c. PC10 02b Hitzler JK, He W, Doyle J, Cairo M, Camitta BM, Chan K, Diaz Perez MA,

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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR PEDIATRIC CANCER Grapevine, TX Friday, February 28, 2014, 12:15 pm 2:15 pm Co Chair: Co Chair: Co Chair: Statisticians: Scientific Director: Adriana Seber, MD, Instituto De Oncologia Pediatrica, Sao Paulo, Brazil Telephone: ; Fax: ; E mail: adrianaseber@graacc.org.br Carrie Kitko, MD, University of Michigan Medical Center, Ann Arbor, MI Telephone: ; Fax: ; E mail: ckitko@med.umich.edu Gregory Hale, MD, All Children's Hospital, St. Petersburg, FL Telephone: ; Fax: ; E mail: haleg@allkids.org Wensheng (Vincent) He, MS, CIBMTR, Milwaukee, WI Telephone: ; Fax: ; E mail: vhe@mcw.edu Jennifer Le Rademacher, PhD; CIBMTR, Milwaukee, WI Telephone: ; Fax: ; E mail: jlerade@mcw.edu Elizabeth Thiel, MD, MS, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; E mail: ethiel@mcw.edu 1. Introduction a. Minutes and overview plan of February, 2013 meeting (Attachment 1) b. Newly appointed chair: Parinda Mehta, MD, Cincinnati Children's Hospital Medical Center; Telephone: ; Fax: ; E mail: parinda.mehta@cchmc.org 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers a. PC10 02a Hitzler JK, He W, Doyle J, Cairo M, Camitta BM, Chan K, Diaz Perez MA, Fraser C, Gross TG, Horan JT, Kennedy Nasser AA, Kitko C, Kurtzberg J, Lehmann L, O'Brien T, Pulsipher MA, Smith FO, Zhang M J, Eapen M, Carpenter PA. Outcome of Transplantation for Acute Myelogenous Leukemia in Children with Down Syndrome. Biology of Blood & Marrow Transplantation Jun 1; 19(6): b. PC10 04 Kelly MJ, Horan JT, Alonzo TA, Eapen M, Gerbing RB, He W, Lange BJ, Parsons SK, Woods WG. Comparable survival for pediatric acute myeloid leukemia with poorrisk cytogenetics following chemotherapy, matched related donor, or unrelated donor transplantation. Pediatric Blood & Cancer. 2014; DOI /pbc Epub 2013 Aug 19. c. PC10 02b Hitzler JK, He W, Doyle J, Cairo M, Camitta BM, Chan K, Diaz Perez MA, Fraser C, Gross TG, Horan JT, Kennedy Nasser AA, Kitko C, Kurtzberg J, Lehmann L, O'Brien T, Pulsipher MA, Smith FO, Zhang M J, Eapen M, Carpenter PA. Outcome of 1

2 Not for publication or presentation Transplantation for Acute Lymphoblastic Leukemia in Children with Down Syndrome. Pediatric Blood & Cancer. 2014; DOI /pbc d. PC10 01 Bitan M, He W, Zhang M J, Abdel Azim H, Ayas MF, Bielorai B, Carpenter PA, Cairo M, Diaz Perez MA, Horan JT, Jodele S, Kitko C, Schultz KR, Kletzel M, Kasow KA, Lehmann L, Mehta PA, Shah N, Pulsipher MA, Prestidge T, Seber A, Shenoy S, Woolfrey AE, Yu LC, Davies SM. Transplantation for Children with Acute Myeloid Leukemia: A Comparison of Outcomes with Reduced intensity and Myeloablative Regimens. Blood. 2014; DOI /blood Studies in progress (Attachment 3) a. PC10 03 HCT for Hypodiploid ALL (P Mehta) Manuscript preparation b. PC09 01 Allo in children with T ALL (M. Burke) (Attachment 4) Analysis 6. Future/proposed studies a. PROP Outcome of Total body irradiation (TBI) versus non TBI (chemotherapy) based conditioning regimens for allogeneic hematopoietic cell transplantation in MLL gene rearranged Acute myeloid leukemia (H Rangarajan, P Satwani) (Attachment 5) b. PROP Outcome of matched sibling donor hematopoietic cell transplantation for children with acute myelogenous leukemia in first complete remission as compared to beyond first complete remission (C Weiner, P Satwani) (Attachment 6) 2

3 Not for publication or presentation Attachment 1 MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR PEDIATRIC CANCER Salt Lake City, Utah Wednesday, February 13, 2013, 2:45 pm 4:45 pm Co Chair: Co Chair: Co Chair: Statisticians: Scientific Director: Paul A. Carpenter, MD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: ; Fax: ; E mail: pcarpent@fhcrc.org Adriana Seber, MD, Instituto De Oncologia Pediatrica, Sao Paulo, BRAZIL Telephone: ; Fax: ; E mail: adrianaseber@graacc.org.br Carrie Kitko, MD, University of Michigan Medical Center, Ann Arbor, MI Telephone: ; Fax: ; E mail: ckitko@med.umich.edu Wensheng (Vincent) He, MS, CIBMTR, Milwaukee, WI Telephone: ; Fax: ; E mail: vhe@mcw.edu Mei Jie Zhang, PhD, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; E mail: meijie@mcw.edu Mary Eapen, MD, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; E mail: meapen@mcw.edu 1. Introduction Dr. Carrie Kitko welcomed the audience and introduced the new co chair, Dr. Gregory Hale from All Children's Hospital. The minutes from the 2012 meeting were approved. 2. Accrual summary Numbers of transplants for pediatric malignancy stratified by graft type and donor were presented as part of the meeting documents. 3. Presentations, published or submitted papers a. PC10 05 Veys P, Wynn R, Ahn KW, Samarasinghe S, He W, Bonney D, Craddock J, Cornish J, Davies SM, Dvorak C, Duerst R, Gross TG, Kapoor N, Krance R, Kitko C, Leung WH, Victor AL, Wagner J, Carpenter PA and Eapen M. Impact of immune modulation with anti T cell antibodies on outcomes after unrelated donor transplantation for acute lymphoblastic leukemia in children and adolescents. Blood 119(25): , b. PC10 02 Hitzler JK, He W, Doyle J, Cairo M, Camitta BM, Chan KW, Diaz MA, Fraser C, Gross TG, Horan JT, Kennedy Nasser AA, Kitko C, Kurtzberg J, Lehmann L, O Brien T, Pulsipher MA, Smith FO, Zhang MJ, Eapen M, Carpenter PA. Outcomes of transplantation for acute myelogenous leukemia in children with Downs Syndrome. Biology of Blood and Marrow Transplantation. In press. c. PC10 04 Kelly MJ, Horan JT, Alonzo TA, Eapen M, Gerbing RB, He W, Lange BJ, Parsons SK, Woods WG. Hematopoietic Cell Transplant versus Chemotherapy As Consolidation 3

4 Not for publication or presentation Attachment 1 Treatment for Pediatric AML with Poor Risk Cytogenetics. Oral Presentation at the American Society of Hematology in Atlanta, Georgia, December d. PC10 02 Hitzler JK, He W, Doyle J, Bitan M, Cairo M, Camitta BM, Chan KW, Diaz MA, Fraser C, Gross TG, Horan JT, Kasow KA, Kennedy Nasser AA, Kitko C, Kurtzberg J, Lehmann L, Mitchell D, O Brien T, Pulsipher MA, Smith FO, Yu LC, Zhang MJ, Eapen M, Carpenter PA. Outcome of transplantation for acute leukemia in Downs Syndrome. Oral presentation at the American Society of Hematology in Atlanta, Georgia, December Studies in progress a. PC10 04 Compare outcomes after chemotherapy and allogeneic transplantation for poor risk acute myeloid leukemia in first complete remission (M. Kelly; collaboration with the Children s Oncology Group) Dr. Mary Eapen presented the findings for Dr. M Kelly. The primary objective was to compare outcomes among poor risk patients with AML in first complete remission treated with chemotherapy vs. transplantation between 1989 and The study period is based on periods for the chemotherapy group i.e., the duration of COG trials. There were 234 eligible cases (chemotherapy only, n=124; matched related donor, n=55; unrelated donor, n=55). The results suggest overall survival is not significantly different for those treated chemotherapy and transplantation. However, the pattern of failure differed: recipients of unrelated donor transplantation had lower relapse risks compared to matched sibling donor transplant recipients but treatment related mortality was higher after unrelated donor transplantation. There were no differences in risks of relapse or treatment related mortality in the groups that received chemotherapy and matched related donor transplantation. There was some concern from audience on the study time period. Both transplantation and chemotherapy strategies have evolved over time and it has been reported that there is an improvement in treatment related mortality rates in the more recent period. This is acknowledged as a limitation the study period in this study has to be limited to the period during which there were COG trials. However, improvements in supportive care had led to lower treatment related mortality risks for both chemotherapy and transplantation and in the absence of published data supporting a survival advantage after unrelated donor transplantation we cannot speculate that the lower risk of relapse offers a survival advantage. There was also concern as to whether the observed survival for patients in the chemotherapy group was driven by transplantation following relapse. Reviewing our data there were 70 patients in the chemotherapy group who relapsed, of these 31 received a second transplant and 12 are alive. Among recipients of matched related donor transplantation, 27 patients relapsed and 11 of these patients received a second transplant; only 4 patients are alive. The corresponding numbers for recipients of unrelated donor transplantation are 16, 2 and 0. The manuscript was submitted February b. PC10 01 Compare outcomes after allogeneic transplantation for acute myeloid leukemia: are there differences after reduced intensity and myeloablative transplant conditioning regimens (M. Bitan) Dr. Bitan presented the study. The primary objective to compare outcomes after 4

5 Not for publication or presentation Attachment 1 reduced intensity (RIC) and myeloablative (MAC) transplant conditioning regimens for AML. Reduced intensity was defined as busulfan dose less than 8 mg/kg or melphalan less than 150 mg/m2. Irradiation containing regimens were considered reduced intensity for TBI dose 200 cgy, 400 cgy or cgy (fractionated). Cases (recipients of RIC transplants) were matched to controls (recipients of MAC transplants). Matching considered 1) age ± 5 years; 2) disease status at transplant; 3) graft type; and 4) year of transplant ± 5 years. Forty two cases were matched to 167 controls (for 41 cases, each case was matched to 4 controls and the remaining case was matched to 3 controls). A total of 90 centers contributed cases and / or controls. N = 18 centers performed both RIC and MAC transplants; N = 14 only RIC transplants; N = 58 only MAC transplants. Results of univariate and multivariate analysis support no significant differences in transplant related mortality, relapse, leukemia free and overall survival. The rationale for choosing a RIC regimen is not collected on CIBMTR Forms. Performance score is collected and was tested in multivariate models poor performance score was associated with higher relapse risks and consequently lower leukemia free and overall survival. Other co morbidities were not tested data on comorbidities were not collected consistently over time. We do know co morbidities predict mortality published reports and the results of a large study that included both pediatric and adult transplant recipients undertaken by Dr. Sorror and colleagues through the Regimen related Toxicity committee of the CIBMTR. c. PC10 03 Allogeneic transplantation for hypodiploid acute lymphoblastic leukemia (P. Mehta) Dr. Mehta presented the update for this study. This study proposes to evaluate the outcomes after allogeneic transplantation in children with hypodiploid ALL and identify the risk factors associated with the outcomes. Ninety one patients were identified; cytogenetic reports were reviewed and confirmed by P. Mehta. The patient, disease and transplant related characteristics were presented; next step is study file preparation and analyses. Planned study: d. PC11 01 Development of a prognostic scoring system to predict relapse of ALL after allogeneic transplantation (N Shah) Dr. Nirali Shah presented the study and the committee was instructed to review this study for both scientific merit and feasibility. The primary aim is to develop a prognostic scoring system on patient, disease, and transplant specific factors predictive for relapse after allogeneic transplantation for ALL. Data from the BMF, the COG and some transplant centers in the US support minimal residual disease (MRD) status is an important prognostic indicator. The study is on hold because the CIBMTR does not have information on MRD and attempts to obtain outside sources for MRD data have not be successful. The study was approved in 2011 because there were assurances that MRD data would be available through the BMF group (the intent then was to validate the US prognostic score using the BMF and the COG). Dr. Shah presented their single institution study that concluded MRD positivity is an independent risk factor for relapse. The investigators (Shah / Wayne) proposed the study move forward but without MRD data. The committee on the other hand remain concerned about the lack of MRD data and the effort spend on developing a prognostic model knowing MRD status pretransplant is an important predictor of relapse. The discussions revealed committee 5

6 Not for publication or presentation Attachment 1 members were not convinced the study would have a high scientific merit without the MRD data. Therefore the study was dropped. 5. Future/ Proposed studies a. PROP Factors predicting treatment related mortality after autologous transplantation in children and adolescents. (E. Perez Albuerne) Dr. David Jacobsohn presented the proposal. The aim of the proposal is to identify factors associated with transplant related mortality and to describe the outcomes of pediatric /adolescent autologous transplantation for malignant diseases. There are about 1000 eligible patients in the CIBMTR database at the research level; 40% of transplants were for neurobalstoma and 25% for central nervous system tumors. The committee members questioned scientific merit of this proposal and were not convinced the study would add much to the existing literature or change clinical practice. The recommendation from the committee members was not to pursue the study any further. Therefore this was not approved. 6. Other business None. The meeting adjourned at 4:20 PM. Working Committee Overview Plan for a. PC10 01 Compare outcomes after allogeneic transplantation for acute myeloid leukemia: are there differences after reduced intensity and myeloablative transplant conditioning regimens. We anticipate submitting the manuscript for peer review April/May b. PC10 03 Allogeneic transplantation for hypodiploid acute lymphoblastic leukemia. Analysis will be completed by June We anticipate submitting the manuscript for peer review October/November c. PC09 01 Allogeneic transplantation for T cell acute lymphoblastic leukemia. We anticipate beginning work on this project July 2013 and completing analysis by December We anticipate submitting the manuscript for peer review April/May Work Assignments for Working Committee Leadership (February 2013) Mary Eapen Adriana Seber Carrie Kitko Gregory Hale PC10 01: Compare outcomes after allogeneic transplantation for acute myeloid leukemia: are there differences after reduced intensity and myeloablative transplant conditioning regimens. PC10 03: Allogeneic transplantation for hypodiploid acute lymphoblastic leukemia. PC09 01: Allogeneic transplantation for T cell acute lymphoblastic leukemia. No assignments; did not attend the meeting 6

7 Not for publication or presentation Attachment 2 Accrual Summary for Pediatric Cancer Working Committee Characteristics of patients aged 18 years with acute and chronic leukemia, myelodyplastic syndrome and lymphoma reported to the CIBMTR between *. HLA identical sibling HCT TED, N (%) Research, N(%) Acute myeloid leukemia Bone Marrow 1431 (71) 339 (70) Peripheral blood 562 (28) 132 (27) Cord Blood 35 ( 2) 16 ( 3) Acute lymphoblastic leukemia Bone Marrow 1823 (72) 309 (61) Peripheral blood 635 (25) 164 (32) Cord Blood 67 ( 3) 33 ( 7) Chronic myeloid leukemia Bone Marrow 240 (65) 78 (70) Peripheral blood 124 (34) 33 (30) Cord Blood 4 ( 1) 0 Myelodysplastic Syndrome Bone Marrow 304 (76) 85 (77) Peripheral blood 88 (22) 20 (18) Cord Blood 9 ( 2) 5 ( 5) Hodgkin lymphoma 30 6 Bone Marrow 13 (43) 2 (33) Peripheral blood 17 (57) 4 (67) Non Hodgkin lymphoma Bone Marrow 159 (69) 23 (48) Peripheral blood 68 (30) 23 (48) Cord Blood 3 ( 1) 2 ( 4) * Cases in 2013 continue to be reported 7

8 Not for publication or presentation Attachment 2 Accrual Summary for Pediatric Cancer Working Committee Characteristics of patients aged 18 years with acute and chronic leukemia, myelodyplastic syndrome and lymphoma reported to the CIBMTR between 2000 and 2013* Other related donor HCT TED, N (%) Research, N(%) Acute myeloid leukemia Bone Marrow 212 (43) 74 (53) Peripheral blood 273 (55) 61 (44) Cord Blood 10 ( 2) 5 ( 4) Acute lymphoblastic leukemia Bone Marrow 272 (45) 70 (44) Peripheral blood 328 (54) 83 (53) Cord Blood 9 ( 1) 5 ( 3) Chronic myeloid leukemia Bone Marrow 44 (56) 20 (59) Peripheral blood 32 (41) 13 (38) Cord Blood 2 ( 3) 1 ( 3) Myelodysplastic Syndrome Bone Marrow 53 (47) 21 (66) Peripheral blood 60 (53) 11 (34) Hodgkin lymphoma 11 2 Bone Marrow 3 (27) 1 (50) Peripheral blood 8 (73) 1 (50) Non Hodgkin lymphoma Bone Marrow 27 (46) 8 (47) Peripheral blood 31 (53) 9 (53) Cord Blood 1 ( 2) 0 * Cases in 2013 continue to be reported 8

9 Not for publication or presentation Attachment 2 Accrual Summary for Pediatric Cancer Working Committee Characteristics of patients aged 18 years with acute and chronic leukemia, myelodyplastic syndrome and lymphoma reported to the CIBMTR between 2000 and 2013* Unrelated donor HCT TED, N (%) Research, N(%) Acute myeloid leukemia Bone Marrow 1044 (39) 540 (37) Peripheral blood 520 (19) 210 (14) Cord Blood 1110 (42) 725 (49) Acute lymphoblastic leukemia Bone Marrow 1621 (42) 785 (38) Peripheral blood 733 (19) 273 (13) Cord Blood 1529 (39) 1000 (49) Chronic myeloid leukemia Bone Marrow 245 (59) 146 (58) Peripheral blood 94 (22) 48 (19) Cord Blood 79 (19) 57 (23) Myelodysplastic Syndrome Bone Marrow 449 (44) 231 (39) Peripheral blood 171 (17) 73 (12) Cord Blood 395 (39) 289 (49) Hodgkin lymphoma 21 7 Bone Marrow 9 (43) 2 (29) Peripheral blood 9 (43) 2 (29) Cord Blood 3 (14) 3 (43) Non Hodgkin lymphoma Bone Marrow 119 (44) 55 (38) Peripheral blood 62 (23) 28 (19) Cord Blood 89 (33) 62 (43) * Cases in 2013 continue to be reported 9

10 Not for publication or presentation Attachment 2 Accrual Summary for Pediatric Cancer Working Committee Characteristics of patients aged 18 years with acute leukemia and lymphoma reported to the CIBMTR between 2000 and 2013* Autologous HCT TED, N (%) Research, N(%) Acute myeloid leukemia Bone Marrow 49 (20) 4 (10) Peripheral blood 200 (80) 37 (90) Cord Blood 2 ( 1) 0 Acute lymphoblastic leukemia 52 5 Bone Marrow 5 (10) 1 (20) Peripheral blood 45 (87) 4 (80) Cord Blood 2 ( 4) 0 Hodgkin lymphoma Bone Marrow 57 ( 6) 2 ( 2) Peripheral blood 869 (94) 86 (98) Non Hodgkin lymphoma Bone Marrow 52 (12) 1 ( 2) Peripheral blood 374 (88) 42 (98) * Cases in 2013 continue to be reported 10

11 Not for publication or presentation Attachment 2 Accrual Summary for Pediatric Cancer Working Committee Number of patients aged 18 years with solid tumor reported to the CIBMTR between 2000 and 2013* Autologous Allogeneic TED Research TED Research Testicular Bone sarcoma(no Ewing sarcoma) Central nervous system tumors Wilm s Tumor Neuroblastoma Retinoblastoma Ewing sarcoma Extragonadal germ cell tumor Medulloblastoma PNET Rhabdomyosarcoma * Cases in 2013 continue to be reported 11

12 Not for publication or presentation Attachment 3 TO: FROM: RE: Pediatric Cancer Working Committee Members Elizabeth Thiel, MD Scientific Director for the Pediatric Cancer Working Committee Studies in Progress Summary PC10 03: Transplantation for treatment of Hypodiploid acute lymphoblastic leukemia (P Mehta): This study proposes to evaluate the outcomes after allogeneic transplantation in children with Hypodiploid ALL and identify the risk factors associated with the outcomes. Seventy eight eligible patients are identified by reviewing the cytogenetic report from transplant centers. The analysis has been completed and a manuscript is expected to be submitted by March PC09 01: Outcomes in children with t cell acute lymphoblastic leukemia following allogeneic hematopoietic cell transplantation (M Burke): This study proposes to describe the outcomes of allogeneic transplantation for children with T cell ALL and identify the risk factors that are associated with the outcomes. The analysis is under way and a manuscript is expected to be submitted by July

13 Not for publication or presentation Attachment 4 CIBMTR PC09 01 OUTCOMES IN CHILDREN WITH T CELL ACUTE LYMPHOBLASTIC LEUKEMIA FOLLOWING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FINAL PROTOCOL Study Chair: Study Statistician: Michael J. Burke, MD Pediatric Leukemia/Lymphoma Program Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: E mail: mmburke@mcw.edu Wensheng (Vincent) He, MS CIBMTR Statistical Center Medical College of Wisconsin Suite C W. Wisconsin Avenue Milwaukee, WI USA Telephone: Fax: E mail: vhe@mcw.edu Jennifer Le Rademacher, PhD CIBMTR Statistical Center Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: E mail: jlerade@mcw.edu Scientific Director: Elizabeth Thiel, MD, MS CIBMTR Statistical Center Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: E mail: ethiel@mcw.edu 13

14 Not for publication or presentation Attachment 4 Working Committee Co Chairs: Working Committee Co Chairs: Working Committee Co Chairs: Adriana Seber, MD Instituto De Oncologia Pediatrica Sao Paulo, Brazil Telephone: Fax: adrianaseber@graacc.org.br Carrie Kitko, MD University of Michigan Medical Center 1500 E. Medical Center Drive Ann Arbor, MI USA Telephone: Fax: E mail: ckitko@med.umich.edu Gregory A. Hale, MD Dept. of Hematology/Oncology All Children s Hospital 501 6th St. South, St. Petersburg, FL Telephone: Fax: gregory.hale@allkids.org 14

15 Not for publication or presentation Attachment HYPOTHESIS: 1.1 Survival outcomes as defined by overall survival (OS) and disease free survival (DFS) in children with T cell acute lymphoblastic leukaemia (T ALL) in second complete remission (CR2) is poor despite receiving hematopoietic cell transplantation (HCT). 1.2 Transplant outcomes for those with early relapse of T ALL (<36mo from Dx) will have inferior outcomes to those transplanted for late relapse (>36 mo from Dx). 2.0 OBJECTIVES: 2.1 Primary Objective: To report leukemia free survival and overall survival of pediatric patients with T ALL who received HCT from Secondary objectives: Acute graft versus host disease (GVHD) Chronic GVHD Transplant related mortality Relapse 3.0 SCIENTIFIC JUSTIFICATION: Each year, children are diagnosed with T cell acute lymphoblastic leukemia (T ALL) in the US. Historically, the diagnosis of T ALL portended a worse prognosis than other forms of childhood ALL, but with the introduction of intensive, high dose, multi agent chemotherapy, outcomes have significantly improved.[1] Recent trials using a BFM based backbone regimen (CCG 1961) and/or intensified therapy with HD MTX ( POG 9404) have further improved outcomes for children with T ALL, but have plateaued in the 70 75% EFS range for the higher risk patients.[2] The long term survival for T ALL patients in CR2, treated with chemotherapy alone (i.e., no transplant) has been very disappointing, with the majority of patients dying of disease regardless of salvage regimen.[3] Whether HCT improves outcomes for T ALL in the relapsed setting is currently unclear. Likewise, whether the timing of relapse impacts transplant related outcomes for T ALL is uncertain. Recently the BFM group has published their findings with transplantation in patients in CR1.[4] Using data from two consecutive trials (BFM90 and 95), these investigators show that T ALL patients with high risk features (prednisone poor response after 1 week of therapy or non response at D+33) benefit from upfront allogeneic transplant (in CR1) compared to the use of chemotherapy alone (DFS was 67%+/ 8% for allo HCT (n=36) vs. 42%+/ 5% for chemotherapy alone (n=120) (p<0.01)). However, to date, the outcomes for patients with relapsed T ALL still remains unclear and under reported. This study, targeting patients 18 years of age with T cell ALL in CR2 who received a HCT between years , would be the largest pediatric HCT study of T ALL ever reported. The analysis would compare HCT outcomes based on CR status, graft source and regimen, site and timing of relapse along with any impact of WBC at Dx may have on HCT outcome. For this relatively high risk group of acute leukemia patients, it is currently unclear what role HCT has in improving outcomes in the relapsed setting. 15

16 Not for publication or presentation Attachment STUDY POPULATION: The study population will include subjects 18 years or younger with the diagnosis of T ALL in CR2 reported in the CIBMTR from 2000 to Patients with predisposing condition or received RIC conditioning regimen will be excluded. 5.0 VARIABLES TO BE DESCRIBED: - Gender (female vs. male) - WBC at diagnosis (<100x 10 9 /L vs. >=100x10 9 /L) - Extramedullary disease prior to transplant (yes/no) - Cytogenetics risk (High risk vs. other vs. normal vs. not reported) - Donor recipient gender match (Female donor, male recipient vs. Other) - Type of conditioning regimen (TBI containing vs. non TBI) - Year of BMT () - GVHD prophylaxis (CSA containing vs. Tacrolimus containing) 6.0 VARIABLES TO BE ANALYZED : Many factors can affect the transplant outcome of children with T ALL and may confound or modify the analysis of endpoints of interest. Important variables are described below: 6.1 Patient related: - Age at transplant (<10 vs. >10 years) - Karnofsky/Lansky performance score at time of transplant (<90% vs. >90%) - Recipient CMV status ( vs. +) 6.2 Disease related: - NCI risk groups (good vs. poor vs. unknown) - Duration of CR1 ( 36 months vs. >36 months) - Site of first relapse prior to transplant (BM+ others vs. CNS or Testes vs. not reported) 6.3 Transplant related: - Donor /HLA match (matched sibling vs. matched URD (BM or PB) vs. CB ) 7.0 OUTCOMES: Outcomes to be described: 7.1 Engraftment: Time to neutrophils (ANC) >0.5 x 10 9 /L (first of 3 consecutive days) and time to platelets 20 x 10 9 /L (first of 3 consecutive days and no platelet transfusions 7 days prior) 7.2 Acute graft versus host disease (GVHD): Occurrence of grade II, III and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD. 7.3 Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the criteria of chronic GVHD 16

17 Not for publication or presentation Attachment 4 Outcomes to be analysed: 7.4 Transplant related mortality (TRM): time to death without evidence of disease relapse. This event will be summarized as cumulative incidence estimate with relapse as the competing risk. 7.5 Relapse: time from date of transplant to onset of leukemia recurrence. This event will be summarized by cumulative incidence estimate with TRM as the competing risk. 7.6 Leukemia free survival: time from date of transplant to treatment failure (death or leukemia recurrence). Subjects will be censored at time of last contact. 7.7 Overall survival: Time to death, patients will be censored at last follow up. 8.0 STUDY DESIGN: For the univariate analysis, the probabilities of survival and leukemia free survival will be calculated using the Kaplan Meier estimator. Values for all other outcomes listed in Section 7.0 will be generated using cumulative incidence estimates. Univariate summary statistics will be computed by groups given in Section 1.0. For the multivariate analysis, Cox model will be used to identify significant risk factors. The variables to be considered in the multivariate models are listed in Sections 6. The assumption of proportional hazards for each factor in the Cox model will be tested using time dependent covariates. When the test indicated differential effects over time (non proportional hazards), models will be constructed breaking the post transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. The proportionality assumptions will be further tested. A stepwise model selection approach will be used to identify all significant risk factors. Factors which are significant at a 5% level will be kept in the final model. 8.0 REFERENCES: 1. Uckun FM, Sensel MG, Sun L, et al. Biology and treatment of childhood T lineage acute lymphoblastic leukemia. Blood 1998:91(3): Reiter A, Schrappe M, Ludwig WD, et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL BFM 86. Blood 1994:84(9): Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia Schrauder A, Reiter A, Gadner H, et al. Superiority of allogeneic hematopoietic stem cell transplantation compared with chemotherapy alone in high risk childhood T cell acute lymphoblastic leukemia: results from ALL BFM 90 and 95. J Clin Oncol 2006:24(36):

18 Not for publication or presentation Attachment 4 Table 1. Characteristics of patients who underwent myeloablative allogeneic stem cell transplantation for T cell ALL in CR2 between 2000 and 2011, reported to the CIBMTR. N(%) Number of patients 112 Number of centers 63 Age at transplant, median (range) 10 (2 18) <=5 22 (20) (30) (50) Recipient sex, male 91 (81) Performance score prior to transplant <90 20 (18) (79) Unknown 4 ( 4) WBC at diagnosis <100x 10 9 /L 44 (39) >=100x10 9 /L 47 (42) Unknown 21 (19) NCI risk groups* Good risk 21 (19) Poor risk 70 (63) Not reported 21 (19) Extramedullary disease prior to transplant No 46 (41) Yes 65 (58) Not reported 1 ( 1) Cytogenetics risk Normal 33 (29) Other 43 (38) High risk (t(9;22), t(4;11), t(8;14), hypodiploid) 4 ( 4) Not reported 32 (29) Duration of CR1, median (range), months 13 (<1 76) (85) >36 15 (13) Not reported 2 ( 2) Site of first relapse BM alone 41 (37) BM + other 24 (21) CNS alone 30 (25) Testes alone 4 ( 4) Not reported 13 (12) 18

19 Not for publication or presentation Attachment 4 N(%) Conditioning regimen TBI + CY 93 (83) TBI + Other 10 ( 9) Bu + Cy 9 ( 8) Donor recipient HLA match** HLA identical Sibling 25 (22) Matched BM/PBSC 17 (14) Mismatched BM/PBSC 15 (13) Matched CB 10 (10) Mismatched CB 45 (40) Donor recipient sex match F donor, M Recipient 38 (34) Other 73 (65) Not reported 1 ( 1) Recipient CMV status Negative 53 (47) Positive 58 (52) Not reported 1 ( 1) Graft type BM 40 (36) PB 17 (15) CB 55 (49) Received ATG or Campath No 63 (56) Yes 49 (44) Year of transplant (55) (45) GVHD prophylaxis CSA + MTX 41 (37) CSA + MMF 26 (23) CSA + Steroid 24 (22) Tacrolimus + MMF 3 ( 3) Tacrolimus + MTX 14 (13) Tacrolimus + Siro 1 ( 1) Cyclophosphamide 1 ( 1) Not reported 2 ( 2) Median (range) follow up, months 60 (3 121) Abbreviations: CMV = cytomegalovirus; CSA = Cyclosporine; MTX = Methotrexate; * NCI risk group: Age and WBC at diagnosis criteria used to define good risk group (children 1 <10 years with WBC <50000/mm 3 ) and poor risk group (all others). 19

20 Not for publication or presentation Attachment 4 ** Best available HLA matching information was used for unrelated. For unrelated donor transplantation, donor recipient HLA match considered allele level HLA typing at HLA A, B, C and DRB1. For umbilical cord blood transplantation, HLA matching considered low resolution match at HLA A and B and allele level at DRB1 20

21 Not for publication or presentation Attachment 5 Study Proposal Study title: Outcome of Total body irradiation (TBI) versus non TBI (chemotherapy) based conditioning regimens for allogeneic hematopoietic cell transplantation in MLL gene rearranged Acute myeloid leukemia Hemalatha Rangarajan, MD, Nationwide Children s Hospital, Hemalatha.Rangarajan@nationwidechildrens.org Prakash Satwani, MD, Columbia University Medical Center, ps2087@columbia.edu Hypothesis: MLL rearranged leukemia s with 11q23 abnormalities are detected in 15 25% children with AML [1]. They are currently classified under the category of AML with recurrent genetic abnormalities. However this subgroup has been recently recognized as a distinctly heterogeneous group with intermediate to poor prognosis. Prognosis depends on a variety of factors including translocation partners (TP), additional cytogenetic aberrations (ACA), onset: de novo or therapy related (t AML). Allogeneic hematopoietic cell transplantation (AlloHCT) is offered as a first line of therapy for t AML. However this is not the case for de novo MLL AML. Currently de novo MLL AML patients are stratified at the end of induction as per the MRD status on the current COG protocol (AAML1031). In patients undergoing AlloHCT, some centers utilize chemotherapy based conditioning and others prefer TBI based conditioning regimens. There have been no studies to date comparing survival outcomes of TBI based conditioning regimens with non TBI based regimens in children with de novo MLL AML. We hypothesize that children and young adults (<21 years) of age with de novo MLL AML have inferior outcomes when they are treated with TBI based versus non TBI based conditioning regimens. Objectives: Primary 1. To compare outcomes of patients treated with TBI based versus chemotherapy based myeloablative conditioning regimens for MLL AML. The specific outcomes to be ascertained include: 2 year event free survival (EFS) 2 year leukemia free survival (LFS) 100 days and 1 year non relapse mortality (NRM) following AlloHCT Secondary 2. To compare the 2 year leukemia free survival in various translocation partners in patients with MLL AML 3. To study risk factors associated with increased risk of relapse in patients with MLL AML Scientific Justification: More than 60 different translocation partners of the MLL gene have been described to date with data emerging regarding the prognosis of each of these translocation partners [2]. Approximately 50% of the pediatric AML cases with MLL rearrangements consist of t (9, 11) (p22, q23). The other 50% predominately include t (6, 11) (q27, q23), t (10, 11) (p12, q23), t (11, 19) (q23, p13.1) and t (11, 19) (q23, p13.3) [3]. MLL rearranged AML patients have intermediate outcomes with 5 year EFS ranging from 32 to 54% and a 4 year OS ranging from 42 62% [3]. Outcomes are noted to be dependent on the translocation partners. For example, t (1, 11) (q21pq23) is a newer prognostic subgroup in pediatric AML. This type of AML has an excellent clinical outcomes (5 year EFS of 92% and OS of 100%) [4]. By contrast t (10, 11) and t (6, 11) have poor prognosis Favorable outcome is also noted based on 21

22 Not for publication or presentation Attachment 5 morphology: i.e. t (9, 11) (p22, q23) with FAB M5 have better prognosis than other FAB subtypes [4, 5]. Additional cytogenetic aberrations such as trisomy 8 etc. are also known to influence outcome [2]. With emerging new information regarding the translocation partners in MLL, the role of AlloHCT in patients with MLL with poor prognosis TP is largely unknown due to the small patient numbers involved. In children with AML, the survival following AlloHCT is not inferior to the patients who receive chemotherapy alone. However, due to short and long term morbidities associated with AlloHCT, the current COG study does not recommend AlloHCT in CR1 for patients with MLL AML. Moreover, TBI is associated with higher incidence of long term morbidities. Due to paucity of outcome data following AlloHCT in children with MLL AML it is difficult for transplant physicians to recommend the best conditioning regimen for patients with MLL AML. Two recent studies in adult patient with AML have demonstrated that busulfan based regimens were superior to TBI based myeloablative conditioning regimens [6, 7]. In children with AML busulfan based regimens have similar survival compared to TBI based regimens as a result of which majority of children currently receive chemotherapy based myeloablative conditioning regimen [8]. However, due to concerns related to potentially higher risk of relapse following AlloHCT in MLL AML patients, some centers prefer to use TBI based myeloablative conditioning regimens. There is clear paucity of literature on the role of conditioning regimens and their influence on outcomes in children with de novo MLL AML. The proposed study seeks to fill this existing gap in literature and might help to change practice. Study Population: Inclusion Criteria Diagnosis: de novo MLL rearranged AML: Age: < 21 years at the time of AlloHCT Therapy: Received MSD or MURD AlloHCT in CR1 or beyond CR1 with either TBI based or non TBI based myeloablative regimens. Years: Exclusion Criteria Therapy related MLL AML AML with MLL resulting from Partial tandem duplication (MLL PTD) Patients with Downs syndrome Patients who underwent autosct. Patient who underwent reduced intensity conditioning Haplo identical donors Study Design: Case Control Study 2 controls: AlloHCT with chemotherapy based regimen will be matched with 1 case of TBI based myeloablative regimens. Matching criteria would be based on age, donor type, translocation partners, and year of AlloHCT. Study risk factors associated with relapse o Age of patient, donor, gender of patient, ethnicity, year of AlloHCT, CR1 vs. CR2 vs. other disease status indications, MSD vs. MUD vs. unrelated cord blood donor, stem cell source, translocation partners (TP), associated cytogenetic aberrations (ACA), TBI vs. chemotherapy based conditioning regimens, acute GVHD, chronic GVHD, VOD. 22

23 Not for publication or presentation Attachment 5 Study risk factors associated with 1 year TRM o Age of patient, donor, gender of patient, ethnicity, year of AlloHCT, CR1 vs. CR2 vs. other disease status indications, MSD vs. MUD vs. unrelated cord blood donor, stem cell source, TBI vs. chemotherapy based conditioning regimens, acute GVHD, chronic GVHD, VOD. Statistical Consideration: The continuous variables were summarized by mean and standard deviation; the categorical variables were summarized by percentage. To compare EFS and OS between TBI vs. non TBI regimens, Kaplan Meir curves will be generated. Unvariate and multivariate analysis will be performed for risk factors associated with relapse and TRM. Data Requirements: CIMBTR from Pre AlloHCT data Date of diagnosis Age at diagnosis MLL translocation partner Additional cytogenetic abnormalities Chemotherapy date of start and end of therapy o BM at end of induction and end of therapy o Disease status: CR1, CR2 and other Transplant related: Conditioning regimen: TBI based: Total dose of TBI /dose per fraction. Details of chemotherapy along with TBI Non TBI based regimens: details of preparative regimen Outcomes: Demographics: median age and range at diagnosis, gender ratio, performance status Disease variable at diagnosis: MLL translocation partner, ACA, number of chemotherapy cycles prior to AlloHCT. Incidence of day 100 and 1 year non relapse mortality, incidence of relapse, agvhd, cgvhd, 2 year EFS, 2 year LFS Long term: incidence of secondary cancers. References: 1. Bernt KM, Armstrong SA. Targeting epigenetic programs in MLL rearranged leukemias. Hematology Am.Soc.Hematol.Educ.Program. 2011;2011: Coenen EA, Raimondi SC, Harbott J, et al. Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL rearranged AML patients: results of an international study. Blood. 2011;117: Balgobind BV, Zwaan CM, Pieters R, Van den Heuvel Eibrink MM. The heterogeneity of pediatric MLL rearranged acute myeloid leukemia. Leukemia. 2011;25: Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114: Rubnitz JE, Raimondi SC, Tong X, et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J.Clin.Oncol. 2002;20:

24 Not for publication or presentation Attachment 5 6. Copelan EA, Hamilton BK, Avalos B, et al. Better leukemia free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared to TBI. Blood Nagler A, Rocha V, Labopin M, et al. Allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total body irradiation plus Cy as conditioning regimen a report from the acute leukemia working party of the European group for blood and marrow transplantation. J.Clin.Oncol. 2013;31: Sisler IY, Koehler E, Koyama T, et al. Impact of conditioning regimen in allogeneic hematopoetic stem cell transplantation for children with acute myelogenous leukemia beyond first complete remission: a pediatric blood and marrow transplant consortium (PBMTC) study. Biol.Blood Marrow Transplant. 2009;15:

25 Not for publication or presentation Attachment 5 Characteristics of Study Population (first myeloablative allo transplants for patients with MLL rearranged AML between 2000 and 2012, patient age<21 years) Variable Non TBI, N(%) TBI containing, N(%) Number of patients Number of centers Age at transplant, median (range), years 4 (<1 21) 10 (1 21) <=5 46 (56) 13 (31) (13) 9 (21) (17) 14 (33) (13) 6 (14) Recipient sex, male 34 (41) 17 (40) Disease status prior to transplant CR1 58 (71) 19 (45) CR2+ 17 (21) 16 (38) Relapse/PIF 7 ( 9) 7 (17) Conditioning regimen Donor type Graft type TBI + Cy 0 35 (83) TBI + Other 0 7 (17) Bu + Cy 61 (74) 0 Bu + Fludara 15 (18) 0 Bu + Melphalan 4 ( 5) 0 Bu + Other 1 ( 1) 0 Fludara + Melphalan 1 ( 1) 0 HLA identical sibling 28 (34) 3 ( 7) Unrelated 54 (66) 39 (93) BM 36 (44) 16 (38) PBSC 13 (16) 9 (21) Cord Blood 33 (40) 17 (40) Year of transplant (20) 14 (33) (80) 28 (67) Median (range) follow up, months 38 (4 106) 49 (23 96) 25

26 Not for publication or presentation Attachment 6 Study Proposal Study Title: Outcome of matched sibling donor hematopoietic cell transplantation for children with acute myelogenous leukemia in first complete remission as compared to beyond first complete remission Chana Weiner, MD, Columbia University Medical Center, chw9070@nyp.org Prakash Satwani, MD, Columbia University Medical Center, ps2087@columbia.edu Hypothesis: Acute myelogenous leukemia (AML) is the second most common type of leukemia in children and remains a great challenge to successfully treat. Significant advances have been made in approaches to therapy over the past few decades and a complete remission (CR) can now be achieved in >90% of children. However, 40 50% of children relapse with chemotherapy alone. While a CR2 can be achieved in most patients, long term survival in this population remains poor, at approximately 10 35%. 1 There is also considerable difference in disease free survival (DFS) rates for children with AML in various risk categories with a 3 year DFS as high as 68±9% for low risk patients versus 20±16% for high risk patients (Alonzo, Abstract Blood 2010). Refinements in risk stratification have helped guide intensity of therapy for subgroups of patients, but the role for allogeneic hematopoietic cell transplantation (AlloHCT) in CR1 remains unclear. The current ongoing phase III North American Children's Oncology Group (COG) AML study risk stratifies children with newly diagnosed AML by cytogenetics, FLT3 mutation status, and minimal residual disease (MRD) status, limiting AlloHCT in CR1 to children with high risk AML (defined as FLT3/ITD mutation positive with high allelic ratio >0.4, cytogenetics positive for monosomy 5 or 7, del(5q), or high MRD at end of Induction I 0.1%). While there has been a general consensus among AML consortiums that the standard of care for low risk patients is chemotherapy alone, there remains great controversy over the role of AlloHCT for standard and high risk in CR1, especially those with a MSD available. While AlloHCT has been shown to decrease the relapse rate in high risk AML, this benefit may be offset by increased transplant related mortality (TRM), especially with matched unrelated donor (MUD) AlloHCT. It is well established that children who receive MSD AlloHCT have better outcomes than those who receive MUD AlloHCT, however, there is little data to show whether MSD outcomes are more favorable in CR1 than beyond CR1 (CR2, partial remission after relapse, or induction failure after relapse)following more heavy pre treatment. 2 We hypothesize that children with standard and high risk AML at diagnosis with a MSD available have overall better outcomes when they receive AlloHCT in CR1 as compared to beyond CR1. Objectives: Primary 1. Compare outcomes of children with standard and high risk AML who receive a MSD AlloHCT in CR1 to those who received a MSD AlloHCT beyond CR1 (CR2, partial remission after relapse, induction failure after relapse) 2 year disease free survival (DFS) Rates of TRM and non relapse mortality at 1 year and 2 years Secondary 2. To compare the incidence of DFS between versus among patients receiving MSD AlloHCT in CR1 and beyond CR1 3. To compare the incidence of TRM between versus among patients receiving MSD AlloHCT in CR1 and beyond CR1. 26

27 Not for publication or presentation Attachment 6 Scientific Justification: The use of AlloHCT as consolidative therapy for standard and high risk AML in children remains a controversial issue with considerable variation in practice worldwide. Over the past decade, there has been a general shift away from offering AlloHCT to children with AML upfront as increasing evidence suggests curability with chemotherapy alone in significant subsets of patients and concerns about TRM counter balancing potential survival benefits. In a recent study Gooley, et al demonstrated a significant decrease in TRM following AlloHCT over a period of one decade. 3 It is well established that children who receive MSD HSCTs have better overall outcomes than those who receive MUD AlloHCT 2, however, in theory, these advantages may become compromised by reserving AlloHCT beyond CR1 following heavier pre treatment and potentially more resistant leukemia. To our knowledge, there has never been a study conducted comparing outcomes of AlloHCT from a MSD in CR1 versus beyond CR1. Such data would serve quite useful in the clinical setting when deciding whether to offer HCT to a child with standard or high risk AML when a MSD is available. United States Experience Horan, et al. combined data from four cooperative group clinical trials (POG 8821, CCG 2891, CCG 2961, and MRC 10), all of which utilized AlloHCT in CR1 for all risk groups if a MSD was available. Their analysis of 1373 pediatric patients with AML in CR1 revealed a statistically significant improved 8 year DFS and OS for those with standard risk AML who received a MSD AlloHCT in CR1 (DFS 58% and OS 62%) versus those who received chemotherapy alone (DFS 39% and OS 51%, P<0.01). No significant differences were found for low and high risk patients. 4 United Kingdom Experience The United Kingdom MRC AML 10 study (data included in the Horan study) designated all pediatric patients ( ) with de novo AML (<14 years of age), regardless of risk group, to AlloHCT in CR1 if a MSD was available. Patients with a donor had a significantly reduced relapse risk than patients without a MSD donor (randomized to receive auto SCT or chemotherapy alone), 26% vs. 42% (P=0.02). However, fewer relapses were counterbalanced by increased TRM (p=0.001) with no difference found in 10 year OS. This data reveals an encouraging reduction in relapse risk for patients with a MSD AlloHCT in CR1 and suggests that reductions in TRM, which have been achieved over the last decade since this trial was completed, may allow for improved OS. The subsequent trial, AML MRC 12 ( ), which risk stratified patients based on cytogenetics and treatment response, offered AlloHCT only to standard and high risk patients with a MSD available and intensified chemotherapy for those without a donor. While five year OS, DFS, EFS, and RR were improved to 66, 61, 56, and 35%, respectively, from the prior MRC AML 10 study (58, 53, 49, and 42%, respectively), the two studies combined did not show a significant improvement in DFS or OS for AlloHCT in CR1 for any risk group, calling the role for AlloHCT into question. 5,6 BFM Experience The AML BFM 98 study ( ), which limited AlloHCT in CR1 even further to children only with high risk AML and a MSD available, also did not support the role for HSCT in CR1. Of 247 total children enrolled, 61 received a MSD AlloHCT and 186 received chemotherapy alone. There was no significant difference found in 5 year DFS or OS between the two groups, except for a subgroup of patients with 11q23 aberrations who benefited from AlloHCT. Late adverse effects, however, occurred more frequently after transplant (P<0.01). This study, however, excluded standard risk patients from receiving MSD AlloHCT in CR1, which, as several studies have suggested, may be the group with the most potential benefit. 7 27