A G E N D A CIBMTR WORKING COMMITTEE FOR HODGKIN AND … · Not for publication or presentation A G...

Not for publication or presentation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: 650-723-0822; Fax: 650-725-8950; E-mail: [email protected] Co-Chair: Silvia Montoto, MD, St. Bartholomew’s Hospital, London, UNITED KINGDOM Telephone: 44 207-601-7456; Fax: 44-207-796-3979; E-mail:[email protected] Co-Chair: David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: 206-667-5000; Fax: 206-667-6124; E-mail: [email protected] Statisticians: Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-805-0681; Fax: 414-805-0714; E-mail: [email protected] Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-456-8375; Fax: 414-805-0714; E-mail: [email protected] Scientific Director: Wael Saber MD, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

a. Minutes of February, 2012 meeting (Attachment 1) b. Newly appointed chair: Sonali Smith, MD; University of Chicago Hospitals;

E-mail: [email protected]

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): 1036-1043, December 2011.

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):1255-1264, December 2011.

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):4256-4262, 2012.

1


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:10.1016/j.bbmt.2012.11.016. 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 2012.

2


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 2012.

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 2013.

4. 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)

Data File Preparation

b LY07-02 Transplant outcomes in the mycosis fungoides and sezary syndrome patients (M Lechowicz)

Manuscript Preparation

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)

Draft Protocol Received

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)

Draft Protocol Received

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 Collection/ Data File Preparation

5. Future/proposed studies

a. PROP 0912-02 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 1112-05 Outcomes of autologous stem cell transplantation for children, adolescents and young adults with relapsed/refractory Hodgkin lymphoma. (P Satwani) (Attachment 7)

3


c. PROP 1112-20 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 1112-30 Impact of mobilization strategies and CD34+ progenitor yields on outcomes of autologous hematopoietic cell transplantation for large B cell lymphoma (R Soiffer) and PROP 1112-65 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 1112-47 Analysis of survival after first relapse post autologous stem cell transplant in Hodgkin’s lymphoma. (A Renteria) (Attachment 10)

Dropped a. PROP 1112-25 Allogeneic transplant for indolent NHL from 1992-2012: 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 1112-39 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 1112-04 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 1112-28 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 1112-04)

e. PROP 1112-23 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 1112-53 Transplant for gamma delta T cell lymphoma. (J Schriber) Due to low number of cases (n=3).

g. PROP 1212-05 Outcome of plasmablastic lymphoma following autologous stem-cell transplantation (N Koshy) Due to low number of cases (n=3).

4

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: Ginna Laport, MD, Stanford University Medical Center, Stanford, CA Telephone: 650-723-0822; Fax: 650-725-8950; E-mail: [email protected] Co-Chair: Silvia Montoto, MD, St. Bartholomew’s Hospital, London, United Kingdom Telephone: 44 207-601-7456; Fax: 44-207-796-3979;

E-mail:[email protected] Co-Chair: David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: 206-667-5000; Fax: 206-667-6124; E-mail: [email protected] Statisticians: Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-805-0681; Fax: 414-805-0714; E-mail: [email protected] Mei-Jie Zhang, PhD, CIBMTR Statistical Center

Phone: 414-456-8375; Fax: 414-456-6530; E-mail: [email protected] Scientific Director: Wael Saber MD, Medical College of Wisconsin, Milwaukee, WI

Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

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 [email protected].

5


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 4886 1562 34863 Research 2321 2693 8222

Hodgkin Lymphoma Registration only 505 212 14793 Research 217 180 2778

3. 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 2012. 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 2011.

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 2011.

6


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 2011.

4. 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 pre-

existing 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 2012.

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 2012.

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 2012.

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 2012.

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 2012.

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 2012.

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 2012.

7


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 2012.

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 HLA-identical 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


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 disease-specific 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 0311-01 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 0611-01 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 1111-12 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 progression-free 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


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 1111-18 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 0401.

h. PROP 1111-46 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 1111-64 Allogeneic transplant for indolent NHL from 1998-2010: 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


Five additional proposals were submitted to the committee but not presented due to the

reasons stated below:

a. PROP 0711-01 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 1111-15 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 1111-34 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 1111-68 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 1111-71 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. LY10-03: Allogeneic hematopoietic stem cell transplantation for lymphoblastic lymphoma/T-cell 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 1111-46): 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 0311-01: Role of transplantation in the management of lymphocyte predominant

Hodgkin’s disease 3. PROP 0611-01: 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 1111-12: 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 1111-18: Comparison of single versus tandem stem cell transplantation for poor-risk Hodgkin lymphoma

6. PROP 1111-64: Allogeneic transplant for indolent NHL from 1998-2010: receipt of rituximab versus rituximab plus ATG versus neither of the two

7. PROP 0711-01: Impact of high dose cytarabine in the induction therapy on post-transplant outcomes in patients with mantle cell lymphoma

8. PROP 1111-15: Outcome after transplant for double-hit lymphoma 9. PROP 1111-34: Outcomes of hematopoietic cell transplantation for primary mediastinal large B-

cell lymphoma 10. PROP 1111-68: Outcomes of hematopoietic stem cell transplant in plasmablastic lymphoma 11. PROP 1111-71: 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


Accrual Summary for Hodgkin and Non-Hodgkin Lymphoma Working Committee: 1990-2012

HLA-identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%)

Anaplastic large cell 128 28 48 76 960 108

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 193 66 57 111 607 149

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

1090

360

319

590

15973

3509

PIF 326 (30) 123 (34) 99 (31) 178 (30) 4056 (25) 800 (23)

CR 1 102 ( 9) 46 (13) 33 (10) 48 ( 8) 2155 (13) 498 (14)

Relapse 1 231 (21) 71 (20) 42 (13) 100 (17) 3349 (21) 977 (28)

CR 2 119 (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 1188 726 310 773 5248 1840

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 1 221 (19) 165 (23) 43 (14) 122 (16) 1086 (21) 441 (24)

CR 2 123 (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 321 171 132 196 564 193

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 621 255 204 430 4268 827

PIF 198 (32) 93 (36) 58 (28) 98 (23) 1003 (24) 210 (25)

CR 1 145 (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


Accrual Summary for Hodgkin & Non-Hodgkin Lymphoma Working Committee: 1990-2012

Continued. HLA-identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%)

Marginal 62 28 21 42 243 33

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 165 40 78 139 529 65

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 345 125 135 267 1124 160

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 412 14 120 30 3656 86

PIF 84 (20) 4 (29) 23 (19) 2 ( 7) 507 (14) 19 (22)

CR 1 30 ( 7) 1 ( 7) 10 ( 8) 0 320 ( 9) 13 (15)

Relapse 1 68 (17) 0 15 (13) 6 (20) 594 (16) 17 (20)

CR 2 21 ( 5) 4 (29) 16 (13) 0 345 ( 9) 10 (12)

Other / Unknown 209 (51) 5 (36) 56 (47) 22 (73) 1890 (52) 27 (31)

Other 754 466 205 690 4186 1459

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 1 116 (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 526 191 215 218 15505 2917

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


Accrual Summary for Hodgkin & Non-Hodgkin Lymphoma Working Committee: 1990-2012

Continued. HLA-identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%)Graft type 5805 2470 1844 3562 52863 11346

BM 1625 (28) 918 (37) 592 (32) 1173 (33) 3969 ( 8) 1906 (17)

PBSC 4059 (70) 1539 (62) 1125 (61) 2083 (58) 46240 (87) 9248 (82)

Other / Unknown 121 ( 2) 13 ( 1) 127 ( 7) 306 ( 9) 2654 ( 5) 192 ( 2)

15


TO: Hodgkin and non-Hodgkin Working Committee Members FROM: Wael Saber, MD, MS, Scientific Director for Lymphoma Working Committee RE: 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 2005. 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 2000-2009. 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 2013. 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 post-transplant 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 2013. 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 1990-2009. Pathology reports were reviewed in all cases to confirm transformation of FL

16


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 2013. 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 2000-2010. 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 pre-transplant 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 2007. 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 1998. 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


MEMORANDUM

TO: LYWC Working Committee

FROM: Wael Saber, MD, MS, Jeanette Carreras, MPH, and Tao Wang, PhD STUDY PI: Veronika Bachanova, MD, Claudio Brunstein and Linda Burns, MD RE: 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 2010. 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


Inclusion/exclusion criteria: Selection criteria Excluded # Remaining #First allogeneic transplant for NHL and HD reported to the CIBMTR from 2000-2010 (CAP modeled) 3886Age ≥ 18 years 216 3670Excluding patients with planned 2nd transplant (reason checked as “planned n=28 or patients with less 6 m from auto to allo HCT n=44) 72 3598Including 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 1641 1957

Excluding cord blood ex-vivo expansion 8 N=1949Additional 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=1840Excluding 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

N=1632CB=142

UNR 8/8=1176UNR 7/8=275 HAPLO=39

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

19


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 0.01.

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


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 55455 Telephone: 612-625-5469 E-mail: [email protected] Claudio Brunstein, MD University of Minnesota Medical Center, Fairview 420 Delaware Street SE, MMC 803 Minneapolis, MN 55455 Telephone: 612-625-3918 Fax: 612-626-2815 E-mail: [email protected] Linda J. Burns, MD University of Minnesota Medical Center, Fairview 420 Delaware Street SE, MMC 480 12-154 Moos Tower Minneapolis, MN 55455 Telephone: 612-624-8144 Fax: 612-625-9988 E-mail: [email protected] Study Statisticians: Jeanette Carreras, MPH CIBMTR-Milwaukee Statistical Center 9200, W. Wisconsin Avenue, Suite C5500 Milwaukee, WI 53236 Telephone: 414-805-0681 Fax: 414-805-0714 E-mail: [email protected] Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI 53226 USA Telephone: 414-456-8375 Fax: 414-456-6513 E-mail: [email protected]

21


Scientific Director: Wael Saber, MD, MS CIBMTR Medical College of Wisconsin 9200 W. Wisconsin Avenue Suite C5500 Milwaukee, WI Telephone: 414-805-0700 Fax: 414-805-0714 E-mail: [email protected] Working Committee Chairs: Ginna Laport, MD Associate Professor of Medicine Division of Bone Marrow Transplant Stanford University Medical Center, Stanford, CA Telephone: 650-723-0822

Fax: 650-725-8950 E-mail: [email protected]

Silvia Montoto, MD

Senior Lecturer St. Bartholomew’s Hospital 45 Little Britain London, UK Telephone: 44 207-601-7456 Fax: 44-207-796-3979 E-mail: [email protected]

David Maloney, MD, PhD Fred Hutchinson Cancer Research Center

1100 Fairview Avenue Seattle, WA Telephone: 206-667-5616


22


1.0 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:

2.1.1 Neutrophil and platelet engraftment; 2.1.2 Acute and chronic graft-versus-host disease; 2.1.3 Non-relapse mortality; 2.1.4 Disease relapse or progression; 2.1.5 Progression-free survival; 2.1.6 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 one-half 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=1840 8 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


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 2000-2010. 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

5.1.1 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


5.1.2 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.

5.1.3 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.

5.1.4 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: 5.2.1 Hematopoietic recovery: The primary measures for hematopoietic recovery will

be: 5.2.1.1 Time to neutrophils (ANC) > 0.5 x109/L sustained for three consecutive

days. This endpoint does not specify whether recovery is engraftment of donor cells or autologous reconstitution.

5.2.1.2 Time to achieve a platelet count of (a) >20 x 109/L independent of platelet transfusions for 7 consecutive days, and (b) >50 x 109/L independent of platelet transfusions for 7 consecutive days.

5.2.2 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. 90-100%

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


Year of transplant: 2000-2003 vs. 2004-2006 vs. 2007-2010 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 107/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 Chi-square 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 procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant. 2003 Apr;31(8):667-678.

2. 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):1050-1055.

3. 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. 2006 Dec;12(12):1326-1334.

4. 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):3521-3529.

26


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. 2008 May;14(5):538-545.

6. 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. 2012 Jan;18(1 Suppl):S161-5

7. 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. 4576–4583

8. 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. 2009 Jun;21 Suppl 1:S31-4.

9. 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. 2009 Feb;15(2):214-222.

10. 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):3804-3807

11. Gluckman E. Ten years of cord blood transplantation: from bench to bedside. Br.J.Haematol. 2009 Oct;147(2):192-199

12. 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. 2009 Jan 10;27(2):256-263

13. 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. 2009 Sep;50(9):1488-93

14. 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. 2010 Apr;16(4):533-42.

27


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 bloodUNR

8/8UNR

7/8 Haplo-

identical

Number of patients 142 1176 275 39Age, median (range), years 45 (19-73) 50 (18-75) 45 (18-71) 54 (18-74)Age at transplant

18-29 yrs 26 (18) 154 (13) 51 (19) 5 (13)30-39 yrs 31 (22) 198 (17) 43 (16) 5 (13)40-49 yrs 31 (22) 240 (20) 74 (27) 5 (13)50-59 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, months

18 (6-139) 20 (6-175) 19 (6-154) 22 (8-55)

Time from autoHCT to alloHCT, months ≤12 13 ( 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 indolent lymphoma

30 (21) 294 (25) 59 (21) 8 (21)

DLBCL/other aggressive B cell lymphoma

39 (27) 282 (24) 70 (25) 15 (38)

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


Table 1 Continued Characteristics of patients Cord blood

UNR 8/8

UNR 7/8

Haplo-identical

Number of patients 142 1176 275 39Disease 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) 0REL 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) 39CNS 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 107/kg, median (range) 2.47 (0.08-10.74) NA

NA NA

TBD 64

29


Table 1. Continued. Characteristics of patients Cord blood

UNR 8/8

UNR 7/8

Haplo-identical

Number of patients 142 1176 275 39Interval from diagnosis to transplant, months

27 (2-203) 34 (3-312) 32 (3-247) 30 (4-193)

3-6 7 ( 5) 20 ( 2) 3 ( 1) 1 ( 3)6-12 19 (13) 136 (12) 24 ( 9) 2 ( 5)12-26 43 (30) 286 (24) 75 (27) 14 (36)26-36 17 (12) 167 (14) 41 (15) 5 (13)36-60 26 (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 2000-2003 21 (15) 338 (29) 97 (35) 5 (13)2004-2006 34 (24) 463 (39) 134 (49) 8 (21)2007-2010 87 (61) 375 (32) 44 (16) 26 (67)

30


Table 1. Continued. Characteristics of patients Cord blood

UNR 8/8

UNR 7/8

Haplo-identical

Number of patients 142 1176 275 39ATG/Campath

ATG and Campath 0 1 (<1) 1 (<1) 0ATG 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 MMF)

5 ( 4) 454 (39) 80 (29) 5 (13)

FK506 + others (except MTX, MMF)

16 (11) 37 ( 3) 7 ( 3) 1 ( 3)

FK506 alone 6 ( 4) 41 ( 3) 17 ( 6) 0CSA + MMF +- others (except FK506)

65 (46) 177 (15) 43 (16) 2 ( 5)

CSA + MTX +- others (except FK506, MMF)

3 ( 2) 124 (11) 33 (12) 0

CSA + others (except FK506, MTX, MMF)

9 ( 6) 23 ( 2) 6 ( 2) 0

CSA alone 2 ( 1) 14 ( 1) 10 ( 4) 0Sirolimus-based 0 4 ( 1) 0 0MMF-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


Table 2. Conditioning regimens (revised) Characteristics of patients Cord blood

UNR 8/8

UNR 7/8

Haplo-identical

Total number of patients 142 1176 275 39Myeloablative 41 302 81 2

Bu/cy +/- others 4 (10) 59 (20) 14 (17) 0Bu/flu +/- others 5 (12) 36 (12) 14 (17) 0Bu +/- others 3 ( 7) 15 ( 5) 0 0Cy/TBI +/- others 20 (49) 158 (52) 36 (44) 1 (50)Thio +/- others 0 2 ( 1) 0 0Flu/mel +/- others 5 (12) 15 ( 5) 11 (14) 0TBI +/- others 4 (10) 16 ( 5) 5 ( 6) 0Others myeloablative 0 1 (<1) 1 ( 1) 1 (50)

RIC 35 512 124 4Bu/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 0Cy/TBI +/- others 1 ( 3) 3 ( 1) 0 0Thio +/- others 0 4 ( 1) 2 ( 2) 0Flu/mel +/- others 18 (51) 204 (40) 44 (35) 2 (50)TBI +/- others 0 19 ( 4) 4 ( 3) 0Flu +/- others 3 ( 9) 8 ( 2) 4 ( 3) 0BEAM +/- others 6 (17) 42 ( 8) 12 (10) 0CBV +/- others 0 15 ( 3) 9 ( 7) 0Mel +/- others 0 23 ( 4) 4 ( 3) 0

NST 66 362 70 33Cy/TBI +/- others 0 1 (<1) 0 0TBI +/- others 0 21 ( 6) 4 ( 6) 0Cy +/- others 0 4 ( 1) 0 1 ( 3)Flu +/- others 66 302 (83) 59 (84) 32 (97)Others NST 0 34 ( 9) 7 (10) 0

32


Table 3. Variables tested in Cox proportional hazards regression models. Main effecta: 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: 2000-2003 vs. 2004-2006 vs. 2007-2010 ATG use: yes vs. no GVHD prophylaxis: CSA +/- others vs. FK506 +/-others vs. others a Included in all models.

33


Table 4: Univariate analysis Outcomes Cord Blood UNR 8/8 UNR 7/8 P-valueTime to ANC>0.5 x 109/L NEval 140 1173 274

@ 28 days 66 (57-73) 94 (92-95) 94 (90-96) <0.001@ 100 days 87 (80-92) 95 (94-96) 95 (92-97) 0.023

Platelet recovery 20 x 109

NEval 122 1152 271 @ 28 days 11 (6-17) 77 (74-79) 71 (65-76) <0.001@ 100 days 68 (59-76) 86 (84-88) 85 (80-89) <0.001

Acute GVHD (II-IV) NEval 142 1176 275

@ 100 days 26 (19-34) 37 (35-40) 49 (43-55) <0.001Chronic GVHD NEval 139 1145 270

@ 1 year 21 (15-29) 46 (43-49) 43 (37-49) <0.001@ 3 years 22 (15-30) 51 (48-54) 48 (42-54) <0.001

Treatment related mortality NEval 142 1174 275

@ 1 year 32 (24-40) 27 (24-29) 39 (33-45) <0.001@ 3 years 38 (29-46) 35 (32-37) 46 (41-52) 0.002

Relapse/Progression NEval 142 1174 275

@ 1 year 26 (19-34) 27 (24-29) 21 (16-26) 0.094@ 3 years 29 (22-37) 32 (29-34) 25 (20-31) 0.107

Progression free survival NEval 142 1174 275 0.062

@ 1 year 42 (34-50) 46 (44-50) 40 (35-46) 0.135@ 3 years 33 (25-42) 33 (31-37) 29 (23-34) 0.186

Overall survival NEval 142 1176 275 0.009

@ 1 year 56 (48-64) 61 (58-63) 49 (43-55) 0.002@ 3 years 44 (35-53) 43 (40-46) 34 (29-40) 0.017

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


Table 5: Univariate analysis for haplo-identical Outcomes Haplo-identicalTime to ANC>0.5 x 109/L NEval 39

@ 28 days 92 (77-98)@ 100 days 97 (83-100)

Platelet recovery 20 x 109 NEval 35

@ 28 days 60 (42-74)@ 100 days 89 (72-96)

Acute GVHD (II-IV) NEval 39

@ 100 days 31 (17-46)Chronic GVHD NEval 38

@ 1 year 11 (3-24)@ 3 years 22 (8-40)

Treatment related mortality NEval 38

@ 1 year 11 (3-24)@ 3 years 22 (8-41)

Relapse/Progression NEval 38

@ 1 year 39 (23-55)@ 3 years 43 (26-60)

Progression free survival NEval 38

@ 1 year 50 (33-67)@ 3 years 35 (18-55)

Overall survival NEval 39

@ 1 year 57 (41-72)@ 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


Table 6. Causes of death Causes of death

Cord blood

UNR 8/8

UNR 7/8

Haplo-identical

Number of deaths 77 733 197 19Graft rejection 2 ( 3) 3 (<1) 1 ( 1) 0Infection 17 (22) 127 (17) 32 (16) 5 (26)IpN 2 ( 3) 17 ( 2) 11 ( 6) 0ARDS 2 ( 3) 22 ( 3) 3 ( 2) 0GVHD 5 ( 6) 93 (13) 27 (14) 0Primary 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) 0Hemorrhage 1 ( 1) 12 ( 2) 8 ( 4) 0Accidental death 0 5 ( 1) 1 ( 1) 0Vascular 1 ( 1) 13 ( 2) 4 ( 2) 0Toxicity 0 24 ( 3) 9 ( 5) 0Unknown-not specified 2 ( 3) 26 ( 4) 5 ( 3) 2 (11)

36


Table 7. Multivariate analysis for TRM:

Factor level count event HR HR_Low HR_Up pvalue

Patient age *overall . . . . . 0.0016

Patient age 18-29 yrs 231 76 1.000 . . .

Patient age 30-39 yrs 272 84 0.879 0.633 1.220 0.4404

Patient age 40-49 yrs 345 150 1.317 0.957 1.813 0.0915

Patient age 50-59 yrs 484 184 1.121 0.815 1.542 0.4827

Patient age ≥60 yrs 259 119 1.637 1.146 2.338 0.0068

group *overall . . . . . 0.0065

group 1= Cord blood 142 51 1.000 . . .

group 3= UNR 8/8 1174 429 0.726 0.532 0.990 0.0433

group 6= UNR 7/8 275 133 0.963 0.681 1.362 0.8305

Time from diagnosis to transplant

*overall . . . . . 0.0063


1= ”<26 month” 641 269 1.000 . . .


2= ”>=26 month” 950 344 0.778 0.649 0.931 0.0063

Lymphoma subset *overall . . . . . 0.0002

Lymphoma subset 1= Hodgkin lymphoma 346 104 1.000 . . .

Lymphoma subset 2= follicular lymphoma

/other indolent lymphoma

382 145 0.935 0.690 1.268 0.6655

Lymphoma subset 3= diffuse large cell lymphoma

/ other aggressive B cell lymphoma

390 185 1.463 1.095 1.954 0.0100

Lymphoma subset 4= mantle cell lymphoma

263 106 0.984 0.697 1.390 0.9287

Lymphoma subset 5= T cell lymphoma 210 73 0.873 0.621 1.229 0.4368

Other comparisons:

Variable Comparison HR HR_Low HR_Up pvalue

group 1 vs.3 1.377 1.01 1.878 0.0433group 6 vs.3 1.326 1.081 1.626 0.0067

* Stratified variables: Gender, Karnofsky score, Disease status, Year of tx.

37


Table 8. Multivariate analysis for Relapse/Progression:


ATG/Campath *overall . . . . . 0.0008

ATG/Campath 1=yes 614 222 1.000 . . .

ATG/Campath 2=no 975 280 0.733 0.611 0.879 0.0008

group *overall . . . . . 0.1049

group 1= Cord blood 141 44 1.000 . . .

group 3= UNR 8/8 1173 384 0.924 0.667 1.279 0.6336

group 6= UNR 7/8 275 74 0.711 0.481 1.051 0.0872

kps *overall . . . . . 0.0084

kps 0=<90% 484 160 1.359 1.111 1.663 0.0028

kps 1= 90% 953 284 1.000 . . .

kps 99= missing 152 58 1.254 0.938 1.675 0.1264

Disease status *overall . . . . . <.0001

Disease status 1= chemosensitive

1050 304 1.000 . . .

Disease status 2= chemoresistant

485 187 1.762 1.454 2.136 <.0001

Disease status 3= missing 54 11 0.665 0.360 1.231 0.1944

Other comparisons:


group 1 vs.3 1.082 0.782 1.499 0.6336group 6 vs.3 0.769 0.595 0.994 0.0452

* Stratified variables: Lymphoma subset, Time from diagnosis to transplant, Year of tx.

38


Table 9. Multivariate analysis for PFS:



Patient age 18-29 yrs 231 173 1.000 . . .

Patient age 30-39 yrs 272 191 0.826 0.668 1.021 0.0775

Patient age 40-49 yrs 345 233 0.858 0.689 1.069 0.1735

Patient age 50-59 yrs 484 327 0.858 0.690 1.067 0.1681

Patient age ≥60 yrs 259 192 1.080 0.844 1.382 0.5427

group *overall . . . . . 0.1227

group 1= Cord blood

142 95 1.000 . . .

group 3= UNR 8/8 1174 814 0.798 0.637 0.998 0.0479

group 6= UNR 7/8 275 207 0.852 0.660 1.101 0.2203

year2gp *overall . . . . . 0.0228

year2gp 1=2000-2003 455 350 1.000 . . .

year2gp 2=2004-2006 631 457 0.900 0.778 1.041 0.1572

year2gp 3=2007-2010 505 309 0.789 0.667 0.934 0.0060

Other comparisons:


group 1 vs.3 1.254 1.002 1.569 0.0479group 6 vs.3 1.068 0.911 1.254 0.4175

* Stratified variables: Karnofsky score, Lymphoma subset, Disease status.

39


Table 10. Multivariate analysis for Overall Survival:



Patient age 18-29 yrs 231 157 1.000 . . .

Patient age 30-39 yrs 272 161 0.704 0.480 1.034 0.0738

Patient age 40-49 yrs 345 213 1.004 0.680 1.482 0.9842

Patient age 50-59 yrs 484 296 0.888 0.596 1.323 0.5586

Patient age ≥60 yrs 261 180 1.307 0.835 2.047 0.2416

group *overall . . . . . 0.2518

group 1= Cord blood 142 77 1.000 . . .

group 3= UNR 8/8 1176 733 0.746 0.471 1.182 0.2123

group 6= UNR 7/8 275 197 0.892 0.542 1.469 0.6529

Other comparisons:


group 1 vs.3 1.340 0.846 2.121 0.2123group 6 vs.3 1.195 0.908 1.572 0.2038

* Stratified variables: Gender, Karnofsky score, Lymphoma subset, History of prior autologous transplantation, Disease status, Conditioning regimen, GVHD prophylaxis, Year of tx.

40


MEMORANDUM

TO: Statistical meeting

FROM: Wael Saber/ Jeanette Carreras/ Mei-Jie Zhang STUDY PI: Alvaro Urbano Ispizua/ Steve Pavletic/Mary Flowers, MD RE: 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 1997-2009 (CAP modeled) 3243Age ≥18 included 92 3151Excluding patients with planned 2nd transplant (reason checked as “planned n=21 or patients with less 6 m from auto to allo HCT n=32) 53 3098Twin transplant (n=40) and other related (n=86) excluded 126 2972Cord blood excluded (HD=41, DLBCL=34, FL=26, Tcell=10, MC=14) 125 2847Ex vivo T-cell depletion excluded (group: exclude CD34 selection and ATG/Campath? see distribution Table1) 115 2732Missing data excluded (donor type=16, conditioning regimen=33) 49 2683 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


CIBMTR LY12-02/GV11-01

ANALYSIS OF GRAFT VERSUS LYMPHOMA (GVLY) EFFECT AFTER ALLOGENEIC

HEMOPOIETIC STEM CELL TRANSPLANTATION (HSCT)

DRAFT PROTOCOL Study Chair: Alvaro Urbano Ispizua, MD

Institute of Hematology and Oncology Servicio de Hematologia Villarroel 170, 08036 Barcelona, Spain Telephone: +34 93 227 5475 Fax: +34 93 227 9811 E-mail: [email protected]

Study Co-Chairs: Steve Pavletic, MD

National Institute of Health, National Cancer Institute 10 Center Drive CRC/Room 12S241 Bethesda, MD Telephone: 301-402-4899 Fax: 301-451-5578 E-mail: [email protected] Mary Flowers, MD Fred Hutchinson Cancer Research Center 1100 Fairview Ave. N., Mail Stop D5-290 Seattle, WA 98109 Telephone: 206-667-5160 Fax: 206-667-1034 Email: [email protected]

Study Statisticians: Jeanette Carreras, MPH CIBMTR 9200, W. Wisconsin Avenue, Suite C5500 Milwaukee, WI 53236 Telephone: 414-805-0681 Fax: 414-805-0714 E-mail: [email protected]

42


Mei-Jie Zhang, PhD CIBMTR Statistical Center 8701 Watertown Plank Road Milwaukee, WI 53226 USA Telephone: 414-456-8375 Fax: 414-456-6513 E-mail: [email protected] Scientific Director: Wael Saber, MD, MS CIBMTR Medical College of Wisconsin 9200 W. Wisconsin Avenue Suite C5500 Milwaukee, WI Telephone: 414-805-0700 Fax: 414-805-0714 E-mail: [email protected] Working Committee Chairs: Ginna Laport, MD Associate Professor of Medicine Division of Bone Marrow Transplant Stanford University Medical Center, Stanford, CA Telephone: 650-723-0822


Silvia Montoto, MD

Senior Lecturer St. Bartholomew’s Hospital 45 Little Britain London, UK Telephone: 44 207-601-7456 Fax: 44-207-796-3979 E-mail: [email protected]

David Maloney, MD, PhD Fred Hutchinson Cancer Research Center

1100 Fairview Avenue Seattle, WA Telephone: 206-667-5616


43


1.0 HYPOTHESIS: 1.1 There is a potent GVLy effect associated with acute and/or chronic GVHD 1.2 The intensity of the GVLy effect is different depending on the subtype of B and T cell

lymphoma 1.3 If demonstrated such association, the results would be of particular usefulness in RIC

transplants

2.0 OBJECTIVES: 2.1 To determine the existence of a GVLy effect associated with acute and/or chronic GVHD

in B cell and T cell lymphomas 2.2 To identify those subtypes of lymphoma in which reduced intensity transplant might be

particularly effective

3.0 SCIENTIFIC JUSTIFICATION: Several retrospective clinical studies have shown a potent graft versus leukaemia effect associated with allogeneic HSCT, particularly in patients with acute myelogenous leukaemia, acute lymphoblastic leukaemia, and chronic myelogenous leukaemia. This finding has been the basis for reducing the intensity of the conditioning regimen (RIC) (1) and for mostly abandoning the practice of T-cell depletion of the graft. Several retrospective studies have suggested the existence of a GVLy effect, especially in follicular lymphomas (2). However, a recent CIBMTR study (3) found no significant differences in relapse rates when results of allogeneic transplantation were compared with syngeneic transplantation and with autologous transplantation. Of note, T-cell depletion of allografts did not influence relapse rate of follicular lymphomas. Several weaknesses of this study must be mentioned: the impact of GVHD on relapse rate was not analysed, low numbers of allogeneic patients were included, the last patient received the transplant in 1998 and unrelated and RIC transplants were excluded. Another more recent CIBMTR study has shown no effect of allo-HSCT, compared to auto-HSCT, on progression/relapse for diffuse large B-cell lymphoma patients (4). Other reports of small series have suggested a GVLy effect in Hodgkin lymphoma and in peripheral T cell-lymphoma (5). Mature lymphoid neoplasms represent approximately 4% of new cancers each year, with an incidence rate of 33 per 100.000 persons per year (6), much higher than the incidence of acute leukaemia. For the most frequent subtypes of lymphoma median average age of patients is 60-65 years. For this aged patients, RIC transplants would be an excellent platform of immunotherapy, if a GVLy effect is clearly demonstrated.

4.0 STUDY POPULATION: Patient eligibility/selection criteria include: Adult patients (older than 18) undergoing HLA-identical sibling or unrelated donor HSCT for lymphoma between 1997 and 2009, reported to the CIBMTR. - Diagnosis of Hodgkin lymphoma or NHL (diffuse large B cell, follicular lymphoma,

peripheral T cell lymphoma, mantle cell lymphoma). - All conditioning regimens (RIC and MAC). - Donor grafts: BM or PBSC.

Exclusions:

44


- Other lymphoid malignancies, such as plasma cell disorders, CLL, ALL, MALT lymphoma, small lymphocytic lymphoma, mediastinal large B cell lymphoma and Burkitt’s lymphoma are excluded.

- Other relative excluded - Cord blood excluded - Ex-vivo T-cell depleted grafts are excluded.

5.0 OUTCOMES:

5.1 Acute and chronic GVHD: Occurrence of grade II, III, and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD, and limited and extensive chronic GVHD. 5.2 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. 5.3 Relapse/progression: progressive disease or recurrences of disease are 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. 5.4 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. 5.1 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.

6.0 VARIABLES TO BE ANALYZED: Patient-related:

– Age at transplant, decades – Gender: male vs. female – Karnofsky performance status transplant: <90% vs. ≥90%

Disease-related:

– Lymphoma histology: follicular lymphoma vs. DLBCL vs. mantle cell vs. peripheral T cell lymphoma vs. Hodgkin lymphoma

– Disease stage at diagnosis: I/II vs. III/IV – B symptoms at diagnosis: yes vs. no – Number of lines of chemotherapy therapy prior to transplant: continuous – Bone Marrow involvement any time prior to transplant: yes vs. no – Disease status at transplant: CR1 vs. PIF-sensitive vs. PIF- resistant vs. CR2+ vs. relapse-

sensitive vs. relapse-resistant vs. relapse-untreated/unknown Transplant-related:

– Interval from diagnosis to transplant: – Prior autologous transplant: yes vs. no – D-R CMV status: +/+ vs. +/- vs. -/+ vs. -/- – D-R sex match: M-M vs. M-F vs. F-M vs. F-F

45


– Conditioning regimen: RIC vs. MAC – Donor type: well matched unrelated vs. partially matched/mismatched URD vs. URD

matching TBD/unknown vs. HLA identical sibling/other related – Graft type: bone marrow vs. peripheral blood vs. cord blood – Year of transplant: 1997-2000 vs. 2001-2004 vs. 2005-2010 – ATG: ATG alone/campath alone vs. missing vs. No ATG or campath – GVHD prophylaxis: CSA +/- others vs. vs. FK506 +/-others vs. others

7.0 STUDY DESIGN: The goal of this study is to compare the effect of GVHD on relapse rate and on progression free survival in patients with all lymphoma cases and by different lymphoma subtypes. Descriptive tables of patient-, disease-, and transplant-related factors by different lymphoma subtypes will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables.

Probabilities of survival and progression-free survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Values for other endpoints included in Sec. 5.0 will be generated using cumulative incidence estimates (29) to account for competing risks.

Multivariate analyses will be performed using Cox proportional hazards models for outcomes listed in Section 5.0. This analysis will treat aGVHD as a time-dependent covariate (patient considered having GVHD only if current study time is greater than his/her onset time of GVHD). Patients belonging to the GVHD group depend on the current study time. This would be the main “treatment” effect. A stepwise model building approach will then be used to identify the significant risk factors associated with the outcomes of relapse, treatment-related mortality, progression-free survival and overall survival. The variables to be considered in the multivariate models are listed in Sections 6.0. The assumption of proportional hazards for each factor in the Cox model will be tested using time-dependent covariates. When the test indicated differential effects over time (non-proportional hazards), models will be constructed breaking the post-transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. The proportionality assumptions will be further tested. A backward stepwise model selection approach will be used to identify all significant risk factors. Each step of model building contained the main “treatment” effect. Factors which are significant at a 5% level will be kept in the final model. The potential interactions between main effect and all significant risk factors will be tested.

46


8.0 REFERENCES: 1. Storb RF, Champlin R, Riddell SR, et al. Non-myeloablative transplants for malignant

disease. Hematology (Am Soc Hematol Educ Program) 2001:375–391. 2. van Besien K, Sobocinski KA, Rowlings PA, et al. Allogeneic bone marrow transplantation

for low grade lymphoma. Blood 1998; 92:1832–1836. 3. Bierman PJ, Sweetenham JW, Loberiza FR, et al. Syngeneic Hematopoietic Stem-Cell

Transplantation for Non-Hodgkin’s Lymphoma: A Comparison With Allogeneic and Autologous Transplantation. J Clin Oncol 21:3744-3753. 2003

4. Lazarus HM, Zhang M-J, Carreras J, et al. A comparison of HLA-identical sibling allogeneic versus autologous transplantation for diffuse large B-cell lymphoma: a report from the CIBMTR. Biol Blood Marrow Transplant - In press, 2009.

5. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect in relapsed peripheral T-cell NHL after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol. 2004 Jun 1; 22(11):2172-6.

6. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006 Jan 1; 107(1):265-76.

47


Table 1. Characteristics of patient who underwent allogeneic transplant for HD and NHL, reported to the CIBMTR from 1997 to 2009, by histology groups.

Variable Hodgkin Disease DLBCL Follicular T cell Mantle cell

Number of patients 480 593 897 202 511Age at transplant, years

Median (range) 32 (18-69) 49 (18-70) 49 (21-70) 45 (18-69) 56 (23-75)18-29 yrs 206 (43) 76 (13) 16 ( 2) 31 (15) 4 ( 1)30-39 yrs 158 (33) 94 (16) 153 (17) 46 (23) 17 ( 3)40-49 yrs 74 (15) 138 (23) 317 (35) 52 (26) 99 (19)50-59 yrs 35 ( 7) 206 (35) 316 (35) 48 (24) 241 (47)≥60 yrs 1 (<1) 18 ( 3) 21 ( 2) 6 ( 3) 50 ( 9)

Sex Male 286 (60) 348 (59) 525 (59) 145 (72) 421 (82)Female 194 (40) 245 (41) 372 (41) 57 (28) 90 (18)

Karnofsky score-90 <90% 167 (35) 277 (47) 429 (48) 102 (50) 207 (41)≥90% 272 (57) 282 (48) 431 (48) 90 (45) 270 (53)Missing 41 ( 9) 34 ( 6) 37 ( 4) 10 ( 5) 34 ( 7)

Disease stage at diagnosis I-II 210 (44) 169 (28) 142 (16) 37 (18) 66 (13)III-IV 240 (50) 372 (63) 716 (80) 147 (73) 404 (79)Unknown 30 ( 6) 52 ( 9) 39 ( 4) 18 ( 9) 41 ( 8)

B-symptoms at diagnosis A 156 (33) 285 (48) 494 (55) 87 (43) 280 (55)B 281 (59) 211 (36) 280 (31) 92 (46) 159 (31)Missing 43 ( 9) 97 (16) 123 (14) 23 (11) 72 (14)

Number of prior chemotherapy lines Median (range) 4 (1-5) 4 (1-5) 4 (1-5) 3 (1-5) 3 (1-5)1 9 ( 2) 35 ( 6) 43 ( 5) 26 (13) 88 (17)2 61 (13) 114 (19) 190 (21) 61 (30) 112 (22)3 98 (20) 136 (23) 212 (24) 50 (25) 110 (22)4 183 (38) 148 (25) 221 (25) 33 (16) 93 (18)5 109 (23) 129 (22) 207 (23) 27 (13) 81 (16)Missing 20 ( 4) 31 ( 5) 24 ( 3) 5 ( 2) 27 ( 5)

BM involvement at any time prior to transplant

No 215 (45) 222 (37) 135 (15) 76 (38) 70 (14)Yes 68 (14) 165 (28) 475 (53) 88 (44) 307 (60)Unknown 197 (41) 206 (35) 287 (32) 38 (19) 134 (26)

48


Table 1. Continued Variable

Hodgkin Disease DLBCL Follicular T cell Mantle cell

Number of patients 480 593 897 202 511Disease status prior to transplant

PIF sensitive 50 (10) 88 (15) 134 (15) 44 (22) 83 (16)PIF resistant 52 (11) 110 (19) 92 (10) 36 (18) 46 ( 9)CR1 11 ( 2) 25 ( 4) 43 ( 5) 20 (10) 74 (14)REL sensitive 148 (31) 126 (21) 238 (27) 26 (13) 105 (21)REL resistant 122 (25) 97 (16) 161 (18) 29 (14) 69 (14)CR2+ 70 (15) 97 (16) 149 (17) 34 (17) 89 (17)REL untreated/unknown 14 ( 3) 12 ( 2) 39 ( 4) 5 ( 2) 12 ( 2)Missing 13 ( 3) 38 ( 6) 41 ( 5) 8 ( 4) 33 ( 6)

Interval from diagnosis to transplant, months*

35 (5-413) 20 (2-309) 38 (1-352) 13 (2-159) 26 (3-175)

Prior autologous transplant No 160 (33) 440 (74) 793 (88) 174 (86) 414 (81)Yes 320 (67) 153 (26) 104 (12) 28 (14) 97 (19)

D-R CMV status +/+ 89 (19) 165 (28) 247 (28) 62 (31) 142 (28)+/- 75 (16) 70 (12) 117 (13) 24 (12) 62 (12)-/+ 111 (23) 146 (25) 226 (25) 51 (25) 118 (23)-/- 181 (38) 184 (31) 281 (31) 56 (28) 162 (32)TBD 24 ( 5) 28 ( 5) 26 ( 3) 9 ( 4) 27 ( 5)

D-R sex match M-M 185 (39) 218 (37) 330 (37) 98 (49) 261 (51)M-F 118 (25) 141 (24) 202 (23) 34 (17) 52 (10)F-M 93 (19) 119 (20) 193 (22) 46 (23) 149 (29)F-F 72 (15) 103 (17) 166 (19) 22 (11) 36 ( 7)TBD 12 ( 3) 12 ( 2) 6 ( 1) 2 ( 1) 13 ( 3)

Conditioning regimens Myeloablative 128 (27) 274 (46) 342 (38) 100 (50) 152 (30)RIC 264 (55) 226 (38) 308 (34) 66 (33) 178 (35)NST 88 (18) 93 (16) 247 (28) 36 (18) 181 (35)

Type of donor HLA-id sibling 104 (22) 240 (40) 473 (53) 89 (44) 216 (42)URD well-matched 220 (46) 212 (36) 244 (27) 71 (35) 194 (38)URD partially matched 118 (25) 93 (16) 96 (11) 23 (11) 63 (12)URD mismatched 25 ( 5) 21 ( 4) 21 ( 2) 4 ( 2) 8 ( 2)URD matching 13 ( 3) 27 ( 5) 63 ( 7) 15 ( 7) 30 ( 6)

49


Table 1 Continued Variable


Number of patients 480 593 897 202 511Graft type

Bone marrow 116 (24) 154 (26) 217 (24) 33 (16) 92 (18)Peripheral blood 364 (76) 439 (74) 680 (76) 169 (84) 419 (82)

Year of transplant 1997-2000 56 (12) 125 (21) 210 (23) 11 ( 5) 87 (17)2001-2004 190 (40) 192 (32) 329 (37) 64 (32) 172 (34)2005-2009 234 (49) 276 (47) 358 (40) 127 (63) 252 (49)

Year of transplant, detailed 1997 9 ( 2) 28 ( 5) 50 ( 6) 3 ( 1) 17 ( 3)1998 14 ( 3) 22 ( 4) 34 ( 4) 3 ( 1) 16 ( 3)1999 10 ( 2) 29 ( 5) 64 ( 7) 1 (<1) 18 ( 4)2000 23 ( 5) 46 ( 8) 62 ( 7) 4 ( 2) 36 ( 7)2001 38 ( 8) 42 ( 7) 79 ( 9) 10 ( 5) 33 ( 6)2002 40 ( 8) 51 ( 9) 90 (10) 19 ( 9) 31 ( 6)2003 59 (12) 50 ( 8) 80 ( 9) 15 ( 7) 61 (12)2004 53 (11) 49 ( 8) 80 ( 9) 20 (10) 47 ( 9)2005 82 (17) 63 (11) 84 ( 9) 29 (14) 56 (11)2006 60 (13) 74 (12) 81 ( 9) 29 (14) 59 (12)2007 55 (11) 60 (10) 75 ( 8) 24 (12) 52 (10)2008 22 ( 5) 41 ( 7) 59 ( 7) 26 (13) 47 ( 9)2009 15 ( 3) 38 ( 6) 59 ( 7) 19 ( 9) 38 ( 7)

ATG-Campath ATG + Campath 1 (<1) 0 0 0 1 (<1)ATG alone 123 (26) 127 (21) 146 (16) 36 (18) 104 (20)Campath alone 40 ( 8) 48 ( 8) 68 ( 8) 18 ( 9) 58 (11)No ATG or Campath 314 (65) 402 (68) 672 (75) 145 (72) 334 (65)Missing 2 (<1) 16 ( 3) 11 ( 1) 3 ( 1) 14 ( 3)

50


Table 1. Continued. Variable


GVHD prophylaxis CD34 selection alone 5 ( 1) 1 (<1) 5 ( 1) 3 ( 1) 2 (<1)CD34 selection + post-tx immune supression

8 ( 2) 13 ( 2) 20 ( 2) 4 ( 2) 9 ( 2)

Cyclophosphamide alone 1 (<1) 0 0 0 0Cyclophosphamide + others 0 0 1 (<1) 0 0FK506 + MMF +- others 92 (19) 90 (15) 111 (12) 29 (14) 88 (17)FK506 + MTX +- others (except MMF)

156 (33) 179 (30) 281 (31) 70 (35) 139 (27)

FK506 + others (except MTX, MMF)

8 ( 2) 18 ( 3) 26 ( 3) 3 ( 1) 18 ( 4)

FK506 alone 17 ( 4) 25 ( 4) 26 ( 3) 5 ( 2) 14 ( 3)CSA + MMF +- others (except FK506)

57 (12) 45 ( 8) 98 (11) 19 ( 9) 97 (19)

CSA + MTX +- others (except FK506, MMF)

88 (18) 137 (23) 221 (25) 41 (20) 86 (17)

CSA + others (except FK506, MTX, MMF)

17 ( 4) 26 ( 4) 26 ( 3) 10 ( 5) 19 ( 4)

CSA alone 20 ( 4) 38 ( 6) 45 ( 5) 9 ( 4) 27 ( 5)Other GVHD prophylaxis** 11 ( 3) 21 ( 4) 37 ( 4) 9 ( 4) 12 ( 2)

DLI post-transplant*** 15 ( 3) 16 ( 3) 21 ( 2) 8 ( 4) 16 ( 3)Median follow up of survivors, median (range) 61 (3-170) 57 (3-170) 63 (3-175)

49 (3-161) 60 (3-168)

Abbreviations: CMV=Cytomegalovirus, TBI=Total body irradiation, LPAM=Melphalan, Flud=Fludarabine, Bu=Busulfan, Cy=CsA=Cyclosporine, MTX=Methotrexate, FK506=Tacrolimus, *Distribution of time from diagnosis to transplant by histology (in months) Histology Minimum 1st Pctl 5th Pctl 25th Pctl Median 75th Pctl 95th Pctl 99 Pctl Maximum HD 5 8 11 22 35 58 127 215 413 DLBCL 2 5 7 12 20 44 120 193 309 FL 1 6 10 22 38 64 139 200 352 T-cell 2 2 5 8 13 20 60 157 159 Mantle cell

3 4 6 11 26 45 85 123 175

**Other GVHD prophylaxis include: FL (3 no GVHD, 3 not specified, 1 ATG+MTX, 1 MAB+MMF+Campath, 1 MMF, 1 MTX+MMF, 1 MTX; DLBCL (5 no GVHD, 7 not specified, 1 IVIM, 1 MAB+Campath, 1 MAB+MMF+Campath, 4 MMF, 2 MTX; Follicular (6 no GVHD, 16 not specified, 1 ATG+Cor+MMF+Siro, 1 ATG+MTX, 1 Cor, 1 Cor+MTX+Siro, 4 MAB+MMF+Campath, 2 MMF, 4 MTX, 1 Urso; T cell (1 no GVHD, 1 not specified, 1 Cor+MMF, 1 Cor+MMF+Siro, 1 MMF, 4 MTX; Mantle cell (2 no GVHD, 9 not specified, 1 MTX). ***76 reported DLI. 20 did not relapse post tx and are alive, 10 did not relapse post tx and dead (request sent for reason for DLI), 7 relapse post tx and are alive (all relapse post DLI) and 39 relapse and dead (31 relapse before DLI, 4 after DLI and 4 has relapse date missing).

51


CIBMTR Study Proposal: 0912-02 Study Title: Autologous transplantation for diffuse large B-cell Lymphomas patients refractory to, or relapsing early after Rituximab-containing first line chemo-immunotherapies. Mehdi Hamadani, MD, West Virginia University, Morgantown, WV; [email protected] Parameswaran Hari, MD, MS; CIBMTR, Medical College of Wisconsin, Milwaukee, WI; [email protected] Specific Aims:

1. To describe outcomes with autologous transplantation of diffuse large B-cell lymphoma (DLBCL) patients with primary refractory disease or early relapse after rituximab based 1st line chemoimmunotherapies (High-risk cohort).

2. To compare outcomes of autologous transplantation in high-risk DLBCL patients against patients experience late relapse after rituximab containing 1st line chemoimmunotherapies (standard-risk cohort). The following outcomes are to be evaluated for both groups:

30 day mortality; 100 day mortality; Neutrophil and platelet engraftment; 100 day and 1 year non-relapse mortality; Disease relapse or progression; Progression-free survival; Overall survival.

Scientific Justification: High dose therapy and autologous hematopoietic stem cell transplantation (HSCT) is considered standard therapy for patients with relapsed chemosensitive diffuse large B-cell lymphoma (DLBCL), and appears to be curative for 40-45% of the patients (1-3). The incorporation of rituximab in the first line chemotherapy has significantly improved survival outcomes of both elderly and younger DLBCL patients (4-7). Autologous HSCT is frequently considered for patients with relapsed or primary refractory DLBCL. Registry data from CIBMTR described the outcomes of autologous HSCT patients with primary refractory DLBCL, in the pre-rituximab era (8). 184 DLBCL patients who never achieved a complete remission with conventional chemotherapy and subsequently received an autotransplant were evaluated. Transplants were performed between 1989 and 1995 and were reported to the ABMTR by 48 centers in North and South America (8). Seventy-nine (44%) of 184 patients achieved a complete remission or a complete remission with residual imaging abnormalities of unknown significance after autotransplantation. Thirty-four (19%) of 184 had a partial remission and 55 (31%) of 184 had no response or progressive disease. The probabilities of progression-free and overall survival at 5 years after transplantation were 31% (95% confidence interval [CI], 24% to 38%) and 37% (95% CI, 30% to 45%), respectively. This analysis is often cited as the rationale for considering high-dose chemotherapy and autologous HSCT in patients with primary refractory DLBCL. Whether these outcomes are maintained in patients treated with rituximab based first line chemoimmunotherapies needs further investigation. In the rituximab-era, the CORAL (9) examined the optimal salvage regimen for patients with relapsed DLBCL as its primary outcome. While the CORAL study data continue to support role of autologous HSCT in most relapsed DLBCL patients with a chemosensitive relapse, it identified a subset of high-risk patients, who did not appear to benefit from this modality. The high-risk feature included prior rituximab therapy, primary refractory disease and disease relapse within a year of diagnosis. In patients with both early

52


relapse (<12 months) and prior rituximab treatment, the 3-year progression free survival was only 23%. We hence propose a registry study to analyze autologous transplantation outcomes of high-risk DLBCL patients (defined as primary refractory disease after 1st line rituximab-based chemoimmunotherapy or disease relapse within 1 year of diagnosis in patients treated with rituximab-based chemoimmunotherapies), relative to the outcomes of DLBCL patients receiving 1st rituximab based chemoimmunotherapies who experienced disease relapse >12month after diagnosis. If exact time of disease relapse is not captured in CIBMTR dataset, then 15 months between diagnosis and autologous-HSCT will be used as a surrogate time frame for patients who relapsed within 1 year of diagnosis (to allow a generally 3 month time period generally required for salvage therapy, stem cell collection and actual transplantation). Patient Eligibility Population: Patient eligibility criteria include:

Histologically proven diagnosis of DLBCL. DLBCL patients who underwent autologous HSCT between 2002 and 2011. First line therapy with rituximab-containing chemoimmunotherapies (If data on 1st line therapy is

not captured in CIBMTR forms, then year of diagnosis [2002 onwards] will be used as surrogate time frame to reflect a time period when rituximab was routinely incorporated in 1st line therapies).

High-risk cohort will be defined as: (1) Patients with primary refractory disease after 1st line rituximab-containing chemoimmunotherapies or (2) Patients undergoing autologous HSCT within 15 months of initial DLBCL diagnosis (or relapsing within 12 months of initial diagnosis, if this information is available).

Standard-risk cohort will include all patients who received rituximab-containing first line chemoimmunotherapies who do meet the criteria of high-risk disease.

Patients with transformation from CLL or indolent histologies will be excluded. Pediatric patients (age <18 years) will be excluded.

Data Collection: Patient, Disease and Transplant-related Variables: Patient-related:

Age at transplant, years Gender: male vs. female Karnofsky performance status transplant: <90% vs. ≥90%

Disease-related: High-risk vs. standard-risk Time from diagnosis to transplant: (<1year vs. others; <15months vs. others; <18months vs.

other) Disease stage at diagnosis: I/II vs. III/IV Disease stage at transplant: I/II vs. III/IV B symptoms at diagnosis and transplant LDH at diagnosis and transplant Number of lines of chemotherapy therapy prior to transplant Bone Marrow involvement at diagnosis: yes vs. no Extranodal involvement: yes vs. no CNS involvement at diagnosis: yes vs. no Cell dose infused

53


Prior history of radiation therapy: yes vs. no Disease status at transplant: chemosensitive vs. resistant Source of stem cells: bone marrow vs. peripheral blood vs. both

Transplant-related: Conditioning regimen: TBI containing vs. non-TBI containing

Transplantation Outcomes Variables:

30-day and 100-day mortality: time to death from any cause within 30 and/or 100 days post transplant

Hematopoietic recovery: The primary measures for hematopoietic recovery will be: - Time to ANC > 0.5 x109/L sustained for three consecutive days. - Time to achieve a platelet count of >50 x 109/L independent of platelet transfusions for 3

consecutive days. Non-relapse mortality (NRM): Any death within the first 28 days of transplant or any death

occurring after day 28 in the absence of overt disease progression. Relapse/Progression: progressive disease or recurrences of disease are events. Progression-free survival (PFS): survival without recurrence or tumor progression. Recurrence or

progression of disease and death are events. Those who survive without recurrence or progression are censored at last contact.

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

Study Design: The goal of this study is to compare the clinical outcomes (as listed in Section 4.0) between high-risk DLBCL patients undergoing autologous transplantation against standard-risk patients, while adjusting for significant patient-, disease-, and transplant-related variables. Descriptive tables of patient, disease, and transplant-related factors will be prepared. Baseline characteristics will be compared between groups using the Chi-square test for categorical variables and Mann–Whitney U test for continuous variables. Progression-free and overall survival will be calculated using the Kaplan-Meier estimator. Cumulative incidence of non-relapse morality (NRM) and relapse risk will be estimated, with relapse as a competing risk for the former and death in remission for the latter. Gary’s test will be used to assess the difference between various subgroups for NRM and relapse rate. Cox proportional hazards models will be constructed for cumulative incidence of NRM, relapse, and for OS and PFS, using a limited backward selection procedure. Variables considered in the model will be those significant at α=0.20 level from the univariable models. Variables remaining in the final models will be significant at α=0.05 level. References:

1. Philip T, Armitage JO, Spitzer G, et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N.Engl.J.Med. . 1987; 316:1493-1498.

2. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N.Engl.J.Med. . 1995;333:1540-1545.

3. Verdonck LF, van Putten WL, Hagenbeek A, et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma. N.Engl.J.Med. . 1995; 332:1045-1051.

4. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24; 346(4):235-42.

54


5. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23;116(12):2040-5.

6. Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91.

7. Pfreundschuh M, Kuhnt E, Trümper L, et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011 Oct;12(11):1013-22. Epub 2011 Sep 21.

8. Vose JM, Zhang MJ, Rowlings PA, et al. Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol. 2001 Jan 15;19(2):406-13.

9. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90.

55


Characteristics of ≥ 18 years old patients who underwent autologous transplantation for refractory diffuse large B-cell lymphoma after rituximab-containing first line chemoimmunotherapy from

2002-2011 reported to the CIBMTR by risk groups* Variable High risk Standard risk

Number of patients 302 438

Number of centers 77 101

Age at transplant

Median (range) 59 (19-77) 60 (20-77)

18-29 yrs 22 ( 7) 18 ( 4)

30-39 yrs 17 ( 6) 28 ( 6)

40-49 yrs 44 (15) 53 (12)

50-59 yrs 85 (28) 112 (26)

≥60 yrs 134 (44) 227 (52)

Sex

Male 179 (59) 264 (60)

Female 123 (41) 174 (40)

Karnofsky score

<90% 117 (39) 111 (25)

90-100% 163 (54) 292 (67)

Missing 22 ( 7) 35 ( 8)

Conditioning regimen

TBI-based 34 (11) 34 ( 8)

BEAM and similar 222 (74) 330 (75)

CBV or similar 24 ( 8) 43 (10)

BuMEL/BuCy 13 ( 4) 20 ( 5)

Others 9 ( 3) 11 ( 3)

Disease status after first chemotherapy line

Non-response (high risk) 44 (15) 0

Progressive disease (high risk) 49 (16) 0

≤12m from diagnosis to pre-tx relapse (high risk) 209 (69) 0

All others (standard risk) 0 438

56


Continued.

Variable High risk Standard risk

Disease status prior to transplant**

Sensitive 236 (78) 396 (90)

Resistant 54 (18) 22 ( 5)

Missing 12 ( 4) 20 ( 5)

Graft type

Bone marrow 6 ( 2) 4 ( 1)

Peripheral blood 296 (98) 434 (99)

Year of HCT

2002 7 ( 2) 18 ( 4)

2003 9 ( 3) 17 ( 4)

2004 15 ( 5) 28 ( 6)

2005 25 ( 8) 25 ( 6)

2006 35 (12) 56 (13)

2007 48 (16) 60 (14)

2008 101 (33) 140 (32)

2009 40 (13) 63 (14)

2010 11 ( 4) 16 ( 4)

2011 11 ( 4) 15 ( 3)

Median follow up of survivors, months 38 (3-96) 40 (2-126)*Exclusions: histologic transformation, less than 18 years of age, non- rituximab containing chemoimmunotherapy High risk cohort was defined as: patients with non-response/progressive disease or patients relapsing within 12 months of initial diagnosis after 1st line rituximab containing chemoimmunotherapy Standard risk cohort was defined as: patients receiving rituximab containing chemoimmunotherapy who do not meet high risk cohort criteria

57


**High_risk: Col Pct |Non-resp|Progress|<=12 dia| Total |onse |ive dise|gnosis a| | |ase |nd pretx| | | | relapse| -----------------+--------+--------+--------+ PIF sensitive | 21 | 25 | 0 | 46 | 47.73 | 51.02 | 0.00 | -----------------+--------+--------+--------+ PIF resistant | 10 | 9 | 0 | 19 | 22.73 | 18.37 | 0.00 | -----------------+--------+--------+--------+ CR1 | 4 | 2 | 0 | 6 | 9.09 | 4.08 | 0.00 | -----------------+--------+--------+--------+ REL sensitive | 5 | 4 | 52 | 61 | 11.36 | 8.16 | 24.88 | -----------------+--------+--------+--------+ REL resistant | 0 | 5 | 17 | 22 | 0.00 | 10.20 | 8.13 | -----------------+--------+--------+--------+ CR2+ | 1 | 2 | 77 | 80 | 2.27 | 4.08 | 36.84 | -----------------+--------+--------+--------+ PIF unknown | 0 | 0 | 0 | 0 | 0.00 | 0.00 | 0.00 | -----------------+--------+--------+--------+ Missing | 3 | 2 | 63 | 68 | 6.82 | 4.08 | 30.14 | -----------------+--------+--------+--------+ Total 44 49 209 302 Standard risk: REL sensitive 93 (21%), REL resistant 18 (4%), CR2+ 146 (33%), PIF unknown 1 (1%), Missing 180 (41%)

58


CIBMTR Study Proposal: 1112-05 Study Title: Outcome of autologous stem cell transplantation for children; adolescents and young adults with relapsed/refractory Hodgkin lymphoma Prakash Satwani, MD; Columbia University, New York, NY; [email protected]

Specific Aims:

To study the 5 year disease-free survival (DFS) and overall survival (OS) following autologous stem cell transplantation (AutoSCT) in children, adolescents and young adults (CAYA) with relapsed/refractory Hodgkin lymphoma.

To analyze risk factors for relapse following AutoSCT in CAYA with relapsed/refractory Hodgkin lymphoma.

Scientific Justification: 1-There has never been a large study conducted in CAYA analyzing risk factors that predict relapse in CAYA with relapsed/refractory Hodgkin lymphoma after AutoSCT. 2-The risk factors that predict relapse following AutoSCT in adults may not have the same impact in CAYA. 3-Due to the large numbers of CAYA enrolled in the CIBMTR database, there is a high probability of identifying risk factors that predicts poor outcome in CAYA following AutoSCT. This data can be utilized for power calculation for future clinical trials for CAYA at very high risk for relapse following AutoSCT. Such potential clinical trials include maintenance of Brentuximab vedotin following AutoSCT or upfront allogeneic stem cell transplantation. Hodgkin lymphoma is the most common cancer in CAYA (1). With the use of chemotherapy alone or with the addition of low dose radiotherapy, the overall survival rate of HL in children is 90%. However, 5-10% of patients with advanced stage HL still relapse (2-3). For those patients who do relapse, long term remissions are rare. For those patients who have refractory/relapse Hodgkin lymphoma, outcome depends on various prognostic factors. In a multicenter study of the Pediatric DAL/GPOH- Hodgkin lymphoma Study Group, 161 patients with progressive and recurrent Hodgkin lymphoma were divided into 3 categories (4). Group 1 (n=51) consisted of patients with progression of disease during treatment or until 3 months after completion of therapy, group 2 (n=57) consisted of patients who relapsed between 3 and 12 months after completion of therapy and group 3 (n=53) consisted of patients who relapsed > 12 months after completion of therapy. The probability of DFS after salvage therapy for group 1 vs. 2 vs. 3 was 41 vs. 55 vs. 86%, respectively. In CAYA with relapsed Hodgkin lymphoma, MAC AutoSCT is the standard approach. Baker et al. demonstrated that the 5-year probability of failure free survival (FFS) in CAYA with refractory/relapsed HL following MAC AutoSCT was 31% (2). In this study, prognostic factors important for FFS were normal pre-transplantation lactate dehydrogenase levels (5-year FFS = 42%), compared with patients with elevated LDH levels (5-year FFS = 0%) (P<.001), and disease sensitivity at the time of MAC Auto SCT with FFS in untreated relapse, sensitive disease, and resistant disease 44%, 35%, and 9%, respectively (P =.06). In a study published by Stanford group (5), the 5yr event free survival (EFS) in CAYA who received MAC AutoSCT for relapse/refractory Hodgkin lymphoma was 53%. Extranodal disease at time of first relapse (p<0.5), the presence of mediastinal mass at the time of transplantation (p<0.5) and primary induction failure (p<0.5) remained significant predictors of poor EFS. In a recently published

59


COG study of CBV regimen followed by MAC AutoSCT, patients who relapse with 12 months of diagnosis with HL had significantly worse EFS (p< 0.001) and OS (p=0.007) when compared to those patients who relapse after 12 months of diagnosis (6). Moskowitz et al. recently reported data in 153 adult patients with chemosensitive Hodgkin lymphoma after ICE (ifosfamide, carboplatin, and etoposide)–based salvage therapy who proceeded to high dose chemo-radiotherapy followed by AutoSCT (7). Patients were evaluated with computed tomography and functional imaging (gallium or fluorodeoxyglucose-positron emission tomography) prior to salvage therapy and again before AutoSCT. Functional imaging status before AuotSCT was the only factor significant for EFS and OS by multivariate analysis (5-year EFS 31% and 75% for FI-positive and negative patients, respectively). In adults with induction failure or early relapse (<12 months remission duration), the progression-free survival (PFS) following AutoSCT ranges from 20% to 50% (8-14). Smith et al. further analyzed the outcome for patients with early relapsed/refractory Hodgkin lymphoma with other risk factors (15). Two hundred and fourteen patients were studied; the event-free survival (EFS) and overall survival (OS) at 6 years for all patients were 45% and 55%, respectively. Factors significant for prognosis in multivariate analysis were extranodal disease and bulky disease (≥5 cm). Patients with 0, 1, or 2 risk factors achieved 6-year EFS of 65%, 47%, and 24% and 6-year OS of 81%, 55%, and 27%, respectively. Patients with the sole risk factor of early relapsed/refractory disease achieved good outcomes in this large series; however, the presence of bulk and/or extranodal disease significantly reduced EFS and OS. Patient Eligibility Population:

Diagnosis- Hodgkin lymphoma Age ≤21 years at the time of AutoSCT Years: 1990-2011

Data Requirements: CIBMRT form 2018- Pre-HSCT Data

Date of diagnosis. Histology of Hodgkin lymphoma. Stage at the time of diagnosis. Presence or absence of B symptoms. Extranodal involvement - Bone marrow, lungs, brain, other sites LDH at diagnosis.

1st line therapy - date of start and end date of therapy, number of cycle. Radiation therapy – yes or no? Best response to 1st line therapy. Date response established? Relapse or disease progression following 1st line therapy - yes or no? Date of relapse.

2nd line therapy- number of patients who received a) Ifosfamide +, Carboplatin and Etoposide; b) Gemcitabine+ vinblastine; c) Ifosfamide+ Vinblastine; and 4) other regimens

Radiation therapy as a part of 2nd line therapy. Best response to second line therapy. Date response established. Relapse or disease progression following 2nd line therapy - yes or no? Date of relapse after 2nd line therapy?

60


Was a PET scan performed at any time between diagnosis and the start of preparative regimen? What was the sensitivity of Hodgkin lymphoma to chemotherapy prior to preparative regimen? What was the disease remission state immediately prior to the preparative regimen? CIBMTR form, 2100, 2200, 2300 and 2118 - Post HSCT data

Preparative regimen Relapse after AutoSCT Date of relapse Subsequent treatment

Study Design:

Retrospective review of CAYA receiving AutoSCT for relapsed/refractory Hodgkin lymphoma. Comparison of risk factors between relapsed and non-relapsed CAYA receiving AutoSCT for

relapsed/refractory Hodgkin lymphoma. Univariate and multivariate analysis for risk factors associated with relapse in patients with early

relapse (<12 months from diagnosis). Exclusion criteria- Planned cellular therapy after AutoSCT.

References:

1. Hochberg J, Waxman IM, Kelly KM, Morris E, Cairo MS. Adolescent non-Hodgkin lymphoma and Hodgkin lymphoma: state of the science. Br J Haematol. 2009 Jan;144(1):24-40.

2. Baker KS, Gordon BG, Gross TG, Abromowitch MA, Lyden ER, Lynch JC, et al. . Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents. J Clin Oncol. 1999 Mar;17(3):825-31.

3. Johnston LJ, Horning SJ. Autologous hematopoietic cell transplantation in Hodgkin's disease. Biol Blood Marrow Transplant. 2000;6(3A):289-300.

4. Schellong G, Dörffel W, Claviez A, Körholz D, Mann G, Scheel-Walter HG, Bökkerink JP, Riepenhausen M, Lüders H, Pötter R, Rühl U; DAL/GPOH. Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group. J Clin Oncol. 2005 Sep 1;23(25):6181-9

5. Lieskovsky YE, Donaldson SS, Torres MA, Wong RM, Amylon MD, Link MP, Agarwal R. High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: results and prognostic indices. J Clin Oncol. 2004 Nov 15;22(22):4532-40.

6. Harris RE, Termuhlen AM, Smith LM, Lynch J, Henry MM, Perkins SL, et al. . Autologous Peripheral Blood Stem Cell Transplantation in Children with Refractory or Relapsed Lymphoma: Results of Children's Oncology Group Study A5962. Biol Blood Marrow Transplant. 2010 Jul 14.

7. Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Moskowitz AJ, Yahalom J, Kewalramani T, Maragulia JC, Vanak JM, Zelenetz AD, Moskowitz CH. Blood. 2010 Dec 2;116(23):4934-7

8. Chopra, R., McMillan, A.K., Linch, D.C., Yuklea, S., Taghipour, G., Pearce, R., Patterson, K.G. & Goldstone, A.H. (1993) The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin’s disease. A

single-center eight-year study of 155 patients. Blood, 81, 1137–1145.

61


9. Nademanee, A., O’Donnell, M.R., Snyder, D.S., Schmidt, G.M., Parker, P.M., Stein, A.S., Smith, E.P., Molina, A., Stepan, D.E. & Somlo, G. (1995). High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin’s disease: results in 85 patients with analysis of prognostic factors. Blood, 85, 1381–1390.

10. Brice, P., Bouabdallah, R., Moreau, P., Divine, M., Andre, M., Aoudjane, M., Fleury, J., Anglaret, B., Baruchel, A., Sensebe, L. & Colombat, P. (1997) Prognostic factors for survival after high-dose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin’s disease: analysis of 280 patients from the French registry. `Societe francaise de greffe de moelle. Bone Marrow Transplantation, 20, 21–26.

11. Horning, S.J., Chao, N.J., Negrin, R.S., Hoppe, R.T., Long, G.D., Hu, W.W., Wong, R.M., Brown, B.W. & Blume, K.G. (1997) High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: analysis of the Stanford University results and prognostic indices. Blood, 89, 801–813.

12. Sweetenham, J.W., Carella, A.M., Taghipour, G., Cunningham, D., Marcus, R., Della Volpe, A., Linch, D.C., Schmitz, N. & Goldstone, A.H. (1999) High-dose therapy and autologous stemcell transplantation for adult patients with Hodgkin’s disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European group for blood and marrow transplantation. Lymphoma working party. Journal of Clinical Oncology, 17, 3101–3109.

13. Majhail, N.S., Weisdorf, D.J., Defor, T.E., Miller, J.S., McGlave, P.B., Slungaard, A., Arora, M., Ramsay, N.K., Orchard, P.J., MacMillan, M.L. & Burns, L.J. (2006) Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma. Biology of Blood and Marrow Transplantation, 12, 1065–1072

14. Ferme, C., Mounier, N., Divine, M., Brice, P.,Stamatoullas, A., Reman, O., Voillat, L., Jaubert, J., Lederlin, P., Colin, P., Berger, F. & Salles, G. (2002) Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: results of the groupe d’etudes deslymphomes de l’adulte H89 trial. Journal of Clinical Oncology, 20, 467–475.

15. Smith SD, Moskowitz CH, Dean R, Pohlman B, Sobecks R, Copelan E, Andresen S, Bolwell B, Maragulia JC, Vanak JM, Sweetenham J, Moskowitz AJ. Autologous stem cell transplant for early relapsed/refractory Hodgkin lymphoma: results from two transplant centres. Br J Haematol. 2011 May;153(3):358-63

.

62


Characteristics of ≤21 years old patients who underwent autologous transplantation for relapsed/refractory Hodgkin lymphoma from 1995-2011 reported to the CIBMTR

Variable N (%)

Number of patients 253

Number of centers 111

Median age at transplant, years 18 (<1-21)

Sex

Male 143 (57)

Female 110 (43)

Karnofsky score

<90% 43 (17)

90-100% 185 (73)

Missing 25 (10)

Disease status prior to transplant

PIF sensitive 44 (17)

PIF resistant 11 ( 4)

REL sensitive 65 (26)

REL resistant 18 ( 7)

CR2+ 103 (41)

REL untreated/unknown 8 ( 3)

PIF unknown 4 ( 2)

Conditioning regimen

TBI-based 5 ( 2)

BEAM and similar 173 (68)

CBV or similar 27 (11)

BuMEL/BuCy 10 ( 4)

Others 38 (15)

Graft type

Bone marrow 22 ( 9)

Peripheral blood 231 (91)

63


Continued.

Variable N (%)

Year of HCT

1995-1996 49 (19)

1997-1998 46 (18)

1999-2000 37 (15)

2001-2002 20 ( 8)

2003-2004 19 ( 8)

2005-2006 31 (12)

2007-2008 37 (15)

2009-2010 12 ( 5)

2011 2 ( 1)

Median follow up of survivors, months 61 (3-197)

64


CIBMTR Study Proposal: 1112-20

Study Title: Comparison of autologous versus allogeneic stem cell transplantation after reduced/non-myeloablative conditioning for relapsed/refractory patients with follicular lymphoma Evgeny Klyuchnikov; University of Hamburg, Hamburg-Eppendorf, Germany; [email protected] Ulrike Bacher, MD; University of Hamburg, Hamburg-Eppendorf, Germany; [email protected] Parameswaran Hari, MD, MS; Medical College of Wisconsin, Milwaukee, WI;

Specific Aims: The primary objective of the study is to compare overall (OS) and progress-free survival(PFS) in patients with relapsed/refractory follicular lymphoma (FL) who underwent reduced-intensity/non-myeloablative allogeneic stem cell transplantation (RIC/NMAC-HSCT) versus autologous stem cell transplantation (auto-HSCT) as second-line approach. Secondary objectives are to compare engraftment data, day +100 transplant-related mortality (TRM), cumulative incidences of TRM and relapse/progression. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD will also be evaluated in those who received allogeneic HSCT.

Scientific Justification: Although auto-HSCT has long been available for patients with relapsed chemosensitive FL1,2 (Table 1) large randomized studies establishing superiority of auto-HSCT over salvage chemoimmunotherapy alone are not available. In the pre-rituximab era, the European Blood and Marrow Transplant (EBMT) group performed the only randomized clinical trial in this setting (CUP trial) aiming to compare salvage chemotherapy alone with chemotherapy followed by either purged or unpurged auto-HSCT in relapsed FL patients. This trial was closed prematurely because of poor accrual, but despite the limited number of patients enrolled (n=89), it showed a significant PFS and OS benefit with auto-HSCT.3 In the rituximab era, Sebban et al. from the GELF (Groupe d’Etude des Lymphomes Folliculaires) conducted another analysis of relapsed FL in patients who received rituximab-based salvage therapies. No statistically significant OS benefit was seen with auto-HSCT (93% at 5 years) when compared with those getting salvage chemoimmunotherapy alone (70% at 5 years).4 In different study, the combined retrospective data from the Dana-Farber Cancer Institute and St Bartholomew’s Hospital suggested prolonged remissions in relapsed FL patients after auto-HSCT; however, this benefit was restricted primarily to patients in second complete remission (CR).5 Thus, auto-HSCT unfortunately is not generally considered a curative modality for FL. Large registry data from the EBMT6 and the CIBMTR7 show no plateau in the relapse rates post-autografting. Furthermore, the risk of second malignancies post auto-HCT is not insignificant, ranging from 5–15% in several large studies.5,6 On the other hand, allogeneic HSCT that permits the use of cell products devoid of tumor cells and prior chemotherapy-induced DNA damage offers the advantages of lymphoma-free grafts and the immunologic graft-versus-lymphoma (GvL) effect, which have been found to confer long-term remission in lymphoma patients.7-9 Clinical evidence of a GvL effect is suggested by a plateau in relapse risk that is reached after 2–5 years of allogeneic HSCT in most studies, indicating that a substantial proportion of lymphoma patients derive long-term disease control from transplantation. One of the most compelling lines of evidence for a GvL effect is the success of allogeneic HSCT after autologous HSCT has failed to result in a durable response or the use of allogeneic HSCT as consolidative therapy after autologous HSCT.10,11 In addition, observations of marked tumor response after withdrawal of immunosuppression and donor lymphocyte infusions (DLIs) in patients who

65


experience relapse after allograft underscore the robustness of the GvL effect in FL and its capacity to maintain long-term remission.12,13 The widespread application of myeloablative allogeneic HSCT, however, is limited by rates of up-front mortality of up to 40%, occurring in part because allogeneic HSCT has traditionally been used in patients with more advanced, chemorefractory disease. To exploit this GvL effect without the toxicity associated with myeloablative HSCT, non-myeloablative HSCT (NMAC) had been suggested in patients with advanced lymphoma.14 Reduced-intensity conditioning (RIC) regimens were first reported in patients with relapsed lymphoma almost 13 years ago and were intended to make allogeneic transplantation feasible for older, heavily pretreated patients (Table 2). The most recent retrospective analysis of RIC versus myeloablative conditioning regimens for FL patients was conducted by the EBMT.15 On multivariate analysis, RIC regimens were associated with a significantly lower NRM and a significantly longer PFS and OS. These results were in contrast to the ones reported in another registry study that compared the outcomes for patients who received various NMAC and RIC regimens with those who received matched sibling grafts after myeloablative conditioning. The NMAC and RIC patients were older, more likely to have ≥2nd CR, more likely to have received rituximab, and more likely to receive peripheral blood stem cells. Despite this difference and the larger population studied no statistically significant differences in PFS, OS, or TRM rates emerged between the NMAC/RIC and myeloablative cohorts.16 Khouri et al. have reported on their 8-year experience with the fludarabine, cyclophosphamide, and rituximab (FCR) regimen in 47 FL patients the majority of whom underwent sibling donor allogeneic HSCT in 2009. At the time of transplant, 62% of patients were in partial remission (PR); after transplantation, 100% experienced a CR. Acute severe GvHD and chronic extensive GvHD occurred in 11% and 36%, respectively. In addition, a unique finding in that report is that 20 of 28 (71%) patients who experienced chronic GvHD had a de novo onset, which had no major negative impact on survival. The 1-year TRM rate was 10%. The PFS and OS were 83% and 85%, respectively.17 Unlike allogeneic HSCT, autologous HSCT has been associated with a TRM rate of <5% but has also been associated with a higher risk of relapse, related to graft contamination and the persistence of minimal residual disease, which results from a lack of a GvL effect. The only prospective comparison being conducted of autologous and allogeneic HSCT for relapsed FL closed early as a result of poor accrual.18 The other comparisons were based on retrospective analyses of registry data, which have shown a lower relapse rate and a longer disease-free survival after allogeneic HSCT than after autologous HSCT. The high TRM rate associated with myeloablative allogeneic HSCT, however, offsets any potential survival benefits (Table 3).7,9 We propose the following observational study in order to test the hypothesis that RIC/NMAC-HSCT may be more effective in achieving complete remission and prolonging relapse-free and perhaps OS than auto-HSCT in relapsed/refractory FL patients registered to the CIBMTR database. Summary of the literature above for autologous HSCT for FL (Table 1):

Autologous HSCT is a feasible treatment in relapsed/refractory FL patients Addition of Rituximab to auto-HSCT could improve survival outcomes TRM <10% (for non-transformed FL) PFS 30-70% OS 50-90% 7-12% of patients experienced secondary malignancies including s-MDS/AML

66


Summary of the literature for NMAC/RIC-HSCT for FL (Table 2): NMAC/RIC HSCT is a feasible treatment in relapsed/refractory FL patients Addition of Rituximab to the allo-HSCT setting could improve survival outcomes TRM/NRM 15-41% Acceptable rates of acute and chronic GvHD in most reports Durable response on DLIs PFS 57-90% OS 54-90%

Summary of the literature above for comparison auto- versus allo-HSCT (Table 3):

Both auto-HSCT and allo-HSCT induce long-term disease control in a proportion of FL patients.

After auto-HSCT most late failures were due to disease recurrence and due to occurrence of secondary malignancy.

In multivariate analysis, an effect of stem cell purging on recurrence rate and OS in the recipients of autologous HSCT was found.

After allo-HSCT the recurrence rate was only 20% with almost all recurrences occurring within the first year of transplantation.

Patient Eligibility Population: The study population will include patients with non-transformed relapsed/refractory FL who had either auto- or RIC/NMAC-HSCT between 1999 and 2010.

Data Requirements: Results of single autologous-HSCT versus RIC/NMAC-HSCT will be compared. Outcome Data: The primary endpoint will be: Progression-free survival: Time to relapse/progression. Events will be summarized by Kaplan-Meier estimates. Cases will be analyzed at the time of last follow-up. Deaths due to transplantation will be competing risks. Overall survival: Time to death. Events will be summarized by Kaplan-Meier estimates. Cases will be analyzed at the time of last follow-up. The secondary outcomes to be studied are:

Neutrophil engraftment after the first and second planned HSCT - Achievement of a continued absolute neutrophil count (ANC) ≥0.5 x 109/L for 3 consecutive days. Death is a competing risk.

Platelet engraftment after the first and second planned HSCT - Achievement of a continued platelet count of greater than 20 and 50 x 109/L. Death is a competing risk.

Complete remission – Achievement of clinical and radiologic evidence of complete remission. 100 day mortality (TRM) - This is defined as death on or before 100 days post-transplant.

Patients alive at last observation with fewer than 100 days of follow-up are not considered censored for this event.

Acute GvHD (in case of allo-HSCT) - Development of Grades II-IV and Grades III-IV acute GvHD using Glucksberg system which grades GvHD based on the pattern and severity of abnormalities in skin, gastrointestinal and liver. Events will be summarized by the cumulative incidence estimate. Cases will be analyzed at time of last follow-up. Death is a competing risk.

67


Chronic GvHD (in case of allo-HSCT) - Development of symptoms in any organ system fulfilling the criteria of limited vs. extensive chronic GVHD. The event will be summarized by the cumulative incidence estimate. Patients will be analysed at last follow-up. Death is a competing risk.

Variables to be analyzed: The following pre-HSCT variables that may have an influence on primary or secondary outcomes will be analyzed. Patient related:

Age Gender: female vs. male Karnofsky score at second transplant: <80 vs ≥ 80 CMV status at transplantation (for allo-HSCT) Chemosensitivity of disease

Donor related (if second HCT is allo):

Age Gender: female vs. male CMV status at transplantation (for allo-HSCT)

Disease related:

Bone marrow involvement Chemo-sensitivity of disease Poor-risk category (primary progressive vs. resistant relapse vs. early relapse ≤1 year post

transplant) Transplant related:

Year of transplant (3-year interval periods between 2000 and 2009) Graft type: BM vs. PBSC CD34+ cell dose Donor type: Autologous, related or unrelated (for allo-HSCT) Conditioning at initial transplant (RIC/NMAC as one group) TBI-based conditioning GvHD prophylaxis (for allo-HSCT) T-cell depletion (for allo-HSCT) ATG use at second transplant (for allo-HSCT) Donor/recipient sex match (for allo-HSCT) M-M vs. M-F vs. F-M vs. F-F HLA match status (for allo-HSCT): well matched vs. partially matched

Sample Requirements:

N/A

Study Design: The study proposed here will analyze CIBMTR data to address the working hypothesis that RIC/NMAC allo-HSCT is associated with more durable remission and possibly longer time to progression and overall survival as compared to autologous HSCT as second-line option in this patient population.

68


CIBMTR forms to retrieve the data: Subsequent HSCT data form (question 507) Planned second HSCT per protocol (question 510) Others

Medians and ranges will be tabulated for continuous demographic variables and percentages for categorical demographic variables. Time to neutrophil and platelet engraftment will be described using cumulative incidence estimates. Complete remission rate after the final transplant will be estimated. Relapse-free and overall survival will be calculated using Kaplan Meier estimates. Acute and chronic GvHD will be described using cumulative incidence estimates. We will calculate 95% confidence intervals for each outcome at specified time points separately for the two groups. We will adjust for covariates that may influence the study endpoints using Cox proportional hazards regression models. The proportional hazards assumption will be assessed for each variable using time-dependent or graphical approach. Time-dependent covariates will be used when non proportional hazards are detected, where the best-fitting model with time-varying risk coefficients will be found by maximizing the partial likelihood. Stepwise regression with alpha=0.05 will be used to build models. Two way interactions will be checked between the main effect and all other variables in the model.

References: 1. Bierman PJ, Vose JM, Anderson JR, Bishop MR, Kessinger A, Armitage JO. High-dose therapy

with autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma. J. Clin. Oncol. 1997; 15: 445-450.

2. Cao TM, Horning S, Negrin RS, Hu WW, Johnston LJ, Taylor TL et al. High-dose therapy and autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission: the Stanford University experience. Biol. Blood Marrow Transplant. 2001; 7: 294-301.

3. Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, Johnsen HE et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J. Clin. Oncol. 2003; 21: 3918-3927.

4. Sebban C, Brice P, Delarue R, Haioun C, Souleau B, Mounier N et al. Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J. Clin. Oncol. 2008; 26: 3614-3620.

5. Rohatiner AZ, Nadler L, Davies AJ, Apostolidis J, Neuberg D, Matthews J et al. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J. Clin. Oncol. 2007; 25: 2554-2559.

6. Montoto S, Canals C, Rohatiner AZ, Taghipour G, Sureda A, Schmitz N et al. Long-term follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study. Leukemia 2007; 21: 2324-2331.

7. 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; 102: 3521-3529.

8. Hosing C, Saliba RM, McLaughlin P, Andersson B, Rodriguez MA, Fayad L et al. Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin's lymphoma. Ann. Oncol. 2003; 14: 737-744.

9. Peniket AJ, Ruiz de Elvira MC, Taghipour G, Cordonnier C, Gluckman E, de WT 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 procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant. 2003; 31: 667-678.

69


10. Branson K, Chopra R, Kottaridis PD, McQuaker G, Parker A, Schey S et al. Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J. Clin. Oncol. 2002; 20: 4022-4031.

11. Escalon MP, Champlin RE, Saliba RM, Acholonu SA, Hosing C, Fayad L et al. Nonmyeloablative allogeneic hematopoietic transplantation: a promising salvage therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior autologous transplantation. J. Clin. Oncol. 2004; 22: 2419-2423.

12. Mandigers CM, Verdonck LF, Meijerink JP, Dekker AW, Schattenberg AV, Raemaekers JM. Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation. Bone Marrow Transplant. 2003; 32: 1159-1163.

13. van Besien KW, de LM, Giralt SA, Moore DF, Jr., Khouri IF, Rondon G et al. Management of lymphoma recurrence after allogeneic transplantation: the relevance of graft-versus-lymphoma effect. Bone Marrow Transplant. 1997; 19: 977-982.

14. Khouri IF, Keating M, Korbling M, Przepiorka D, Anderlini P, O'Brien S et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J. Clin. Oncol. 1998; 16: 2817-2824.

15. Avivi I, Montoto S, Canals C, Maertens J, Al-Ali H, Mufti GJ et al. Matched unrelated donor stem cell transplant in 131 patients with follicular lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Br. J. Haematol. 2009; 147: 719-728.

16. Hari P, Carreras J, Zhang MJ, Gale RP, Bolwell BJ, Bredeson CN et al. Allogeneic transplants in follicular lymphoma: higher risk of disease progression after reduced-intensity compared to myeloablative conditioning. Biol. Blood Marrow Transplant. 2008; 14: 236-245.

17. Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 2008; 111: 5530-5536.

18. Laport G, Bredeson CN, Tomblyn M, et.al. Autologous versus reduced intensity allogeneic hematopoietic cell transplantation for patients with follicular non-Hodgkin's lymphoma (FL) beyond first complete response or first partial response. J. Clin. Oncol. 2008; 26(Abstract 7041).

19. Sabloff M, Atkins HL, Bence-Bruckler I, Bredeson C, Fergusson D, Genest P et al. A 15-year analysis of early and late autologous hematopoietic stem cell transplant in relapsed, aggressive, transformed, and nontransformed follicular lymphoma. Biol. Blood Marrow Transplant. 2007; 13: 956-964.

20. Tarella C, Zanni M, Magni M, Benedetti F, Patti C, Barbui T et al. Rituximab improves the efficacy of high-dose chemotherapy with autograft for high-risk follicular and diffuse large B-cell lymphoma: a multicenter Gruppo Italiano Terapie Innnovative nei linfomi survey. J. Clin. Oncol. 2008; 26: 3166-3175.

21. Thomson KJ, Morris EC, Milligan D, Parker AN, Hunter AE, Cook G et al. T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J. Clin. Oncol. 2010; 28: 3695-3700.

22. Pinana JL, Martino R, Gayoso J, Sureda A, de la Serna J, Diez-Martin JL et al. Reduced intensity conditioning HLA identical sibling donor allogeneic stem cell transplantation for patients with follicular lymphoma: long-term follow-up from two prospective multicenter trials. Haematologica 2010; 95: 1176-1182.

70


Summary of previously published auto-HSCT studies in relapsed FL patients (FL-NT, non-transformed follicular lymphoma; FL-T, transformed follicular lymphoma)

Study Montoto et al.,6 Leukemia, 2007

Rohatiner et al.,5 JCO, 2007

Sabloff et al.,19 BBMT, 2007

Sebban et al.,4 JCO, 2008

Tarella et al.,20 JCO, 2008

Study characterization

Multicenter retrospective EBMT

Single center retrospective St. Bartholomew Hospital, London, UK

Single center retrospective Ottawa Hospital, Canada

Prospective randomized multicenter Groupe d’Etude des Lymphomes Folliculaires, France

Multicenter retrospective Gruppo Italiano Terapie Innnovative nei Linfomi

Number of patients

693 patients (CR1 19%)

121 patients 115 patients 254 patients 223 patients

Characterization of HSCT

Auto-HSCT Auto-HSCT

Auto-HSCT, all unpurged

Rituximab/auto-HSCT; auto-HSCT; Rituximab GELF86/94

Rituximab/auto-HSCT vs auto-HSCT

Overall survival 10-year OS 52% 10-year OS 54% 5-year OS FL-NT: 57% FL-T: 56%

5-year OS R-Chemo: 70% Auto-HSCT: 63% R-Auto-HSCT: 93%

5-year OS 55%

Progression-free survival

10-year PFS 31%

10-year PFS 48% 5-year PFS FL-NT: 46% FL-T: 25%

5-year PFS R-Chemo: 39% Auto-HSCT: 46% R-Auto-HSCT: 67%

5-year PFS 74%

Transplant-related mortality

5-year TRM 9% 9% had second cancers

(Not reported) TRM (day +100): FL-NT: 3% FL-T: 0% NRM FL-NT: 16% FL-T: 1%

(Not reported) ~3%

71


Conclusions On multivariate analysis, younger age and CR1 correlated with longer PFS. Shorter OS was associated with older age, chemoresistant disease, BM+PBSC as combined source of stem cells due to poor PBSC harvest and TBI-containing regimens. This long follow-up study shows a plateau in the PFS curve, suggesting that a selected group of patients might be cured with auto-HSCT.

Patients in CR2 had greater survival benefit; 12.4% of patients experienced s-MDS/AML.

Unpurged auto-HSCT is an effective tool in the treatment of relapsed, aggressive FL-NT and FL-T. Patients with chemosensitive disease had better outcomes. 7% of patients experienced second malignancies.

FL patients getting rituximab-based salvage at relapse did not benefit from auto-HSCT.

Rituximab administration with auto-HSCT improved OS and PFS.

72


Summary of previously published NMAC/RIC-HSCT studies in relapsed FL patients Study Khouri et al.,17

Blood, 2008 Thomson et al.,21 JCO, 2010

Pinana et al.,22 Haematologica, 2010

Study characterization Single center retrospective MD Anderson Cancer Center

Multicenter prospective University College Hospital, London

Multicenter prospective Grupo Español de Linfomas/ Transplante de Médula Osea

Number of patients 47 patients 82 patients 37 patients

Type of conditioning NMAC-HSCT RIC-HSCT RIC-HSCT

Conditioning regimen Rituximab/Flu/Cy Alemtuzumab/Flu/Mel

Flu/Mel

Type of allograft MRD 96% MRD 47% MRD 100%

Graft versus Host Disease aGvHD 11% cGvHD 36%

aGvHD 13% cGvHD 32%

aGvHD 51% cGvHD 53%

Progression/Disease free survival

8-year PFS 83% 4-year PFS MRD: 90% MUD: 64%

4-year DFS 57%

Overall survival

8-year OS 85% 4-year OS MRD: 90% MUD: 63%

4-year OS 54%

Transplant(non-relapse)-related mortality

7/47 (15%) patients died NRM at 4 years 15%

15/37 (41%) patients died

Conclusions NMAC-HSCT is an effective treatment for patients with recurrent FL and compares favorably to alternative approaches in advanced patients with chemosensitive disease.

Excellent long-term survival, low rates of GvHD, durable DLI responses; better OS after MRD-HSCT; after no autograft and for chemosensitive disease

Lower OS due to increased GvHD rate

73


Comparison of auto- and allo-HSCT for FL patients (van Besien et al., CIBMTR, JCO, 2003)7

Patient’s cohort Allo-HSCT Auto-HSCT (purged)

Auto-HSCT (unpurged)

Number of patients 176 patients 131 patients 597 patients Donor type MRD 100% - - Type of conditioning TBI-based 68% Chemo-based 66% Chemo-based 69% Graft versus Host Disease

aGvHD 37% cGvHD 24%

-

-

Disease-free survival 5-year DFS 45% 5-year DFS 39% 5-year DFS 31% Overall survival 5-year OS 51% 5-year OS 62% 5-year OS 55% Transplant-related mortality

TRM at 5 year 30% TRM at 5 year 14% TRM at 5 year 8%

Relapse rate Relapse at 5 year 21% Relapse at 5 year 43%

Relapse at 5 year 58%

74


Characteristics of patients who underwent autologous or RIC/NST allogeneic HCT for non- transformed relapsed/refractory follicular lymphoma from 1999-2011 reported to the CIBMTR

Variable AlloHCT* AutoHCT



Age at transplant

Median (range) 52 (27-74) 55 (23-79)

20-29 yrs 6 ( 1) 5 ( 1)

30-39 yrs 38 ( 9) 32 ( 6)

40-49 yrs 123 (30) 135 (27)

50-59 yrs 173 (42) 159 (32)

>=60 yrs 73 (18) 167 (34)

Sex

Male 234 (57) 300 (60)

Female 179 (43) 198 (40)

Karnofsky score

<90% 110 (27) 114 (23)

90-100% 286 (69) 338 (68)

Missing 17 ( 4) 46 ( 9)

Histology

Follicular small 187 (45) 145 (29)

Follicular mixed 155 (38) 171 (34)

Follicular large 71 (17) 182 (37)

Conditioning regimen-auto

TBI-based NA 60 (12)

BEAM and similar 333 (67)

CBV or similar 63 (13)

BuMEL/BuCy 20 ( 4)

Others 22 ( 4)


PIF sensitive 68 (16) 95 (19)

PIF resistant 37 ( 9) 21 ( 4)

REL sensitive 126 (31) 188 (38)

REL resistant 81 (20) 40 ( 8)

CR2+ 80 (19) 148 (30)

REL untreated/unknown 21 ( 5) 6 ( 1)

75


Table 4. Continued.

Variable AlloHCT AutoHCT

Type of donor

HLA-id sibling 207 (50) 0

Other relative 15 ( 4) 0

URD well-matched 70 (17) 0

URD partially matched 32 ( 8) 0

URD mismatched 5 ( 1) 0

URD matching unknown 1 (<1) 0

URD matching to be classified 83 (20) 0

Autologous 0 498

D-R sex match

M-M 126 (31) NA

M-F 83 (20)

F-M 80 (19)

F-F 72 (17)

Missing 52 (13)

D-R CMV status

+/+ 123 (30) NA

+/- 46 (11)

-/+ 94 (23)

-/- 126 (31)

Missing 24 ( 6)

Graft type

Bone marrow 54 (13) 2 (<1)

Peripheral blood 342 (83) 496 (99)

Cord blood 17 ( 4) 0

76


Table 4. Continued.

Variable AlloHCT AutoHCT

Year of HCT

1999 17 ( 4) 70 (14)

2000 20 ( 5) 32 ( 6)

2001 36 ( 9) 36 ( 7)

2002 48 (12) 24 ( 5)

2003 47 (11) 9 ( 2)

2004 30 ( 7) 33 ( 7)

2005 30 ( 7) 70 (14)

2006 30 ( 7) 73 (15)

2007 44 (11) 49 (10)

2008 39 ( 9) 42 ( 8)

2009 39 ( 9) 55 (11)

2010 17 ( 4) 2 (<1)

2011 16 ( 4) 3 ( 1)

Median follow up of survivors, months 51 (3-148) 57 (3-155)*No prior autoHCT

77


CIBMTR Study Proposal 1112-30 Study Title Impact of mobilization strategies and CD34+ progenitor yields on outcomes of autologous hematopoietic cell transplantation for large B -cell lymphoma Robert J. Soiffer, MD; Dana-Farber Cancer Institute, Boston, MA [email protected] Eric Jacobsen, MD; Dana Farber Cancer Institute, Boston, MA; [email protected] Specific Aims

- To determine whether type of mobilization strategy (cytokine alone v cytokine + chemotherapy) influences outcomes in terms of relapse, progression-free and overall survival (PFS and OS in large cell lymphoma

- To determine whether the number of CD34 cells infused influences outcome - (above accepted minimal thresholds)

Scientific Justification: Within the transplant community there remains variability in the approach to stem cell mobilization both in terms of method (cytokine alone v cytokine + chemotherapy) and in terms of targeted number of CD34 to be used for hematopoietic reconstitution. No large prospective randomized study has adequately addressed these questions. Most mobilization studies have focused on impact of CD34 cell yield on engraftment and very few have examined long term transplant outcomes. There remains controversy over what the target CD34 count should be for infusion. New agents such as plerixafor might augment CD34 yield though it remains uncertain if that provides any long term clinical benefit to patients. Patient Population Patients with DLBCL undergoing autologous transplantation from utilizing mobilized peripheral blood stem cells will be included. Patients mobilized with G-CSF alone or G-CSF + chemotherapy will be compared. Patients mobilized with GM-CSF instead of G-CSF could be included if there are adequate numbers for analysis. Otherwise, they would be excluded. Patients receiving plerixa for would be excluded. Variables to be analyzed Demographics:

- Age - Gender

Disease characteristics::

- Type of first-line treatment received (use of rituximab) - Response to first-line treatment - Use of radiotherapy - Type of second-line treatment received (if applicable) - Interval between first and second line treatment (if applicable) - Type of third-line treatment received (if applicable) - Response to third-line treatment and how assessed (if applicable)

Prognostic factors (as available):

- IPI at diagnosis - SaaIPI at relapse/progression

78


Mobilization variables: - Cytokine vs Cytokine + chemotherapy - Number of collection days - Number of CD34+ cells collected - Number of CD34 cells collected on first mobilization day (if available) - Need for re-mobilization

Transplantation factors:

- Conditioning regimen - CD34 dose infused - Era of transplant

Transplantation outcome:

- Relapse - PFS - OS - WBC engraftment - Platelet engraftment - Non-relapse mortality - Myelodysplasia

Study Design Comparison of the 2- and 5- year PFS and OS between patients mobilized with cytokine alone v chemotherapy + cytokine. We will also perform a multivariate analysis for PFS and OS with type of mobilization as the main variable, using the significant factors among the above as covariates. We will also compare relapse and non-relapse mortality between the 2 groups using competing risks methods also accounting for the impact of CD34 number infused. Assessment of the 2- and 5- year PFS and OS using total CD34 cell number infused as a linear variable as well as the CD34 cell yield on the first day of collection.

79


Characteristics of patients who underwent autologous HCT for mobilized peripheral blood stem cells for DLBCL from 1995-2011 reported to the CIBMTR*

Variable GCSF alone GCSF + Chemo



Age at transplant Median (range) 56 (5-81) 55 (7-77)

<10 yrs 1 (<1) 2 (<1)10-19 yrs 9 ( 1) 8 ( 1)20-29 yrs 41 ( 5) 73 ( 6)30-39 yrs 64 ( 9) 109 ( 9)40-49 yrs 125 (17) 230 (20)50-59 yrs 238 (32) 306 (26)>=60 yrs 271 (36) 448 (38)

Sex Male 451 (60) 683 (58)Female 298 (40) 493 (42)

Karnofsky score <90% 245 (33) 357 (30)90-100% 465 (62) 762 (65)Missing 39 ( 5) 57 ( 5)

Conditioning regimen TBI-based 91 (12) 115 (10)BEAM and similar 533 (71) 789 (67)CBV or similar 43 ( 6) 154 (13)BuMEL/BuCy 36 ( 5) 68 ( 6)Others 46 ( 6) 50 ( 4)

Disease status prior to transplant PIF sensitive 134 (18) 194 (16)PIF resistant 38 ( 5) 58 ( 5)CR1 98 (13) 175 (15)REL sensitive 190 (25) 338 (29)REL resistant 48 ( 6) 72 ( 6)CR2+ 187 (25) 252 (21)REL untreated/unknown 9 ( 1) 12 ( 1)PIF unknown 0 3 (<1)Missing 45 ( 6) 72 ( 6)

CD34 x 107/kg, median (range) 0.34 (0.002-6) 0.43 (0.001-9)

80


Continued. Variable GCSF alone GCSF + ChemoYear of HCT

1995 40 ( 5) 44 ( 4)1996 72 (10) 86 ( 7)1997 67 ( 9) 88 ( 7)1998 67 ( 9) 88 ( 7)1999 53 ( 7) 75 ( 6)2000 35 ( 5) 77 ( 7)2001 46 ( 6) 70 ( 6)2002 36 ( 5) 78 ( 7)2003 20 ( 3) 40 ( 3)2004 28 ( 4) 48 ( 4)2005 35 ( 5) 70 ( 6)2006 49 ( 7) 95 ( 8)2007 53 ( 7) 86 ( 7)2008 100 (13) 145 (12)2009 30 ( 4) 52 ( 4)2010 7 ( 1) 23 ( 2)2011 11 ( 1) 11 ( 1)

Median follow up of survivors, months 60 (4-198) 60 (3-199)*Plerixafor excluded (n=77). GM-CSF excluded (n=19)

81


CIBMTR Study Proposal: 1112-47 Study Title: Analysis of survival after first relapse post autologous stem cell transplant in Hodgkin’s lymphoma Anne S. Renteria, MD; Mount Sinai Medical Center, New York, NY; [email protected] Adriana K. Malone, MD; Mount Sinai Medical Center, New York, NY; [email protected] Mount Sinai Medical Center Box 1410 Luis Isola, MD; Mount Sinai Medical Center, New York, NY; [email protected] Specific Aims: The main objective is to determine the overall survival of patients who relapse with Hodgkin’s lymphoma (HL) after undergoing autologous stem cell transplant (ASCT). We will perform a milestone analysis starting with the time patients relapse post first ASCT and determine differences in survival for those patients who receive a second hematopoietic stem cell transplant (HSCT), whether autologous or allogeneic, and those who do not undergo a second HSCT. Scientific Justification: Currently, the standard treatment for relapsed or primary refractory HL is salvage chemotherapy followed by high dose chemoradiotherapy, followed by ASCT [1-3]. In this setting, ASCT is an effective therapy with overall survival (OS) rates estimated at approximately 55% at 5 years [4,5]. But 30 to 50% of the patients will have progression of disease after ASCT [6]. In contrast to non-Hodgkin’s lymphoma (NHL), relatively long survival can be observed after recurrent HL post ASCT using supportive therapy and standard HL treatment regimens. Clear and evidence-based recommendations for the best therapeutic strategy are limited [7-10]. New drugs are available for the treatment of recurrent HL such as brentuximab, bendamustine, and pralatrexate [11,12]. At the same time, improvements in mobilization, donor identification and allogeneic transplantation have enabled more second transplants to occur for patients with relapsed HL post-ASCT. Few retrospective studies evaluating outcomes of first relapse after ASCT have been published, and rely on small numbers of patients, thus limiting conclusions. A second ASCT [13, 14], or an allogeneic transplant [15-19] can be used as salvage in selected patients and can result in prolonged remissions. There is limited data on which to base recommendations as to therapy for relapsed HL post ASCT and management mostly relies on provider’s choice. Most studies on ASCT for HL focus on the positive outcomes such as OS and disease free survival (DFS) using ASCT as the initial time for analysis and relapse or death as the endpoint. The survival and outcomes of patients who relapse after ASCT have received relatively little attention. We propose to investigate the survival of patients who relapsed after a first ASCT for HL and either did or did not undergo a second transplant. We hypothesize that over the last 15 years, changes in conventional chemotherapy and transplant therapy significantly impacted the outcomes of these two cohorts. We envision that in the near future a prospective randomized study will be required to compare different salvage approaches for HL relapses post-ASCT. The data gathered from this proposal will serve to design and appropriately power such prospective study. Patient Eligibility Population:

No age requirement Patients with HL who relapsed post first ASCT Recipients of first ASCT between 1995 and 2010 and who relapsed

82


Data Requirements: Data collection forms needed: 2000, 2006, 2018, 2100, 2118, 2300, 2802, 2900 Collection of supplemental data: N/A Study involves combining CIBMTR data with data from another group: no List of variables from the existing CIBMTR data collection forms needed to be analyzed, and

desired outcome variables: Patient characteristics from recipient baseline database:

Age Gender Ethnicity Karnofsky performance score, Significant co-morbidities

Disease characteristics prior to the ASCT:

Date of diagnosis, histology at diagnosis Disease stage at diagnosis and at ASCT Year of transplant Response to therapy (including sensitivity of the lymphoma to chemotherapy and disease

remission state) prior to the start of the preparative regimen HSCT characteristics:

Pre-collection therapy to enhance product collection Product was treated for removal of malignant cells Number of CD34+ cells

For the patients undergoing an allogeneic transplant after relapse, additional data from recipient baseline database:

Date of relapse Time of achievement of second remission to transplant Date of ASCT before the allogeneic HSCT Also source of stem cells, type of donor

- conditioning regimen - manipulation of stem cells - number of CD34+ cells - type of GVHD prophylaxis - incidence of acute GVHD

- organ involved - reported stage

- incidence of chronic GVHD - organ involved - reported stage

After of the ASCT and the second HSCT:

Best response to the transplant and time for its achievement Any planned post-HSCT treatment

- maintenance therapy

83


Disease status Characteristics of the disease relapse if any

- nodal - extranodal - splenic

Method of assessment 100-day post-HSCT assessment

- vital status - functional status

Death and cause of death, if lost for follow up Patients who relapsed after the ASCT and did not receive another transplant:

Best response to the ASCT, Any planned post-HSCT treatment

- maintenance therapy Date of relapse Characteristics of the disease relapse

- nodal - extranodal - splenic

Method of assessment - functional status

Death and cause of death, if lost for follow up Survival:

Date of death Date of last follow up

Sample Requirements: N/A Study Design: This is a milestone study which starts at the time of relapse after first ASCT with a primary endpoint of death from any cause. Patient-, disease- and transplant-related factors will be compared between the two cohorts (HSCT versus no HSCT), using Chi-square test for categorical and Mann-Whitney test for continuous variables. Probabilities of survival and lymphoma-free survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. The post ASCT therapies (HSCT versus no HSCT) will be compared using proportional hazards regression models. Adjusted probability of DFS and OS will be computed based on final Cox regression model, stratified by treatment groups, and weighted by the pooled sample proportion value for all significant risk factor. The secondary endpoints include time to progression, treatment related mortality, and incidence of acute and chronic GVHD.

84


References: 1. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow

transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomized trial. Lancet 1993; 341:1051-54.

2. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomized trial. The Lancet 2002;359:2065-71.

3. Schmitz N, Haverkamp H, Josting A, et al. Long term follow up in relapsed Hodgkin’s disease (HD): updated results of the HD-R1 study comparing conventional chemotherapy to high-dose chemotherapy with autologous haemopoietic stem cell transplantation of the German Hodgkin Study Group and the Working Party Lymphoma of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2005, ASCO Annual Meeting Proceedings 2005;23:6508.

4. Chopra R, McMillian A, Linch D, et al. The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin’s disease. A single-center eight-year study of 155 patients. Blood 1993; 81:1137-45.

5. Sureda A, Arranz R, Iriondo A, et al. Autologous stem-cell transplantation for Hodgkin’s disease: results and prognostic factors in 494 patients from the Grupo Español de Linfomas/Transplante Autólogo de Médula Osea Spanish Cooperative Group. J Clin Oncol 2001;19:1395-1404.

6. Paltiel O, Rubinstein C, Or R, et al. Factors associated with survival in patients with progressive disease following autologous transplant for lymphoma. Bone Marrow Transplantation 2003;31:565-9.

7. Bartlett N, Niedzwiecki D, Johnson JL, et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804. Ann Oncol 2007;18:1071-1079.

8. Santoro A, Magagnoli M, Spina M, et al. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin’s lymphoma. Haematologica 2007;92:35-41.

9. Gopal AK, Press OW, Shustov AR, et al. Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma 2010; 51:1523-1529.

10. Sohier WD, Wong RKL, Aisenberg AC. Vinblastine in the treatment of advanced Hodgkin’s disease. Cancer 1968; 22:467-72.

11. Chen RW, Gopal AK, Smith SE, et al. Results from a pivotal phase II study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma (HL). ASCO Meeting Abstracts 2011; 29:8031.

12. Moskowitz AJ, Hamlin PA, Jr., Gerecitano J, et al. Bendamustine is highly active in heavily pre-treated relapsed and refractory Hodgkin lymphoma and serves as a bridge to allogeneic stem cell transplant. ASH Annual Meeting Abstracts 2009; 114:720.

13. Lin TS, Avalos BR, Penza SL, et al. Second autologous stem cell transplant for multiply relapsed Hodgkin’s disease. Bone Marrow Transplantation 2002; 29:763-7.

14. Fung HC, Stiff P, Nademanee A, et al. Final report on tandem autologous stem cell transplantation for patients with primary progressive or poor risk recurrent Hodgkin’s lymphoma – a two institution study. ASH Annual Meeting Abstracts 2005; 106:2071.

15. Akpek G, Ambinder RF, Piantadosi S, et al. Long term results of blood and marrow transplantation for Hodgkin’s lymphoma. J Clin Oncol 2001; 19:4314-21.

16. Peniket AJ, Elvira MCRd, Taghipour G, 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 procedure-related mortality rate than autologous transplantation. Bone Marrow Transplantation 2003; 31:667-78.

85


17. Anderson J, Litzow M, Appelbaum F, et al. Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin’s disease: the 21-year Seattle experience. J Clin Oncol 1993; 11:2342-2350.

18. Freytes CO, Loberiza FR, Rizzo JD, et al. Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry. Blood 2004; 104:3797-803.

19. Robinson SP, Schmitz N, Taghipour G, et al. Reduced intensity allogeneic stem cell transplantation for Hodgkin’s disease. Outcome depends primarily on disease status at the time of transplantation. ASH Annual Meeting Abstracts 2004; 104:2322.

86


Characteristics of patients who underwent an autologous or allogeneic transplantation after relapsed autologous transplant for Hodgkin’s lymphoma from 1995-2011 reported to the CIBMTR

Variable 2nd AlloHCT 2nd AutoHCT

1st AutoHCT

(no 2nd HCT

post relapse)**

Number of patients 83* 18 413

Age at transplant

Median (range) 31 (13-53) 31 (19-53) 36 (11-77)

10-19 yrs 8 (10) 2 (11) 37 ( 9)

20-29 yrs 30 (36) 6 (33) 103 (25)

30-39 yrs 28 (34) 5 (28) 104 (25)

40-49 yrs 10 (12) 1 ( 6) 84 (20)

>=50 yrs 7 ( 8) 4 (22) 85 (20)

Sex

Male 48 (58) 12 (67) 248 (60)

Female 35 (42) 6 (33) 165 (40)

Karnofsky score

<90% 31 (37) 6 (33) 150 (36)

90-100% 51 (61) 12 (67) 241 (58)

Missing 1 ( 1) 0 22 ( 5)

Histology

Lymphocyte-rich 1 ( 1) 1 ( 6) 12 ( 3)

Nodular sclerosis 56 (67) 16 (89) 296 (72)

Mixed cellularity 12 (14) 1 ( 6) 52 (13)

Lymphocyte depleted 1 ( 1) 0 3 ( 1)

Others 13 (16) 0 50 (11)

Conditioning regimen-alloHCT

Myeloablative 11 (13) NA NA

Non-myeloablative 66 (80)

TBD 6 ( 8)

Conditioning regimen-autoHCT

TBI-based NA 2 (11) 26 ( 6)

BEAM and similar 8 (44) 242 (59)

CBV or similar 3 (17) 69 (17)

BuMEL/BuCy 0 47 (11)

Others 5 (28) 29 ( 7)

87


Continued.


1st AutoHCT

(no 2nd HCT

post relapse)


PIF sensitive 3 ( 4) 1 ( 6) 62 (15)

PIF resistant 0 0 37 ( 9)

CR1 2 ( 2) 0 24 ( 6)

REL sensitive 24 (29) 10 (56) 139 (34)

REL resistant 21 (25) 2 (11) 48 (12)

CR2+ 19 (23) 3 (17) 67 (16)

REL untreated/unknown 6 ( 7) 2 (11) 6 ( 1)

PIF unknown 0 0 1 (<1)

Missing 8 (10) 0 29 ( 7)

Type of donor

HLA-id sibling 68 (82) 0 0

Other relative 4 ( 5) 0 0

URD matching to be classified 11 (13) 0 0

Autologous 0 18 413

D-R sex match-alloHCT

M-M 24 (29) NA NA

M-F 16 (19)

F-M 24 (29)

F-F 18 (22)

Missing 1 ( 1)

D-R CMV status-alloHCT

+/+ 21 (25) NA NA

+/- 15 (18)

-/+ 10 (12)

-/- 30 (36)

Missing 7 ( 8)

Graft type

Peripheral blood 83 18 413

88


Continued.


1st AutoHCT

(no 2nd HCT

post relapse)

Year of HCT

1995 1 ( 1) 1 ( 6) 20 ( 5)

1996 3 ( 4) 1 ( 6) 32 ( 8)

1997 2 ( 2) 3 (17) 26 ( 6)

1998 0 5 (28) 47 (11)

1999 6 ( 7) 0 39 ( 9)

2000 4 ( 5) 2 (11) 17 ( 4)

2001 6 ( 7) 1 ( 6) 18 ( 4)

2002 13 (16) 1 ( 6) 21 ( 5)

2003 6 ( 7) 2 (11) 15 ( 4)

2004 8 (10) 0 15 ( 4)

2005 8 (10) 0 20 ( 5)

2006 5 ( 6) 1 ( 6) 27 ( 7)

2007 3 ( 4) 1 ( 6) 25 ( 6)

2008 7 ( 8) 0 48 (12)

2009 6 ( 7) 0 20 ( 5)

2010 3 ( 4) 0 15 ( 4)

2011 2 ( 2) 0 8 ( 2)

GVHD prophylaxis -alloHCT

Ex vivo T-cell depletion alone 1 ( 1) NA NA

CD34 selection alone 1 ( 1)

CD34 selection + post-tx immune supression 1 ( 1)

FK506 + MMF +- others 10 (12)

FK506 + MTX +- others (except MMF) 11 (13)

CSA + MMF +- others (except FK506) 20 (24)

CSA + MTX +- others (except FK506, MMF) 17 (20)

CSA + others (except FK506, MTX, MMF) 2 ( 2)

CSA alone 12 (14)

Other GVHD prophylaxis 8 (10)

Median follow up of survivors, months 37 (3-142) 72 (13-168) 44 (3-195)*14 out of 83 in the post-alloHCT reported persistant disease as reason for re-transplant. **Data on non-transplant salvage therapy not available.

89

A G E N D A CIBMTR WORKING COMMITTEE FOR HODGKIN AND … · Not for publication or presentation A G...

Documents

Transcript of A G E N D A CIBMTR WORKING COMMITTEE FOR HODGKIN AND … · Not for publication or presentation A G...