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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR PEDIATRIC CANCER Salt Lake City, Utah Wednesday, February 13, 2013, 2:45 pm 4:45 pm Co-Chair: Paul A. Carpenter, MD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: ; Fax: ; pcarpent@fhcrc.org Co-Chair: Adriana Seber, MD, Instituto De Oncologia Pediatrica, Sao Paulo, BRAZIL Telephone: ; Fax: ; adrianaseber@graacc.org.br Co-Chair: Carrie Kitko, MD, University of Michigan Medical Center, Ann Arbor, MI Telephone: ; Fax: ; ckitko@med.umich.edu Statisticians: Wensheng (Vincent) He, MS, CIBMTR, Milwaukee, WI Telephone: ; Fax: ; vhe@mcw.edu Mei-Jie Zhang, PhD, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; meijie@mcw.edu Scientific Director: Mary Eapen, MD, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; meapen@mcw.edu 1. Introduction a. Minutes of February, 2012 meeting (Attachment 1) b. Newly appointed chair: Gregory Hale, MD; All Children's Hospital; Phone: ; Fax: ; haleg@allkids.org 2. Accrual summary (Attachment 2) 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, 2012 Jun 21: 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, Submitted. 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 Treatment for Pediatric AML with Poor-Risk Cytogenetics. Presented at the American Society of Hematology in Atlanta, Georgia, December

2 Not for publication or presentation d. PC10-02 Hitzler JK, He W, Doyle J, Bitan M, Cairo M, Camitta BM, Chan KW, Diaz MA, Fraser C, Gross TG, Horan JT, Kasow KA, Kennedy-Nasser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. Presented at the American Society of Hematology in Atlanta, Georgia, December Studies in progress (Attachment 3) a. PC10-04 HCT for children with poor risk AML Manuscript Preparation (M. Kelly et al) b. PC10-01 RIC HCT for children with AML (M. Bitan, Analysis P. Mehta and S. Jodele) (Attachment 4) c. PC10-03 HCT for children with Hypodiploid ALL Protocol Development (P. Mehta and S. Jodele) d. PC09-01 Allo in children with T-ALL (M. Burke) Protocol Development 5. Planned studies a. PC11-01 Development of a prognostic scoring system to predict relapse of pediatric ALL after allo HCT (N Shah et al) Protocol Development 6. Future/ Proposed studies a. PROP Factors predicting treatment-related mortality in pediatric autologous transplant. (E. Perez-Albuerne ) (Attachment 5) 7. Other business 2

3 Not for publication or presentation Attachment 1 MINUTES CIBMTR WORKING COMMITTEE FOR PEDIATRIC CANCER San Diego, California Wednesday, February 1, 2012, 2:45 pm 4:45 pm Co-Chair: Paul A. Carpenter, MD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: ; Fax: ; pcarpent@fhcrc.org Co-Chair: Adriana Seber, MD, Instituto De Oncologia Pediatrica, Sao Paulo, BRAZIL Telephone: ; Fax: ; adrianaseber@graacc.org.br Co-Chair: Carrie Kitko, MD, University of Michigan Medical Center, Ann Arbor, MI Telephone: ; Fax: ; ckitko@med.umich.edu Statisticians: Vincent He, MS, CIBMTR, Milwaukee, WI Telephone: ; Fax: ; vhe@mcw.edu Mei-Jie Zhang, PhD, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; meijie@mcw.edu Scientific Director: Mary Eapen, MD, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; meapen@mcw.edu 1. Introduction Dr. Paul Carpenter welcomed the audience. The minutes from the 2010 meeting were approved. Dr. Paul Carpenter announced the new CIBMTR effort, the Forms Revision Process. All data collection forms are undergoing revision over the next two years, starting with the following: CRID (2804), Pre-TED (2400), Baseline (2000), Infectious Disease Markers (2004), HLA (2005), Infusion (2006), AML (2010/2110), ALL (2011/2111), MDS (2014/2114), JMML (2015/2115), Plasma Cell Disorders (2016/2116), Amyloidosis (2017/2117), Lymphoma (2018/2118) and Waldenstrom's Macroglobulinemia (2019/2119). The revised forms will coincide with the development of the new FormsNet application. Members are encouraged to become a member of the Forms Revision Review Committee in order to capture all the relevant information needed to produce high-quality studies. Suggestions for forms should be forwarded to Emilie Meissner at emeissne@nmdp.org. 2. Accrual summary Numbers of transplants for pediatric malignancy stratified by graft type and donor were presented as part of the meeting documents. 3. Published or submitted papers a. PC05-02 Nemecek ER, Ellis K, He W, Bunin NJ, Bajwa RS, Cheerva A, Cairo MS, Dvorak C, Duval M, Davies S, Eapen M, Gross TG, Hussein AA, MacMillan ML, Mehta PA, Pulsipher MA, Seber A, Woolfrey AE, Frangoul HA, Carpenter PA. Outcome of myeloablative conditioning and unrelated donor hematopoietic cell transplantation for childhood acute lymphoblastic leukemia in third remission. Biology of Blood & Marrow Transplantation 17: ,

4 Not for publication or presentation Attachment 1 b. D Woodard P, Carpenter PA, Davies SM, Gross TG, He W, Zhang MJ, Horn BN, Margolis DA, Perentesis JP, Sanders JE, Schultz KR, Seber A, Woods WG, Eapen M. Unrelated donor bone marrow transplantation for myelodysplastic syndrome in children. Biology of Blood & Marrow Transplantation. 17: , c. 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. Submitted. 4. Studies in progress a. PC10-04 HCT for children with poor risk AML (M. Kelly et al; collaboration with the Children s Oncology Group) Dr. Michael Kelly presented the update of this study. The primary objective is to compare outcomes among poor risk patients with AML in first complete remission treated with chemotherapy vs. transplantation. There are 300 eligible cases (Chemotherapy only, n=149; Matched family donor, n=79; Unrelated donor, n=72). Of the 151 transplant cases, 122 were from CIBMTR databasea (HLA-identical sibling, n=50; Unrelated, n=72). The CIBMTR study file was given to the COG. The next step is for COG to merge their data and that from the CIBMTR and perform the analysis. There was some concern about the study inclusion period inclusion of patients treated over a decade ago differs from current era. Both transplantation and chemotherapy strategies have evolved over time and treatment period will be considered as a covariate in all analysis. The other concern is the inclusions of patients transplanted in regions were chemotherapy regimens might differ from COG regimens. Further exploration of the CIBMTR dataset identified 20 patients transplanted in the Middle-east, South America and Asia. Correspondence with study team: a subset analysis excluding these 20 patients will be performed to ensure the inclusion of these 20 patients will not change the final outcome. b. PC10-02 Outcomes of HCT for leukemia in children with Down s syndrome (J. Hitzler) Dr. Hitzler presented the results. Twenty-eight AML and 27 ALL patients with Down yndrome (DS) transplanted after 1999 are included in the study. The patient, disease, transplant characteristics and univariate analysis of outcomes were presented. In addition, the results of a matched-pair analysis (DS vs. Non-DS AML patients) were also presented. Cases and controls were matched on: age, disease status, cytogenetics, donor HLA and graftype.interestingly, transplant-related mortality risks were not significantly different between DS and non-ds atients. Relapse risks were significantly higher in DS patients leading to significantly lower leukemia-free and overall survival rates in these patients compared to non-ds patients. A similar analysis could not be undertaken for ALL due to limited sample size. It was suggested an extensive description of ALL cases might help physicians considering transplantation for DS patients with ALL. Also suggested: two separate papers, one focusing on AML and the other ALL c. PC11-01 Development of a prognostic scoring system to predict relapse of pediatric ALL after allogeneic HCT (N Shah et al)dr. Nirali Shah presented the update of the study. The primary aim is to develop a prognostic scoring system based on patient, disease, and transplant-specific factors predictive for relapse after allogeneic HCT in pediatric patients with ALL. The CIBMTR data does not have information on minimal residual disease (MRD). The plan is to develop a predictive score without considering MRD the CIBMTR cases will serve as training and validation sets. Thereafter, the scoring system will be assessed using ALL-REZ dataset from BFM group (JCO 2009 paper) which has MRD information. The ALL-REZ dataset only included patients transplanted in CR2 and CR3 and no cord blood transplants The CIBMTR data has

5 Not for publication or presentation Attachment 1 ALL patients who are potentially eligible. The transplants in Europe, Asia and Middle East were excluded which allows future analysis and validation using BMF dataset. IC/NST transplants and patients transplanted in primary induction failure were also excluded. The next step is study design and analysis. Dr. Pulsipher mentioned that COG has a dataset of about 100 patients hat has MRD information. This can also be used as a validation dataset, but we will need to make sure that these patients are removed from the CIBMTR dataset. d. PC10-03 HCT for children with Hypodiploid ALL (P. Mehta and S. Jodele) there are 170 potentially eligible patients. The supplemental data cytogenetic report forms have been received for 144 patients. The final round of data request will be completed by March 2012; Dr. Mehta appealed to the audience to respond to the last request. e. PC09-01 Allo in children with T-ALL (M. Burke) The additional data collection - site of first relapse prior to transplant for about 80 unrelated cases with missing data (these data were collected using NMDP legacy data collection forms for ALL) is in the process. 6. Planned studies a. PC10-01 RIC HCT for children with AML (M. Bitan, P. Mehta and S. Jodele) There were no statistical hours assigned in b. PC11-02 Development of a prognostic scoring system to predict relapse of pediatric AML after allo HCT (N Shah et al) There were no statistical hours assigned in Future/ Proposed studies a. PROP Marrow harvest characteristics and outcomes of HLA identical donor HCT in children (R. Goya and M. Pulsipher) Dr. Goyal presented the proposal. The primary aim is to study the relationship between marrow volume and cell dose with outcomes of HLA identical donor HCT in children. A major goal of this proposal is to be able to define a minimum marrow volume per kilogram to be collected from donors that would be sufficient to engraft in recipients where the donor is of lower body weight than the recipient. This is problematic from first principles of donor safety where the standard practice is not to exceed a certain marrow harvest volume of ml/kg donor body weight. This is not an issue when the donor is much larger than the recipient since this ceiling volume is not reached. The committee noted that it is cell dose rather than cell volume that is the accepted key metric with relevance to engraftment. A major problem with this proposal is that marrow harvest technique is a major confounder. That is, hemodilute harvests due to inappropriate large volume marrow single aspirates, or worse, intraoperative transfusion to allow further hemodilute marrow to be collected, will negate a meaningful analysis of the relationship between marrow volume and cell dose which is key to this analysis. Several members of the committee commented on two publications from Seattle in the 1980s that described the safety and success of marrow collections from pediatric patients, including very small children. Since the major concern that leads to this proposal is whether the very smallest of donors can result in engraftment among the largest recipients one suggestion was to examine the relationship of engraftment among only those donor:recipient pairs where recipient minus donor body weight discrepancy is greatest. After considering published literature there was consensus that any recommendations from the proposed study are unlikely to advance pediatric hematopoietic transplantation. Consequently, the recommendation from the committee members was not to pursue this further. The meeting adjourned at 4:25 PM 5

6 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 Nov, 2012*. HLA-identical sibling HCT TED, N (%) Research, N(%) Acute myeloid leukemia Bone Marrow 2833 (79) 1211 (85) Peripheral blood 683 (19) 186 (13) Cord Blood 57 ( 2) 31 ( 2) Acute lymphoblastic leukemia Bone Marrow 3834 (81) 1591 (84) Peripheral blood 783 (17) 246 (13) Cord Blood 93 ( 2) 61 ( 3) Chronic myeloid leukemia Bone Marrow 666 (79) 320 (84) Peripheral blood 166 (20) 53 (14) Cord Blood 15 ( 2) 6 ( 2) Myelodysplastic Syndrome Bone Marrow 611 (82) 282 (84) Peripheral blood 112 (15) 37 (11) Cord Blood 19 ( 3) 15 ( 4) Hodgkin lymphoma Bone Marrow 25 (56) 9 (64) Peripheral blood 20 (44) 5 (36) Non-Hodgkin lymphoma Bone Marrow 316 (78) 135 (80) Peripheral blood 85 (21) 31 (18) Cord Blood 4 ( 1) 2 ( 1) * Cases in 2012 continue to be reported 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 1990 and Nov, 2012* Other related donor HCT TED, N (%) Research, N(%) Acute myeloid leukemia Bone Marrow 432 (55) 154 (67) Peripheral blood 338 (43) 77 (33) Cord Blood 14 ( 2) 0 Acute lymphoblastic leukemia Bone Marrow 696 (62) 278 (75) Peripheral blood 414 (37) 93 (25) Cord Blood 17 ( 2) 1 (<1) Chronic myeloid leukemia Bone Marrow 113 (66) 41 (68) Peripheral blood 55 (32) 19 (32) Cord Blood 2 ( 1) 0 Myelodysplastic Syndrome Bone Marrow 129 (62) 57 (81) Peripheral blood 75 (36) 13 (19) Cord Blood 3 ( 1) 0 Hodgkin lymphoma 15 3 Bone Marrow 6 (40) 2 (67) Peripheral blood 9 (60) 1 (33) Non-Hodgkin lymphoma Bone Marrow 58 (58) 16 (70) Peripheral blood 40 (40) 7 (30) Cord Blood 2 ( 2) 0 * Cases in 2012 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 1990 and Nov, 2012* Unrelated donor HCT TED, N (%) Research, N(%) Acute myeloid leukemia Bone Marrow 1579 (49) 1022 (52) Peripheral blood 507 (16) 210 (11) Cord Blood 1159 (36) 751 (38) Acute lymphoblastic leukemia Bone Marrow 3006 (56) 1905 (59) Peripheral blood 708 (13) 268 ( 8) Cord Blood 1669 (31) 1079 (33) Chronic myeloid leukemia Bone Marrow 618 (76) 437 (79) Peripheral blood 96 (12) 50 ( 9) Cord Blood 95 (12) 64 (12) Myelodysplastic Syndrome Bone Marrow 751 (56) 506 (59) Peripheral blood 175 (13) 70 ( 8) Cord Blood 416 (31) 287 (33) Hodgkin lymphoma 21 9 Bone Marrow 10 (48) 3 (33) Peripheral blood 6 (29) 2 (22) Cord Blood 5 (24) 4 (44) Non-Hodgkin lymphoma Bone Marrow 161 (49) 88 (49) Peripheral blood 67 (20) 28 (16) Cord Blood 103 (31) 63 (35) * Cases in 2012 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 leukemia and lymphoma reported to the CIBMTR between 1990 and Nov, 2012* Autologous HCT Registration, N (%) Research, N(%) Acute myeloid leukemia Bone Marrow 526 (63) 290 (76) Peripheral blood 309 (37) 91 (24) Cord Blood 2 (<1) 0 Acute lymphoblastic leukemia Bone Marrow 216 (65) 104 (77) Peripheral blood 113 (34) 31 (23) Cord Blood 2 ( 1) 0 Hodgkin lymphoma Bone Marrow 169 (14) 59 (26) Peripheral blood 1061 (86) 168 (74) Non-Hodgkin lymphoma Bone Marrow 190 (25) 56 (35) Peripheral blood 557 (75) 105 (65) * Cases in 2012 continue to be reported 9

10 Not for publication or presentation Attachment 3 TO: FROM: RE: Pediatric Cancer Working Committee Members Mary Eapen, MD, MS Scientific Director for the Pediatric Cancer Working Committee Studies in Progress Summary Studies in progress PC10-04: Treatment outcomes for children with poor risk acute myeloid leukemia (M Kelly): This is a collaborative study with Children s Oncology Group. The primary aim of this study is to more accurately estimate the 5-year overall survival, event-free survival, and relapse rate in children and adolescents with poor risk AML treated with either: HLA matched related donor hematopoietic stem cell transplantation (HSCT), unrelated donor HSCT, or chemotherapy only and to compare these outcomes. The data of the patients who have received a HSCT for intermediate risk AML in first complete remission and poor risk AML patients treated with chemotherapy only was provided by COG. The CIBMTR provided the data of patients who have received a HSCT for poor risk AML in first complete remission. The analysis has been completed and a manuscript is being prepared by the COG. The manuscript is expected to be submitted by July PC10-01: Stem cell transplantation for children with acute myeloid leukemia Comparing outcomes of transplantation between reduced intensity and myeloablative conditioning regime (M Bitan/P Mehta): This study proposes to assess the outcomes of children with AML transplanted using RIC preparative regimens and compare them with the outcomes of AML patients transplanted using myeloablative preparative regimens. The matched pair analysis is under way and a manuscript is expected to be submitted by July PC10-03 Transplantation for treatment of Hypodiploid acute lymphoblastic leukemia (P Mehta/ S Jodele): 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 two eligible patients are identified by reviewing the cytogenetic report from transplant centers. The data file preparation is under way. PC09-01: Outcomes in children with t-cell acute lymphoblastic leukemia following allogeneic hematopoietic cell transplantation (M Burke): This study proposes to analyze the outcomes of allogeneic transplantation for children with T-cell ALL and identify the risk factors that are associated with the outcomes. A draft protocol is available for review. Studies previously proposed, but not initiated PC11-01: Development of a prognostic scoring system to predict relapse of pediatric ALL after allogeneic HCT (N Shah et al.): The primary aim is to develop a prognostic scoring system based on patient, disease, and transplant-specific factors predictive for relapse after allogeneic HCT in pediatric patients with ALL. * Please note no statistical hours are assigned for PC09-01, PC11-01 between July 1, 2012 and June 30,

11 Not for publication or presentation Attachment 4 CIBMTR PC10-01 STEM CELL TRANSPLANTATION FOR CHILDREN WITH ACUTE MYELOID LEUKEMIA COMPARING OUTCOME BETWEEN REDUCED INTENSITY AND MYELOABLATIVE CONDITIONING REGIMENS PROTOCOL Study Co-Chair: Study Co-Chair: Study Co-Chair: Study Statistician: Menachem Bitan, MD PhD Tel-Aviv Sourasky Medical Center 6 Weizmann St., Tel Aviv, Israel Telephone: Fax: menachembi@tasmc.health.gov.il Parinda Mehta, MD Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati, OH Telephone: Fax: parinda.mehta@cchmc.org Sonata Jodele, MD Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati, OH Telephone: sonata.jodele@cchmc.org Wensheng (Vincent) He, MS CIBMTR Statistical Center Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: vhe@mcw.edu 11

12 Not for publication or presentation Attachment 4 Scientific Director: Working Committee Co-Chair: Working Committee Co-Chair: Working Committee Co-Chair: Mary Eapen, MD, MS CIBMTR Statistical Center Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: meapen@mcw.edu Paul Carpenter, MD Fred Hutchinson Cancer Research Center 4800 Sandpoint Way Seattle, WA USA Telephone: Fax: pcarpent@fhcrc.org 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: ckitko@med.umich.edu 12

13 Not for publication or presentation Attachment HYPOTHESIS: Reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) has improved the accessibility of transplantation in patients previously ineligible, but clinical utility in children is yet not well established. Transplant related toxicity is anticipated to be milder in children with acute myeloid leukemia (AML) in first complete remission (CR1) or second complete remission (CR2), prepared for stem cell transplantation (SCT) with RIC compared to patients conditioned with myeloablative regimens. However, it is not established whether disease control will be adequate. RIC has been used to salvage children with AML who relapse after the first transplantation with a second transplant, and in those with significant co-morbidities who would not tolerate a fully myeloablative preparative regimen prior to first transplant. In this study we propose to examine the available data regarding outcomes of RIC in children with AML treated with both first and second transplants and compare it to AML pediatric patients with the same characteristics who received myeloablative conditioning regimen, in order to determine if there is a place for the RIC approach in children. 2.0 OBJECTIVES: 2.1 Report outcomes of children with AML transplanted in first remission, and beyond first remission using RIC preparative regimens as compared to fully myeloablative regimens, including: Overall survival Event-free survival Incidence of GVHD Time to engraftment of neutrophils Time to engraftment of platelets 2.2 Outcomes of RIC-transplant and myeloablative transplant in children with AML comparing donor type /donor-recipient HLA match. 2.3 Compare outcome of RIC-transplant and myeloablative transplant in children with AML done on year period SCIENTIFIC JUSTIFICATION: Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for acute myelogenous leukemia (AML) (1-2). In the setting of myeloablative conditioning (MAC) SCT, it enables the administration of high-dose chemotherapy to eradicate leukemia and provides the benefit of the graft versus leukemia (GVL) effect. Thus, it has been considered to be the treatment of choice for children with AML in CR1 (3). However, with the excellent results obtained with chemotherapy alone, and the known risks and long-term side effects of HSCT, the decision to proceed to transplantation after achieving CR1 remains controversial. In recent years, RIC HSCT regimens have been demonstrated to be safe and efficacious in a wide range of hematologic malignancies (4). The low regimen related toxicity and morbidity have dramatically extended the availability of allogeneic HSCT to a large and important group of patients previously ineligible. All RIC protocols depend upon intensive immunosuppression in order to permit donor engraftment and to establish donor-recipient chimerism, which rapidly develops into full-donor chimerism with withdrawal of immunosuppression or donor lymphocyte infusions (DLIs). Control of disease is afforded principally by the GVL effect and to a lesser extent by the chemotherapy administered during conditioning. As most RIC regimens use relatively low doses of chemotherapy, the transplant related toxicity is significantly reduced. Recently, Olle Ringden and colleagues published a summary of the European experience with RIC protocols for 13

14 Not for publication or presentation Attachment 4 transplants from unrelated donors (UD), in adult patients. These authors conclude that RIC-UD transplants are associated with higher relapse in AML patients younger than 50 years of age and decreased non-relapse mortality (NRM) in those older than 50 years, compared with MAC-UD. Leukemia-free survival (LFS) was similar after both conditioning regimens, regardless of age (5). Another recent study of pediatric patients, defined the efficacy of a RIC regimen in pediatric patients ineligible for myeloablative transplantation (6). Forty-seven patients with a variety of diagnoses were enrolled and conditioned with busulfan/fludarabine/antithymocyte globulin. The authors conclude that favorable outcomes can be achieved with RIC approaches in pediatric patients in remission who are ineligible for myeloablative transplantation. The lack of wellestablished documentation of the advantages and disadvantages in RIC regimens specifically designed for pediatric AML patients in large cohorts means that the CIBMTR is the only organization with a series of cases sufficient to try to draw conclusions. 4.0 STUDY POPULATION: The following patients will be included in this study; Allogeneic HCT for AML using reduced intensity regimens defined as busulfan <8 mg/kg, melphalan <150 mg/m 2 and TBI dose 200 cgy or TBI dose < 500 cgy single dose or TBI dose <800 cgy fractionated Allogeneic HCT for AML using myeloablative conditioning Age 18 years at HSCT. Bone marrow, peripheral blood progenitor cells or cord blood. Matched related and matched/mismatched donors. First allogeneic transplants only Transplant period Exclude: patients with Down s sydrome, Fanconi anemia, and secondary AML The study will use a matched pair analysis. Cases will be matched to controls on: Age 5 years Disease stage (CR1 / CR 2 / relapse or induction failure) Graft type (BM / PBSC / CB). Year of transplant five years. 5.0 OUTCOMES: Univariate probabilities only: 5.1 Engraftment: Time to neutrophils (ANC) >0.5 x 109/L (first of 3 consecutive days) and time to platelets 20 x 109/L (first of 3 consecutive days and no platelet transfusions 7 days prior). The following outcomes will be compared by regimen intensity (matched-pair analysis) in multivariate analysis: 5.2 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. 14

15 Not for publication or presentation Attachment Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the criteria of chronic GVHD 5.4 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. 5.5 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. 5.6 Leukemia free survival: time from date of transplant to treatment failure (death or leukemia recurrence). Subjects will be censored at time of last contact. 5.7 Overall survival: Time to death, patients will be censored at last follow-up. 6.0 VARIABLES CONSIDERED IN MULTIVARIATE ANALYSIS: Main effect: transplant conditioning regimen intensity: reduced intensity vs. myeloablative 6.1 Patient-related: - Performance score (<90% vs. >90%) - Recipient CMV serostatus (positive vs. negative) 6.2 Disease-related: - Cytogenetics: poor risk vs. other vs. not reported 6.3 Transplant-related: - Matched sibling vs. matched unrelated donor vs. mismatched unrelated donor - GVHD prophylaxis (cyclosporine containing vs. tacrolimus containing). - In vivo T-cell depletion (yes vs. no) 7.0 STUDY DESIGN: Reduced intensity conditioning transplant recipients (cases) will be matched to myeloablative conditioning transplant recipients (controls) using matching criteria of age within 5 years; disease stage (CR1 vs CR 2 vs relapse or induction failure); graft type (BM vs. PBSC vs. CB); year of transplant within 5 years. The considered matching is 1 case to 4 matched controls in the following way: (1) Reduced intensity conditioning transplant recipient will be selected randomly. Any myeloablative conditioning transplant recipient satisfies the matching criteria will be considered as a potential matched control; (2) The matched control with the smallest difference in age among all potential matched controls will be selected; (3) Step 1 will be repeated among the remaining cases; (4) Steps 1-3 will be repeated four times. The final matched cohorts included 42 reduced intensity conditioning transplant recipients and 167 myeloablative conditioning transplant recipients (41 cases were found with 4 matches and 1 case with 3 matches). This yielded 209 subjects in the current analysis. Subject-, disease- and transplant-related variables for the two study groups will be compared using the conditional logistic regression method to adjust the matching pairs. 15

16 Not for publication or presentation Attachment 4 Probability of overall survival will be calculated using the Kaplan-Meier estimator. Values for other endpoints will be generated using cumulative incidence estimates. Multivariate analysis will be performed by fitting a Cox model stratified on matched-pairs. To further adjust potential imbalance risk factors between reduced and myeloablative transplant cohorts, a backward stepwise model building procedure will be used to identify any risk factors which are associated with the outcome. Variables used to build the final model are listed in Section 6. Any significant risk factors will be adjusted in the final stratified Cox model stratified on matched pairs. All p-values are two-sided. 8.0 REFERENCES: 1. Davies SM, Rowe JM, Appelbaum FR. Indications for hematopoietic cell transplantation in acute leukemia. Biol Blood Marrow Transplant. 2008; 14(1 Suppl 1): Appelbaum FR: Allogeneic hematopoietic stem cell transplantation for acute leukemia. Semin Oncol 1997; 24: , 3. Neudorf S, Sanders J, Kobrinsky N, Alonzo TA, Buxton AB, Gold S et al. Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival. Blood 2004; 103: Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998; 91: Ringde n O, Labopin M, Ehninger G, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol Aug 3. [Epub ahead of print]. 6. Pulsipher MA, Kenneth M. Boucher KM, Wall D, et al. Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood. 2009; 114:

17 Not for publication or presentation Attachment 4 Table 1. Patients, disease and transplant characteristics Characteristics of patients: RIC N(%) Myeloablative N(%) P-value a Number of patients b Number of centers c Age at transplant, median (range) 15 (1-18) 10 (<1-16) < y 15 (36) 78 (47) y 27 (64) 89 (53) Sex 0.24 Male 19 (45) 93 (56) Female 23 (55) 74 (44) Karnofsky/Lansky performance score prior to transplant <90 16 (38) 25 (15) (57) 130 (78) Unknown 2 ( 5) 12 ( 7) Disease status at transplantation CR1 16 (38) 64 (38) CR2 20 (48) 79 (48) Relapse or induction failure c 6 (14) 24 (14) Cytogenetics risk Favorable 6 (14) 16 (10) Intermediate 27 (64) 79 (47) Poor 6 (14) 16 (10) Unknown 3 ( 7) 56 (34) Conditioning regimen TBI + cyclophosphamide + fludarabine d 6 (14) 4 ( 2) TBI + cyclophosphamide 2 ( 5) 57 (34) TBI + other chemotherapeutic agents 4 (10) 6 ( 4) Busulfan + cyclophosphamide _ 72 (43) Busulfan + melphalan _ 15 ( 9) Busulfan + fludarabine 8 (19) 12 ( 7) Melphalan + fludarabine 15 (36) _ Cyclophosphamide + fludarabine 4 (10) _ Cyclophosphamide + melphalan 2 ( 5) _ Melphalan + etopside _ 1 ( 1) Cyclophosphamide + etopside 1 ( 2) _ Donor type 0.17 HLA-identical sibling 7 (17) 50 (30) Matched adult unrelated 18 (43) 42 (25) Mismatched adult unrelated 5 (12) 27 (16) Matched cord blood 1 ( 2) 6 ( 4) Mismatched cord blood 11 (26) 42 (25) 17

18 Not for publication or presentation Attachment 4 Table 1. Continued. Characteristics of patients: RIC N(%) Myeloablative N(%) P-value a Negative 10 (24) 63 (38) Positive 32 (76) 101 (60) Unknown 0 3 ( 2) In vivo T-cell depletion 0.24 No 22 (52) 103 (62) Yes 20 (48) 64 (38) Graft type BM 15 (36) 60 (36) PBSC 15 (35) 59 (35) Cord blood 12 (29) 48 (29) Year of transplant (52) 77 (46) (48) 90 (54) GVHD prophylaxis <0.001 FK506 + MMF 6 (14) 8 ( 5) FK506 + MTX 5 (12) 28 (17) FK506 alone 3 ( 7) 5 ( 3) CSA + MMF 14 (33) 16 (10) CSA + MTX 6 (14) 80 (48) CSA + steroid 4 (10) 22 (13) CSA alone 4 (10) 8 ( 5) Median (range) follow-up, months 52 (12-97) 60 (3-124) a P-value stratified on matched pairs b 42 matched case-control pairs (41 cases were found with 4 matches and 1 case with 3 matches) c N=18 centers performed both myeloablative and reduced intensity transplants; N=14 centers only performed reduced intensity transplants; N=58 centers only performed myeloablative transplants. c Disease status at transplant was primary induction failure for 2 patients in RIC group and 7 patients in Myeloablative group; d TBI dose in reduced intensity group: 200cGy, N=8; 450 cgy, N=1; 600 cgy and fractionated, N=3; TBI dose in myeloablative group: 550 cgy, N=2; 1200 cgy, N=29; 1320 cgy, N=16; 1350 cgy, N=9; 1400 cgy, N=6; 1440 cgy, N=5. Completeness index FU as of 12/31/11 NMA/RIC Myeloablative 1 year years

19 Not for publication or presentation Attachment 5 CIBMTR Study Proposal: Study Title: Factors Predicting Treatment-Related Mortality in Pediatric Autologous Transplant Evelio D Perez-Albuerne, MD, PhD; Children's National Medical Center / George Washington University, Washington, DC; eperez@cnmc.org Specific Aims: Analyze the CIBMTR data on pediatric autologous transplant for malignant disease to identify factors that are associated with an increased risk of treatment-related mortality (TRM) in pediatric autologous transplant for malignant disease. Report descriptive statistics on rates of TRM, cause of death, early relapse, and patient, disease and transplant characteristics in pediatric autologous transplant for malignant disease. Scientific Justification: Autologous hematopoietic cell transplant (HCT) is used to treat a variety of pediatric malignancies. Although autologous HCT patients experience a much lower rate of transplant-related mortality (TRM) compared to allogeneic HCT patients, TRM rates of 0-9.8% have been reported for pediatric autologous HCT in the last decade 1-8 We performed an analysis of 162 autologous PBSC transplants done at Children's National Medical Center (CNMC). There were two episodes of TRM, for a rate of 1.2%. A multivariate analysis of factors including total nucleated cells /kg infused, total CD34+/kg infused, product CD34+ fraction in the infusion, conditioning chemotherapy, diagnosis, and age was carried out. Outcome variables were fever, bacteremia, intensive care requirement, and death (occurring between the time of stem cell infusion and neutrophil recovery). Factors found to have a significant effect on the rate of those transplant toxicity events included a negative association with the patient s age at transplant (odds ratio 0.88, p = 0.001), and positive relationship with diagnoses of neuroblastoma (odds ratio 2.76, p=0.006) and other (not medulloblastoma or supratentorial PNET) CNS tumor (odds ratio 2.55, p=0.011). Patients less than 1 year of age had the highest incidence of toxicity events, and this is the only group that included deaths. A bivariate analysis of the effect of age on toxicity was done to determine the age group at highest risk of toxicity, which was age < 1 year old 9, 10. We hypothesize that the larger CIBMTR data set will also show increased rate of TRM in pediatric autologous transplant patients < 1 year old and in those with a diagnosis of neuroblastoma. There are a few other reports published in the last decade that examined age and other risk factors for toxicity after transplant. Some of these studies found an association between very young age at transplant and increased toxicity, but others did not. Analysis of 166 children who received autologous PBSC transplant in Madrid had an overall TRM rate of 6.9% by day 180. Patients not in complete remission at the time of transplant had significantly higher TRM, but this group found no significant association between TRM and age, gender, conditioning, or number of CD34+ cells infused 1. A group in Hong Kong analyzed risk factors for sinusoidal obstructive syndrome (SOS) in 144 autologous and allogeneic HCT and found that age < 3 years and busulfan/cyclophosphamide conditioning were significant risk factors for the development of SOS 11 Although having a much lower TRM than allogeneic transplant, TRM still does occur in a few percent of autologous transplant patients. A larger fraction of these patients also experience significant transplantrelated morbidity. Because TRM is uncommon, the number of patient deaths at any one center will be small, making it difficult for centers to assess the risk factors for TRM. Use of the larger CIBMTR dataset will allow for identification of patterns that would be difficult or impossible to detect in a single center's 19

20 Not for publication or presentation Attachment 5 data. In our study at CNMC, we hypothesized that if a factor truly increased the risk of TRM, it would also increase the risk of at least some less severe toxicities. This hypothesis was confirmed in our data. Identification of factors increasing autologous transplant TRM will allow the intensity of post-transplant care to be appropriately adjusted for low and high-risk populations; this should decrease the risk of TRM. For example, at CNMC, we routinely discharge brain tumor patients home after the HCT, but are now discussing keeping those patients < 1 year-old in the hospital until neutrophil count recovery. Patient Eligibility Population: Age: < 19 years Disease: any cancer Year of Transplant: Donor type: autologous Data Requirements: Data collection forms needed: 2400 Pre-Transplant Essential Data 2450 Post-Transplant Essential Data No supplemental data is required. The study does not involve combination with an outside database. Variables to be analyzed: Predictor: Gender Age at transplant Disease Performance status Secondary malignancy (i.e. 'yes' to history of prior solid tumor or therapy-related AML/MDS) Comorbid conditions History of invasive fungal infection Conditioning - Intensity (myeloablative versus non-myeloablative or RIC) - Radiation in preparative regimen (none, TBI, other radiation) - Chemotherapy (containing busulfan, other agents, none) Prior HSCT - analyze by number of previous Malignant disease status at last evaluation prior to transplant Transplant Center Time from diagnosis to transplant Outcomes: Death - Cause of death Relapse/Progression Sample Requirements* None 20

21 Not for publication or presentation Attachment 5 Study Design: The proposed study will be a retrospective analysis of information in the CIBMTR database. On the post- TED form, the diagnosis of central nervous system tumors is not subdivided in a way that would allow for an analysis to confirm or not confirm the single-institution result of a higher risk of toxicity with nonmedulloblastoma / supratentorial PNET brain tumors. The post-ted forms also, unfortunately, do not capture information on the other post-transplant toxicities examined in the CNMC study: fever, bacteremia, intensive care requirement. Because of this, the proposed study focuses on TRM. The data will be subjected to multivariate analysis using Cox proportional hazard models for TRM. For the purpose of this study, TRM will be defined as death occurring in first 100 days after transplant (or prior to the next transplant, whichever is shorter), and before relapse / progression. Relapse / progression will be treated as a competing risk. A subsequent transplant will be treated as a censoring event. One model will be constructed with age and diagnosis dichotomized: age < 1 year versus 1 year, diagnosis neuroblastoma versus all others. Those were the factors significantly associated with increased toxicity (including TRM) in the CNMC study described above. A second model will be constructed with age as a continuous variable and the full set of categories for diagnosis. We will report descriptive statistics on the incidence of TRM and the cause of death. We will also report descriptive statistics for the listed predictor variables in the analyzed patient group. References: 1. Foncillas, M. A. et al. Engraftment syndrome emerges as the main cause of transplant-related mortality in pediatric patients receiving autologous peripheral blood progenitor cell transplantation. J Pediatr Hematol Oncol 26, (2004). 2. Park, J. E. et al. Efficacy of high-dose chemotherapy and autologous stem cell transplantation in patients with relapsed medulloblastoma: a report on the Korean Society for Pediatric Neuro- Oncology (KSPNO)-S-053 study. J Korean Med Sci 25, (2010). 3. Sung, K. W. et al. Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma: the Korean Society of Pediatric Hematology-Oncology experience over 6 years ( ). J Korean Med Sci 25, (2010). 4. Spreafico, F. et al. Treatment of high-risk relapsed Wilms tumor with dose-intensive chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic stem cell support: experience by the Italian Association of Pediatric Hematology and Oncology. Pediatr Blood Cancer 51, 23-8 (2008). 5. Fraser, C. J. et al. Autologous stem cell transplantation for high-risk Ewing's sarcoma and other pediatric solid tumors. Bone Marrow Transplant 37, (2006). 6. Lieskovsky, Y. E. et al. High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: results and prognostic indices. J Clin Oncol 22, (2004). 7. Anak, S. et al. Allogeneic versus autologous versus peripheral stem cell transplantation in CR1 pediatric AML patients: a single center experience. Pediatr Blood Cancer 44, (2005). 8. Cesaro, S. et al. High-dose melphalan with autologous hematopoietic stem cell transplantation for acute myeloid leukemia: results of a retrospective analysis of the Italian Pediatric Group for Bone Marrow Transplantation. Bone Marrow Transplant 28, (2001). 9. Dubrovsky, L. et al. Pediatric autologous peripheral blood stem cell harvest: factors affecting time to engraftment and transplant toxicity. Biol Blood Marrow Transplant 16, S249 (2010). 10. Dubrovsky, F. et al. Analysis of Pediatric Autologous PBSC Apheresis and Transplant: Age is a Major Factor Affecting Post-Transplant Toxicity. Pediatr Blood Cancer 59, (2012). 11. Cheuk, D. K. et al. Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 40, (2007). 21

22 Not for publication or presentation Attachment Ozkaynak, M. F. et al. A pilot study of addition of amifostine to melphalan, carboplatin, etoposide, and cyclophosphamide with autologous hematopoietic stem cell transplantation in pediatric solid tumors-a pediatric blood and marrow transplant consortium study. J Pediatr Hematol Oncol 30, (2008). 13. Won, S. C. et al. Autologous peripheral blood stem cell transplantation in children with non- Hodgkin's lymphoma: A report from the Korean society of pediatric hematology-oncology. Ann Hematol 85, (2006). 22

23 Not for publication or presentation Attachment 5 Characteristic of patients who received an autologous HCT, and were reported to the CIBMTR between 2000 and 2010 in autologous research level database Characteristics of patients N (%) Number of patients 992 Number of centers 108 Age, median (range), years 5 (<1-18) (70) (30) Sex Male 575 (58) Female 417 (42) Performance status <90% 203 (20) % 733 (74) Missing 56 ( 6) Graft type Bone marrow 48 ( 5) Peripheral blood 939 (95) Cord blood 5 (<1) Time from diagnosis to transplant, median (range), months 7 (<1-1000) Disease AML 25 ( 3) ALL 2 (<1) Other leukemia 1 (<1) CML 1 (<1) MDS 1 (<1) NHL-non Hodgkin lymphoma 29 ( 3) HD-Hodgkin lymphoma 68 ( 7) MYE-plasma cell disorder, multiple myeloma 4 (<1) Other Malignancies 861 (87) Sub-group of other malignancies Head and neck 1 (<1) Lung cancer, small cell 1 (<1) Renal Carcinoma/Kidney 1 (<1) Testicular 9 ( 1) Ovary (epithelial) 5 (<1) Sarcoma, NOS 3 (<1) Soft tissue sarcoma (Include PNET) 8 (<1) Bone sarcoma (excluding Ewing sarcoma) 12 ( 1) Central nervous system tumors 108 (13) Wilms Tumor 24 ( 3) Neuroblastoma 408 (47) Retinoblastoma 10 ( 1) Ewing sarcoma 42 ( 5) Germ cell tumor 9 ( 1) 23

24 Not for publication or presentation Attachment 5 Continued. Characteristics of patients N (%) Medulloblastoma 141 (16) PNET 12 ( 1) Rhabdomyosarcoma 10 ( 1) Neurogenic sarcoma 1 (<1) Other malignancy, specify 38 ( 4) Soft tissue sarcoma, (excluding Ewing family tumors) 2 (<1) Ewing family tumors of bone (includes PNET) 12 ( 1) Ewing family tumors, extraosseous (includes PNET) 4 (<1) Year of transplant (34) (40) (26) Median follow-up of survivors ( range) months 39 (1-126) 24