A G E N D A CIBMTR WORKING COMMITTEE FOR HODGKIN AND NON-HODGKIN LYMPHOMA Salt Lake City, UT Thursday, February 14, 2013, 2:45 pm - 4:45 pm

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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR HODGKIN AND NON-HODGKIN LYMPHOMA Salt Lake City, UT Thursday, February 14, 2013, 2:45 pm - 4:45 pm Co-Chair: Ginna Laport, MD, Stanford University Medical Center, Stanford, CA Telephone: ; Fax: ; glaport@stanford.edu Co-Chair: Silvia Montoto, MD, St. Bartholomew s Hospital, London, UNITED KINGDOM Telephone: ; Fax: ; s.montoto@qmul.ac.uk Co-Chair: David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: ; Fax: ; dmaloney@fhcrc.org Statisticians: Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; jcarrera@mcw.edu Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; meijie@mcw.edu Scientific Director: Wael Saber MD, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; wsaber@mcw.edu 1. Introduction a. Minutes of February, 2012 meeting (Attachment 1) b. Newly appointed chair: Sonali Smith, MD; University of Chicago Hospitals; smsmith@medicine.bsd.uchicago.edu 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers a. LY04-01 Hale GA, Shrestha S, Le Rademacher J, Burns LJ, Gibson J, Inwards DJ, Freytes CO, Bolwell BJ, Hsu JW, Slavin S, Isola L, Rizzieri DA, Gale RP, Laport GG, Montoto S, Lazarus HM, Hari PN. Alternate donor hematopoietic cell transplantation (HCT) in non-hodgkin lymphoma using lower intensity conditioning: a report from the CIBMTR. Biol Blood Marrow Transplant 18 (7): , December b. LY06-02 Freytes CO, Zhang MJ, Carreras J, Burns LJ, Gale RP, Isola L, Perales MA, Seftel M, Vose JM, Miller AM, Gibson J, Gross TG, Rowlings PA, Inwards DJ, Pavlovsky S, Martino R, Marks DI, Hale GA, Smith SM, Schouten HC, Slavin S, Klumpp TR, Lazarus HM, Van Besien K and Hari PN. Outcome of lower-intensity allogeneic transplantation in non- Hodgkin lymphoma after autologous transplant failure. Biol Blood Marrow Transplant 18(8): , December c. LY08-03 Bacher U, Klyuchnikov E, Le-Rademacher J, Carreras J, Armand P, Bishop MR, Bredeson CN, Cairo MS, Fenske TS, Freytes CO, Gale RP, Gibson J, Isola LM, Inwards DJ, Laport GG, Lazarus HM, Maziarz RT, Wiernik PH, Schouten HC, Slavin S, Smith SM, Vose JM, Waller EK, Hari PN. Conditioning regimens for allotransplants for diffuse large B-cell lymphoma :myeloablative or reduced intensity? Blood, 120(20): ,

2 Not for publication or presentation d. LY08-01 Maramattom LV, Hari PN, Burns LJ, Carreras J, Arcese W, Cairo MS, Costa LJ, Fenske TS, Lill M, Freytes CO, Gale RP, Gross TG, Hale GA, Hamadani M, Holmberg LA, Hsu JW, Inwards DJ, Lazarus HM, Marks DI, Maloney DG, Maziarz RT, Montoto S, Rizzieri DA, Wirk B, Gajewski JL. Autologous and allogeneic transplantation for Burkitt lymphoma outcomes and changes in utilization: a report from the CIBMTR. Biol Blood Marrow Transplant. [Epub ahead of print] doi: /j.bbmt Epub 2012 NOV 27. e. LY04-03 Maziarz RT, Wang Z, Zhang MJ, Bolwell BJ, Chen AI, Fenske TS, Freytes CO, Gale RP, Gibson J, Hayes-Lattin BM, Holmberg L, Inwards DJ, Isola LM, Khoury HJ, Lewis VA, Maharaj D, Munker R, Phillips GL, Rizzieri DA, Rowlings PA, Saber W, Satwani P, Waller EK, Maloney DG, Montoto S, Laport GG, Vose JM, Lazarus HM, Hari PN. Autologous hematopoietic cell transplantation for non-hodgkin lymphoma with CNS involvment. Submitted, Blood. f. LY06-05 Smith SS, Burns LJ, van Besien K, LeRademacher J, He W, Fenske T, Suzuki R, Hsu JW, Schouten HC, Hale GA, Holmberg LA, Sureda A, Freytes CO, Maziarz RT, Inwards DJ, Gale RP, Gross TG, Cairo MS, Costa LJ, Lazarus HM, Wiernik PH, Maharaj D, Laport GG, Montoto S, Hari PN. Autologous or allogeneic hematopoietic stem cell transplantation for systemic mature T-cell non-hodgkin lymphoma. Submitted, JCO. g. LY06-06 Hahn T, McCarthy PL, Carreras J, Zhang MJ, Lazarus HM, Laport GG, Montoto S, Hari PN. Simplified validated prognostic model for progression-free survival autologous transplantation for relapsed or refractory Hodgkin lymphoma. Submitted, BBMT. h. LY10-01a Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS, Gale RP, Gibson J, Hale GA, Hari PN, Hsu JW, Inwards DJ, Kamble RT, Klein A, Maharaj D, Marks DI, Rizzieri DA, Savani BN, Schouten HC, Waller EK, Wirk B, Laport GG, Montoto S, Maloney DG, Lazarus HM. Impact of pretransplant conditioning regimens on outcomes of allogeneic transplantation for chemotherapy-unresponsive diffuse large B-cell lymphoma and grade-iii follicular lymphoma. Submitted, BBMT. i. LY10-01b Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS, Gale RP, Gibson J, Hale GA, Hari PN, Hsu JW, Inwards DJ, Kamble RT, Klein A, Maharaj D, Marks DI, Rizzieri DA, Savani BN, Schouten HC, Waller EK, Wirk B, Lazarus HM. Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis from the CIBMTR. Submitted, BBMT. j. LY10-01a Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS, Gale RP, Gibson J, Hale GA, Hari PN, Hsu JW, Inwards DJ, Kamble RT, Klein A, Maharaj D, Marks DI, Rizzieri DA, Savani BN, Schouten HC, Waller EK, Wirk B, Laport GG, Montoto S, Maloney DG, Lazarus HM. Impact of pretransplant conditioning regimens on outcomes of allogeneic transplantation for chemotherapy-unresponsive diffuse large B-cell lymphoma and grade-iii follicular lymphoma. Oral presentation at the American Society of Hematology in Atlanta, GA, December

3 Not for publication or presentation k. LY10-01b Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS, Gale RP, Gibson J, Hale GA, Hari PN, Hsu JW, Inwards DJ, Kamble RT, Klein A, Maharaj D, Marks DI, Rizzieri DA, Savani BN, Schouten HC, Waller EK, Wirk B, Lazarus HM. Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis from the CIBMTR. Oral presentation at the American Society of Hematology in Atlanta, GA, December l. LY09-01 Wirk B, Burns L, Fenske T, Hu Z, Laport GG, Montoto S, Maloney D, Saber W. Clinical outcomes of hematopoietic cell transplantation in patients with diffuse large B cell lymphoma transformed from follicular lymphoma. Oral presentation at the BMT Tandem Meetings in Salt Lake City, UT, February Studies in progress (Attachment 3) a. LY06-03 Allogeneic hematopoietic cell transplantation for relapsed follicular lymphoma: impact of donor type and prognostic risk score for survival (A Sureda) b LY07-02 Transplant outcomes in the mycosis fungoides and sezary syndrome patients (M Lechowicz) c. LY08-02 Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle cell lymphoma (T Fenske) d. LY09-01 Clinical outcomes of hematopoietic cell transplantation in patients with diffuse large B cell lymphoma transformed from follicular lymphoma (B Wirk) e. LY10-02 Umbilical cord blood versus unrelated or related donor allogeneic hematopoietic cell transplantation for patients with lymphoma (V Bachanova) (Attachment 4) f. LY10-03 An updated comparison of allogeneic versus autologous hematopoietic stem cell transplantation for lymphoblastic lymphoma (A Chen) g. LY11-01 Study the outcome of patients undergoing high dose therapy followed by autologous stem cell transplant for patient with primary central nervous system lymphoma (S Montoto) h. LY12-01 Positron Emission Tomography Imaging Prior to AlloHCT for Lymphoma (V Bachanova) i. LY12-02/GV11-01 Graft-vs-lymphoma post allogeneic hematopoietic cell transplantation (A Urbano-Ispizua/S Pavletic/M Flowers) (Attachment 5) j. SC10-06 (Funded CIBMTR Research Study): BuCyE vs. BEAM for autologous transplants in lymphoma (M Pasquini) Data File Preparation Manuscript Preparation Manuscript Preparation Manuscript Preparation Manuscript Preparation Draft Protocol Received Data File Preparation Draft Protocol Received Data File Preparation Data Collection/ Data File Preparation 5. Future/proposed studies a. PROP Autologous transplantation for diffuse large B-cell lymphomas patients refractory or relapsing early after Rituximab-containing first line chemoimmunotherapies. (M Hamadani) (Attachment 6) b. PROP Outcomes of autologous stem cell transplantation for children, adolescents and young adults with relapsed/refractory Hodgkin lymphoma. (P Satwani) (Attachment 7) 3

4 Not for publication or presentation c. PROP Comparison of autologous versus allogeneic stem cell transplantation after reduced/non-myeloablative conditioning for relapsed/refractory patients with follicular lymphoma. (E Klyuchnikov) (Attachment 8) d. PROP Impact of mobilization strategies and CD34+ progenitor yields on outcomes of autologous hematopoietic cell transplantation for large B cell lymphoma (R Soiffer) and PROP Impact of mobilization regimen on the outcomes of autologous stem cell transplantation for multiple myeloma and non-hodgkin lymphoma (G Uy) (Attachment 9) e. PROP Analysis of survival after first relapse post autologous stem cell transplant in Hodgkin s lymphoma. (A Renteria) (Attachment 10) Dropped a. PROP Allogeneic transplant for indolent NHL from : receipt of Rituximab versus Rituximab plus ATG versus neither of the two. (M Christopeit) Due low number of cases and strong correlation between Rituximab and ATG and donor type. b. PROP Autologous and Allogeneic Hematopoietic Cell Transplantation for Patients with Primary Mediastina Lymphoma (PML). (V Bachanova) Due to lack of data on this histologic subtype c. PROP Outcomes of first line autologous hematopoietic cell transplantation for poor risk diffuse large B cell lymphoma. (B Wirk) Due to feasibility-chemo comparison group not available. d. PROP Upfront versus salvage autologous hematopoietic cell transplantation in patients with high-risk diffuse large B cell lymphoma and Hodgkin lymphoma. (G Akpek) Due to appropriate chemo comparison group (same as PROP ) e. PROP Retrospective matched pair analysis of follicular lymphoma patients undergoing hematopoietic progenitor cell transplantation. When is the right time to transplant? (P Caimi) Due to insufficient data on control group f. PROP Transplant for gamma delta T cell lymphoma. (J Schriber) Due to low number of cases (n=3). g. PROP Outcome of plasmablastic lymphoma following autologous stem-cell transplantation (N Koshy) Due to low number of cases (n=3). 4

5 Not for publication or presentation Attachment 1 MINUTES CIBMTR WORKING COMMITTEE FOR HODGKIN & NON-HODGKIN LYMPHOMA San Diego, California Friday, February 3, 2012, 12:15 pm - 2:15 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: Ginna Laport, MD, Stanford University Medical Center, Stanford, CA Telephone: ; Fax: ; glaport@stanford.edu Silvia Montoto, MD, St. Bartholomew s Hospital, London, United Kingdom Telephone: ; Fax: ; s.montoto@qmul.ac.uk David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: ; Fax: ; dmaloney@fhcrc.org Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; jcarrera@mcw.edu Mei-Jie Zhang, PhD, CIBMTR Statistical Center Phone: ; Fax: ; meijie@mcw.edu Wael Saber MD, Medical College of Wisconsin, Milwaukee, WI Telephone: ; Fax: ; wsaber@mcw.edu 1. Introduction The CIBMTR Hodgkin and Non-Hodgkin Lymphoma Working Committee was called to order at 12:20 pm on Friday, February 3, 2012, by Dr. Ginna Laport. Attendees were asked to have their name badges scanned for attendance purposes and to maintain the committee membership roster, and to fill out the Working Committee evaluations and voting sheets for proposals. The CIBMTR new guidelines for voting on proposals were discussed. The new guidelines are based on a scale from 1 to 9; 1= high scientific impact, 9= low scientific impact. These are consistent across all Working Committees. Previously accepted proposals where no work has been done were to be weighed against the new proposals in order to select the studies with highest impact. Each presentation was limited to 5 minutes (maximum 3-4 overheads) to allow for adequate time for discussion (5 minutes) for the new proposals. The minutes of the February 2011 meeting were approved without modifications. Dr. Wael Saber 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 the Lymphoma Working Committee Leadership or Emilie Meissner at emeissne@nmdp.org. 5

6 Not for publication or presentation Attachment 1 2. Accrual summary Due to the full agenda, the accrual summary of registration and research cases between 1995 and 2011 were not presented to the committee but were available as part of the Working Committee attachments: HLA-identical Alternative Donor Autologous Non-Hodgkin Lymphoma Registration only Research Hodgkin Lymphoma Registration only Research Presentations, published or submitted papers Due to the full agenda, the 2011 presentations and published papers were mentioned but not presented. Dr. Ginna Laport noted the low productivity of the Working Committee in the past year compared to previous years but stressed the eight manuscript in preparation that are expected to be submitted by June Two papers were in press and four presentations were given during the past year. These include: a. LY04-01 Hale GA, Shrestha S, Le-Redemacher J, Burns LJ, Gibson J, Inwards DJ, Freytes CO, Bolwell BJ, Hsu JW, Slavin S, Isola L, Rizzieri DA, Gale RP, Laport G, Montoto S, Lazarus HM, Hari PN. Alternate donor hematopoietic cell transplantation in non-hodgkin lymphoma using lower intensity conditioning: a report from the CIBMTR. In Press. b. LY06-02 Freytes CO, Zhang MJ, Carreras J, Burns LJ, Gale RP, Isola L, Perales MA, Seftel M, Vose JM, Miller AM, Gibson J, Gross TG, Rowlings PA, Inwards DJ, Pavlovsky S, Martino R, Marks DI, Hale GA, Smith SM, Schouten HC, Slavin S, Klumpp TR, Lazarus HM, Van Besien K and Hari PN. Less intense allogeneic transplantation for non-hodgkin lymphoma relapsing after autologous transplantation. In Press. c. LY06-03 Sureda A, Zhang M, Schouten H, Hari P, Canals C, Attal M, Burns L, Freytes C, Gale RP, Gibson J, Hale G, Laport G, Lazarus HM, Marks D, Maziarz R, McCarthy P, Miller A, Milone G, Montoto S, Perales MA, Russel NH, Thompson K, Vernant JP, Dreger P, Pasquini MC. Comparison of unrelated and sibling donor allogeneic hematopoietic cell transplantation for follicular lymphoma. Oral presentation at 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, June d. LY06-06 Hahn T, McCarthy PL, Carreras J, Zhang M-J, Lazarus HM, Laport G, Montoto S, Hari P. Comparison of prognostic models for autologous hematopoietic stem cell transplantation for relapsed Hodgkin lymphoma. Oral presentation at the American Society of Hematology in San Diego, CA, December

7 Not for publication or presentation Attachment 1 e. LY08-03 Bacher U, Klyuchnikov E, Carreras J, Le-Rademacher J, Laport G, Montoto S, Maloney D, Hari P. Comparison of reduced and standard conditioning in allogeneic stem cell transplantation in patients with B-cell non-hodgkin s lymphoma. Oral presentation at the American Society of Hematology in San Diego, CA, December Studies in progress The studies which made progress during the past year were not presented in order to provide reasonable time to the new proposals for presentation and discussion. Attendees were asked to review the materials to assess the progress of ongoing studies. These were: a. LY04-03: Outcomes of autologous transplants for patients with non-hodgkin lymphoma with preexisting CNS involvement versus non-cns involvement (R Maziarz): This study proposes to compare the outcomes of autologous HCT with NHL between patients with CNS involvement identified at any time prior to transplant versus non-cns involvement. A draft manuscript is underway and it is expected to be submitted by July b. LY06-03: Comparison of unrelated and sibling donor allogeneic hematopoietic cell transplantation for follicular lymphoma (A Sureda): This study proposes to compare the outcomes of unrelated versus HLA-identical sibling HCT for follicular non-hodgkin s lymphoma. A draft manuscript is underway and it is expected to be submitted by July c. LY06-05: Comparison of autologous vs. allogeneic stem cell transplantation for T-cell NHL (S Smith): This study proposes to compare the outcomes of autologous versus HLA-identical sibling versus unrelated donor transplants in patients < 60 years old with relapsed mature T-cell non- Hodgkin s lymphoma. A draft manuscript is underway and it is expected to be submitted by July d. LY06-06: Comparison of prognostic models for autologous hematopoietic stem cell transplantation for relapsed Hodgkin lymphoma (P McCarthy): This study proposes to develop a prognostic model for progression-free survival based on pre-transplant factors for relapsed/refractory Hodgkin-lymphoma. A draft manuscript is underway and it is expected to be submitted by July e. LY07-02: Transplant outcomes in the mycosis fungoides and sezary syndrome patients (M Lechowicz): This study proposes to describe the outcomes of cutaneous T-cell lymphoma/sezary syndrome patients following allogeneic transplants. A draft manuscript is underway and it is expected to be submitted by July f. LY08-01: Outcomes of allogeneic and autologous hematopoietic progenitor cell transplant for Burkitt s lymphoma (J Gajewski): This study proposes to describe the outcomes of autologous and allogeneic transplants for Burkitt s lymphoma. A draft manuscript is underway and it is expected to be submitted by July g. LY08-02: Outcomes of patients with mantle cell lymphoma treated with autologous versus allogeneic transplantation (T Fenske): This study proposes to compare the outcomes of autologous versus myeloablative versus reduced intensity conditioning/non-myeloablative for mantle cell non-hodgkin lymphoma. A draft manuscript is underway and it is expected to be submitted by July

8 Not for publication or presentation Attachment 1 h. LY08-03: Comparison of reduced and standard conditioning in allogeneic stem cell transplantation in patients with B-cell non-hodgkin s lymphoma (U Bacher): This study proposes to compare the outcomes and complications of reduced intensity conditioning/non-myeloablative versus myeloablative transplants in patients 18 years of age with diffuse large B-cell lymphoma. A draft manuscript is underway and it is expected to be submitted by July i. LY09-01: Clinical outcomes of hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma transformed from chronic lymphocytic leukemia, follicular lymphoma or waldenstrom macroglobulinemia (B Wirk/L Burns): This study proposes to compare the outcomes of autologous versus reduced intensity conditioning/non-myeloablative versus myeloablative transplants for diffuse large B cell lymphoma transformed from a well differentiated lymphoid neoplasm (chronic lymphocytic leukemia r follicular lymphoma). A draft protocol is available for review. j. LY10-01: Outcomes of allogeneic stem cell transplantation for patients with chemorefractory aggressive non-hodgkin s lymphomas (M Hamadani): This study proposes to compare the outcomes of myeloablative versus reduced intensity conditioning/non-myeloablative transplants for patients with chemorefractory aggressive NHL. A draft protocol is available for review. k. LY11-01: High-dose chemotherapy with autologous stem cell rescue in patients with primary central nervous system lymphoma: Impact of the conditioning regimen (S Montoto): This study proposes to compare the outcome of patients receiving autologous stem cell rescue transplants for primary central nervous system lymphoma, either at first remission (CR/PR1) or at relapse, according to the conditioning regimen received. The study population will include patients reported to the CIBMTR, EBMT and MSKCC. The data file is underway. 5. Previous accepted studies but not initiated and new proposed studies Drs. Montoto and Maloney led this section. The previously accepted proposals (LY10-02, LY10-03 and LY11-02) had a low priority within the Working Committee and no work has been done since these were approved. These studies were weighted against the new proposals in order to select the studies with highest impact. These were the followings: a. LY10-02 Umbilical cord blood versus unrelated or relate donor allogeneic hematopoietic cell transplantation for patients with Lymphoma (V Bachanova) Dr. Burns presented this proposal in Dr. Bachanova s absence. The purpose of this study is to compare the clinical outcomes between patients undergoing an allogeneic hematopoietic cell transplant from unrelated umbilical cord blood versus matched unrelated or sibling donor for non-hodgkin s and Hodgkin s lymphoma. There are 183 cord blood, 1330 HLAidentical sibling and 876 well-matched unrelated patients that underwent allogeneic transplants for NHL and HL transplanted between 2000 and 2010 and reported to the CIBMTR. It was suggested to restrict histology (further discussion will take place in regards to which histologies will be included) and only compare cords versus haploidentical transplant recipients versus unrelated donor transplant recipients. b. LY10-03 An updated comparison of allogeneic versus autologous hematopoietic stem cell transplantation for lymphoblastic lymphoma (A Chen/R Maziarz) Dr. Maziarz presented this proposal. The purpose of this proposal is to compare outcomes after allogeneic versus autologous hematopoietic stem cell transplantation for lymphoblastic lymphoma in the modern era. There are 27 autologous and 115 allogeneic 8

9 Not for publication or presentation Attachment 1 transplants for precursor T-lymphoblastic lymphoma transplanted between 1997 and 2007 and reported to the CIBMTR. It was suggested to drop the autologous transplant recipients given the small number, and only conduct a descriptive cohort analysis. A limited multivariate analysis could be conducted to identify prognostic factors associated with favorable outcomes. Another suggestion was to include T-cell ALL (n=444; ALL diseasespecific form submitted) and do a collaborative study with Oregon Health & Science University and King Faisal Specialist Hospital and Research Centre. c. LY11-02 Development of a prognostic scoring system to predict the relapse of diffuse large B-cell lymphoma DLBCL after allogeneic transplants (R Salit) Dr. Salit presented this proposal. The purpose of this proposal is (1) to develop a prognostic scoring system based on patient, disease, and transplant-specific factors that is predictive of relapse after allogeneic hematopoietic stem cell transplantation in patients with diffuse large B-cell lymphoma and (2) to assess the association of the variables identified within this scoring system with transplantation outcomes and outcomes after relapse. There are 605 patients >18 years of age who underwent allogeneic transplant for in patients for diffuse large B-cell lymphoma transplanted between 1995 and 2008 and reported to the CIBMTR. It was noted the lack of PET scan data not collected in the CIBMTR legacy forms (patients transplanted 2007). d. PROP Role of transplantation in the management of lymphocyte predominant Hodgkin s disease. (J Hsu) Dr. Hsu presented this proposal. The purpose of this study is to clarify the role of transplantation in the management of lymphocyte predominant Hodgkin s disease. Outcomes will include: transplant-related mortality, progression-free survival, overall survival and long term complications. There are 226 patients who underwent an autologous transplant for lymphocyte predominant Hodgkin s disease transplanted between 1995 and 2010 and reported to the CIBMTR. Only 78 out of the 226 have detailed disease, pre- and post-transplant clinical information. It was suggested to collect pathology reports in order to confirm diagnosis although this will require contacting centers. e. PROP Comparison between total body irradiation and non-tbi based conditioning regimens for autologous and allogeneic hematopoietic cell transplant in patients with diffuse large B-cell non-hodgkin s lymphoma (J Hsu) Dr. Hsu presented this proposal. The purpose of this study is to determine the effect of TBI in the conditioning regimen in both autologous and allogeneic HCT for B-cell non- Hodgkin s Lymphoma on efficacy and toxicity outcomes. There are 2442 (allo TBI, n=127; allo no TBI, n=195; auto TBI, n=246, auto no TBI, n=1874) patients 18 years old who underwent autologous or HLA matched allogeneic transplant for large B-cell lymphoma transplanted between 1995 and 2010 and reported to the CIBMTR. It was suggested to restrict the population to only allogeneic transplants. f. PROP A retrospective assessment of outcomes of patients who have undergone allogeneic stem cell transplant for follicular lymphoma based on histocompatibility leukocyte antigen type. (B Hill) Dr. Hill presented this proposal. The purpose of this study is (1) to compare progressionfree survival and overall survival of patients with follicular lymphoma who have undergone fully matched allogeneic transplants based on patient HLA allele type and (2) to compare the incidence of individual HLA allele haplotypes among follicular lymphoma patients who have undergone allogeneic transplants and compare it to an unselected population of 9

10 Not for publication or presentation Attachment 1 follicular lymphoma patients as well as healthy race-matched controls. There are 1145 (HLA-identical sibling, n=582; identical twin, n=18; other related, n=28; unrelated, n=516) patients 18 years old who underwent allogeneic transplant for follicular lymphoma transplanted between 1995 and 2010 and reported to the CIBMTR. It was suggested to submit the proposal to the NMDP Bioinformatics Research in order to include all patients on an intent to treat basis linked to activating an unrelated donor search. Restricting to just patients that proceeded to transplant will skew the dataset towards common haplotypes. g. PROP Comparison of single versus tandem stem cell transplantation for poor-risk Hodgkin lymphoma. (G Akpek) Dr. Akpek presented this proposal. The purpose of this study is to compare outcomes of patients with poor-risk Hodgkin lymphoma who underwent single autologous HCT versus tandem (auto-auto or auto-allo) transplants. There are 243 single autologous transplants, 75 planned tandem autologous transplants and 543 auto-allo patients who underwent a stem cell transplant with poor risk Hodgkin lymphoma transplanted between 1995 and 2010 and reported to the CIBMTR. It was commented to restrict the population to single autologous and true tandem transplants since the 543 cases that underwent auto-allo were very likely transplanted as a salvage therapy. Additionally, the question is being addressed by the SWOG clinical trial h. PROP Role of positron emission tomography (PET) imaging prior to allogeneic hematopoietic cell transplantation in predicting outcomes for non- Hodgkin and Hodgkin lymphoma. (V Bachanova) Dr. Bachanova presented this proposal. The purpose of this study is to determine the role of positron emission tomography imaging performed prior to start of preparative regimen for allogeneic transplants in predicting the recurrence, lymphoma-free survival and overall survival in patients with non-hodgkin lymphoma (NHL, B and T cell) and Hodgkin lymphoma. There are 404 (25 HD; 379 NHL) patients with positive PET scan and 124 (3 HD; 118 NHL) patients with negative PET scan who underwent allogeneic transplants from 2008 and 2010 and reported to the CIBMTR. It was suggested to restrict histology and to determine the timing of the PET scan although this would require secondary data collection. i. PROP Allogeneic transplant for indolent NHL from : receipt of rituximab versus rituximab plus ATG versus neither of the two. (M Christopeit) Dr. Hari presented this proposal in Dr. Christopeit s absence. The purpose of this study is to compare incidence of relapse, non-relapse-mortality (infect, GVHD) and all-cause mortality of patients with indolent lymphoma transplanted from an allogeneic (related or unrelated) donor after RIC with Rituximab, Rituximab and ATG, neither of the two and no other T-cell-depleting agent (e. g. alemtuzumab) as a means of conditioning, and in the case of Rituximab up to six months before. There are 157 Rituximab only (HLA-identical, n=88; other relative, n=3; well-matched unrelated, n=18; partially-matched unrelated, n=3; mismatched unrelated, n=3; unrelated matching to be determined, n=42), 92 rituximab+atg+campath (HLA-identical, n=4; other relative, n=2; well-matched unrelated, n=31; partially-matched unrelated, n=11; mismatched unrelated, n=1; unrelated matching to be determined, n=43) and 1470 patients who did not receive Rituximab/ATG/Campath and underwent allogeneic transplants for non-hodgkin lymphoma and CLL transplanted between 1998 and 2010 and reported to the CIBMTR. 10

11 Not for publication or presentation Attachment 1 Five additional proposals were submitted to the committee but not presented due to the reasons stated below: a. PROP Impact of high dose cytarabine in the induction therapy on post-transplant outcomes in patients with mantle cell lymphoma (M Norkin): Overlaps with approved study LY08-02 Outcome of patients with mantle cell lymphoma treated with autologous versus allogeneic transplantation. b. PROP Outcome after transplant for double-hit lymphoma. (L Holmberg): Not doable due to the requirement of secondary data collection on double-hit/igh-bcl2 and MYC. c. PROP Outcomes of hematopoietic cell transplantation for primary mediastinal large B-cell lymphoma. (B Wirk): Not doable due to the requirement of secondary data collection and low number of reported cases. d. PROP Outcomes of hematopoietic stem cell transplant in plasmablastic lymphoma (E Ayala): Not doable due to the low number of reported cases (n=4). e. PROP Outcomes of hematopoietic cell transplantation in patients with primary central nervous system lymphoma (E Ayala): Overlaps with approved study LY11-01 High-dose chemotherapy with autologous stem cell rescue in patients with primary central nervous system lymphoma: Impact of the conditioning regimen. 6. Other business The combine GVHD/Lymphoma study GV11-01 Analysis of graft versus Lymphoma effect after allogeneic HCT (Alvaro Ispizua/ Steve Pavletic/ Mary Flowers) will now reside in the Lymphoma Working Committee (given that the disease focus is lymphoma it was decided that this study belongs to the lymphoma committee). The purpose of this study is (1) to determine the existence of a GVL effect associated with acute and/or chronic GVHD in B cell and T cell lymphomas and (2) to identify those subtypes of lymphoma in which reduced intensity transplant might be effective. After the new proposals were presented, each participant in the meeting had the opportunity to rate each proposal using paper ballots. Based on the voting results, current scientific merit and the impact of the study on the field the following studies will move forward: Studies in Progress: 1. LY04-03: Auto for CNS lymphoma 2. LY06-03: Sibling vs. MUD for follicular NHL 3. LY06-05: Auto vs. allo for T-cell NHL 4. LY06-06: Prognostic model for outcome of HCT for HD 5. LY07-02: HCT in mycosis fungoides/sezary syndrome 6. LY08-01: Allo and auto HCT for Burkitt's/Non-Burkitt-like Lymphoma 7. LY08-02: Auto vs. allo for mantel cell lymphoma 8. LY08-03: RIC vs. standard conditioning in allo HCT for B-cell NHL 9. LY09-01: HCT for transformed DLBCL 10. LY10-01: Allo HCT for chemorefractory aggressive NHL 11. LY10-02: UCB allo HCT for lymphoma 11

12 Not for publication or presentation Attachment LY10-03: Allogeneic hematopoietic stem cell transplantation for lymphoblastic lymphoma/tcell leukemia 13. LY11-01: High-dose therapy+auto HCT for primary CNS lymphoma: impact of conditioning Previous accepted studies but not initiated and new proposed studies: 14. LY12-01 (PROP ): Positron emission tomography imaging prior to allohct for lymphoma 15. LY12-02/GV11-01: Graft-vs-lymphoma post allohct The following proposals and previously approved studies were dropped due to lack of pertinent data and assessment of lower scientific priority at the time of publication: 1. LY11-02: Development of a prognostic scoring system to predict the relapse of diffuse large B- cell lymphoma DLBCL after allogeneic transplants 2. PROP : Role of transplantation in the management of lymphocyte predominant Hodgkin s disease 3. PROP : Comparison between total body irradiation and non-tbi based conditioning regimens for autologous and allogeneic hematopoietic cell transplant in patients with diffuse large B-cell non-hodgkin s lymphoma 4. PROP : A retrospective assessment of outcomes of patients who have undergone allogeneic stem cell transplant for follicular lymphoma based on histocompatibility leukocyte antigen type. (B Hill) 5. PROP : Comparison of single versus tandem stem cell transplantation for poor-risk Hodgkin lymphoma 6. PROP : Allogeneic transplant for indolent NHL from : receipt of rituximab versus rituximab plus ATG versus neither of the two 7. PROP : Impact of high dose cytarabine in the induction therapy on post-transplant outcomes in patients with mantle cell lymphoma 8. PROP : Outcome after transplant for double-hit lymphoma 9. PROP : Outcomes of hematopoietic cell transplantation for primary mediastinal large B- cell lymphoma 10. PROP : Outcomes of hematopoietic stem cell transplant in plasmablastic lymphoma 11. PROP : Outcomes of hematopoietic cell transplantation in patients with primary central nervous system lymphoma Without additional comments, the meeting was adjourned at 1:55 pm. 12

13 Not for publication or presentation Attachment 2 Accrual Summary for Hodgkin and Non-Hodgkin Lymphoma Working Committee: HLA-identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%) Anaplastic large cell PIF 31 (24) 6 (21) 13 (27) 18 (24) 219 (23) 20 (19) CR 1 26 (20) 2 ( 7) 10 (21) 14 (18) 243 (25) 28 (26) Relapse 1 16 (13) 5 (18) 2 ( 4) 4 ( 5) 124 (13) 19 (18) CR 2 27 (21) 6 (21) 7 (15) 24 (32) 248 (26) 25 (23) Other / Unknown 28 (22) 9 (32) 16 (33) 16 (21) 126 (13) 16 (15) Burkitt/small noncleaved PIF 28 (15) 10 (15) 9 (16) 21 (19) 126 (21) 25 (17) CR 1 47 (24) 16 (24) 12 (21) 13 (12) 191 (31) 60 (40) Relapse 1 35 (18) 8 (12) 7 (12) 16 (14) 64 (11) 24 (16) CR 2 41 (21) 19 (29) 16 (28) 36 (32) 125 (21) 20 (13) Other / Unknown 42 (22) 13 (20) 13 (23) 25 (23) 101 (17) 20 (13) Diffuse large cell /Immunoblastic PIF 326 (30) 123 (34) 99 (31) 178 (30) 4056 (25) 800 (23) CR ( 9) 46 (13) 33 (10) 48 ( 8) 2155 (13) 498 (14) Relapse (21) 71 (20) 42 (13) 100 (17) 3349 (21) 977 (28) CR (11) 30 ( 8) 43 (13) 70 (12) 3552 (22) 660 (19) Other / Unknown 312 (29) 90 (25) 102 (32) 194 (33) 2861 (18) 574 (16) Follicular PIF 329 (28) 203 (28) 97 (31) 213 (28) 1292 (25) 385 (21) CR 1 86 ( 7) 54 ( 7) 14 ( 5) 52 ( 7) 471 ( 9) 220 (12) Relapse (19) 165 (23) 43 (14) 122 (16) 1086 (21) 441 (24) CR (10) 97 (13) 30 (10) 89 (12) 889 (17) 290 (16) Other / Unknown 429 (36) 207 (29) 126 (41) 297 (38) 1510 (29) 504 (27) Lymphoblastic PIF 54 (17) 28 (16) 16 (12) 23 (12) 98 (17) 31 (16) CR 1 97 (30) 55 (32) 24 (18) 33 (17) 211 (37) 86 (45) Relapse 1 45 (14) 23 (13) 14 (11) 30 (15) 73 (13) 26 (13) CR 2 71 (22) 44 (26) 37 (28) 57 (29) 72 (13) 27 (14) Other / Unknown 54 (17) 21 (12) 41 (31) 53 (27) 110 (20) 23 (12) Mantle PIF 198 (32) 93 (36) 58 (28) 98 (23) 1003 (24) 210 (25) CR (23) 52 (20) 50 (25) 81 (19) 2320 (54) 382 (46) Relapse 1 96 (15) 39 (15) 27 (13) 83 (19) 228 ( 5) 78 ( 9) CR 2 63 (10) 25 (10) 23 (11) 80 (19) 261 ( 6) 66 ( 8) Other / Unknown 119 (19) 46 (18) 46 (23) 88 (20) 456 (11) 91 (11) 13

14 Not for publication or presentation Attachment 2 Accrual Summary for Hodgkin & Non-Hodgkin Lymphoma Working Committee: Continued. HLA-identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%) Marginal PIF 18 (29) 11 (39) 9 (43) 14 (33) 66 (27) 9 (27) CR 1 4 ( 6) 5 (18) 1 ( 5) 4 (10) 40 (16) 4 (12) Relapse 1 10 (16) 1 ( 4) 5 (24) 5 (12) 32 (13) 4 (12) CR 2 8 (13) 2 ( 7) 0 4 (10) 35 (14) 5 (15) Other / Unknown 22 (35) 9 (32) 6 (29) 15 (36) 70 (29) 11 (33) NK T cell PIF 46 (28) 15 (38) 20 (26) 30 (22) 106 (20) 11 (17) CR 1 38 (23) 11 (28) 25 (32) 42 (30) 168 (32) 28 (43) Relapse 1 18 (11) 7 (18) 2 ( 3) 8 ( 6) 66 (12) 6 ( 9) CR 2 26 (16) 3 ( 8) 12 (15) 33 (24) 98 (19) 13 (20) Other / Unknown 37 (22) 4 (10) 19 (24) 26 (19) 91 (17) 7 (11) T cell PIF 119 (34) 51 (41) 39 (29) 79 (30) 281 (25) 35 (22) CR 1 82 (24) 23 (18) 36 (27) 64 (24) 409 (36) 56 (35) Relapse 1 42 (12) 17 (14) 8 ( 6) 34 (13) 140 (12) 27 (17) CR 2 34 (10) 20 (16) 22 (16) 36 (13) 156 (14) 21 (13) Other / Unknown 68 (20) 14 (11) 30 (22) 54 (20) 138 (12) 21 (13) NHL Not specified PIF 84 (20) 4 (29) 23 (19) 2 ( 7) 507 (14) 19 (22) CR 1 30 ( 7) 1 ( 7) 10 ( 8) ( 9) 13 (15) Relapse 1 68 (17) 0 15 (13) 6 (20) 594 (16) 17 (20) CR 2 21 ( 5) 4 (29) 16 (13) ( 9) 10 (12) Other / Unknown 209 (51) 5 (36) 56 (47) 22 (73) 1890 (52) 27 (31) Other PIF 253 (34) 166 (36) 58 (28) 166 (24) 1061 (25) 309 (21) CR 1 93 (12) 87 (19) 25 (12) 89 (13) 737 (18) 253 (17) Relapse (15) 63 (14) 33 (16) 82 (12) 845 (20) 334 (23) CR 2 81 (11) 48 (10) 28 (14) 73 (11) 645 (15) 217 (15) Other / Unknown 211 (28) 102 (22) 61 (30) 280 (41) 898 (21) 346 (24) Hodgkin PIF 144 (27) 41 (21) 49 (23) 47 (22) 3355 (22) 588 (20) CR 1 30 ( 6) 14 ( 7) 9 ( 4) 15 ( 7) 989 ( 6) 213 ( 7) Relapse 1 90 (17) 55 (29) 25 (12) 40 (18) 3682 (24) 817 (28) CR 2 38 ( 7) 13 ( 7) 23 (11) 27 (12) 3223 (21) 535 (18) Other / Unknown 224 (43) 68 (36) 109 (51) 89 (41) 4256 (27) 764 (26) 14

15 Not for publication or presentation Attachment 2 Accrual Summary for Hodgkin & Non-Hodgkin Lymphoma Working Committee: Continued. HLA-identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%) Graft type BM 1625 (28) 918 (37) 592 (32) 1173 (33) 3969 ( 8) 1906 (17) PBSC 4059 (70) 1539 (62) 1125 (61) 2083 (58) (87) 9248 (82) Other / Unknown 121 ( 2) 13 ( 1) 127 ( 7) 306 ( 9) 2654 ( 5) 192 ( 2) 15

16 Not for publication or presentation Attachment 3 TO: FROM: RE: Hodgkin and non-hodgkin Working Committee Members Wael Saber, MD, MS, Scientific Director for Lymphoma Working Committee Studies in Progress Summary LY06-03: Allogeneic hematopoietic cell transplantation for relapsed follicular lymphoma: impact of donor type and prognostic risk score for surviva. (A Sureda). This study compared the outcomes of 702 recipients of allogeneic HCT for FL (198 unrelated and 504 sibling donors) from 171 centers world-wide reporting to the CIBMTR or EBMT between 1997 and This study shows that unrelated HCTs are performed later in the treatment course for FL; in higher risk patients; most commonly with reduced intensity conditioning; and in multivariate analysis adjusting for baseline differences between the 2 groups, unrelated HCTs were significantly associated with worse PFS and OS compared to sib HCT. This study was submitted to JCO and based on reviewer s comments and internal discussion inclusion criteria will be modified with different transplant years to pick up a more modern cohort. Data file preparation is underway. LY07-02: Allogeneic hematopoietic cell tansplantation for primary cutaneous T cell lymphoma (M Lechowicz). This study describes outcomes of 133 subjects with cutaneous T cell lymphoma (CTCL) reported to the Center for the International Blood and Marrow Transplant (CIBMTR) from Treatment-related mortality (TRM) at 1 and 3 years was 10% (95 % CI 5-17%) and 12% (95 % CI 6-19%) respectively. Risk of disease progression was 55% (95% CI 45-65%) at 1 year and 58% (95% CI 47-68%) at 3 years. Progression free survival (PFS) at 1 and 3 years was 35% (95% CI 25-45%) and 30% (95% CI 21-41%) respectively. Survival at 1 and 3 years was 57% (95% CI 48-65%) and 38% (95% CI 29-48%) respectively. A draft manuscript is underway and it is expected to be submitted before July LY08-02: Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantion for chemotherapy-sensitive mantle cell lymphoma (T Fenske). This study analyzes the outcomes of 519 patients with chemotherapy-sensitive mantle cell lymphoma receiving a first HCT between 1996 and 2007 based on whether transplant occurred early or late in the disease course. There were 249 AutoHCT and 50 AlloHCT patients in the early cohort and 132 AutoHCT and 88 AlloHCT patients in the late cohort. In both cohorts, non-relapse mortality (NRM) was significantly higher and progression/relapse lower in the AlloHCT group. AutoHCT and AlloHCT resulted in similar overall survival from transplant for both the early (at 5 years: 62% AlloHCT versus 61% AutoHCT, p=0.951) and the late cohorts (at 5 years: 31% AlloHCT versus 44% AutoHCT, p=0.202). Within the early cohort, relapse/progression at 5 years posttransplant was lower in the AlloHCT group (15% AlloHCT versus 32% AutoHCT, p=0.009). Multivariate analysis of survival from diagnosis identified a survival benefit for the early HCT cohort relative to the late cohort (for both AutoHCT and AlloHCT). A draft manuscript is underway and it is expected to be submitted before July LY09-01: Clinical outcomes of hematopoietic cell transplantation in patients with diffuse large B cell lymphoma transformed from follicular lymphoma. (B Wirk). This study describes 155 patients (age>18 years) from 89 centers with transformation of FL to DLBCL reported to the CIBMTR who had autohct or allohct from Pathology reports were reviewed in all cases to confirm transformation of FL 16

17 Not for publication or presentation Attachment 3 to DLBCL. This is the largest epidemiologic series analyzing outcomes of HCT in transformed DLBCL. Patients were classified into 3 groups consisting of autohct (N=108), allohct (N=33), allohct (N=14) after prior autohct (performed for FL) with median ages of 56, 49, 51 years (yr) who received median of 3, 4, 5 lines of chemotherapy prior to HCT, respectively. The size of the cohort did not allow multivariate analysis. Transformation >1 yr vs <1yr from diagnosis (dx) yielded improvement in 1 yr PFS for the autohct (61% [95% CI 51-71%] vs 29% [95% CI 11-53%]; p=.01) and allohct groups (44% [95% CI 24-64%] vs 11% [95% CI 0-38%]; p=.03). Transformation > 1 yr vs <1 yr from dx also had better 2 yr OS in the allohct group (43% [95% CI 24-64%] vs 11% [95% CI 0-38%]; p=.03). A draft manuscript is underway and it is expected to be submitted before July Oral presentation at the BMT Tandem Meetings in Salt Lake City, UT, February 2013 LY10-02: Umbilical cord blood versus 8/8 HLA matched unrelated donor versus 7/8 MUD allogeneic hematopoietic cell transplantation for patients with lymphoma (V Bachanova). The goal of this study is to determine the antilymphoma effect and survival outcomes of patients with non-hodgkin and Hodgkin lymphoma reported to CIBMTR between The study compares transplant outcomes following umbilical cord blood (UCB) HCT (n=142) as compared with adult unrelated donor sources (8 of 8 (n=1176) and 7 out of 8 match unrelated donor (n=275)). Cord blood recipients were more likely to have chemosensitive disease immediately prior to transplantation, and they were more likely to receive pretransplant radiation. They also had the shortest interval between diagnosis and HCT and more recent HCT period. Fully matched MUD HCT recipients tended to be older, have higher proportion of mantle cell lymphoma, included more male patients and less likely to have Hodgkin disease. 7/8 MUD HCT recipients were more likely to have a KPS <90. Final analyses have been completed and a draft manuscript is underway. LY10-03: An updated comparison of allogeneic versus autologous hematopoietic stem cell transplantation for lymphoblastic lymphoma (A Chen). One of the specific aims is to compare the overall survival after allogeneic vs autologous hematopoietic stem cell transplantation for lymphoblastic lymphoma in the modern era. There are 27 autologous and 115 allogeneic patients that underwent hematopoietic cell transplantation for patients with lymphoblastic lymphoma reported to the CIBMTR between 1997 and Draft protocol is available for review. LY11-01: High dose therapy followed by autologous stem cell transplant for patients with Primary Central Nervous System Lymphoma: Impact of the conditioning regimen (S Montoto). The study aim is to analyse the outcome of patients receiving autologous stem cell transplant for PCNSL and compare PFS and OS according to the conditioning regimen received. Total number of potential cases are CIBMTR=15, EBMT=90 and MSKCC=25. Will not include HIV+ cases and will verify how many cases are reported before Data file preparation is in progress. LY12-01: Positron Emission Tomography Imaging Prior to AlloHCT for Lymphoma. (V Bachanova). The purpose of this study is to determine the role of positron emission tomography imaging performed prior to start of preparative regimen for allogeneic transplants in predicting the recurrence, lymphoma-free survival and overall survival in patients with non-hodgkin lymphoma (NHL, B and T cell) and Hodgkin lymphoma. There are 404 (25 HD; 379 NHL) patients with positive PET scan and 124 (3 HD; 118 NHL) patients with negative PET scan who underwent allogeneic transplants from 2008 and 2010 and reported to the CIBMTR. Draft protocol is available for review. LY12-02/GV11-01: Graft-vs-lymphoma post allogeneic hematopoietic cell transplantation. (A Urbano- Ispizua/S Pavletic/M Flowers). The purpose of this study is to determine the existence of a GVL effect associated with acute and/or chronic GVHD in B cell and T cell lymphomas and to identify those subtypes of lymphoma in which reduced intensity transplant might be effective. Protocol is in development. 17

18 Not for publication or presentation Attachment 4 MEMORANDUM TO: FROM: STUDY PI: RE: LYWC Working Committee Wael Saber, MD, MS, Jeanette Carreras, MPH, and Tao Wang, PhD Veronika Bachanova, MD, Claudio Brunstein and Linda Burns, MD CIBMTR Study # LY10-02: Umbilical cord blood versus 8/8 HLA matched unrelated donor (MUD) versus 7/8 MUD allogeneic hematopoietic cell transplantation (HCT) for patients with lymphoma Enclosed is a description and results of univariate and multivariate analysis in adult patient population with lymphoma that underwent umbilical cord blood versus 8/8 HLA matched unrelated donor (MUD) versus 7/8 MUD allogeneic hematopoietic cell transplantation (HCT) from 2000 to Very few patients were transplanted outside of the US, so we restricted the study to US patients only. Objective: To compare outcomes between patients undergoing an HCT from umbilical cord blood (n=145) vs. 8/8 HLA MUD (n=1214) vs. 7/8 HLA MUD (n=286) for non-hodgkin and Hodgkin lymphoma. We will also describe outcomes of patients undergoing HLA-haploidentical donor HCT for non-hodgkin and Hodgkin lymphoma (n=47). The latter will not be compared due to small sample size Table 1 summarizes baseline characteristics of the three groups that will be compared as well as the haplo group. Median follow up was shortest in the cord blood recipients (~ 2 years). This will have to be taken into account when we interpret the results. Notable differences among the three groups (cords vs. 8/8 MUD vs. 7/8 MUD) include the following: - 8/8 MUD HCT recipients tended to be older and included more male patients - Cord blood recipients had higher KPS scores. - 8/8 MUD group were less likely to have Hodgkin disease and more likely to have Mantle cell lymphoma - Cord blood recipients were more likely to have chemosensitive disease immediately prior to transplantation, and they were more likely to have received radiation between diagnosis and transplantation. They also had the shortest interval between diagnosis and HCT. They were more likely to be recent HCT. Univariate analysis: Cord blood recipients had inferior neutrophil and platelet engraftment rates. However, they had lower risk of acute and chronic GVHD. 7/8 MUD HCT recipients experienced higher risk of TRM. No difference in PFS among the three groups. 7/8 MUD HCT group had inferior overall survival. Cords and 8/8 MUD HCT group had similar survival. Despite of the fact that no direct comparison was made between the haplo group and the other 3 groups, the PFS and OS rates appear to be quite similar to the 8/8 MUD and cords and appear to be higher than the 7/8 MUD HCT recipients. 18

19 Not for publication or presentation Attachment 4 Inclusion/exclusion criteria: Selection criteria Excluded # Remaining # First allogeneic transplant for NHL and HD reported to the CIBMTR from (CAP modeled) 3886 Age 18 years Excluding patients with planned 2 nd transplant (reason checked as planned n=28 or patients with less 6 m from auto to allo HCT n=44) Including cord blood or 8/8 HLA matched unrelated donor or 7/8 MUD only (exclusions: HLA sibs=1271, Unrelated mismatched=330, twins=27, parent matched=5, child matched=4, other related matched=4) *Potential missing cases has been confirmed & added to the dataset Excluding cord blood ex-vivo expansion 8 N=1949 Additional exclusions after path report revision (exclusions: ALL aggressive NK-cell leukemia=11, precursor B-lymphoblastic=24, primary CNS=1, large granular lymphocytic=1, precursor T- lymphoblastic=51, lymphoid malignancy=10, precursor T/NKcell=1, not lymphoma=10) 109 N=1840 Excluding 1 HLA disparities for HLA-haploidentical donors (including 2+ mismatches only) 39 N=1801 Restricting to US only center (exclusions: 11 Canada {1 haploidentical and 10 UNR 8/8}, 56 Europe {3 CB, 3 haploidentical, 43 UNR 8/8 and 7 UNR 7/8},25 Asia {8 CB, 5 haploidentical, 12 UNR 8/8}, 8 Australia/New Zealand {1 CB, 7 UNR 8/8}, 8 Mideast/Africa{3 haploidentical, 5 UNR 8/8}, 1 Central/South America {1 CB}) 109 N=1692 Excluding ex-vivo T-cell depletion (& CD34) per stats meeting (NEW) 60 Completeness index follow up as of 12/31/2011: o Overall=89%. Per year: 1yr=100%, 2yrs=97%, 3yrs=93% and 5yrs=82%. o Cord blood=81%. Per year: 1yr=99%, 2yrs=88%, 3yrs=76% and 5yrs=57%. o 8/8 unrelated=90%. Per year: 1yr=100%, 2yrs=98%, 3yrs=95% and 5yrs=85%. o 7/8 unrelated=91%. Per year: 1yr=100%, 2yrs=99%, 3yrs=99% and 5yrs=93%. o HLA haplo-identical=70%. Per year: 1yr=93%, 2yrs=75%, 3yrs=62% and 5yrs=42%. Tables: Table 1: Characteristics for patients & Table 2: Revised conditioning regimens Table 3: Variables to be tested in multivariate analysis Table 4: Univariate analysis & Table 5: Unviariate analysis for haploidentical Table 6: Causes of death Table 7: Multivariate analysis for TRM Table 8: Multivariate analysis for Relapse/Progression Table 9: Multivariate analysis for PFS Table 10: Multivariate analysis for OS N=1632 CB=142 UNR 8/8=1176 UNR 7/8=275 HAPLO=39 19

20 Not for publication or presentation Attachment 4 Multivariate Analysis (by Tao Wang): We build multivariate models using the Cox s proportional hazards model. All the clinical variables were tested for the affirmation of the proportional hazards assumption. Factors violating the proportional hazards assumption were adjusted through stratification. Then a stepwise model building procedure was used in developing models for each outcome with a threshold of 0.05 for both entry and stay in the model. Interactions between the main variable and the adjusted covariates were tested at the significance level of Comments: Based on the likelihood analysis for overall survival, we choose the optimal cut-off point as 26 month for time from diagnosis to transplant. Conclusion: UNR 8/8 has less risk of TRM than Cord blood. UNR 8/8 also has less risk of TRM than UNR 7/8. But no significant difference was detected between UNR 7/8 and Cord blood for TRM. No significant interactions between the group variable and the adjusted covariates were detected in any of the models. 20

21 Not for publication or presentation Attachment 4 CIBMTR LY10-02 UMBILICAL CORD BLOOD VERSUS 8/8 HLA-MATCHED UNRELATD DONOR (MUD) VERSUS 7/8 MUD ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH LYMPHOMA Study Chairs: Veronika Bachanova, MD University of Minnesota Medical Center, Fairview 420 Delaware Street SE, MMC 803 Minneapolis, MN Telephone: bach0173@umn.edu Claudio Brunstein, MD University of Minnesota Medical Center, Fairview 420 Delaware Street SE, MMC 803 Minneapolis, MN Telephone: Fax: bruns072@umn.edu Linda J. Burns, MD University of Minnesota Medical Center, Fairview 420 Delaware Street SE, MMC Moos Tower Minneapolis, MN Telephone: Fax: burns019@umn.edu Study Statisticians: Jeanette Carreras, MPH CIBMTR-Milwaukee Statistical Center 9200, W. Wisconsin Avenue, Suite C5500 Milwaukee, WI Telephone: Fax: jcarrera@mcw.edu Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI USA Telephone: Fax: meijie@mcw.edu 21

22 Not for publication or presentation Attachment 4 Scientific Director: Working Committee Chairs: Wael Saber, MD, MS CIBMTR Medical College of Wisconsin 9200 W. Wisconsin Avenue Suite C5500 Milwaukee, WI Telephone: Fax: wsaber@mcw.edu Ginna Laport, MD Associate Professor of Medicine Division of Bone Marrow Transplant Stanford University Medical Center, Stanford, CA Telephone: Fax: glaport@stanford.edu Silvia Montoto, MD Senior Lecturer St. Bartholomew s Hospital 45 Little Britain London, UK Telephone: Fax: silvia.montoto@cancer.org.uk David Maloney, MD, PhD Fred Hutchinson Cancer Research Center 1100 Fairview Avenue Seattle, WA Telephone: Fax: dmaloney@fhcrc.org 22

23 Not for publication or presentation Attachment HYPOTHESIS: We hypothesize that transplant outcomes of patients with lymphoma undergoing umbilical cord blood transplantation versus 8/8 HLA MUD versus 7/8 MUD transplantation are similar and survival comparable. 2.0 OBJECTIVES: 2.1 To compare the clinical outcomes between patients undergoing an allogeneic hematopoietic cell transplant (HCT) from unrelated umbilical cord blood (UCB) versus 8/8 MUD versus 7/8 MUD for non-hodgkin s (NHL) and Hodgkin s lymphoma (HL). The following outcomes are to be evaluated for the groups: Neutrophil and platelet engraftment; Acute and chronic graft-versus-host disease; Non-relapse mortality; Disease relapse or progression; Progression-free survival; Overall survival. 2.2 To determine patient- and donor-, disease-, and transplant- related factors associated with favorable progression-free (PFS) and overall survival (OS). 2.3 To describe outcomes listed in 2.1 for patients with lymphoma undergoing HCT from an HLA-haploidentical donor. 3.0 SCIENTIFIC JUSTIFICATION: Allogeneic donor HCT (allo HCT) is frequently applied to treat relapsed lymphoma. Multiple single institution and registry data analyses have demonstrated lower relapse rates after allogeneic donor HCT compared to autologous HCT and promising PFS of 30-60% (1-5). Reduced intensity conditioning (RIC) regimens have further reduced treatment related mortality (TRM) particularly in high risk or older patients.(3,5) However, patients have only a 25% likelihood of HLA matching with a sibling and about onehalf of US patients find an 8 of 8 unrelated donor. The chance of finding an 8 of 8 allele level, HLA-A, -B, -C, -DRB1 matched unrelated donor for U.S. ethnic minorities is only 10% to 35% (source: NMDP). For all others donor options include a) a mismatched adult unrelated donor b) cord blood units, or c) a partial family match. Thus, transplant centers have been investigating the use of alternative stem cell sources such umbilical cord blood and haplo-identical related donor in order to provide the opportunity of allogenic stem cell transplantation to all patients (6). Mismatched unrelated donor allogeneic transplant. Lee et al.(7) reported on the impact of allele level matching at HLA-A, -B, -C, and -DRB1 on the outcomes of unrelated donor bone marrow (BM) myeloablative transplantation for myeloid malignancies (n=3857 patient donor pairs, n= of 8 matched). The key findings of this study were that the 5-year OS for 8 of 8 allele matched grafts (37%) was better than 7 of 8 (29%) or 6 of 8 (22%) matching. A single mismatch increased the mortality risk by 25% compared to a matched transplant. Subgroup analysis suggested that single mismatches at HLA-B and -C may be better tolerated than HLA-A and - DRB1. Mismatch for DQB or DPB did not affect survival of these patients with malignancy. There is limited data on mismatched unrelated donor transplants for lymphoma. There are several advantages of a partially, 7 of 8 matched unrelated donor transplantation: 1) 80% probability of identifying a donor, 2) adequate cell dose for engraftment; 3) predictable time to hematopoietic recovery, and 4) likely availability of donor lymphocytes if needed.(6) Therefore, for patients with lymphoma indicated for an 23

24 Not for publication or presentation Attachment 4 allogenic stem cell transplant and no full match is available, 7 of 8 match represent a viable option. Umbilical cord blood transplant HCT using 0-2 HLA mismatched unrelated UCB unit(s) has become a valuable alternative source of stem cells for many pediatric and adult patients with hematologic malignancies who lack a suitable HLA matched donor (8-11). Brunstein et al. studied 65 patients with advanced lymphoid malignancies receiving an UCB graft after RIC and reported low incidence of TRM (15%) with promising 3 year PFS and OS of 34% and 55%, respectively (9). For patients with HL, Majhail et al. observed sustained engraftment following RIC UCB HCT with a reduction in relapse rate and promising OS comparable to sibling allo HCT (10). Recently, EMBT and Eurocord evaluated 104 adult patients who underwent UCB HCT for lymphoid malignancies (12). Sixty-four percent of patients received RIC. Nine percent did not engraft. At one year, the PFS was 40%, non-relapse mortality was 28% and cumulative incidence of relapse or disease progression was 31%. Median time to relapse was 3 months (range 1-33 months). Chemo sensitive disease, use of low-dose total body irradiation (TBI) and higher cell dose were factors associated with significantly better outcome. In multivariate analysis, only the use of double UCT remained associated with lower risk of relapse. Aggregate data from referenced reports showed that UCB resulted in acceptable rates of donor engraftment and promising transplant outcomes not widely different from matched unrelated donor HCT. Data on use of haplo-identical donor HCT for patients with lymphoma are limited. Few series included patients with NHL and HL showing promising survival (13,14). The advantages of haploidentical related donors include almost universal availability, potential for additional progenitor and immune cells available for cellular therapies, and options to select donors for greater NK cell alloreactivity. The disadvantages include the need for either ex vivo or in vivo T cell depletion or aggressive immune-suppression regimens, delayed immune reconstitution, and potentially increase the risk of opportunistic infections and relapse (13). The goal of this study is to determine the antilymphoma effect and survival outcomes of patients with lymphoma following UCB HCT as compared with adult unrelated donor sources (8 of 8 and 8 of 7 match unrelated donor). The effect of patient age, lymphoma subset, remission status, conditioning regimen, acute and chronic GVHD on relapse and OS requires a significant number of patients with multicenter data such as is available from the CIBMT registry. 4.0 STUDY POPULATION Patient selection criteria includes patients 18 years of age with NHL and HL receiving an UCB, HLA haplo-identical related donor or 8/8 or 7/8 MUD using any conditioning between HLA haplo-identical donor is defined as a family member (family, child, sibling or other related) who shares one complete HLA haplotype with the recipient and is variably HLA mismatched on the non-shared haplotype. Two or more HLA mismatches are included. Cord blood ex-vivo expansion will be excluded. Restricted to US only centers. Ex-vivo T-cell depletion will be excluded. 5.0 OUTCOMES: 5.1 For multivariate analysis Non-relapse mortality: death without relapse or progression, where relapse or progression are competing risks. Those who survive without recurrence or progression are censored at the time of last contact. 24

25 Not for publication or presentation Attachment Relapse / progression: progressive disease or recurrence of disease is counted as events. Treatment related death, defined as death without relapse or progression, is the competing event. Those who survive without recurrence or progression are censored at the time of last contact Progression-free survival (PFS): survival without recurrence or tumor progression. Recurrence of progression of disease and death are counted as events. Those who survive without recurrence or progression are censored at the time of last contact Overall survival: time to death. Death from any cause will be considered an event. Surviving patients will be censored at the time of last follow-up. 5.2 Descriptive only: Hematopoietic recovery: The primary measures for hematopoietic recovery will be: Time to neutrophils (ANC) > 0.5 x10 9 /L sustained for three consecutive days. This endpoint does not specify whether recovery is engraftment of donor cells or autologous reconstitution Time to achieve a platelet count of (a) >20 x 10 9 /L independent of platelet transfusions for 7 consecutive days, and (b) >50 x 10 9 /L independent of platelet transfusions for 7 consecutive days Incidence of acute and chronic GVHD: Occurrence of grade II, III, and/or IV skin, gastrointestinal or liver abnormalities and limited and extensive chronic GVHD. 6.0 VARIABLES TO BE ANALYZED: Patient-related: Age: continuous; by decades Gender: male vs. female Karnofsky score: <90% vs % Disease-related: Histology: Hodgkin lymphoma vs. diffuse large cell lymphoma vs. follicular lymphoma vs. mantle cell lymphoma vs. other indolent lymphoma vs. T cell lymphoma Disease status pre-transplant: sensitive vs. resistant Prior radiation: yes vs. no History of prior auto HCT: yes vs. no B symptoms at transplant: yes vs. no CNS involvement at transplant: yes vs. no Transplant-related: Time from diagnosis to transplant: continuous Conditioning regimen: RIC/NST vs. myeloablative Recipient CMV status: + vs. - 25

26 Not for publication or presentation Attachment 4 Year of transplant: vs vs ATG use: yes vs. no GVHD prophylaxis: CSA +/- others vs. FK506 +/-others vs. others (not specified) 7.0 VARIABLES TO BE DESCRIBED: Graft-related: Number of UCB units (single vs double) Number of HLA disparities for UCB (0-1 vs 2) UCB total of nucleated cell infuses x 10 7 /kg 8.0 STUDY DESIGN: The goal of this study is to compare the clinical outcomes, as listed in Section 5.0, between patients undergoing cord blood or 8/8 MUD or 7/8 MUD HCT for lymphoma, while adjusting for significant patient-, disease-, and transplant-related variables listed in Section 6.0. Patient-, disease- and transplant- related factors will be compared between groups using the Chisquare test for categorical variables and the Wilcoxon sample test for continuous variables. The probabilities of progression-free and overall survival will be calculated using the Kaplan-Meier estimator. Values for other endpoints included in Sec. 5.0 will be generated using cumulative incidence estimates to account for competing risks. Cox proportional hazards regression will be used to compare the three graft types. The variables to be considered in the multivariate models are listed in Section 6.0. The assumption of proportional hazards for each factor in the Cox model will be tested by adding a time-dependent covariate. When test indicates 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 assumption will be further tested. A stepwise model selection approach will be used to identify all significant risk factors. Each step of model building contained the main effect for donor types. The risk factors with significant level of p < 0.05 will be included in the model. The potential interaction between main effect of graft effect and all significant covariates will be examined. Given that the median follow-up in the cord blood group is 26 months no inference will be made beyond 3 years post-transplant. 9.0 REFERENCES: 1. Peniket AJ, Ruiz de Elvira MC, Taghipour G, Cordonnier C, Gluckman E, de Witte T, et al. An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is associated with a lower relapse rate but a higher procedurerelated mortality rate than autologous transplantation. Bone Marrow Transplant Apr;31(8): Ratanatharathorn V, Uberti J, Karanes C, Abella E, Lum LG, Momin F, et al. Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-hodgkin's lymphoma. Blood 1994 Aug 15;84(4): Rodriguez R, Nademanee A, Ruel N, Smith E, Krishnan A, Popplewell L, et al. Comparison of reduced-intensity and conventional myeloablative regimens for allogeneic transplantation in non-hodgkin's lymphoma. Biol.Blood Marrow Transplant Dec;12(12): van Besien K, Loberiza FR,Jr, Bajorunaite R, Armitage JO, Bashey A, Burns LJ, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003 Nov 15;102(10):

27 Not for publication or presentation Attachment 4 5. Tomblyn M, Brunstein C, Burns LJ, Miller JS, MacMillan M, DeFor TE, et al. Similar and promising outcomes in lymphoma patients treated with myeloablative or nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol.Blood Marrow Transplant May;14(5): Anasetti C, Aversa F, Brunstein CG Back to the future: mismatched unrelated donor, haploidentical related donor, or unrelated umbilical cord blood transplantation? Biol Blood Marrow Transplant Jan;18(1 Suppl):S S.J. Lee, J. Klein, M. Haagenson et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation Blood, 110 (2007), pp Rocha V, Mohty M, Gluckman E, Rio B, Eurocord, Reduced-Intensity Conditioning Subcommittee of the Acute Leukaemia Working Party, et al. Reduced-intensity conditioning regimens before unrelated cord blood transplantation in adults with acute leukaemia and other haematological malignancies. Curr.Opin.Oncol Jun;21 Suppl 1:S Brunstein CG, Cantero S, Cao Q, Majhail N, McClune B, Burns LJ, et al. Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation. Biol.Blood Marrow Transplant Feb;15(2): Majhail NS, Weisdorf DJ, Wagner JE, Defor TE, Brunstein CG, Burns LJ. Comparable results of umbilical cord blood and HLA-matched sibling donor hematopoietic stem cell transplantation after reduced-intensity preparative regimen for advanced Hodgkin lymphoma. Blood 2006 May 1;107(9): Gluckman E. Ten years of cord blood transplantation: from bench to bedside. Br.J.Haematol Oct;147(2): Rodrigues CA, Sanz G, Brunstein CG, Sanz J, Wagner JE, Renaud M, et al. Analysis of risk factors for outcomes after unrelated cord blood transplantation in adults with lymphoid malignancies: a study by the Eurocord-Netcord and lymphoma working party of the European group for blood and marrow transplantation. J.Clin.Oncol Jan 10;27(2): Wang HX, Yan HM, Liu J, Duan LN, Wang ZD, Zhu L, Xue M, Guo Z. Haploidentical hematopoietic stem-cell transplantation for non-hodgkin lymphoma with bone marrow involvement.leuk Lymphoma Sep;50(9): Symons HJ, Leffell MS, Rossiter ND, Zahurak M, Jones RJ, Fuchs EJ. Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant Apr;16(4):

28 Not for publication or presentation Attachment 4 Table 1. Characteristics of patients that underwent allogeneic hematopoietic cell transplantation for NHL and HL reported to the CIBMTR between 2000 and 2010, by graft type. Characteristics of patients Cord blood UNR 8/8 UNR 7/8 Haploidentical Number of patients Age, median (range), years 45 (19-73) 50 (18-75) 45 (18-71) 54 (18-74) Age at transplant yrs 26 (18) 154 (13) 51 (19) 5 (13) yrs 31 (22) 198 (17) 43 (16) 5 (13) yrs 31 (22) 240 (20) 74 (27) 5 (13) yrs 38 (27) 373 (32) 73 (27) 12 (31) 60 yrs 16 (11) 211 (18) 34 (12) 12 (31) Sex Male 79 (56) 749 (64) 164 (60) 28 (72) Female 63 (44) 427 (36) 111 (40) 11 (28) Karnofsky score <90% 37 (26) 349 (30) 98 (36) 7 (18) 90% 96 (68) 709 (60) 152 (55) 28 (72) Missing 9 ( 6) 118 (10) 25 ( 9) 4 (10) Previous autologous transplant No 78 (55) 691 (59) 141 (51) 32 (82) Yes 64 (45) 485 (41) 134 (49) 7 (18) Interval from autohct to allohct, 18 (6-139) 20 (6-175) 19 (6-154) 22 (8-55) months Time from autohct to allohct, months ( 9) 114 (10) 28 (10) 2 ( 5) >12 51 (36) 371 (32) 106 (39) 5 (13) No prior autologous 78 (55) 691 (59) 141 (51) 32 (82) Histology Hodgkin Disease 39 (27) 233 (20) 74 (27) 9 (23) Follicular lymphoma/other 30 (21) 294 (25) 59 (21) 8 (21) indolent lymphoma DLBCL/other aggressive B cell 39 (27) 282 (24) 70 (25) 15 (38) lymphoma Mantle 13 ( 9) 212 (18) 38 (14) 6 (15) Mature T cell and NK cell neoplasm 21 (15) 155 (13) 34 (12) 1 ( 3) 28

29 Not for publication or presentation Attachment 4 Table 1 Continued Characteristics of patients Cord blood UNR 8/8 UNR 7/8 Haploidentical Number of patients Disease status prior to transplant PIF sensitive 23 (16) 143 (12) 27 (10) 5 (13) PIF resistant 13 ( 9) 128 (11) 34 (12) 2 ( 5) CR1 15 (11) 72 ( 6) 13 ( 5) 0 REL sensitive 34 (24) 315 (27) 77 (28) 10 (26) REL resistant 22 (15) 230 (20) 58 (21) 4 (10) CR2+ 26 (18) 220 (19) 54 (20) 13 (33) REL untreated/unknown 2 ( 1) 26 ( 2) 7 ( 3) 2 ( 5) Missing 7 ( 5) 42 ( 4) 5 ( 2) 3 ( 8) BM involvement at anytime prior to transplant No 52 (37) 379 (32) 102 (37) 12 (31) Yes 45 (32) 464 (39) 91 (33) 9 (23) Unknown 45 (32) 333 (28) 82 (30) 18 (46) B-symptoms at diagnosis A 42 (30) 557 (47) 113 (41) 18 (46) B 64 (45) 458 (39) 124 (45) 11 (28) Missing 36 (25) 161 (14) 38 (14) 10 (26) CNS at anytime prior to transplant No CNS 138 (97) 1150 (98) 268 (97) 39 CNS prior to dx or tx 4 ( 3) 26 ( 2) 7 ( 3) 0 Prior radiation No 26 (18) 425 (36) 81 (29) 8 (21) Yes 116 (82) 751 (64) 194 (71) 31 (79) Number of UCB units NA NA NA Single 52 (37) Double 90 (63) Number of UCB HLA disparities NA NA NA 6/6 4 ( 3) 5/6 33 (23) 4/6 65 (46) TBD 40 (28) UCB total of nucleated cell infuses x 10 7 /kg, median (range) 2.47 ( ) NA NA NA TBD 64 29

30 Not for publication or presentation Attachment 4 Table 1. Continued. Characteristics of patients Cord blood UNR 8/8 UNR 7/8 Haploidentical Number of patients Interval from diagnosis to transplant, 27 (2-203) 34 (3-312) 32 (3-247) 30 (4-193) months ( 5) 20 ( 2) 3 ( 1) 1 ( 3) (13) 136 (12) 24 ( 9) 2 ( 5) (30) 286 (24) 75 (27) 14 (36) (12) 167 (14) 41 (15) 5 (13) (18) 254 (22) 65 (24) 6 (15) >60 29 (20) 289 (25) 63 (23) 9 (23) Missing 1 ( 1) 24 ( 2) 4 ( 1) 2 ( 5) Conditioning regimen MYE+TBI 24 (17) 177 (15) 42 (15) 1 ( 3) MYE+no TBI 17 (12) 125 (11) 39 (14) 1 ( 3) RIC/NST+TBI 70 (49) 219 (19) 48 (18) 26 (66) RIC/NST+no TBI 31 (22) 655 (55) 146 (53) 11 (28) D-R sex match NA M-M 531 (45) 112 (41) 15 (38) M-F 277 (24) 58 (21) 2 ( 5) F-M 189 (16) 51 (19) 13 (33) F-F 132 (11) 53 (19) 9 (23) Missing 47 ( 4) 1 (<1) 0 D-R CMV status NA +/+ 216 (18) 53 (19) 7 (18) +/- 136 (12) 35 (13) 12 (31) -/+ 402 (34) 83 (30) 3 ( 8) -/- 405 (34) 104 (38) 13 (33) Missing 17 ( 1) 0 4 (10) R CMV + 79 (56) 622 (53) 136 (49) 10 (26) - 61 (43) 552 (47) 138 (50) 28 (72) Missing 2 ( 1) 2 (<1) 1 (<1) 1 ( 3) Graft type NA Bone marrow 259 (22) 74 (27) 20 (59) Peripheral blood 913 (78) 201 (73) 14 (41) Year of transplant (15) 338 (29) 97 (35) 5 (13) (24) 463 (39) 134 (49) 8 (21) (61) 375 (32) 44 (16) 26 (67) 30

31 Not for publication or presentation Attachment 4 Table 1. Continued. Characteristics of patients Cord blood UNR 8/8 UNR 7/8 Haploidentical Number of patients ATG/Campath ATG and Campath 0 1 (<1) 1 (<1) 0 ATG alone 51 (36) 296 (25) 88 (32) 6 (15) Campath alone 1 ( 1) 138 (12) 38 (14) 3 ( 8) No ATG or Campath 89 (63) 740 (63) 148 (54) 29 (74) Unknown 1 ( 1) 1 (<1) 0 1 ( 3) GVHD prophylaxis Cyclophosphamide + others 0 1 (<1) 0 19 (49) FK506 + MMF +- others 29 (20) 277 (24) 75 (27) 6 (15) FK506 + MTX +- others (except 5 ( 4) 454 (39) 80 (29) 5 (13) MMF) FK506 + others (except MTX, 16 (11) 37 ( 3) 7 ( 3) 1 ( 3) MMF) FK506 alone 6 ( 4) 41 ( 3) 17 ( 6) 0 CSA + MMF +- others (except 65 (46) 177 (15) 43 (16) 2 ( 5) FK506) CSA + MTX +- others (except 3 ( 2) 124 (11) 33 (12) 0 FK506, MMF) CSA + others (except FK506, 9 ( 6) 23 ( 2) 6 ( 2) 0 MTX, MMF) CSA alone 2 ( 1) 14 ( 1) 10 ( 4) 0 Sirolimus-based 0 4 ( 1) 0 0 MMF-based (no sirolimus) 1 ( 1) 7 ( 1) 1 (<1) 3 ( 8) Other GVHD prophylaxis** 6 ( 4) 17 ( 2) 3 ( 2) 3 ( 8) Median FU of survivors (range), months 25 (6-73) 57 (6-129) 65 (12-125) 14 (3-58) Abbreviations: CR = complete remission; PIF = primary induction failure; REL = relapse; GVHD = graft versus host disease; MTX = methotrexate; CsA = cyclosporine; FK506 = tacrolimus. * HLA haplo-identical donor is defined as a family member (family, child, sibling or other related) who shares one complete HLA haplotype with the recipient and is variably HLA mismatched on the non-shared haplotype. Siblings, parent, child and other related with 2 antigen mismatched were selected. Siblings, parent, child and other related with HLA information missing was requested and mismatched cases were added to the dataset. **Other GVHD prophylaxis includes: ATG only=1, ATG/MTX=1, Cor=1, MTX only=1, Missing=25. 31

32 Not for publication or presentation Attachment 4 Table 2. Conditioning regimens (revised) Characteristics of patients Cord blood UNR 8/8 UNR 7/8 Haploidentical Total number of patients Myeloablative Bu/cy +/- others 4 (10) 59 (20) 14 (17) 0 Bu/flu +/- others 5 (12) 36 (12) 14 (17) 0 Bu +/- others 3 ( 7) 15 ( 5) 0 0 Cy/TBI +/- others 20 (49) 158 (52) 36 (44) 1 (50) Thio +/- others 0 2 ( 1) 0 0 Flu/mel +/- others 5 (12) 15 ( 5) 11 (14) 0 TBI +/- others 4 (10) 16 ( 5) 5 ( 6) 0 Others myeloablative 0 1 (<1) 1 ( 1) 1 (50) RIC Bu/cy +/- others 1 ( 3) 14 ( 3) 0 1 (25) Bu/flu +/- others 6 (17) 173 (34) 45 (36) 1 (25) Bu +/- others 0 7 ( 1) 0 0 Cy/TBI +/- others 1 ( 3) 3 ( 1) 0 0 Thio +/- others 0 4 ( 1) 2 ( 2) 0 Flu/mel +/- others 18 (51) 204 (40) 44 (35) 2 (50) TBI +/- others 0 19 ( 4) 4 ( 3) 0 Flu +/- others 3 ( 9) 8 ( 2) 4 ( 3) 0 BEAM +/- others 6 (17) 42 ( 8) 12 (10) 0 CBV +/- others 0 15 ( 3) 9 ( 7) 0 Mel +/- others 0 23 ( 4) 4 ( 3) 0 NST Cy/TBI +/- others 0 1 (<1) 0 0 TBI +/- others 0 21 ( 6) 4 ( 6) 0 Cy +/- others 0 4 ( 1) 0 1 ( 3) Flu +/- others (83) 59 (84) 32 (97) Others NST 0 34 ( 9) 7 (10) 0 32

33 Not for publication or presentation Attachment 4 Table 3. Variables tested in Cox proportional hazards regression models. Main effect a : Cord blood vs. UNR 8/8 vs. UNR 7/8 Patient-related variables: Age: optimal cut-off point Gender: male vs. female Karnofsky performance status at transplant: 90% vs. <90% vs. missing Disease-related: Lymphoma subset: Hodgkin lymphoma vs. Non-Hodgkin lymphoma (diffuse large cell lymphoma/other aggressive B cell lymphoma vs. follicular lymphoma/ other indolent lymphoma vs. mantle cell lymphoma vs. T cell lymphoma) History of prior autologous transplantation: yes vs. no Disease status at HCT: chemosensitive vs. chemoresistant Prior radiation: yes vs. no B symptoms at transplant: yes vs. no CNS involvement at transplant: yes vs. no Transplant-related: Time from diagnosis to transplant: optimal cut-off point Conditioning regimen: myeloablative -TBI vs. myeloablative- no TBI vs. RIC/NST-TBI vs. RIC/NST-no TBI Recipient CMV status: + vs. - Year of transplant: vs vs ATG use: yes vs. no GVHD prophylaxis: CSA +/- others vs. FK506 +/-others vs. others a Included in all models. 33

34 Not for publication or presentation Attachment 4 Table 4: Univariate analysis Outcomes Cord Blood UNR 8/8 UNR 7/8 P-value Time to ANC>0.5 x 10 9 /L NEval days 66 (57-73) 94 (92-95) 94 (90-96) 100 days 87 (80-92) 95 (94-96) 95 (92-97) Platelet recovery 20 x 10 9 NEval days 11 (6-17) 77 (74-79) 71 (65-76) 100 days 68 (59-76) 86 (84-88) 85 (80-89) <0.001 Acute GVHD (II-IV) NEval days 26 (19-34) 37 (35-40) 49 (43-55) <0.001 Chronic GVHD NEval year 21 (15-29) 46 (43-49) 43 (37-49) 3 years 22 (15-30) 51 (48-54) 48 (42-54) <0.001 Treatment related mortality NEval year 32 (24-40) 27 (24-29) 39 (33-45) 3 years 38 (29-46) 35 (32-37) 46 (41-52) Relapse/Progression NEval year 26 (19-34) 27 (24-29) 21 (16-26) 3 years 29 (22-37) 32 (29-34) 25 (20-31) Progression free survival NEval year 42 (34-50) 46 (44-50) 40 (35-46) 3 years 33 (25-42) 33 (31-37) 29 (23-34) Overall survival NEval year 56 (48-64) 61 (58-63) 49 (43-55) 3 years 44 (35-53) 43 (40-46) 34 (29-40) Abbreviations: ANC = neutrophil recovery; TRM = treatment-related mortality; PFS = progression-free survival; PROB = probability; CI = confidence interval. *Probabilities of neutrophil and platelet recovery, platelet recovery, acute GVHD, chronic GVHD, treatment-related mortality and progression/relapse were calculated using the cumulative incidence estimate. Progression-free survival and overall survival was calculated using the Kaplan-Meier product limit estimate. 34

35 Not for publication or presentation Attachment 4 Table 5: Univariate analysis for haplo-identical Outcomes Haplo-identical Time to ANC>0.5 x 10 9 /L NEval 28 days days 97 (83-100) Platelet recovery 20 x 10 9 NEval 28 days days 89 (72-96) Acute GVHD (II-IV) NEval 100 days 31 (17-46) Chronic GVHD NEval 1 year 11 3 years 22 (8-40) Treatment related mortality NEval 1 year 11 3 years 22 (8-41) Relapse/Progression NEval 1 year 39 3 years 43 (26-60) Progression free survival NEval 1 year 50 3 years 35 (18-55) Overall survival NEval 1 year 57 3 years 46 (27-65) Abbreviations: ANC = neutrophil recovery; TRM = treatment-related mortality; PFS = progression-free survival; PROB = probability; CI = confidence interval. *Probabilities of neutrophil and platelet recovery, platelet recovery, acute GVHD, chronic GVHD, treatment-related mortality and progression/relapse were calculated using the cumulative incidence estimate. Progression-free survival and overall survival was calculated using the Kaplan-Meier product limit estimate. 35

36 Not for publication or presentation Attachment 4 Table 6. Causes of death Causes of death Cord blood UNR 8/8 UNR 7/8 Haploidentical Number of deaths Graft rejection 2 ( 3) 3 (<1) 1 ( 1) 0 Infection 17 (22) 127 (17) 32 (16) 5 (26) IpN 2 ( 3) 17 ( 2) 11 ( 6) 0 ARDS 2 ( 3) 22 ( 3) 3 ( 2) 0 GVHD 5 ( 6) 93 (13) 27 (14) 0 Primary disease 22 (29) 285 (39) 64 (32) 8 (42) Organ failure 19 (25) 96 (13) 30 (15) 4 (21) 2nd malignancy 4 ( 5) 10 ( 1) 2 ( 1) 0 Hemorrhage 1 ( 1) 12 ( 2) 8 ( 4) 0 Accidental death 0 5 ( 1) 1 ( 1) 0 Vascular 1 ( 1) 13 ( 2) 4 ( 2) 0 Toxicity 0 24 ( 3) 9 ( 5) 0 Unknown-not specified 2 ( 3) 26 ( 4) 5 ( 3) 2 (11) 36

37 Not for publication or presentation Attachment 4 Table 7. Multivariate analysis for TRM: Factor level count event HR HR_Low HR_Up pvalue Patient age *overall Patient age yrs Patient age yrs Patient age yrs Patient age yrs Patient age 60 yrs group *overall group 1= Cord blood group 3= UNR 8/ group 6= UNR 7/ Time from diagnosis to transplant *overall Time from diagnosis to transplant 1= <26 month Time from diagnosis to transplant 2= >=26 month Lymphoma subset *overall Lymphoma subset 1= Hodgkin lymphoma Lymphoma subset Lymphoma subset Lymphoma subset 2= follicular lymphoma /other indolent lymphoma 3= diffuse large cell lymphoma / other aggressive B cell lymphoma 4= mantle cell lymphoma Lymphoma subset 5= T cell lymphoma Other comparisons: Variable Comparison HR HR_Low HR_Up pvalue group 1 vs group 6 vs * Stratified variables: Gender, Karnofsky score, Disease status, Year of tx. 37

38 Not for publication or presentation Attachment 4 Table 8. Multivariate analysis for Relapse/Progression: Factor level count event HR HR_Low HR_Up pvalue ATG/Campath *overall ATG/Campath 1=yes ATG/Campath 2=no group *overall group 1= Cord blood group 3= UNR 8/ group 6= UNR 7/ kps *overall kps 0=<90% kps 1= 90% kps 99= missing Disease status *overall..... <.0001 Disease status 1= chemosensitive Disease status 2= chemoresistant <.0001 Disease status 3= missing Other comparisons: Variable Comparison HR HR_Low HR_Up pvalue group 1 vs group 6 vs * Stratified variables: Lymphoma subset, Time from diagnosis to transplant, Year of tx. 38

39 Not for publication or presentation Attachment 4 Table 9. Multivariate analysis for PFS: Factor level count event HR HR_Low HR_Up pvalue Patient age *overall Patient age yrs Patient age yrs Patient age yrs Patient age yrs Patient age 60 yrs group *overall group 1= Cord blood group 3= UNR 8/ group 6= UNR 7/ year2gp *overall year2gp 1= year2gp 2= year2gp 3= Other comparisons: Variable Comparison HR HR_Low HR_Up pvalue group 1 vs group 6 vs * Stratified variables: Karnofsky score, Lymphoma subset, Disease status. 39

40 Not for publication or presentation Attachment 4 Table 10. Multivariate analysis for Overall Survival: Factor level count event HR HR_Low HR_Up pvalue Patient age *overall Patient age yrs Patient age yrs Patient age yrs Patient age yrs Patient age 60 yrs group *overall group 1= Cord blood group 3= UNR 8/ group 6= UNR 7/ Other comparisons: Variable Comparison HR HR_Low HR_Up pvalue group 1 vs group 6 vs * Stratified variables: Gender, Karnofsky score, Lymphoma subset, History of prior autologous transplantation, Disease status, Conditioning regimen, GVHD prophylaxis, Year of tx. 40

41 Not for publication or presentation Attachment 5 MEMORANDUM TO: FROM: STUDY PI: RE: Statistical meeting Wael Saber/ Jeanette Carreras/ Mei-Jie Zhang Alvaro Urbano Ispizua/ Steve Pavletic/Mary Flowers, MD CIBMTR Study # LY12-02/GV11-01: Analysis of Graft versus Lymphoma effect after allogeneic hemopoietic stem cell transplantation For protocol approval: next step send protocol to LYWC/GVWC Enclosed is the protocol for CIBMTR study # LY12-02/GV11-01: Analysis of Graft versus Lymphoma effect after allogeneic hematoopoietic stem cell transplantation Objective: To identify a graft vs. lymphoma (GVLy) effect after HSCT for lymphoma by comparing lymphoma recurrence in patients with and without acute and/or chronic GVHD To identify those subtypes of lymphoma in which reduced intensity transplant might be particularly effective Inclusion/exclusion criteria: Selection criteria Excluded # Remaining # First allogeneic transplant for HD and NHL (DLBCL, FL, peripheral T- cell and mantle cell) reported to the CIBMTR from (CAP modeled) 3243 Age 18 included Excluding patients with planned 2 nd transplant (reason checked as planned n=21 or patients with less 6 m from auto to allo HCT n=32) Twin transplant (n=40) and other related (n=86) excluded Cord blood excluded (HD=41, DLBCL=34, FL=26, Tcell=10, MC=14) Ex vivo T-cell depletion excluded (group: exclude CD34 selection and ATG/Campath? see distribution Table1) Missing data excluded (donor type=16, conditioning regimen=33) Completeness index follow up: o Overall=80%. Per year: 1yr=98%, 2yrs=96%, 3yrs=93% and 5yrs=84%. o HD=84%. Per year: 1yr=99%, 2yrs=97%, 3yrs=95% and 5yrs=88%. o DLBCL=79%. Per year: 1yr=99%, 2yrs=96%, 3yrs=94% and 5yrs=84%. o FL=77%. Per year: 1yr=98%, 2yrs=96%, 3yrs=93% and 5yrs=84%. o Peripheral T-cell=79%. Per year: 1yr=96%, 2yrs=92%, 3yrs=88% and 5yrs=76%. o Mantle cell=98%. Per year: 1yr=96%, 2yrs=93%, 3yrs=93% and 5yrs=83%. 41

42 Not for publication or presentation Attachment 5 CIBMTR LY12-02/GV11-01 ANALYSIS OF GRAFT VERSUS LYMPHOMA (GVLY) EFFECT AFTER ALLOGENEIC HEMOPOIETIC STEM CELL TRANSPLANTATION (HSCT) DRAFT PROTOCOL Study Chair: Study Co-Chairs: Alvaro Urbano Ispizua, MD Institute of Hematology and Oncology Servicio de Hematologia Villarroel 170, Barcelona, Spain Telephone: Fax: aurbano@clinic.ub.es Steve Pavletic, MD National Institute of Health, National Cancer Institute 10 Center Drive CRC/Room 12S241 Bethesda, MD Telephone: Fax: pavletis@mail.nih.gov Mary Flowers, MD Fred Hutchinson Cancer Research Center 1100 Fairview Ave. N., Mail Stop D5-290 Seattle, WA Telephone: Fax: mflowers@fhcrc.org Study Statisticians: Jeanette Carreras, MPH CIBMTR 9200, W. Wisconsin Avenue, Suite C5500 Milwaukee, WI Telephone: Fax: jcarrera@mcw.edu 42