or death from any cause and overall survival (OS) is time to death from any cause. Surviving patients will be censored at time of last follow up. Probabilities of LFS and OS will be calculated using Kaplan-Meier methods and compared between regimens using the log-rank test. Multivariate analyses will be performed using proportional hazards models for OS, LFS, TRM, GVHD and relapse using Cox model. Potential imbalances of donor relationship, cell source, and use of ATG in the preparative regimen will be analyzed.

References: 1. Topcuoglu, P., et al., Case-matched comparison with standard versus reduced intensity conditioning

regimen in chronic myeloid leukemia patients. Annals of hematology, 2012. 91(4): p. 577-86. 2. Crawley, C., et al., Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an

analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood, 2005. 106(9): p. 2969-76.

3. Warlick, E., et al., Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood, 2012. 119(17): p. 4083-90.

43


Characteristics of patients undergoing allo-HCT for CML, 2003-2013

Variable MA RIC



Patient-related

Age at transplant, median 48 (40-60) 50 (40-60)

Age at transplant

40-50 yrs 296 (61) 47 (47)

≥ 50 yrs 192 (39) 54 (53)

Gender

Male 269 (55) 47 (47)

Female 219 (45) 54 (53)

Karnofsky score

90-100% 340 (70) 69 (68)

< 90% 107 (22) 26 (26)

Missing 41 (8) 6 (6)

Disease-related

Time to HSCT from diagnosis, months 20 (1-296) 23 (5-123)

Time to HSCT from diagnosis

0-6 months 48 (10) 5 (5)

6-12 months 91 (19) 17 (17)

≥ 12 months 348 (71) 78 (77)

Missing 1 (<1) 1 (<1)

Disease status prior to transplant

CP1 236 (48) 62 (61)

AP 114 (23) 16 (16)

CP2+ 138 (28) 23 (23)

TKI combination

No TKI 107 (22) 18 (18)

Imatinib + Dasatinib + Nilotinib 38 (8) 4 (4)

Imatinib + Dasatinib 63 (13) 8 (8)

Imatinib + Nilotinib 8 (2) 2 (2)

Dasatinib + Nilotinib 1 (<1) 0

Imatinib 267 (55) 67 (66)

Dasatinib 2 (<1) 1 (<1)

Nilotinib 1 (<1) 0

Missing 1 (<1) 1 (<1)

Interferon

No 427 (88) 82 (81)

Yes 60 (12) 18 (18)

Missing 1 (<1) 1 (<1)

44


Variable MA RIC

WBC at diagnosis, 109/L 121 (1-720) 137 (1-969)

WBC at diagnosis

≤ 25 × 109/L 55 (11) 8 (8)

> 25 × 109/L 363 (74) 76 (75)

Missing 70 (14) 17 (17)

Blast in marrow at diagnosis, % 2 (<1-90) 5 (<1-92)

Blast in marrow at diagnosis

< 5% 117 (24) 13 (13)

5-10% 26 (5) 9 (9)

10-20% 12 (2) 2 (2)

> 20% 14 (3) 7 (7)

Missing 319 (65) 70 (69)

WBC prior to HCT, 109/L 6 (<1-432) 5 (<1-76)

WBC prior to HCT

≤ 25 × 109/L 432 (89) 96 (95)

> 25 × 109/L 50 (10) 4 (4)

Missing 6 (1) 1 (<1)

Blast in marrow prior to HCT, % 1 (<1-52) 1 (<1-10)

Blast in marrow prior to HCT

< 5% 316 (65) 78 (77)

5-10% 37 (8) 7 (7)

10-20% 22 (5) 3 (3)

> 20% 4 (<1) 0

Missing 109 (22) 13 (13)

Transplant-related

Year of transplant

2003-2004 198 (41) 53 (52)

2005-2006 154 (32) 24 (24)

2007-2008 66 (14) 13 (13)

2009-2010 60 (12) 8 (8)

2011-2012 8 (2) 2 (2)

2013 2 (<1) 1 (<1)

Graft type

Bone marrow 145 (30) 16 (16)


Type of donor


Well-matched unrelated 196 (40) 39 (39)

Partially-matched unrelated 69 (14) 16 (16)

Mis-matched unrelated 17 (3) 7 (7)

45


Variable MA RIC

Unrelated (matching indeterminable) 12 (2) 0

Donor-recipient sex match

M-M 180 (37) 28 (28)

M-F 117 (24) 34 (34)

F-M 87 (18) 17 (17)

F-F 102 (21) 20 (20)

Missing 2 (<1) 2 (2)


+/+ 157 (32) 30 (30)

+/- 42 (9) 8 (8)

-/+ 128 (26) 24 (24)

-/- 132 (27) 33 (33)

Missing 29 (6) 6 (6)

Donor age, median (URD) 36 (19-59) 36 (20-50)

Donor age (URD)

10-19 3 (<1) 0

20-29 59 (12) 16 (16)

30-39 93 (19) 13 (13)

40-49 59 (12) 16 (16)

50-59 15 (3) 1 (<1)

Missing 65 (13) 16 (16)

ATG/Campath

ATG + CAMPATH 1 (<1) 0

ATG alone 83 (17) 43 (43)

CAMPATH alone 14 (3) 12 (12)

No ATG or CAMPATH 387 (79) 46 (46)

Missing 3 (<1) 0

GVHD prophylaxis

Ex-vivo T-cell depletion 21 (4) 1 (<1)

CD34 selection 6 (1) 3 (3)

Cyclophosphamide 4 (<1) 0

FK506 + MMF +- other(s) 40 (8) 9 (9)

FK506 + MTX +- other(s) 178 (36) 32 (32)

FK506 + other(s) 17 (3) 3 (3)

FK506 alone 8 (2) 1 (<1)

CSA + MMF +- other(s) 9 (2) 14 (14)

CSA + MTX +- other(s) 183 (38) 24 (24)

CSA + other(s) 6 (1) 3 (3)

CSA alone 4 (<1) 10 (10)

Other(s) 5 (1) 0

46


Variable MA RIC

Missing 7 (1) 1 (<1)

Median follow-up of survivors (range), months 72 (2-122) 73 (2-121)

Selection exclusion table


1st allo-HCT for CML 14510

Year of HCT: 2003-2013 12425 2085

Age: 40-60 1236 849

Disease status: CP/AP (excluding CR = 89, BP = 75, missing = 10) 174 675

Graft source: BM, PBSC (excluding cord blood = 29) 29 646

Donor type: matched sibling, URD (excluding twin = 1, other relatives = 13, missing = 2) 16 630

Conditioning intensity: MA, RIC (excluding NMA = 18, TBD = 15, missing = 7) 40 590

EXCLUSION:


47



Study Title: Outcome of allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia with antecedent history of Philadelphia-negative myeloproliferative Neoplasm

Vikas Gupta, MD, Blood and Marrow Transplant Program, Princess Margaret Cancer Center, Toronto, ON, Canada, [email protected]

Hypothesis: Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for selected patients with leukemic transformation from Philadelphia-negative myeloproliferative Neoplasm (MPN); and prognostic factors for outcome of HCT in this setting are not known.

Objectives: Primary 1. Outcome of HCT in patients with leukemic transformation from Philadelphia-negative MPN 2. To identify patient, disease and transplant related factors associated with outcome

Secondary 1. To study the graft-versus-leukemia effect in this setting

Scientific Rationale: Philadelphia-negative MPNs are a group of phenotypically related clonal hematopoietic cell diseases characterized by overproduction of mature myeloid cells and a prolonged clinical course. Transformation to AML occurs in approximately 5-10% of these neoplasms after 10 years, and is associated with extremely poor prognosis.

The median survival of patients after leukemic transformation is 3-4 months; and none of the conventional treatment options are known to improve the survival of these patients(1-3). There are few small case series which have shown that HCT has the potential of long-term disease control in some selected patients with leukemic transformation from Ph negative MPN.

In a study from Princess Margaret Cancer Center, Toronto, 75 consecutive patients diagnosed with LT from ph-MPN were studied. Out of these 75 patients, 39 patients were treated with curative intent (chemotherapy +/-HCT); and subsequently 17 patients were able to undergo HCT in either CR or chronic MPN phase. The survival of patients post-HCT was significantly improved compared to patients who achieved CR/cMPN phase but did not receive HCT (2-year OS 47% versus 15%, p=0.03)(2).

All the studies reporting on HCT outcomes in patients with LT from ph- negative MPN are summarized in table 1 (1-8) In a recent study from EBMT, 46 patients with leukemic transformation from a previous MPN were analyzed,. 3-year progression-free and overall survival was 26% and 33%, respectively. Survival was better for patients achieving remission before transplant. Due to limited sample size, a meaningful multivariate analysis could not be done(8).

It is not known which patients with this complication benefit from the option of HCT. Due to small sample size, it was not possible to analyze prognostic factors associated with outcomes in any of these studies.

Due to rarity of this complication, prospective studies pose a logistic challenge as even the major centers with special interest in MPNs treat a few patients with MPN every year. Therefore, observational studies through a large data source such as CIBMTR will be important to study the transplant outcomes of this

48


rare disease. The outcomes of this study will help in understanding which patients with LT benefit from HCT; and will assist leukemia and transplant physician in decision making as well as improving the transplant practices in this group of patients.

Study Population: Using the CIBMTR database, patients with AML and a preceding h/o Philadelphia negative MPN undergoing HCT between 1996 and 2013 and meet the following criteria will be identified.

Inclusion criteria: 1. Diagnosis of AML prior to HCT 2. Age 18 years and above 3. Prior to AML transformation, patients had preceding h/o one of the following:

a. Polycythemia rubra vera (PV) or post-PV myelofibrosis b. Essential thrombocythemia (ET) or post ET myelofibrosis c. Primary Myelofibrosis (PMF)

4. HCT using any type of donor

Exclusion criteria: 1. Syngeneic transplantation 2. Positive for Philadelphia chromosome or BCR-ABL 3. In vitro T-cell depletion

Outcomes of interest:

Hematopoietic recovery: Time to neutrophils (ANC) > 0.5 × 109/L (first of 3 consecutive days) and time to platelets ≥ 20 × 109/L (first of 3 consecutive days and no platelet transfusions 7 days prior)

Acute GVHD: Occurrence of grade II, III and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD.

Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the criteria of chronic GVHD

Relapse: disease recurrence or persistence. This event will be summarized by cumulative incidence estimate with TRM as the competing risk

Treatment-related mortality: time to death without evidence of disease relapse. This event will be summarized as cumulative incidence estimate with relapse/progression as the competing risk.

Leukemia-free survival: will be defined as time to relapse, leukemia transformation or death from any cause. Patients are censored at last follow-up.

Overall survival: Time to death, patients censored at last follow-up

Variables to be analyzed: Patient-related:

- Age - Gender - Performance scores: <90 vs ≥90 - Co-morbidities (depending on availability of data)

Disease-related: - Aetiology of MPN: PV vs. PPV-MF vs. ET vs. PET-MF vs. PMF - Remission status prior to HCT: CR versus Blasts in BM<5% but not meeting CR definition (chronic

MPN phase) vs. active leukemia - Type of leukemic reduction therapy prior to HCT: 3+7 or high-dose Cytarabine based versus

hypomethylating agent (Decitabine or Azacitidine) or others - Duration between diagnosis of MPN and AML: > 5-years vs. 2-5 years vs. < 2-years

49


- MPN therapies: none vs. ≤ 2 vs. ≥ 3 - Spleen status : Splenectomy versus not palpable spleen versus splenomegaly - Cytogenetics: abnormal versus normal versus unknown - Cytogenetics (classified as SWOG) favorable versus intermediate-normal versus intermediate

abnormal versus adverse versus unknown - Cytogenetics (only in patients with available cytogenetics results): normal karyotype versus

abnormal but not monosomal karyotype versus monosomal karyotype - Time from diagnosis of AML to transplant: <6 months versus 6-12 months versus >12 months - WBC count at the diagnosis of AML - JAK 2 mutation status any time prior to HCT: present/absent/unknown

Transplant-related: - Conditioning therapy: Myeloablative versus reduced intensity - Graft type: BM versus PB versus CB - Donor type: HLA identical sibling versus other related versus well matched URD vs. partially

matched URD/ mismatched URD vs. cord blood - GVHD prophylaxis: Calcineurin inhibitor (CsA or FK 506) + Methotrexate versus calcineurin

inhibitor (CsA or FK 506) + Mycophenolate versus others - Serotherapy used (ATG or Alemtuzumab or Campath): yes/no - Year of transplant: 1991-1995 vs. 1996-2000 vs. 2001-2005 vs. 2006-2011 - Donor-recipient gender match: M-M vs M-F vs F-M vs F-F - Donor-recipient CMV serostatus: +/+ vs. +/- vs. -/+ vs. -/- - CD34+cell dose x 106/kg for PB Tx / TNC for BM grafts - Planned Growth factor initiated within 7 days post-transplant: yes/no

Analysis plan: Patient-, disease-, and transplant-related variables for the study cohort will be described. Univariate probabilities of LFS and survival will be calculated using the Kaplan-Meier estimator; the log-rank test will be used for univariate comparisons. Probabilities of hematopoietic recovery, acute and chronic GVHD, treatment-related mortality and relapse will be calculated using cumulative incidence curves to accommodate competing risks. Assessment of potential risk factors for outcomes of interest will be evaluated in multivariate analyses using Cox proportional hazards regression

50


Table 1: Summary of literature review on outcome of LT from Philadelphia negative MPN

Studies including all patients with LT from MPN Patients treated with induction therapy Patients undergoing HCT

STUDY PRECEEDING MPN n

Median OS n

Favorable response Median OS n

% pre-treated

% in CR/CRi/cMPN 2-year OS

Mesa et al. (2005)(1)

PMF, PPV-MF, PET-MF 91 2.6 24 10 (42%) 3.9 0 - - -

Tam et al. (2008)(3) all Ph-MPNs 74 5 41 18 (46%) not reported 8 62.5% 75% 73%

Noor et al. (2010)(6) all Ph-MPNs 23 4.6 20 12 (60%) 6 3 100% not reported

not reported

Cherington et al. (2012)(4) ET, PV, PMF 13

not reported 10 6 (60%) not reported 8 100% 62.5% 75%

Kennedy et al, (2013)(2) Princess Margaret Toronto data all Ph-MPNs 75 6.5 38 29 (76%) 9.2 17 94% 100% 47%

Transplant-focused studies

Ciurea et al. (2010)(5)

PMF, PPV-MF, PET-MF - - - - - 14 93% 43% 49%

Mascarenas et al. (2010)(7)

PMF, PPV-MF, PET-MF - - - - - 5 20% ≤20% 53%

Alchalby et al (2014)(8) All Ph-neg MPNs 46 N/A <20%

33% at 3 years

51


References: 1. Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105(3):973-7. Epub 2004/09/25. 2. Kennedy JA, Atenafu EG, Messner HA, Craddock KJ, Brandwein JM, Lipton JH, et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood. 2013;121(14):2725-33. Epub 2013/01/31. 3. Tam CS, Nussenzveig RM, Popat U, Bueso-Ramos CE, Thomas DA, Cortes JA, et al. The natural history and treatment outcome of blast phase BCR-ABL- myeloproliferative neoplasms. Blood. 2008;112(5):1628-37. Epub 2008/06/21. 4. Cherington C, Slack JL, Leis J, Adams RH, Reeder CB, Mikhael JR, et al. Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase. Leukemia research. 2012;36(9):1147-51. Epub 2012/05/15. 5. Ciurea SO, de Lima M, Giralt S, Saliba R, Bueso-Ramos C, Andersson BS, et al. Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2010;16(4):555-9. Epub 2009/12/17. 6. Noor SJ, Tan W, Wilding GE, Ford LA, Barcos M, Sait SN, et al. Myeloid blastic transformation of myeloproliferative neoplasms--a review of 112 cases. Leukemia research. 2011;35(5):608-13. Epub 2010/08/24. 7. Mascarenhas J, Navada S, Malone A, Rodriguez A, Najfeld V, Hoffman R. Therapeutic options for patients with myelofibrosis in blast phase. Leukemia research. 2010;34(9):1246-9. Epub 2010/07/16. 8. Alchalby H, Zabelina T, Stubig T, van Biezen A, Bornhauser M, Di Bartolomeo P, et al. Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation: a study from the Myeloproliferative Neoplasm Subcommittee of the CMWP of the European Group for Blood and Marrow Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014;20(2):279-81. Epub 2013/11/10.

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Baseline characteristics of patients undergoing allo-HCT for MPN between 1996 and 2013

Variable N (%)

Number of patients 199

Number of centers 87

Age, median (range) 56 (20-74)

Age in decades

18-29 6 (3)

30-39 10 (5)

40-49 37 (19)

50-59 87 (44)

60-69 51 (26)

≥ 70 8 (4)

Gender

Male 117 (59)

Female 82 (41)

Karnofsky score

90-100% 101 (51)

< 90% 92 (46)

Missing 6 (3)

White blood count at diagnosis

≤ 30 × 109/L 117 (59)

30-100 × 109/L 23 (12)

> 100 × 109/L 5 (3)

Missing 54 (27)

Etiology of MPN

Polycythemia vera 50 (25)

Essential thrombocythemia 59 (30)

Myelofibrosis with myeloid metaplasia 37 (19)

Other myelofibrosis or myelosclerosis 26 (13)

Chronic idiopathic myelofibrosis 27 (14)

Disease status prior to HCT

Blasts in BM < 5% but not CR 23 (12)

CR 93 (47)

Active leukemia (PIF and relapse) 81 (41)

Missing 2 (1)

Cytogenetics scoring

Favorable 2 (1)

Intermediate 88 (44)

Poor 45 (23)

TBD (needs rev.) 22 (11)

Not tested 11 (6)

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Variable N (%)

Missing 31 (16)

Induction therapy

7+3 68 (34)

7+3 + other 24 (12)

Hypomethylating agent 3 (2)

Other 104 (52)

Duration between diagnosis of MPN and AML, median (range) 4 (<1-33)

Duration between diagnosis of MPN and AML

< 2 years 65 (33)

2-5 years 36 (18)

> 5 years 75 (38)

Missing 23 (12)

Time from diagnosis to HCT, median (range) 5 (<1-133)

Time from diagnosis to HCT

0-3 months 134 (67)

3-6 months 40 (20)

≥ 6 months 25 (13)

Conditioning regimen intensity

Myeloablative 113 (57)

RIC 43 (22)

NMA 27 (14)

TBD 14 (7)

Missing 2 (1)

Graft source

Bone marrow 42 (21)

Peripheral blood 144 (72)

Cord blood 13 (7)

Type of donor

Cord blood 13 (7)

HLA identical sibling 67 (34)

Other relatives 6 (3)

Well-matched unrelated 68 (34)

Partially-matched unrelated 34 (17)

Mismatched unrelated 5 (3)

Unrelated (matching cannot be determined) 6 (3)

Donor/recipient sex match

M-M 75 (38)

M-F 42 (21)

F-M 42 (21)

F-F 37 (19)

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Variable N (%)

Missing 3 (2)

Donor/recipient CMV match

+/+ 51 (26)

+/- 17 (9)

-/+ 57 (29)

-/- 55 (28)

Missing 19 (10)

GVHD prophylaxis

CsA/FK506 + MMF 55 (28)

CsA/FK506 + MTX 107 (54)

Other 33 (17)

Missing 4 (2)

ATG/Campath

ATG alone 42 (21)

CAMPATH alone 7 (4)

No ATG or CAMPATH 143 (72)

Missing 7 (4)

Year of transplant

1996-1997 12 (6)

1998-1999 10 (5)

2000-2001 16 (8)

2002-2003 19 (10)

2004-2005 29 (15)

2006-2007 32 (16)

2008-2009 41 (21)

2010-2011 20 (10)

2012-2013 20 (10)

Median follow-up of survivors (range), months 59 (3-179)

Selection Table


1st allo HCT for AML transformed from MPN 242

Year of HCT: 1996-2013 11 231

Age 18 years and above 8 223

All donor except syngeneic twin 2 221

Exclude ex-vivo T-cell depletion 18 203

EXCLUSION:


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Documents

2015 Chronic Leukemia Agenda