not for publication or presentation...not for publication or presentation c. ly13-01 hamadani m,...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR LYMPHOMA San Diego, CA Friday, February 13, 2015, 12:15 – 2:15 pm

Co-Chair: David Maloney, MD, PhD, Fred Hutchinson Cancer Center, Seattle, WA; Telephone: 206-667-5616; Fax: 206-667-6124; E-mail: [email protected]

Co-Chair: Sonali Smith, MD, The University of Chicago, Chicago, IL; Telephone: 773-702-4400; Fax: 773-702-0963; E-mail: [email protected]

Co-Chair: Anna Sureda, MD, PhD, Hospital Duran i Reynals, Barcelona, Spain; Telephone: +34 9326 07750; Fax: +34 9326 07353; E-mail: [email protected]

Statisticians: Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-7387; Fax: 414-955-6513; E-mail: [email protected]

Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0681; Fax: 414-805-0714; E-mail: [email protected]

Alyssa DiGilio, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0660; Fax: 414-805-0714; E-mail: [email protected]

Scientific Director: Mehdi Hamadani, MD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

a. Minutes and Overview Plan from February 2014 meeting (Attachment 1) b. Introduction of incoming Co-Chair: Timothy Fenske, MD; Medical College of Wisconsin; Email:

[email protected]

2. Accrual Summary (Attachment 2)

3. Presentations, published or submitted papers

a. LY09-01 Wirk B, Fenske TS, Hamadani M, Zhang M-J, Hu Z-H, Akpek G, Aljurf MD, Armand P, Ayala E, Bachanova V, Bolwell B, Cairo MS, Cashen A, Chen Y-B, Costa LJ, Farhan S, Freytes CO, Gajewski JL, Gibson J, Hale GA, Holmberg LA, Hsu JW, Inwards DJ, Kamble RT, Maharaj D, Maziarz RT, Munker R, Nath R, Reddy NM, Reeder CB, Rizzieri DA, Sauter CS, Savani BN, Schouten HC, Sureda A, Vose JM, Waller EK, Wiernik PH, Gale RP, Burns LJ, Saber W. Outcomes of hematopoietic cell transplantation for diffuse large B cell lymphoma transformed from follicular lymphoma. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2014 Jul 1; 20(7):951-959.

b. LY07-02 Lechowicz MJ, Lazarus HM, Carreras J, Laport GG, Cutler CS, Wiernik PH, Hale GA, Maharaj D, Gale RP, Rowlings PA, Freytes CO, Miller AM, Vose JM, Maziarz RT, Montoto S, Maloney DG, Hari PN. Allogeneic hematopoietic cell transplantation for mycosis fungoides and sezary syndrome. Bone Marrow Transplantation. 2014 Nov 1; 49(11):1360-1365.

1


c. LY13-01 Hamadani M, Hari PN, Zhang Y, Carreras J, Akpek G, Aljurf MD, Ayala E, Bachanova V, Chen AI, Chen Y-B, Costa LJ, Fenske TS, Freytes CO, Ganguly S, Hertzberg MS, Holmberg LA, Inwards DJ, Kamble RT, Kanfer EJ, Lazarus HM, Marks DI, Nishihori T, Olsson R, Reddy NM, Rizzieri DA, Savani BN, Solh M, Vose JM, Wirk B, Maloney DG, Smith SM, Montoto S, Saber W. Early failure of frontline rituximab-containing chemoimmunotherapy in diffuse large B-cell lymphoma does not predict futility of autologous hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2014 Nov 1; 20(11):1729-1736.

d. LY10-02 Bachanova V, Burns LJ, Wang T, Carreras J, Gale RP, Wiernik PH, Ballen KK, Wirk B, Munker R, Rizzieri DA, Chen Y-B, Gibson J, Akpek, Costa LJ, Kamble RT, Aljurf MD, Hsu JW, Cairo MS, Schouten HC, Bacher U, Savani BN, Wingard JR, Lazarus HM, Laport GG, Montoto S, Maloney DG, Smith SM, Brunstein C, Saber W. Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor. Bone Marrow Transplantation. doi:10.1038/bmt.2014.259. Epub 2014 Nov 17.

e. LY12-02/GV11-01 Alvaro Urbano Ispizua, Steve Pavletic, Mary Flowers, Mei-Jie Zhang, Jeanette Carreras, Sonali Smith, David Maloney, Silvia Montoto, Corey Cutler, Steve Spellman, Mukta Arora, and Wael Saber. Association of graft vs. host disease with a lower relapse/progression rate after allogeneic hemopoietic stem cell transplantation with reduced intensity conditioning in patients with follicular and mantle cell lymphoma. Submitted

f. LY12-01 Veronika Bachanova, Linda Burns, Kwang Woo Ahn, Jeanette Carreras, David Maloney, Anna Sureda, Sonali Smith, Mehdi Hamadani. Positive pre-allogeneic hematopoietic cell transplantation PET scan in patients with non-Hodgkin lymphoma predicts higher risk of relapse but has no impact on survival. Oral presentation at the BMT Tandem Meetings in San Diego, CA, February 2015.

g. LY13-02 Prakash Satwani, Kwang Woo Ahn, Jeanette Carreras, David Maloney, Anna Sureda, Sonali Smith, Mehdi Hamadani. Risk Factors Predicting Outcomes of Autologous Hematopoietic Cell Transplantation in Children, Adolescents and Young Adults (CAYA) with Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma: A CIBMTR Analysis. Oral presentation at the BMT Tandem Meetings in San Diego, CA, February 2015.

4. Studies in progress (Attachment 3)

a. LY12-01 Positron Emission Tomography Imaging Prior to AlloHCT for lymphoma (V Bachanova)

Manuscript Preparation

b. LY13-02 Outcome after AutoHCT for CAYA with relapsed/refractory Hodgkin lymphoma (P Satwani)

Manuscript Preparation

c. LY13-03 Auto vs NMA/RIC for relapsed/refractory follicular lymphoma (E Klyuchnikov)

Analysis

d. LY06-03 Sib vs MUD for follicular NHL/EBMT with CIBMTR (A Sureda) Data File Preparation e. LY14-02 AlloHCT for DLBCL after a failed AutoHCT (T Fenske) Protocol Development

5. Future/proposed studies

a. PROP 1410-09 Comparison of allogeneic stem cell transplantation to autologous stem cell transplantation for patients with early relapsed and primary refractory diffuse large B cell lymphoma (N Ghosh) (Attachment 4)

b. PROP 1410-10 Does Autologous Stem Cell Transplant Overcome the Increased Risk of Death in Patients with Follicular Lymphoma Relapsing Early after First Line Chemoimmunotherapy? (C Casulo/J Friedberg) (Attachment 5)

c. PROP 1411-17/1411-93 Hematopoietic Cell Transplantation for NK/T-cell Non-Hodgkin Lymphoma (S Barta/H Fung/G Akpek) (Attachment 6)

2


d. PROP 1411-35 Allogeneic Hematopoietic Stem Cell Transplantation in HTLV-1 associated Adult T-cell Lymphoma/Leukemia (P Dahi/C Sauter/MA Perales) (Attachment 7)

e. PROP 1411-15 Hematopoietic cell transplantation (HCT) outcomes for relapsed or refractory marginal zone lymphomas (B William/B Hill/H Lazarus) (Attachment 8)

f. PROP 1411-83 A retrospective review of outcomes with allogeneic and autologous transplant outcomes for t cell large granular lymphocytic lymphoma and gamma-delta T cell lymphoma (J Gajewski/R Maziarz) (Attachment 9)

g. PROP 1408-02/1411-27 Alternative Donor Allogeneic Hematopoietic Transplantation Strategies for Lymphoid Malignancies in Adult Patients: Comparing Matched Unrelated versus Haploidentical Related Donor Transplantation (A Kanate/A Mussetti/K Dabaja) (Attachment 10)

h. PROP 1411-06/1411-36/1412-13 Comparing Outcomes between Haploidentical and HLA Matched Related Donor Transplants for Patients with Lymphoid Malignancies (R Karmali/N Gosh/V Rocha) (Attachment 11)

Dropped proposed studies

a. LY14-01: Updated prognostic information for lymphoma survivors beyond 1 year from allogeneic hematopoietic cell transplantation. A landmark CIBMTR analysis (A Lazaryan). Dropped due to feasibility.

b. PROP 1408-01 Comparison of twin and autologous transplants for Non-Hodgkin Lymphoma (M Mir) Dropped due to limited by heterogeneity and feasibility-low number of twin patients.

c. PROP 1408-03 Role of FDG‐PET prior to allogeneic transplantation in predicting outcomes for patients with relapsed or refractory Hodgkin lymphoma: A CIBMTR Analysis (A Lazaryan) Dropped due to feasibility-supplemental data and low number of patients (n=70).

d. PROP 1409-01 Allogeneic transplantation for older patients with non-Hodgkin Lymphoma (V Bachanova) Dropped due to overlap with LK07-03c.

e. PROP 1409-06 Outcome following autologous hematopoietic cell transplantation (AHCT) in plasmablastic lymphoma (PBL): A combined analysis of CIBMTR and EBMT data (M Al Malk) Dropped due to feasibility-low number of patients (n=3).

f. PROP 1409-08 Outcomes of upfront autologous stem cell transplantation in adult mantle cell lymphoma - is there an ideal induction regimen? (L Veltri) Dropped due to feasibility.

g. PROP 1401-01 Case control study of busulfan, melphalan, and thiotepa (BuMelTt) versus alternative myeloablative conditioning regimens in autologous hematopoietic stem cell transplant for relapsed/refractory Hodgkin’s Lymphoma (HL) (J Brammer) Dropped due to feasibility-low number of patients (n=3).

h. PROP 1410-06 Comparison of outcomes for patients with relapsed/refractory mantle cell lymphoma after RIT-based versus standard autologous stem cell transplantation (E Klyuchnikov) Dropped due to feasibility-low number of patients (n=7).

i. PROP 1410-14 Comparison of consolidation with allogeneic versus autologous hematopoietic cell transplantation for patients with relapsed/refractory diffuse large B cell lymphoma achieving a partial metabolic response to salvage chemotherapy (D Landsburg) Dropped due to feasibility-supplemental data.

j. PROP 1411-04 Identifying Prognostic Factors and Treatment Strategies that Impact Clinical Outcomes in Patients with Primary Central Nervous System Lymphoma (PCNSL) undergoing Autologous Stem Cell Transplantation in the Rituximab Era (R Karmali) Dropped due to feasibility-low number of patients (n=24).

k. PROP 1411-05 Impact of Obesity and Diabetes on Outcomes after Autologous Hematopoietic Stem Cell Transplantation in Aggressive Lymphomas (R Karmali) Dropped due to feasibility-supplemental

3


data.

l. PROP 1411-08 Multi-center retrospective study of outcomes of autologous hematopoietic cell transplantation for patients with EBER-ISH/LMP positive relapsed/refractory Hodgkin lymphoma (P Satwani) Dropped due to feasibility.

m. PROP 1411-25 Prognostic model for patients with DLBCL relapsing after auto-HCT (L Costa) Dropped due to feasibility-supplemental data.

n. PROP 1411-34 Prognostic model for relapsed Diffuse Large B Cell Lymphoma undergoing consolidation with hematopoietic cell transplant (HCT) (A Hallack Neto) Dropped due to feasibility-supplemental data.

o. PROP 1411-48 Is Reduced Intensity BEAM as equally effective as BEAM for relapsed Diffuse Large B-cell Lymphoma in 2nd Remission? (M Sharma) Dropped due to feasibility.

p. PROP 1411-51 Retrospective comparative study of blood or bone marrow transplantation for relapsed/refractory Hodgkin lymphoma by donor type (J Kanakry) Dropped due to overlap with LY10-02 and low number of patients (n=27 in haploidentical cohort).

q. PROP 1411-52 Impact of mobilization strategies with plerixafor versus chemomobilization with cyclophosphamide for non-Hodgkin lymphoma (NHL) on outcomes after autologous stem cell transplant (C Vigil) Dropped due to feasibility-supplemental data.

r. PROP 1411-62 Impact of brentuximab vedotin on outcomes of allogeneic hematopoietic cell transplantation for relapsed or refractory Hodgkin lymphoma (B Wirk) Dropped due to feasibility-low number of patients (n=5).

s. PROP 1412-07 Brentuximab Vedotin used to bridge patients into successful reduced intensity allogeneic or second autologous stem cell transplantation in relapsed or refractory Hodgkin’s lymphoma post autologous stem cell transplantation (S Altouri) Dropped due to feasibility-low number of patients (n=5).

t. PROP 1411-91 Outcomes Following Allogeneic Stem Cell Transplant for Relapsed Primary or Secondary Central Nervous System Lymphoma (S Jaglowski) Dropped due to low number of cases.

u. PROP 1411-70 Autologous stem cell transplant in elderly patients with Hodgkin Lymphoma (MA Perales) Dropped due to feasibility-low number of patients (n=39).

v. PROP 1412-06 Efficacy of BCNU vs. non- BCNU containing conditioning regimens on the outcomes of autologous stem cell transplantation for relapsed Diffuse large B-cell lymphoma and Hodgkin’s Lymphoma (S Altouri) Dropped due to overlap with SC10-06.

6. Other Business

4

Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR HODGKIN AND NON-HODGKIN LYMPHOMA Grapevine, TX Thursday, February 27, 2014, 12:15 pm – 2:15 pm 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] Co-Chair: Sonali Smith, MD, University of Chicago Hospitals, Chicago, IL Telephone: 773-834-2895; Fax: 773-702-0963; 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: Mehdi Hamadani 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 12:16 pm on Thursday, February 27, 2014, by Dr. Silvia Montoto. Working Committee Leadership was introduced and audience was asked to fill out the Working Committee evaluations and voting sheets for proposals. Dr. Mehdi Hamadani introduced Dr. Anna Sureda as the newly appointed Chair for the Hodgkin & Non-Hodgkin Lymphoma Working Committee starting March 1, 2014. Dr. Montoto was acknowledged for all of her efforts during these past years as Co-Chair. Dr. Rodney Sparapani was introduced as the incoming PhD statistician and Dr. Hamadani as the incoming Scientific Director. Dr. Wael Saber was acknowledged for all of his efforts and statistical expertise these past years as Scientific Director. Working Committee goals, expectations and limitations were discussed as well as the CIBMTR guidelines for voting by Dr. David Maloney. The 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. Each proposal was limited to 5 minutes (maximum 3-4 overheads) to allow for adequate time for discussion. Rules of authorship were discussed. Authors must meet the following 3 conditions to assure authorship: 1) substantial and timely contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically for important intellectual content; 3) final approval of the version to be published. The minutes of the February 2013 meeting were approved. A significant increase in productivity of the Working Committee was reported including 8 published/submitted papers, 3 manuscripts in preparation, 2 presentations at the American Society of Hematology in New Orleans, LA and 1 presentation at the BMT Tandem Meetings in Grapevine, TX.

2. Accrual summary

Due to the full agenda, the accrual summary of registration and research cases between 2000 and 2013 were not presented to the committee but were available as part of the Working Committee

5

mailto:[email protected]


attachments:

HLA-identical Alternative Donor Autologous

Non-Hodgkin Lymphoma

Registration only 3973 1418 5262

Research 1313 3121 673

Hodgkin Lymphoma

Registration only 368 174 11521

Research 82 198 1424

3. Presentations, published or submitted papers

Due to the full agenda, the 2013 presentations and published papers were mentioned but not presented. 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. British Journal of Haematology. 2013 Sep 1; 162(5):648-656.

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. Journal of Clinical Oncology. 2013 Sep 1; 31(25):3100-3109.

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. Biology of Blood & Marrow Transplantation. 2013 May 1; 19(5):746-753. 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. Biology of Blood & Marrow Transplantation. 2013 Apr 1; 19(4):625-631. 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. In Press, Biology of Blood & Marrow Transplantation. LY08-02 Fenske TS, Zhang MJ, Carreras J, Ayala E, Burns LJ, Cashen A, Costa LC, Freyte CO, Gale RP, Hamadani M, Holmberg LA, Inwards DJ, Lazarus HM, Maziarz RT, Munker R, Perales

6


MA, Rizzieri DA, Schouten HC, Smith SM, Waller EK, Wirk BM, Laport GG, Maloney DG, Montoto S, and Hari PN. Autologous or reduced-intensity allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle cell lymphoma: analysis of transplant timing and modality. In Press, Journal of Clinical Oncology. LY07-02 Lechowicz MJ, Lazarus HM, Carreras J, Laport GG, Cutler CS, Wiernik PH, Hale GA, Maharaj D, Gale RP, Rowlings PA, Freytes CO, Miller AM, Vose JM, Maziarz RT, Montoto S, Maloney DG, Hari PN. Allogeneic hematopoietic cell transplantation for cutaneous T cell lymphoma. Submitted.

LY09-01 B Wirk, Fenske TS, Hamadani M, Hu ZH, Akpek G, Aljurf MD, Armand P, Ayala, E, Bachanova V, Bolwell B, Cairo MS, Cashen A, Chn YB, Costa LJ, Farhan S, Freytes CO, Gajewski JL, Gibson J, Hale GA, Holmerg LA, Hsu JW, Inwards DJ, Kamble RT, Maharaj D, Maziarz RT, Munker R, Nath R, Reddy NM, Reeder CB, Rizzieri DA, Sauter CS, Savani BN, Shouten HC, Sureda A, Vose JM, Waller EK, Wiernik PH, Gale RP, Burns LJ, Saber W. Outcomes of hematopoietic cell transplantation for diffuse large B cell lymphoma transformed from follicular lymphoma. Submitted.

LY10-02 Veronika Bachanova, Claudio Brunstein, Linda Burns, Tao Wang, Jeanette Carreras, Ginna Laport, Sonali M. Smith, Silvia Montoto, David Maloney and Wael Saber. Alternative Donor Transplantation for Adults with Lymphoma: Comparison of Umbilical Cord Blood versus 8/8 HLA-matched Donor (URD) versus 7/8 URD. Oral presentation at the American Society of Hematology in New Orleans, LA, December 2013; Manuscript Preparation.

LY12-02/GV11-01 Alvaro Urbano Ispizua, Steve Pavletic, Mary Flowers, Mei-Jie Zhang, Jeanette Carreras, Sonali Smith, David Maloney, Silvia Montoto, Corey Cutler, Steve Spellman, Mukta Arora, and Wael Saber. Association of graft vs. host disease with a lower relapse/progression rate after allogeneic hemopoietic stem cell transplantation with reduced intensity conditioning in patients with follicular and mantle cell lymphoma. Presentation at the American Society of Hematology in New Orleans, LA, December 2013; Manuscript Preparation.

4. Studies in progress The studies in progress 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:

LY10-02: Alternative donor transplantation for adults with lymphoma: comparison of umbilical cord blood versus 8/8 HLA-matched URD versus 7/8 URD (V Bachanova). We compared outcomes of 1593 non-Hodgkin and Hodgkin lymphoma patients who underwent alternative donor HCT from 2000-2010. UCB (n=142), 8/8 HLA URD (n=1176) and 7/8 matched URD (n=275) HCT recipients were followed for 25, 57 and 65 months, respectively. In multivariate analysis 7/8 URD had 1.3-fold higher risk of TRM than the 8/8 URD. Acute graft-versus-host disease risk were higher with URD donors compared to UCB group (8/8 URD HR 1.47 [95% CI 1.0-2.17]; p=0.049 and 7/8 URD HCT HR 2.12 [95%CI 1.52-2.95]; p<0.001). Manuscript will be submitted soon after the BMT Tandem meetings.

LY12-02/GV11-01: Association of graft-versus-host disease with a lower relapse/progression rate after allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in

7


patients with follicular and mantle cell lymphoma. A CIBMTR analysis (A Urbano-Ispizua/S Pavletic/M Flowers). RIC transplantation is an established platform of immunotherapy for lymphoma due to the graft-vs.-lymphoma (GVLy) effect. The objective of this study was to determine if GVLy was associated with aGVHD or cGVHD in B cell and T cell lymphomas, and to analyze whether this effect differs in myeloablative and RIC transplants. Inclusion criteria were patients older than 18 years undergoing HLA-identical sibling or unrelated donor HSCT between 1997 and 2009, with diagnosis of HL, DLBCL, follicular lymphoma (FL), peripheral T-NHL, and MCL. Twin transplants, cord blood, and ex vivo T-cell depletion cases were excluded. Landmark analysis will be performed and manuscript is underway and will be submitted before July 1st, 2014. 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 and a conference call for further collaboration will be scheduled after the BMT Tandem meetings. LY13-01: Autologous transplantation for diffuse large B cell lymphomas patients refractory to, or relapsing early after rituximab-containing first line chemo immunotherapies (M Hamadani). Among patients with chemosensitive DLBCL at transplant (CR2, PR1/PR2) that received rituximab-containing induction chemoimmunotherapy and either never responded to that first line or subsequently relapsed, we will compare post transplantation outcomes in Early Rituximab Failure (ERF) patients (refractory or relapsed within 1 year since diagnosis) vs. Late Rituximab Failure (LRF) patients (relapsed greater than a year since diagnosis). Abstract is submitted to 2014 Annual Meetings of ASCO and manuscript is underway and will be submitted before July 1st, 2014. 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. Patients with PET scan negative/positive who underwent allogeneic transplants from 2008 and 2010 and reported to the CIBMTR will be analyzed. Protocol is in development. LY13-02: Outcome of autologous hematopoietic cell transplantation for children, adolescents, and young adults with relapsed/refractory hodgkin lymphoma (P Satwani). Autologous stem cell transplantation (AutoSCT) has become a standard of care in children, adolescents and young adults (CAYA) with relapsed/refractory Hodgkin Lymphoma (HL). However, due to a small number of patients reported in few retrospective and prospective studies, the risk factors associated with poor outcomes have not been well established. We hypothesize that after receiving AutoSCT, CAYA relapsing with HL within 1 year of original diagnosis, and CAYA with refractory HL, will have significantly poor 2 year overall survival (OS) and disease-free survival (DFS) compared to those who relapse after 1 year of original diagnosis. Protocol is in development.

8


LY13-03: Comparison of autologous versus allogeneic hematopoietic cell transplantation after reduced/non-myeloablative conditioning for relapsed/refractory patients with follicular lymphoma (E Klyuchnikov). This study intends to compare overall (OS) and progress-free survival (PFS) in patients aged ≥18 years 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. Protocol is in development.

5. Future/ Proposed studies

PROP 1304-03 Comparison between Total Body Irradiation and non-TBI based conditioning regimens for allogeneic hematopoietic cell transplant in patients with diffuse large B-cell non-Hodgkin’s Lymphoma (J Hsu). Dr. Hsu presented the study. This study will determine the effect of TBI in the conditioning regimen in allogeneic HCT for diffuse large B-cell non-Hodgkin’s Lymphoma on efficacy and toxicity outcomes. The amount of TBI may also have a significant effect on outcomes. A CIBMTR analysis of 502 patients with ALL who received a matched sibling allograft in first or second remission using either Cy/TBI or VP16/TBI conditioning found no significant differences in TRM, leukemia free survival, cumulative incidence of relapse, and overall when comparing dose of TBI for patients who were transplanted in CR1. There are also differences in late effects between TBI and non-TBI containing conditioning regimens. A recent report by the CIBMTR on late effects in 1718 patients with aplastic anemia who underwent a matched sibling or matched unrelated donor transplant found a greater proportion of late effects in patients exposed to TBI. Because radiation is considered an effective treatment modality for DLBCL, registry analysis will include TBI vs. non-TBI containing regimens as a covariate in the analysis. This study will investigate the role of TBI in allogeneic conditioning regimens of patients with DLBCL. There are 465 TBI and 555 non TBI patients with AlloHCT for DLBCL registered to the CIBMTR between 2000-2012. The Working Committee suggested dividing myeloablative and RIC/NST since it might have a different outcome effect. PROP 1304-04 Impact of conditioning regimen on outcomes of autologous hematopoietic cell transplantation for relapsed follicular and diffuse large B-cell lymphomas (B William) Dr. William presented the study. This study will determine the impact of the conditioning regimen used for autologous HCT for follicular and diffuse large B-cell non-Hodgkin’s Lymphoma on efficacy and toxicity outcomes. There are 43 TBI and 347 non TBI patients with autoHCT for relapsed/refractory follicular lymphoma reported to the CIBMTR between 2000-2012. If accepted, the Committee suggested including Rituximab in the analysis. PROP 1310-17 Transplant Outcomes in Nodular Lymphocyte Predominant Hodgkin Lymphoma (G Akpek) Dr. Akpek presented the study. The study proposed will analyze CIBMTR data to address the working hypothesis that patients with relapsed or primary refractory NLPHL have greater than 50% probability of surviving without progression at 5 years following HCT. The study aims to generate data on standard transplant outcomes after autologous and allogeneic HCT in patients with NLPHL and to identify variables associated with favorable survival outcomes. There are 306 patients with AutoHCT for Hodgkin lymphoma registered to the CIBMTR between 2004-2013. The Committee suggested restricting the study to 2007-2013. Transformed lymphoma cannot be analyzed since it is not collected on the registration forms. Only 26 of 306 patients have research detailed information.

9


Dr. Montoto mentioned the high percentage (44%) of CR2 prior to transplant status reported. PROP 1311-01 Outcomes of diffuse large B-cell lymphoma with skeletal involvement after autologous hematopoietic cell transplantation (B Wirk) Dr. Wirk presented the study. This study aims to analyze the outcomes of autologous hematopoietic cell transplantation for diffuse large B-cell lymphoma with or without skeletal involvement. There are 131 bone involvement and 1158 non bone involvement patients with AutoHCT for relapse/refractory DLBCL reported to the CIBMTR between 2000-2012. Dr. Wirk suggested including Rituximab in the analysis. Dr. Philip Rollings suggested looking at the PET scan to confirm skeletal involvement. Matched-pair analysis was suggested and sites of skeletal involvement would need to be reported. PROP 1311-08 High-Dose Therapy and Autologous Transplantation for Intravascular Large B-cell Lymphoma (M Hamadani) Dr. Abraham Kanate presented the study. The study aims to describe the outcomes with high-dose therapy (HDT) and autologous hematopoietic cell transplantation of intravascular large B-cell lymphoma (IVLBCL) and to identify patient-, disease-, and HCT-related characteristics that are associated with post-HCT outcomes among patients with IVLBCL. There are 213 registration only and 35 research patients with autoHCT for IVLBCL reported to the CIBMTR from 2006-2012. Study pitfalls: unknown denominator (selection bias), question of best timing cannot be answered, uncertain if analysis will be clinically useful or will it inform practice. Dr. Montoto asked going back to the centers to identify how many patients they have. It was concluded not worth the effort since this special supplemental request will take at least a year. PROP 1311-68 Outcome of Hematopoietic Cell Transplantation in non-Hodgkin’s Lymphoma patients aged 70 years or older (K Wudhikarn) Dr. Wudhikarn presented the study. There are 3 hypothesis for this study: 1) Hematopoietic cell transplantation (HCT) for Non-Hodgkin’s Lymphoma (NHL) patients age 70 years or older is an effective treatment strategy; 2) transplant related complications of HCT in NHL patients aged 70 years or older are higher than NHL patients who undergo HCT at a younger age; 3) survival outcomes of HCT in NHL patients aged 70 years or older are inferior to patients in the younger age group of 65-69 years old. This study aims to describe the characteristics of NHL patients aged 70 years or older who undergo autologous or allogeneic HCT. There are 347 patients between 65-69 years of age and 73 ≥70 years of age with alloHCT in NHL registered to the CIBMTR from 2000-2012. There are 3390 patients between 65-69 years of age and 1642 ≥70 years of age with autoHCT in NHL registered to the CIBMTR from 2000-2012. Committee members mentioned the higher number of autoHCT patients as compared to alloHCT. It was suggested to look at comorbidities & Sorror score and look only at ≥70 years of age vs. rest. PROP 1311-75 Trends in allograft use and survival after reduced intensity/non-myeloablative conditioning allogeneic hematopoietic cell transplantation for Hodgkin lymphoma: 1999-2013 (V Bachanova) Dr. Bachanova presented the study. This study aims to describe and compare outcomes in Hodgkin lymphoma (HL) patients undergoing a reduced intensity /non-myeloablative (RIC/NST) allogeneic cell transplant (alloHCT) in 3 time periods: (1999-2004 vs. 2005-2009 vs. 2010-2013) and to describe changes in utilization of alloHCT and in 1) patient 2) disease and 3) transplant characteristics, including the treatment with brentuximab, prior to allograft during these 3 time periods. There are 157 patients transplanted between 1999-2004, 140 in 2005-2009 and 91 in 2010-2013 with alloHCT

10


in NHL registered to the CIBMTR. Myeloablative conditioning regimen was excluded. Year of transplant cut-offs were questioned by the Committee and especially the later years. Committee suggested waiting 1-2 years to increase number of patients to increase scientific interest. It was also suggested to include myeloablative regimens. Suggested to include prior therapy and rituximab prior to transplant. Dr. Timothy Fenske suggested looking and those patients who had an alloHCT following an autoHCT. Audience agreed that additional follow-up is needed and suggested to distinguish between HLA-identical siblings, haplo-identical donors and cord blood grafts. PROP 1311-76 Hematopoietic cell transplantation outcomes for relapsed or refractory marginal zone lymphomas (B William) Dr. William presented the study. This study aims to descriptive study to analyze trends in utilization and outcomes of autologous and/or allogeneic HCT in relapsed or refractory marginal zone lymphomas (MZL). We have 151 alloHCT and 250 autoHCT patients with MZL registered to the CIBMTR from 2000-2012. Committee members suggested describing FLIPI score in the study. Potential collaboration with EBMT on a combined analysis for allogeneic transplant outcomes was discussed. A total of 413 non-transplanted MZL were presented from various institutions for collaboration: University Hospitals Case Medical Center (n=99), Cleveland Clinical Foundation (n=218) and University of Nebraska Medical Center (n=96). PROP 1311-77 Hematopoietic Stem Cell Transplantation for Hepatosplenic T-cell Lymphoma (M Alghamdi) Dr. Alghamdi presented the study. This study aims to analyze outcomes of hematopoietic cell transplantation (HCT) for hepatosplenic T-cell lymphoma. Given the low incidence of HSTCL and the absence of prospective studies with HCT for HSTCL, analysis of cumulative registry data remains the best way to study the safety and efficacy of HCT in this disease. There are 72 alloHCT and 35 autoHCT patients for Hepatosplenic T-cell Lymphoma registered to the CIBMTR from 1999-2012. Working Committee members mentioned a similar ASH abstract with potential patient overlap from the University of Nebraska that was presented in 2013. PROP 1311-79 Updated prognostic information for lymphoma survivors beyond 1 year from allogeneic hematopoietic cell transplantation. A landmark CIBMTR analysis (A Lazaryan) Dr. Lazaryan presented the study. This study aims to generate updated individualized prognostic models for outcomes of allograft recipients with lymphoma who survive beyond the 1st year after allo-HCT. There are 621 follicular lymphoma, 196 DLBCL and 114 Hodgkin disease patients who survived more than 1 year post alloHCT for relapsed/refractory lymphoma reported to the CIBMTR from 1990-2010. Committee members suggested to restrict to 1997, eliminate Hodgkin disease and include transformed cases to eliminate older cases. It was suggested to do a landmark analysis of each subsequent year to prognosticate survival. Dr. Patrick Stiff reiterated the importance of this study. Members suggested that performing the calculator is not the primary objective. Primary outcome will be survival and secondary outcomes include non-relapse mortality, relapse/progression, disease-free survival and acute and chronic GVHD. PROP 1311-85 Evaluation of potential anti-lymphoma clinical benefit with sirolimus-based graft-versus-host disease prevention after allogeneic hematopoietic cell transplantation (J Mathews) Dr. Mathews presented the study. The study aims to determine the existence of anti-lymphoma effect with sirolimus-based GVHD prophylaxis and to discern subtypes of lymphoma in which sirolimus-based GVHD prophylaxis might be particularly effective. There are 149 sirolimus-based and 1488 no sirolimus- based alloHCT lymphoma patients reported to the CIBMTR from 2002-2012. In a retrospective study, Armand et al. compared the outcomes of patients who received sirolimus

11


for GVHD prophylaxis with those patients who received allogeneic HCT with a combination of a calcineurin inhibitor and methotrexate. Overall survival was significantly superior in the sirolimus group and the benefit was restricted to patients undergoing reduced-intensity conditioning. Sirolimus was associated with decreased incidence of disease progression. In addition, the effect of sirolimus persisted after adjusting for the occurrence of GVHD. Therefore, the study hypothesizes that the use of sirolimus-based GVHD prophylaxis may reduce the incidence of lymphoma progression compared to combination regimens of a calcineurin inhibitor and methotrexate. The Committee suggested a possible matched-pair analysis. 149 patients were previously reported by different institutions and uncertain how much can be added to these reports. Dr. Robert Peter Gale reiterated the importance of not using an observational database in these types of studies since we will get the same results as the clinical trial. PROP 1311-89 Outcome of patients with relapsed diffuse large B-cell lymphoma treated with allogeneic hematopoietic cell transplantation following a failed autologous HCT (T Fenske) Dr. Tara Graff presented the study. This study aims to 1) determine overall survival (OS), progression-free survival (PFS), relapse/progression and treatment-related mortality (NRM) at 1 year, 3 years and 5 years in DLBCL patients who underwent an allo-HCT following a failed auto-HCT; 2) to determine the impact of age on OS, PFS, relapse/progression and NRM at 1 year, 3 years and 5 years, using different age cutoffs (50, 60, or 70 years); 3) to determine the impact of time elapsed from auto-HCT to allo-HCT on OS, PFS, relapse/progression and NRM at 1 year, 3 years and 5 years, using different time cutoffs (0-6 months, 6-12 months, or >12 months); 4) to determine the impact of performance status (PS), HCT comorbidity index (HCT-CI), disease status, and donor type (related vs unrelated) on OS, PFS, relapse/progression and NRM at 1 year, 3 years and 5 years; and 5) to define a specific group of patients (using some combination of age, PS, HCT-CI, time from auto-HCT and disease status and donor type), for whom allo-HCT is a reasonable option. There are 133 alloHCT after an autoHCT transplanted for relapsed DLCBL from 2005-2011 reported to the CIBMTR. Committee member suggested to perform a matched control of those patients who relapsed after an autoHCT but did not undergo an alloHCT and compare outcomes. CIBMTR does not collect treatment for relapse. It was informed that University of Nebraska published this idea with fewer numbers of cases. Nine additional proposals were submitted to the committee but not presented due to the reasons stated below:

PROP 1309-05 Comparison of syngeneic with autologous transplant for patients with Hodgkin’s lymphoma (K Van Besien). Dropped due to low number {n=23 cases received syngeneic transplant (research and registration) from 2000-2013}. PROP 1310-18 Impact of brentuximab vedotin on outcomes of allogeneic hematopoietic cell transplantation for relapsed or refractory Hodgkin lymphoma (B Wirk). No patients in the allogeneic database received brentuximab from 2005-2012. PROP 1310-20 A Comparison of Busulfan/Cyclophosphamide/Etoposide with BCNU/Etoposide/Cytarabine/Melphalan for Patients Undergoing Autologous Stem Cell Transplant for Relapsed Hodgkin’s Lymphoma (J Cohen). Overlap with SC10-06. PROP 1311-13 Clinical Outcomes in Patients with HIV related lymphoma undergoing autologous HSCT (H Haddad). Dropped due to low number of patients (n=48 HIV+).

12


PROP 1311-16 Impact of Radioimmunotherapy (RIT) Exposure on Survival after Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma (R Karmali). Dropped due to low number of patients (n=64 RIT exposure). PROP 1311-22 The Impact of Conditioning Regimen Intensity on the Outcomes of Allogeneic Hematopoietic Cell Transplantation for Patients with Lymphoma who have Chemo-sensitive Disease (N Ghosh). Overlap with LY12-02. PROP 1311-47 The Prognostic Impact of Cytogenetic and Molecular Abnormalities on Autologous Hematopoietic Cell Transplant Outcomes for Patients with Diffuse Large B Cell Lymphoma (B Trottier). Dropped due to no cytogenetic information available for lymphoma. PROP 1311-52 Impact of Post-Hematopoietic Cell Transplantation (HCT) Rituximab (R) on Progression-Free and Overall Survival in B-cell non-Hodgkin Lymphoma (B-NHL) Patients Undergoing Reduced-Intensity Conditioning Allogeneic HCT (C Sauter). Dropped due to low number (31 post transplant Rituximab). PROP 1312-07 Outcomes of hematopoietic cell transplantation in Adult T cell leukemia-lymphoma (AE Hallack Neto). Dropped due to low number of cases (Registration=103 AlloHCT & 34AutoHCT; Research=61 AlloHCT & 4 AutoHCT).

6. Other business After the new proposals were presented, each participant in the meeting had the opportunity to rate each proposal using paper ballots. Without additional comments, the meeting was adjourned at 2:15 pm.

13


Working Committee Overview Plan for 2014-2015

a. LY10-02 Umbilical cord blood versus unrelated donor allogeneic hematopoietic cell transplantation for patients with lymphoma. We anticipate submitting the manuscript for peer-review before July 1, 2014.

b. LY12-02/GV11-01 Graft-vs-lymphoma post allogeneic hematopoietic cell transplantation. We anticipate finalizing the landmark analysis and submitting the manuscript for peer-review before July 1, 2014.

c. LY06-03 Allogeneic hematopoietic cell transplantation for relapsed follicular lymphoma: impact of donor type and prognostic risk score for survival. Final dataset from EBMT is expected, no later than June 30, 2014. The combined analysis with EBMT is expected to start by July 1, 2014 (pending EBMT collaboration). We anticipate a finalized analysis by July 1, 2015.

d. LY13-01 Autologous transplantation for diffuse large B-cell lymphomas patients refractory or relapsing early after Rituximab-containing first line chemoimmunotherapies. We anticipate submitting the manuscript for peer-review before July 1, 2014.

e. LY12-01 Positron Emission Tomography Imaging Prior to AlloHCT for Lymphoma. We anticipate finalizing the data file before July 1, 2014 and submitting the manuscript for peer-review before July 1, 2015.

f. LY13-02 Outcomes of autologous stem cell transplantation for children, adolescents and young adults with relapsed/refractory Hodgkin lymphoma. We anticipate finalizing the data file before July 1, 2014 and submitting the manuscript for peer-review before July 1, 2015.

g. LY13-03 Comparison of autologous versus RIC allogeneic stem cell transplantation for relapsed/refractory patients with follicular lymphoma. We anticipate finalizing the data file before July 1, 2014 and submitting the manuscript for peer-review before July 1, 2015.

h. LY14-01 (PROP 1311-79) Updated prognostic information for lymphoma survivors beyond 1 year from allogeneic hematopoietic cell transplantation. A landmark CIBMTR analysis. We anticipate finalizing the protocol before July 1, 2015.

i. LY14-02 (PROP 1311-89) Outcome of patients with relapsed diffuse large B-cell lymphoma treated with allogeneic hematopoietic cell transplantation following a failed autologous HCT. We anticipate finalizing the analysis before July 1, 2015.

14


Work Assignments for Working Committee Leadership (March 2014)

David Maloney LY12-01: Positron Emission Tomography Imaging Prior to AlloHCT for Lymphoma. LY14-01 (PROP 1311-79) Updated prognostic information for lymphoma survivors beyond 1 year from allogeneic hematopoietic cell transplantation. A landmark CIBMTR analysis

Sonali Smith LY14-02 (PROP 1311-89) Outcome of patients with relapsed diffuse large B-cell lymphoma treated with allogeneic hematopoietic cell transplantation following a failed autologous HCT

Anna Sureda LY06-03: Allogeneic hematopoietic cell transplantation for relapsed follicular

lymphoma: impact of donor type and prognostic risk score for survival

Wael Saber LY10-02: Umbilical cord blood versus unrelated donor allogeneic hematopoietic cell transplantation for patients with lymphoma. LY12-02/GV11-01: Graft-vs-lymphoma post allogeneic hematopoietic cell transplantation.

Mehdi Hamadani LY13-01: Autologous transplantation for diffuse large B-cell lymphomas patients refractory or relapsing early after Rituximab-containing first line chemoimmunotherapies. LY13-02: Outcomes of autologous stem cell transplantation for children, adolescents and young adults with relapsed/refractory Hodgkin lymphoma. LY13-03: Comparison of autologous versus RIC allogeneic stem cell transplantation for relapsed/refractory patients with follicular lymphoma.

15


Accrual Summary for Hodgkin and Non-Hodgkin Lymphoma Working Committee: 2000-2014

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

Anaplastic large cell 132 29 42 90 968 122

PIF 14 (11) 5 (17) 3 ( 7) 8 ( 9) 84 ( 9) 9 ( 7)

CR 1 24 (18) 3 (10) 9 (21) 14 (16) 271 (28) 38 (31)

Relapse 1 17 (13) 5 (17) 2 ( 5) 4 ( 4) 115 (12) 22 (18)

CR 2 33 (25) 9 (31) 6 (14) 29 (32) 240 (25) 30 (25)

Other / Unknown 44 (33) 7 (24) 22 (52) 35 (39) 258 (27) 23 (19)

Burkitt/small noncleaved 132 41 43 85 476 74

PIF 17 (13) 5 (12) 4 ( 9) 12 (14) 47 (10) 12 (16)

CR 1 32 (24) 10 (24) 9 (21) 13 (15) 157 (33) 28 (38)

Relapse 1 18 (14) 5 (12) 4 ( 9) 13 (15) 47 (10) 5 ( 7)

CR 2 34 (26) 16 (39) 12 (28) 37 (44) 111 (23) 19 (26)

Other / Unknown 31 (23) 5 (12) 14 (33) 10 (12) 114 (24) 10 (14)

Diffuse large cell /Immunoblastic

813

218

262

658

14389

2052

PIF 182 (22) 57 (26) 45 (17) 181 (28) 1437 (10) 228 (11)

CR 1 82 (10) 35 (16) 34 (13) 69 (10) 2133 (15) 379 (18)

Relapse 1 161 (20) 29 (13) 29 (11) 91 (14) 2623 (18) 390 (19)

CR 2 100 (12) 18 ( 8) 35 (13) 102 (16) 3743 (26) 533 (26)

Other / Unknown 288 (35) 79 (36) 119 (45) 215 (33) 4453 (31) 522 (25)

Follicular 953 444 289 770 3719 844

PIF 113 (12) 69 (16) 29 (10) 111 (14) 329 ( 9) 54 ( 6)

CR 1 74 ( 8) 33 ( 7) 20 ( 7) 58 ( 8) 397 (11) 100 (12)

Relapse 1 151 (16) 100 (23) 36 (12) 121 (16) 660 (18) 171 (20)

CR 2 108 (11) 64 (14) 33 (11) 100 (13) 794 (21) 175 (21)

Other / Unknown 507 (53) 178 (40) 171 (59) 380 (49) 1539 (41) 344 (41)

Lymphoblastic 155 50 87 126 287 41

PIF 16 (10) 8 (16) 7 ( 8) 19 (15) 15 ( 5) 2 ( 5)

CR 1 48 (31) 13 (26) 16 (18) 25 (20) 125 (44) 23 (56)

Relapse 1 25 (16) 7 (14) 8 ( 9) 19 (15) 25 ( 9) 3 ( 7)

CR 2 28 (18) 13 (26) 25 (29) 42 (33) 37 (13) 6 (15)

Other / Unknown 38 (25) 9 (18) 31 (36) 21 (17) 85 (30) 7 (17)

Mantle 514 186 175 480 4654 736

PIF 79 (15) 38 (20) 20 (11) 66 (14) 255 ( 5) 53 ( 7)

CR 1 137 (27) 42 (23) 43 (25) 102 (21) 2806 (60) 461 (63)

Relapse 1 75 (15) 25 (13) 20 (11) 85 (18) 201 ( 4) 27 ( 4)

CR 2 61 (12) 23 (12) 23 (13) 98 (20) 274 ( 6) 49 ( 7)

Other / Unknown 162 (32) 58 (31) 69 (39) 129 (27) 1118 (24) 146 (20)

16


Accrual Summary for Hodgkin & Non-Hodgkin Lymphoma Working Committee: 2000-2014 Continued. HLA-identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%)

Marginal 61 26 21 51 253 30

PIF 8 (13) 8 (31) 6 (29) 12 (24) 20 ( 8) 6 (20)

CR 1 5 ( 8) 3 (12) 0 7 (14) 41 (16) 3 (10)

Relapse 1 9 (15) 1 ( 4) 4 (19) 6 (12) 32 (13) 3 (10)

CR 2 7 (11) 2 ( 8) 1 ( 5) 6 (12) 42 (17) 7 (23)

Other / Unknown 32 (52) 12 (46) 10 (48) 20 (39) 118 (47) 11 (37)

NK T cell 176 44 64 175 522 70

PIF 25 (14) 5 (11) 10 (16) 29 (17) 45 ( 9) 6 ( 9)

CR 1 46 (26) 10 (23) 20 (31) 60 (34) 192 (37) 33 (47)

Relapse 1 15 ( 9) 6 (14) 3 ( 5) 9 ( 5) 52 (10) 5 ( 7)

CR 2 28 (16) 5 (11) 10 (16) 43 (25) 92 (18) 12 (17)

Other / Unknown 62 (35) 18 (41) 21 (33) 34 (19) 141 (27) 14 (20)

T cell 345 122 139 352 1226 185

PIF 86 (25) 33 (27) 34 (24) 85 (24) 106 ( 9) 17 ( 9)

CR 1 94 (27) 27 (22) 36 (26) 90 (26) 497 (41) 83 (45)

Relapse 1 38 (11) 12 (10) 8 ( 6) 35 (10) 136 (11) 19 (10)

CR 2 36 (10) 19 (16) 21 (15) 45 (13) 166 (14) 23 (12)

Other / Unknown 91 (26) 31 (25) 40 (29) 97 (28) 321 (26) 43 (23)

NHL Not specified 111 3 55 4 686 17

PIF 8 ( 7) 1 (33) 5 ( 9) 1 (25) 52 ( 8) 4 (24)

CR 1 7 ( 6) 0 4 ( 7) 0 76 (11) 2 (12)

Relapse 1 12 (11) 1 (33) 3 ( 5) 1 (25) 36 ( 5) 1 ( 6)

CR 2 3 ( 3) 0 10 (18) 0 77 (11) 3 (18)

Other / Unknown 81 (73) 1 (33) 33 (60) 2 (50) 445 (65) 7 (41)

Other 536 203 202 582 3124 495

PIF 108 (20) 59 (29) 39 (19) 146 (25) 363 (12) 66 (13)

CR 1 81 (15) 24 (12) 26 (13) 108 (19) 821 (26) 155 (31)

Relapse 1 52 (10) 21 (10) 30 (15) 61 (10) 414 (13) 50 (10)

CR 2 64 (12) 12 ( 6) 28 (14) 62 (11) 559 (18) 76 (15)

Other / Unknown 231 (43) 87 (43) 79 (39) 205 (35) 967 (31) 148 (30)

Hodgkin 364 88 174 218 12124 1589

PIF 97 (27) 20 (23) 31 (18) 52 (24) 1499 (12) 213 (13)

CR 1 21 ( 6) 5 ( 6) 6 ( 3) 21 (10) 1026 ( 8) 156 (10)

Relapse 1 48 (13) 27 (31) 17 (10) 35 (16) 2557 (21) 315 (20)

CR 2 32 ( 9) 9 (10) 18 (10) 30 (14) 3129 (26) 397 (25)

Other / Unknown 166 (46) 27 (31) 102 (59) 80 (37) 3913 (32) 508 (32)

17


Accrual Summary for Hodgkin & Non-Hodgkin Lymphoma Working Committee: 2000-2014 Continued. HLA-identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%)

Graft type 4292 1454 1553 3591 42428 6255

BM 598 (14) 139 (10) 416 (27) 719 (20) 629 ( 1) 68 ( 1)

PBSC 3649 (85) 1312 (90) 1051 (68) 2497 (70) 40834 (96) 6094 (97)

Other / Unknown 45 ( 1) 3 (<1) 86 ( 6) 375 (10) 965 ( 2) 93 ( 1)

18


TO: Lymphoma Working Committee Members

FROM: Mehdi Hamadani, MD; Scientific Director for the Lymphoma Working Committee

RE: Studies in Progress Summary

LY12-01: Positron Emission Tomography Imaging Prior to AlloHCT for Lymphoma (V Bachanova) Adult patients with follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma and T- or NK-cell NHL undergoing alloHCT between 2007-12 were eligible. Chemorefractory pts (by CT criteria), and cases where interval between PET scan and alloHCT was >3 months were excluded. Three hundred and thirty six patients eligible for this analysis were divided into PET+ve and PET-ve groups, based on pre alloHCT PET status, as determined by individual transplant centers. On multivariate analysis, PET+ve status was associated with a higher risk of relapse/progression, but was not predictive of inferior OS, PFS or NRM. PET status had no impact on incidence of grade II-IV acute GVHD and chronic GVHD. The study is in the manuscript preparation phase. LY13-02: Outcome of autologous hematopoietic cell transplantation for children, adolescents, and young adults with relapsed/refractory hodgkin lymphoma (P Satwani) CAYA (age <30yrs) with Rel/Ref classical HL undergoing autoHCT during 1995-2010 were eligible. On multivariate analysis non-ABVD/ABVD-like 1st line therapy (RR 1.8; p=0.03) was associated with a higher NRM. Factors predicting higher risk of R/P included Lansky score or KPS<90, extranodal disease, resistant disease and CBV conditioning. Long first complete remission was associated with a reduced R/P risk. MVA for PFS identified END, resistant disease and KPS<90 as risk factors for therapy failure; while LgCR1 was predictive of reduced therapy failure risk. Finally for OS, non-ABVD/ABVD-like 1st line therapy, END and resistant disease were associated with higher mortality; while LgCR1 and peripheral blood graft were associated with reduced mortality risk. The study is in the manuscript preparation phase. LY13-03: Comparison of autologous versus allogeneic hematopoietic cell transplantation after reduced/non-myeloablative conditioning for relapsed/refractory patients with follicular lymphoma (E Klyuchnikov) This study intends to compare overall and progress-free survival in patients aged ≥18 years with relapsed/refractory follicular lymphoma who underwent reduced-intensity/non-myeloablative allogeneic stem cell transplantation versus autologous stem cell transplantation as second-line approach. Analysis is underway. LY06-03: Allogeneic hematopoietic cell transplantation for relapsed follicular lymphoma: impact of donor type and prognostic risk score for survival (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

19


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 in collaboration with the EBMT. Studies previously proposed, but not initiated LY04-02: Outcome of patients with relapsed diffuse large B-cell lymphoma treated with allogeneic hematopoietic cell transplantation following a failed autologous HCT (T Fenske) This study will describe the transplantation outcomes of DLBCL patients undergoing an allo-HCT, after relapsing after a prior auto-HCT. Also will compare “Post Auto-HCT Relapse Survival” of DLBCL patients undergoing an allo-HCT after relapsing following a prior auto-HCT against a cohort of patients NOT undergoing an allo-HCT following a post auto-HCT relapse/progression. The study protocol is under development.

20


Study Proposal 1410-09 Study Title: Comparison of allogeneic stem cell transplantation to autologous stem cell transplantation for patients with early relapsed and primary refractory diffuse large B cell lymphoma Nilanjan Ghosh, MD, PhD, Director of Lymphoma program, Department of Hematologic Oncology and

Blood Disorders, Levine Cancer Institute/Carolinas Health Care System, [email protected]

Specific Aims: 1. To compare the efficacy i.e. progression free survival and overall survival of allogeneic stem cell

transplant to autologous stem cell transplant (LY13-01) for diffuse large B cell lymphoma which has relapsed less than 1 year after diagnosis or has been refractory to primary therapy (early treatment failure).

2. To compare the toxicity i.e. non relapse mortality and relapse rate of allogeneic stem cell transplant to autologous stem cell transplant (LY13-01) for relapsed diffuse large B cell lymphoma which has relapsed less than 1 year after diagnosis or has been refractory to primary therapy (early treatment failure).

3. To identify factors that are associated with relapse, PFS and OS after allogeneic stem cell transplantation. The following factors will be studied for their association with outcomes: disease characteristics at diagnosis, early relapse vs. late relapse, chemosensitive vs. chemorefractory, type of salvage chemotherapy regimen, type of conditioning regimen, graft type, type of donor, and disease status prior to transplant.

Scientific Justification: Curative treatment options for relapsed or refractory lymphoma are limited. Both autologous and allogeneic hematopoietic stem cell transplantation (allo HCT) have been used in this setting [1-3]. Allo HCT offers advantages over autologous SCT: a) graft-versus-lymphoma effect, b) lymphoma free grafts, and c) use of cell products which have not been exposed to prior chemotherapy induced DNA damage. For patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL), salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is widely considered as the standard treatment for patients with chemo-sensitive disease. The CORAL study reported the 3 year PFS of 53% with salvage chemotherapy combined with rituximab in the patients who underwent ASCT in the setting of chemo-sensitive disease [4]. However, patients who relapsed <12 months from diagnosis had a 3 year PFS of only 23%. In a recent report from the CIBMTR, patients with primary refractory disease or early relapse after an initial rituximab chemotherapy regimen had a 3 year PFS and OS of 44% and 50% respectively [5]. Although the results reported in this study are better than were reported in the CORAL study, a significant number of patients relapse following an autologous transplant. Allo HCT has been explored in lymphoma with the expectation of a graft vs. lymphoma effect and a graft without tumor contamination. Historically, several studies have shown a low rate of relapse with allo SCT. Traditionally, the benefit of reduced relapse from this procedure did not translate into an overall survival benefit due to high non relapse mortality [6-9]. A CIBMTR analysis comparing outcomes in DLBCL patients undergoing autologous or myeloablative allo SCT performed between 1995 and 2003 showed that MA allo SCT was associated with higher TRM, treatment failure and mortality when compared to auto SCT. However, allo HCT recipients were more

21


likely to had high risk features including older age, more pretreatment and chemoresistant disease [10]. Similarly, a retrospective study from the Washington University School of Medicine, showed that auto SCT provided superior outcomes compared to allo SCT in patients with early relapse or primary refractory diffuse large B cell lymphoma. However, in comparison with auto SCT, majority of the allo SCT were performed before 2003 and included a higher proportion of patients who were heavily pretreated and had primary refractory and chemoresistant disease at the time of transplant [11]. Since the potential advantages from allo SCT might be minimized by NRM, allo SCT with RIC or NMA conditioning has been tested as a means to reduce NRM. However, these two modalities are difficult to compare because the patient and disease characteristics in individuals undergoing RIC/NMA are different from those receiving MA regimens. Patients receiving RIC/NMA allo SCT tend to be older, more heavily pre-treated and have more comorbidities. 2-4 year PFS ranging from 35-48% has been reported with allo SCT using RIC/NMA conditioning in this setting [12-14]. The NRM in these studies has been 23-32%. More recently, the German High Grade Lymphoma study group conducted a prospective trial of allo-SCT with MA conditioning for patients with primary refractory disease, early relapse (<12 months) or relapse after ASCT. At 3 years the PFS and NRM were 40% and 35% respectively [15]. Castagna et. al. reported a 2 year PFS and NRM of 63% and 16.3% using Haploidentical donors and NMA conditioning in advanced lymphomas [16]. In this study which included transplants from 2009-12, 55% patients had a prior auto SCT and 14% patients had a prior allo SCT. These evolving trends of improved progression free survival and lower NRM suggest that allo SCT can be a useful in the treatment of high risk lymphomas. Currently, the decision to use allo SCT for diffuse large B cell lymphoma is based on physician preference and varies widely across instructions. Analysis of results with allo SCT in DLBCL from the CIBMTR is likely to provide a basis for an evidence based approach for the use of this treatment modality. It may allow identification of subsets of patients who benefit most from this approach. In the absence of prospective randomized data, a matched pair comparison of a high risk allo SCT group (relapsed less than 1 year after diagnosis) with a subset of closely matched auto SCT patients may allow physicians to make unbiased decisions regarding transplantation for these high risk patients. Patient Eligibility Population:

Diagnosis of diffuse large B cell lymphoma

Treatment with allogeneic stem cell transplantation

Data Requirements:

Data collection forms: 2000 R3.0, 2005 R4.0, 2006 R3.0, 2018 R2.0, 2100 R3.0, 2118 R2.0, 2200 R3.0, 2300 R3.0, 2400 R3.0, 2450 R3.0, 2451 R2.0.

Autologous stem cell transplant population as a comparator: LY1301

No supplemental data collection

Do not need to combine CIBMTR data with other groups Variables: 1. Patient: Age, Karnofsky score at diagnosis and pre-transplant 2. Disease: a) Stage, b) Extranodal involvement, c) CNS involvement, d) Bone marrow involvement, e)

LDH, f) B symptoms. 3. Pre-transplant treatment: a) Number of therapies b) Rituximab for B cell lymphoma, c) Prior auto

HCT c) Pre-transplant disease remission: CR, CRu,PR, PET negative CR, first remission or subsequent remission.

22


4. Transplant: a) Conditioning regimens, b) Graft type, c) Type of donor, d) graft source, e) year of transplant, f) duration between diagnosis and allo HCT, g) duration between auto-HCT and allo HCT, h) GVHD prophylaxis

5. Outcomes: a) Time to ANC and platelet recovery, b) Day 100 Acute GVHD (II-IV), c) Chronic GVHD at years 1 and 3, d) NRM day 100, 1 year, 3 year, e) Relapse rate at 1 year, 3 years, f) PFS at 1 and 3 years, g) OS at 1 and 3 years.

Sample requirements: None Study Design: The CIBMTR database has transplant data from more than 500 transplant transplantation centers. This resource has been invaluable in answering seminal questions in SCT. The overall analysis is exploratory and will test multiple variables (patient factors, disease factors, pre-transplant treatment, transplant factors) on outcomes such as relapse rate, PFS, NRM, OS. The CIBMTR database has all the variables needed to test this hypothesis. Statistical methodology: Probabilities of PFS and OS will be calculated using the Kaplan-Meier product limit estimate. Probabilities of relapse, NRM, acute and chronic GVHD and engrafment will be calculated using cumulative incidence curves to accommodate for competing risks. The intensity of conditioning regimens will be categorized as MAC or RIC or NMA using established consensus criteria [17]. Associations among patient, disease, pre-transplant remission status and transplantation related variables and outcomes will be evaluated using a multivariate Cox proportional hazards regression. A stepwise selection multivariate model will be built to identify covariates that influence outcomes. Covariates with a p<0.05 will be considered significant. For the group of patients who relapsed less than 1 year from diagnosis, a matched pair comparison of the allo SCT group with a subset of closely matched auto SCT patients selected by propensity score matching will be performed as reported previously [10]. The propensity score is the probability of receiving an allo SCT and is calculated based on a logistic regression model. The logistic regression model will include patient and disease oriented risk factors. Multivariate analysis will be performed by fitting a Cox model stratified on matched-pairs. References 1. Philip, T., 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(23): p. 1540-5.

2. van Kampen, R.J., et al., Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol, 2011. 29(10): p. 1342-8.

3. Bishop, M.R., et al., Clinical evidence of a graft-versus-lymphoma effect against relapsed diffuse large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation. Ann Oncol, 2008. 19(11): p. 1935-40.

4. Gisselbrecht, C., et al., Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol, 2010. 28(27): p. 4184-90.

5. Hamadani, M., et al., Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant, 2014.

23


6. Chopra, R., et al., Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol, 1992. 10(11): p. 1690-5.

7. Jones, R.J., et al., Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood, 1991. 77(3): p. 649-53.

8. Ratanatharathorn, V., et al., Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood, 1994. 84(4): p. 1050-5.

9. Schimmer, A.D., et al., Allogeneic or autologous bone marrow transplantation (BMT) for non-Hodgkin's lymphoma (NHL): results of a provincial strategy. Ontario BMT Network, Canada. Bone Marrow Transplant, 2000. 26(8): p. 859-64.

10. Lazarus, H.M., 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, 2010. 16(1): p. 35-45.

11. Ghobadi, A., Nolley E, Liu J, McBride, A, Stockerl-Goldstein K and Cashen A, Retrospective comparison of allogeneic vs autologous transplantation for diffuse large B-cell lymphoma with early relapse or primary induction failure. Bone Marrow Transplant, 2014. e pub ahead of print.

12. Rezvani, A.R., et al., Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol, 2008. 143(3): p. 395-403.

13. Sirvent, A., et al., Low nonrelapse mortality and prolonged long-term survival after reduced-intensity allogeneic stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma: report of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Biol Blood Marrow Transplant, 2010. 16(1): p. 78-85.

14. Thomson, K.J., et al., Favorable long-term survival after reduced-intensity allogeneic transplantation for multiple-relapse aggressive non-Hodgkin's lymphoma. J Clin Oncol, 2009. 27(3): p. 426-32.

15. Glass, B., et al., Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol, 2014. 15(7): p. 757-66.

16. Castagna, L., et al., Nonmyeloablative conditioning, unmanipulated haploidentical SCT and post-infusion CY for advanced lymphomas. Bone Marrow Transplant, 2014.

17. Bacigalupo, A., et al., Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant, 2009. 15(12): p. 1628-33.

24


Characteristics of patients with HCT for early relapsed and primary refractory diffuse large B cell

lymphoma

Variable AlloHCT

AutoHCT

(Study LY13-01)

Number of patients 77 300

Age at transplant, years

Median 49 (21-70) 58 (19-77)

18-29 6 ( 8) 16 ( 5)

30-39 17 (22) 18 ( 6)

40-49 17 (22) 48 (16)

50-59 19 (25) 84 (28)

≥60 18 (23) 134 (45)

Sex

Male 47 (61) 189 (63)

Female 30 (39) 111 (37)

Karnofsky score

<90% 34 (44) 95 (32)

90-100% 39 (51) 185 (62)

Missing 4 ( 5) 20 ( 7)

Prior autologous transplant N/A

No 58 (75)

Yes 19 (25)

Disease stage at diagnosis

I-II 22 (29) 60 (20)

III-IV 51 (66) 219 (73)

Unknown 4 ( 5) 21 ( 7)

Disease stage at transplant

CR 13 (17) 43 (14)

I-II 9 (12) 35 (12)

III-IV 25 (32) 42 (14)

Not restaged/unknown 30 (39) 180 (60)

Disease status preHCT

PR 60 (78) 199 (66)

CR 17 (22) 101 (34)

25


Variable

AlloHCT

AutoHCT

(Study LY13-01)


Year of transplant

1999-2000 2 ( 3) 3 ( 1)

2001-2002 4 ( 5) 15 ( 5)

2003-2004 16 (21) 34 (11)

2005-2006 21 (27) 82 (27)

2007-2008 22 (29) 115 (38)

2009-2010 8 (10) 40 (13)

2011 4 ( 5) 11 ( 4)

Median follow-up of survivors, median (range) 72 (3-147) 48 (3-147)

26


Study Proposal 1410-10 Study Title: Does Autologous Stem Cell Transplant Overcome the Increased Risk of Death in Patients with Follicular Lymphoma Relapsing Early after First Line Chemoimmunotherapy? Carla Casulo, MD, Wilmot Cancer Institute, University of Rochester, [email protected] Jonathan W. Friedberg , MD, M.M.Sc, Wilmot Cancer Institute, University of Rochester,

[email protected] Hypothesis: 20% of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of initial chemoimmunotherapy. Recent data from the National LymphoCare Study (NLCS) identified that early POD in FL has poor outcomes. To that end, we hypothesize that patients with FL with relapsed disease may be able to overcome the negative impact of early progression through consolidation with autologous stem cell transplant (ASCT). Specific Aims: 1. To determine the progression free (PFS) and overall survival (OS) of patients with FL undergoing

ASCT for relapsed disease within 2 years of chemoimmunotherapy 2. To determine whether ASCT abrogates the negative prognostic impact of early relapse following

primary chemoimmunotherapy Scientific Justification: The implementation of ASCT for FL is a commonly used strategy in the relapsed setting, and randomized data demonstrates an OS benefit when compared to conventional chemotherapy, solidifying the role of salvage chemotherapy followed by ASCT in this setting1,2-4. Both prospective and retrospective studies have demonstrated high response rates, and a suggestion of long-term survival5,4. Moreover, outcomes are improved when ASCT is performed after first or second remission, compared to following subsequent remissions, with plateaus in both PFS and OS5-7. Whether remission duration impacts outcome after ASCT for relapsed FL is not known. However this may be an important consideration, since our recent data from the National LymphoCare Study (NLCS) has established that progression of FL within two years of primary treatment with chemoimmunotherapy is significantly associated with poor outcomes8. Until recently stratification of risk in the setting of disease progression of FL, and its influence on subsequent patient survival, has not been previously validated. Depth and duration of response to previous treatments have been proposed as prognostic indicators without widespread acceptance, however the timing of progression in FL may be an underappreciated adverse risk factor. We analyzed data from the NLCS to identify patients with FL

27


who are at high risk for death following R-CHOP treatment to determine whether early progression predicts for inferior OS in this disease, and we validated our findings in an independent cohort. This data was presented as an oral abstract at the 2013 American Society of Hematology Meeting. We sought to understand whether time to progression after diagnosis in patients who received first-line chemoimmunotherapy may be a factor impacting survival outcomes in FL. We found that early disease progression defines a group of patients at substantially greater risk of death beyond two years, compared to a reference group of patients treated with R-CHOP for the same indications without progression. Progression of disease within 2 years of initial therapy with R-CHOP was significantly associated with poor outcomes. Overall survival at 5 years was 50% in the early progressor group and 95% in a reference group of patients not progressing within 2 years of treatment (Figure 1). Independent of clinical prognostic indices, early progression was significantly associated with worse overall survival, with a hazard ratio of 12.3.

28


Figure 1: Overall Survival Following Diagnosis in Patients who Received R-CHOP in the NLCS. This figure shows OS from progression in patients who received R-CHOP chemotherapy. Patient with early progression have poor survival compared to a reference group without early progression after R-CHOP. Two-year OS (95% CI) was 68% (58.2–76.3). Five-year OS (95% CI) was 50% (39.4–59.2). At 2 years, OS in the reference group was 97% (94.6–98.1) and at 5 years was 90% (86.2–92.4). Based on the survival benefit observed with ASCT in relapsed FL, it would be relevant to characterize the optimal time to introduce this treatment modality. Should high risk patients relapsing early after primary chemoimmunotherapy be offered ASCT, or should ASCT be delayed until the next remission is attained, regardless of when relapse occurred? Introduction of ASCT after early failure of first line chemoimmunotherapy may be more important than timing it after attainment of remission, given that other variables affect achievement of remission, such as lines of therapy required. In the largest series of BEAM based ASCT in FL, 57% of patients undergoing ASCT at first relapse had a length of remission under two years6. Outcomes specific to this sub-population are not available. To better understand the impact of early relapse on ASCT outcome, we seek to determine PFS and OS of patients with FL undergoing ASCT who relapsed within 2 years of first line chemoimmunotherapy. We hypothesize that ASCT in this context may be able to overcome the negative impact of early disease progression. Should we establish that ASCT for patients with FL relapsing early confers better outcomes, it could support a strategy of aggressive second-line treatments, including ASCT, in this setting. Patient Eligibility Population: Eligible patients include those with FL of any stage, treated with chemoimmunotherapy in the first line setting, and relapsed within the first two years of treatment. Patients should have received ASCT for relapsed disease at first relapse. Patients must not have transformed histology, should not have received ASCT in the first line setting (for example as consolidation, or without relapse). Data Requirements: 1. Form 2018 R3.0: Hodgkin and Non Hodgkin Lymphoma (LYM) Pre-HSCT Data (diagnostic data, etc)

2. Form 2118 R3.0: Hodgkin and Non Hodgkin Lymphoma (LYM) Post-HSCT Data (response, etc)

3. Form 2200 R3.0: Six Months to Two Years Post –HSCT Data (heme recovery, survival, etc)

4. Form 2300 R3.0: Yearly Follow-up for Greater Than Two Years Post-HSCT Data (secondary malignancy, toxicity etc)

5. Form 2400 R4.0: Pre-Transplant Essential Data (comorbidities, details on stem cell product, cell dose, t cell deplete, etc)

6. Form 2900 R2.0: Recipient Death Data

Study Design: This study involves the evaluation of existing data and documents in the form of data available through the CIBMTR, and historical data from another cohort (NLCS dataset referenced above). A list of patients that meet the above criteria through the CIBMTR should be accessible through the forms noted above. Patients will be classified as recipients of ASCT for relapsed FL. They will then be subcategorized by date from first relapse, and grouped into early relapse (within 2 years or less from first line treatment) or later relapse (after 2 years from first line treatment).

29


A descriptive analysis of key demographic and baseline characteristics, including FLIPI, LDH, race, ECOG performance status, B symptoms, nodal sites, hemoglobin, bone marrow involvement, histologic grade, age, gender, and stage will be assessed. A log-rank test will be performed to compare OS, from time of first progression, between patients who relapse early and receive ASCT and patients who relapse early and do not receive ASCT. Historical data is available for the cohort of patients who relapse early and do not receive ASCT. Cox proportional hazards model will be used to estimate the hazard ratio associated with ASCT, as well as to identify additional risk factors from baseline and demographic characteristics collected. References: 1. Schouten HC, Qian W, Kvaloy S, 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003;21:3918-27.

2. Sabloff M, Atkins HL, Bence-Bruckler I, et al. A 15-year analysis of early and late autologous hematopoietic stem cell transplant in relapsed, aggressive, transformed, and nontransformed follicular lymphoma. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2007;13:956-64.

3. Pettengell R, Schmitz N, Gisselbrecht C, et al. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013;31:1624-30.

4. Robinson SP, Canals C, Luang JJ, et al. The outcome of reduced intensity allogeneic stem cell transplantation and autologous stem cell transplantation when performed as a first transplant strategy in relapsed follicular lymphoma: an analysis from the Lymphoma Working Party of the EBMT. Bone marrow transplantation 2013;48:1409-14.

5. Evens AM, Vanderplas A, LaCasce AS, et al. Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: a comprehensive analysis from the NCCN lymphoma outcomes project. Cancer 2013;119:3662-71.

6. Kothari J, Peggs KS, Bird A, et al. Autologous stem cell transplantation for follicular lymphoma is of most benefit early in the disease course and can result in durable remissions, irrespective of prior rituximab exposure. British journal of haematology 2014.

7. Vose JM, Bierman PJ, Loberiza FR, et al. Long-term outcomes of autologous stem cell transplantation for follicular non-Hodgkin lymphoma: effect of histological grade and Follicular International Prognostic Index. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2008;14:36-42.

8. Casulo C BM, Dawson K, et al. Early Relapse of Follicular Lymphoma After R-CHOP Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. Blood Supplement, abstract 2013.

30


Characteristics of patients who received an autologous transplantation for follicular lymphoma

relapsing early after first Line chemoimmunotherapy reported to the CIBMTR from 2000-2012*

Variable N (%)

Number of cases 169


Median 56 (23-79)

18-29 3 ( 2)

30-39 11 ( 7)

40-49 40 (24)

50-59 54 (32)

≥60 61 (36)

Sex

Male 99 (59)

Female 70 (41)

Karnofsky score

<90% 42 (25)

90-100% 111 (66)

Missing 16 ( 9)

Sub disease

Follicular I 43 (25)

Follicular II 62 (37)

Follicular III 64 (38)

Conditioning regimen-auto

TBI-based 20 (12)

BEAM and similar 111 (66)

CBV or similar 30 (18)

BuMEL/BuCy 5 ( 3)

Others 3 ( 2)

Graft type

Bone marrow 1 ( 1)

Peripheral blood 168 (99)

31


Table. Continued.

Variable N (%)

Number of cases 169

Year of transplant

2001 3 ( 2)

2002 3 ( 2)

2003 4 ( 2)

2004 9 ( 5)

2005 20 (12)

2006 37 (22)

2007 19 (11)

2008 28 (17)

2009 41 (24)

2010 1 ( 1)

2011 3 ( 2)

2012 1 ( 1)

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

*Selection criteria: First autoHCT for FL between 2000-2012 (n=705), R+ plus other drugs in the first chemo line

(n=266), progression/stable disease or CR/PR (within 2 years from first line therapy to 1st

line relapse) (n=188), at

least 100 day form received (n=173) and consent cases (N=169)

32


Study Proposal 1411-17/1411-93 Study Title: Hematopoietic Cell Transplantation for NK/T-cell Non-Hodgkin Lymphoma Stefan Klaus Barta, MD, MS, MRCP(UK), Temple University Health System/Fox Chase Cancer Center, [email protected] Henry Chi Hang Fung, MD, FRCPE, Temple University Health System/Fox Chase Cancer Center, [email protected] Görgün Akpek, MD, MHS, Banner MD Anderson Cancer Center, [email protected] Hypothesis: We wish to better characterize clinical outcomes post hematopoietic cell transplantation in patients with Natural Killer/T-cell Lymphoma Specific Aims:

1. To describe clinical outcomes [progression-free survival (PFS), overall survival (OS), and non-relapse mortality (NRM)] following autologous or allogeneic hematopoietic cell transplantation in patients with extranodal NK/T-cell lymphoma

2. To identify the impact of patient-, disease-, and transplant-related factors on the outcomes PFS, OS and NRM.

Scientific Justification: Natural Killer (NK)/T-cell lymphoma is an aggressive lymphoma, that is strongly associated with Epstein-Barr virus (EBV).1 While rare in the US, it occurs more commonly in Asia, Central and South America.2 NK/T-cell lymphomas have traditionally been associated with a poor prognosis when treated with anthracycline-containing chemotherapy with a median OS and failure-free survival (FFS) of only 7.8 and 5.8 months respectively.3,4 This is at least in part related to increased expression of the multidrug-resistance mediating P-glycoprotein.5 However, since the use of concurrent chemoradiotherapy (CCRT) for localized disease,6,7 and introduction of asparaginase-based chemotherapy, such as the SMILE 8 or AspaMetDex9 regimens, outcomes have improved (5-year OS 50%; 4-year disease-free-survival (DFS) 64%).8 Established poor prognostic factors are advanced stage, higher International Prognostic Index (IPI) scores, non-nasal phenotype, bone and skin involvement, and high circulating EBV-DNA levels.4,8,10

The role of hematopoietic cell transplantation (HCT) for this rare disease remains unclear, especially in the current era of CCRT and asparaginase-based therapy. Before more effective therapies for NK/T-cell lymphomas had become the standard of care, autologous HCT (autoHCT) was commonly used as consolidative therapy in first remission (CR1). While autoHCT was associated with 50-70% long-term survival, a case-control study suggested benefit only for high-risk patients.11-13 Allogeneic hematopoietic cell transplantation (alloHCT) is mainly reserved for poor-risk NK/T-cell lymphoma patients with a reported OS and PFS in the pre-SMILE era of only 30-40%.14 A more recent retrospective analysis of outcomes for alloHSCT in NK/T-cell lymphoma by the Asia Lymphoma Study Group (ALSG) reported a 5-year OS of 57%, and a 5-year EFS of 51%.15 Although better than earlier results, these outcomes are comparable with what has been reported with the SMILE regimen alone in the relapsed refractory setting.8 Interpretation of HCT data in NK/T-cell lymphomas is limited by the small sample size and heterogeneity of the studies.16 Therefore, the current role for both autologous and allogeneic HCT remains largely undefined.

33


The objective of our proposed study is the better define outcomes and factors impacting outcomes for autoHCT and alloHCT in patients with NK/T-cell lymphoma. Because of the rarity of this specific subtype of mature T-cell NHL, we propose to combine CIBMTR data with data from the Asia Lymphoma Study Group (ALSG). Patient Eligibility Population: Patients with NK/T-cell NHL aged 18-65 who received a first autologous HCT or allogeneic HCT between 2000 and 2013. Patients with other mature T-cell NHL will be excluded as well as patients receiving their second HCT, and identical twin donor transplantations will be excluded. The same eligibility criteria will apply for patients treated by the ASLG. Data Requirements: Data from the CIBMTR and the Asia Lymphoma Study Group will be combined and a pooled analysis of the data will be performed.

Primary outcomes will be overall survival (OS), progression-free survival (PFS) and non-relapse mortality (NRM). Secondary outcomes will be the incidence of acute graft-versus-host disease (AGVHD), chronic graft-

versus-host-disease (CGHVD) as well as cause of death (COD), and hematopoietic recovery (defined as

time to ANC > 0.5 x 109/L sustained for 3 consecutive days, and time to achieve platelet count >20 x

109/L without support of transfusions for 7 continuous days).

We will also analyze the association of the following patient- treatment-, and disease-related factors on primary and secondary outcomes: Patient-related factors:

- age at transplantation, - Karnofsky performance score (< 90 vs. ≥90), - gender: male vs. female - race: Caucasian vs. African American vs. Hispanic vs. others

Disease-related factors: - “B” symptoms - number of lines of therapy before transplantation - disease stage at diagnosis, - extranodal involvement at diagnosis, - nasal type (primary involved sites including nasopharynx, paranasal sinuses, tonsils or - Waldeyer’s ring, ororpharynx) vs. non-nasal type17 - International Prognostic Index score (age, ECOG performance status, LDH, number of - involved extranodal sites, Ann Arbor Stage),18 - NK/T-cell lymphoma prognostic index (LDH, B-symptoms, Ann Arbor Stage, regional - lymph node status),19 - time from diagnosis to HCT (continuous or <12 vs. 12-18 vs. 18-24 vs. >24 mos) - disease status before HCT (i.e. CR1; CR2; primary induction failure; relapsed) - chemotherapy sensitivity (sensitive vs. resistant), and - EBV viral load (if available);

Treatment-related variables: - conditioning regimen,

34


- graft type (bone marrow or peripheral blood stem cells), - year of transplantation, - alloHCT vs. autoHCT, and - location of transplantation (i.e. CIBMTR site vs. ALSG site) For AlloHCT recipients: - myeloablative or reduced intensity, - donor-recipient sex match, - donor-recipient cytomegalovirus status, - donor type (HLA-identical sibling vs. matched unrelated vs. mismatched unrelated), and - GVHD prophylaxis (T-cell depletion vs. other).

This data can be abstracted from the following collection forms: “Form 2018: Hodgkin and Non-Hodgkin Lymphoma (LYM) Pre-HCT Data” and “Form 2118: Hodgkin and Non-Hodgkin Lymphoma (LYM) Post-HCT Data”. Sample Requirements: No samples are required Study Design: Data from both CIBMTR and the Asia Lymphoma Study Group will be pooled and analyzed as one dataset. We will calculate probabilities for PFS (time from transplant to death or lymphoma relapse/progression) and OS (time from transplant to death of any cause) using the Kaplan-Meier method. Probabilities of NRM (defined as death of any cause in the first 100 days or death without evidence of lymphoma relapse/progression), lymphoma relapse/progression, AGVHD and CGVHD will be calculated by using cumulative incidence curves to accommodate competing risks. The association of other variables with the primary and secondary outcomes will be determined using a multivariate Cox proportional hazard regression model. After discussions with Dr. Sonali Smith and obtaining preliminary estimates from the CIBMTR database, it appears that data for at least 99 patients undergoing alloHCT and 51 patients undergoing autoHCT for NK/T-cell NHL is available. Additionally, Dr. Yok Lam Kwong, Chair of the Division of Hematology, Oncology and Bone Marrow Transplantation at the University of Hong Kong, and Chair of the Asia Lymphoma Study Group, has shown strong interest in collaboration and confirmed his interest during an in-person meeting at ASH 2014 in San Francisco. References: 1. Swerdlow SH, Jaffe ES, Brousset P, et al: Cytotoxic T-cell and NK-cell lymphomas: current questions

and controversies. Am J Surg Pathol 38:e60-71, 2014 2. Swerdlow SH ea, eds. : WHO Classification of Tumours of Haematopoietic and LymphoidTissues. 4th

ed. International Agency for Research on Cancer: Lyon, 2008., 2008 3. Au W-y, Weisenburger DD, Intragumtornchai T, et al: Clinical differences between nasal and

extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project, 2009

4. Chim CS, Ma SY, Au WY, et al: Primary nasal natural killer cell lymphoma: long-term treatment outcome and relationship with the International Prognostic Index. Blood 103:216-21, 2004

5. Yamaguchi M, Kita K, Miwa H, et al: Frequent expression of P-glycoprotein/MDR1 by nasal T-cell lymphoma cells. Cancer 76:2351-6, 1995

35


6. Tsai HJ, Lin SF, Chen CC, et al: Long-term results of a phase II trial with frontline concurrent chemoradiotherapy followed by consolidation chemotherapy for localized nasal natural killer/T-cell lymphoma. Eur J Haematol, 2014

7. Yamaguchi M, Tobinai K, Oguchi M, et al: Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin Oncol 27:5594-600, 2009

8. Kwong Y-L, Kim WS, Lim ST, et al: SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group, 2012

9. Jaccard A, Petit B, Girault S, et al: L-asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature. Ann Oncol 20:110-6, 2009

10. Suzuki R: Pathogenesis and treatment of extranodal natural killer/T-cell lymphoma. Semin Hematol 51:42-51, 2014

11. Lee J, Au W-Y, Park MJ, et al: Autologous Hematopoietic Stem Cell Transplantation in Extranodal Natural Killer/T Cell Lymphoma: A Multinational, Multicenter, Matched Controlled Study. Biology of Blood and Marrow Transplantation 14:1356-1364, 2008

12. Chen AI, McMillan A, Negrin RS, et al: Long-Term Results Of Autologous Hematopoietic Cell Transplantation For Peripheral T Cell Lymphoma: The Stanford Experience. Biology of Blood and Marrow Transplantation 14:741-747, 2008

13. Kim HJ, Bang SM, Lee J, et al: High-dose chemotherapy with autologous stem cell transplantation in extranodal NK//T-cell lymphoma: a retrospective comparison with non-transplantation cases. Bone Marrow Transplant 37:819-824, 2006

14. Ennishi D, Maeda Y, Fujii N, et al: Allogeneic hematopoietic stem cell transplantation for advanced extranodal natural killer/T-cell lymphoma, nasal type. Leuk Lymphoma 52:1255-61, 2011

15. Tse E, Chan TS, Koh LP, et al: Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: a multicentre analysis from the Asia Lymphoma Study Group. Bone Marrow Transplant 49:902-6, 2014

16. Tse E, Kwong Y-L: How I treat NK/T-cell lymphomas, 2013 17. Kwong YL: Natural killer-cell malignancies: diagnosis and treatment. Leukemia 19:2186-94, 2005 18. A Predictive Model for Aggressive Non-Hodgkin's Lymphoma. New England Journal of Medicine

329:987-994, 1993 19. Lee J, Suh C, Park YH, et al: Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model

from a retrospective multicenter study. J Clin Oncol 24:612-8, 2006

36


Characteristics patients who received a first allogeneic transplant for NK/T-cell lymphoma between 2010 and 2012 registered with the CIBMTR

Characteristic ALLO - Allogeneic AUTO - Autologous

Number of patients 378 484 Research only cases 99 51 Year of transplant, N (%) 2000-2002 47 (12) 112 (23) 2003-2005 40 (11) 89 (18) 2006-2008 84 (22) 87 (18) 2009-2011 150 (40) 153 (32) 2012 57 (15) 43 (9) Age, in years, median (range) 36 (1-75) 47 (2-78) Age,in years, N (%) 0 - 9 24 (6) 6 (1) 10 - 19 61 (16) 13 (3) 20 - 29 59 (16) 63 (13) 30 - 39 78 (21) 81 (17) 40 - 49 66 (17) 103 (21) 50 - 59 52 (14) 116 (24) 60 - 69 33 (9) 87 (18) 70+ 5 (1) 15 (3) Gender, N (%) Male 235 (62) 341 (70) Female 143 (38) 143 (30) Disease, N (%) Extranodal NK/ T-cell lymphoma, nasal type 72 (19) 141 (29) Other T/NK-cell lymphoma 306 (81) 343 (71) Graft Source, N (%) Bone Marrow 77 (20) 8 (2) Peripheral Blood 270 (71) 476 (98) Cord Blood 31 (8) 0 Donor, N (%) HLA-identical sibling 180 (48) -- Other Related donor 34 (9) -- Unrelated donor 164 (43) --

37


Study Proposal 1411-35 Study Title: Allogeneic Hematopoietic Stem Cell Transplantation in HTLV-1 associated Adult T-cell Lymphoma/Leukemia Parastoo Bahrami Dahi, MD, Memorial Sloan Kettering Cancer Center, [email protected] Craig S. Sauter, MD, Memorial Sloan Kettering Cancer Center, [email protected] Miguel-Angel Perales, MD, Memorial Sloan Kettering Cancer Center, [email protected] Hypothesis: Allogeneic transplant can improve survival in patients with HTLV-1 associated lymphoma. Specific Aims: 1. To assess outcomes of allogeneic transplantation after myeloablative or reduced intensity/ non-

myeloablative conditioning in patients with HTLV-1 associated lymphoma: 1.1 Transplant-related mortality; 1.2 Disease relapse or progression; 1.3 Progression-free survival; 1.4 Overall survival; 1.5 Cause of death; 1.6 Acute graft-versus-host disease (GVHD); 1.7 Chronic GVHD.

Scientific Justification: Adult T-cell lymphoma/leukemia (ATLL) is an aggressive T-cell malignancy associated with viral infection of lymphocytes by human T-lymphotropic virus-1 (HTLV-1). ATLL carries a dismal prognosis (1-4). Allogeneic hematopoietic stem cell transplantation (HSCT) has been explored as a promising treatment option for long-term survival in Japanese series (5-7). Data on HSCT in patients of non-Japanese descent is extremely limited (8). The impact of HSCT on survival of non-Japanese patients with HTLV-1 associated ATLL is yet to be elucidated and in the absence of randomized clinical trials, a registry analysis is indicated to further evaluate the benefit of HSCT in these patients. Patient Eligibility Population: This study will include adult patients 18 years or older with HTLV-1 associated ATLL that have received HSCT between 01/2000 and 12/2013 from 7-8/8 HLA-matched related or unrelated donor, or from a 4-6/6 donor-recipient HLA-match cord blood unit (either single-unit or double-unit), after a reduced intensity/ non-myeloablative or myeloablative conditioning reported to the CIBMTR. Recipients of prior allografts will be excluded. Data Requirements: The proposal will utilize data collected by the CIBMTR pre- and post-HSCT, which includes infectious disease markers form #2004, Hodgkin and non-Hodgkin lymphoma pre-transplant data form #2018, Hodgkin and non-Hodgkin lymphoma post-transplant data form #2118, 100 day post-HSCT data form #2100, pre-transplant essential data form #2400, post-transplant essential data form #2450, chimerism studies form #2451, selective post-transplant selective data form #2455, and recipient death data form #2900. The parameters to be assessed are outlined below.

38


Potential predictors will be tested for their association with survival and for an interaction with any significant donor factors Patient characteristics:

Disease and disease stage

Remission status

Patient age at transplant

Patient gender

Patient HTLV-1 serostatus (HTLV-1+ vs. -)

HCT-CI (0 vs. 1-2 vs. 3+)

Patient race/ethnicity (White, African-American, Hispanic, Asian, other)

Time from diagnosis to transplantation

Patient HLA type – HLA-A, B, C, DRB1, DQ

Patient weight

Prior autologous transplant Transplant characteristics:

Myeloablative vs. reduced-intensity/non-myeloablative

TBI or no TBI

GVHD prophylaxis: calcineurin inhibitor based (CSA or Tacrolimus)], no calcineurin inhibitor (sirolimus, corticosteroid, methotrexate, ATG or Campath). (Note: Ex vivo T cell depletion is excluded).

Peripheral blood or bone marrow or cord blood

Year of transplant Donor characteristics:

Donor age (<32, 33-50, > 50)

Donor weight

Donor sex (to calculate M/M, F/M, M/F, F/F)

Donor HTLV-1 status (to calculate D-/R-, D+/R-, D-/R+; D+/R+)

Donor HLA type – HLA-A, B, C, DRB1, DQ (to calculate 8/8 vs. 7/8 vs. 6.8 plus locus of mismatch plus DQ (DQ matched vs. mismatched)

Cord blood HLA match to the recipient (4/6; 5/6; 6/6 HLA-match) Outcome measures:

Engraftment: Time to absolute neutrophil count >500 cells/mm3 for 3 consecutive laboratory readings Time to unsupported platelets >20 x 109 cells/L and >50 x 109 cells/L

GVHD:

Acute GVHD (aGVHD) Incidence of grade II-IV acute GVHD (aGVHD) (subset evaluating grade III-IV aGVHD) Time to aGVHD GVHD after day 100 Incidence of chronic GVHD (cGVHD) Severity of GVHD after day 100

Mortality: Time to mortality Day 100, 6 months and 1 year mortality Treatment related mortality at 6 months and 1 year

39


Cause of mortality

Disease relapse: Incidence of disease relapse or progression Time to disease relapse or progression

Study Design: A retrospective study will be conducted utilizing CIBMTR data. Patients will be eligible for inclusion if they received allogeneic transplant for the treatment of HTLV-1 associated ATLL between the years of 2000 and 2013. Recipients of prior allograft will be excluded. The objectives of this analysis are to determine transplant-related mortality, disease recurrence or progression, PFS, overall survival, and cause of death in the described study population according to donor type, donor HTLV-1 status and conditioning regimen. Incidences of neutrophil and platelet engraftment, donor chimerism, acute and chronic GVHD and relapse will be estimated using the cumulative incidence function. PFS and OS will be estimated using Kaplan-Meier methodology. References:

1. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemialymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol. 1991;79(3):428- 437.

2. Vose J, Armitage J, Weisenburger D, et al. International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124-4130.

3. Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977; 50(3):481-492.

4. Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: A proposal from an international consensus.

5. Utsunomiya A, Miyazaki Y, Takatsuka Y, et al. Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001; 27(1):15-20.

6. Okamura J, Utsunomiya A, Tanosaki R, et al. Allogeneic stem-cell transplantation with reduced conditioning intensity as a novel immunotherapy and antiviral therapy for adult T-cell leukemia/lymphoma. Blood. 2005;105(10):4143-4145.

7. Fukushima T, Miyazaki Y, Honda S, et al. Allogeneic hematopoietic stem cell transplantation provides sustained long-term survival for patients with adult T-cell leukemia/lymphoma. Leukemia. 2005;19(5):829-834.

8. Bazarbachi A, Cwynarski K, Boumendil A, et al. Outcome of patients with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP. Bone Marrow Transplant. 2014; 49, 1266-1268.

40


Characteristics of ≥18 years of age patients with an allogeneic Hematopoietic Stem Cell Transplantation in HTLV-1 associated Adult T-cell Lymphoma/Leukemia from 2000-2013

Variable Registration only Research



Median 48 (19-73) 53 (19-70)

10-19 1 ( 1) 1 ( 1)

20-29 15 (15) 5 ( 7)

30-39 14 (14) 6 ( 9)

40-49 26 (26) 14 (20)

50-59 30 (30) 32 (46)

≥60 15 (15) 12 (17)

Sex

Male 52 (51) 36 (51)

Female 49 (49) 34 (49)

Karnofsky score

<90% 37 (37) 41 (59)

90-100% 51 (50) 14 (20)

Missing 13 (13) 15 (21)

Donor type

HLA-identical siblings 50 (50) 27 (39)

Other relative 13 (13) 6 ( 9)

Unrelated 38 (38) 37 (53)

Graft type

Bone marrow 19 (19) 20 (29)

Peripheral blood 77 (76) 42 (60)

Cord blood 5 ( 5) 8 (11)

Year of transplant

2001 8 ( 8) 4 ( 6)

2002 3 ( 3) 4 ( 6)

2003 5 ( 5) 6 ( 9)

2004 3 ( 3) 10 (14)

2005 6 ( 6) 8 (11)

2006 4 ( 4) 12 (17)

41



Year of transplant (continued)

2007 9 ( 9) 6 ( 9)

2008 4 ( 4) 5 ( 7)

2009 14 (14) 4 ( 6)

2010 7 ( 7) 1 ( 1)

2011 17 (17) 2 ( 3)

2012 14 (14) 2 ( 3)

2013 7 ( 7) 6 ( 9)

GVHD prophylaxis

T-cell depletion ± other 0 2 ( 3)

CD34 select ± other 3 ( 3) 1 ( 1)

Cyclophosphamide ± others 4 ( 4) 1 ( 1)

Tacrolimus + MMF 5 ( 5) 4 ( 6)

Tacrolimus + MTX 25 (25) 16 (23)

Tacrolimus alone 8 ( 8) 8 (11)

CSA + MMF 12 (12) 3 ( 4)

CSA + MTX 21 (21) 17 (24)

CSA alone 16 (16) 18 (26)

Other GVHD Prophylaxis 7 ( 7) 0

Median follow-up of survivors, months 25 (3-140) 25 (3-136)

42


Study Proposal 1411-15 Study Title: Hematopoietic cell transplantation (HCT) outcomes for relapsed or refractory marginal zone lymphomas Basem M. William, MD, Case Western Reserve University, [email protected] Brian T. Hill, MD, PhD, Cleveland Clinic Foundation, [email protected] Hillard M. Lazarus, MD, Case Western Reserve University, [email protected] Specific Aims: We propose a descriptive study to analyze trends in utilization and outcomes of autologous and/or allogeneic HCT in relapsed or refractory marginal zone lymphomas (MZL). Primary outcomes measures include:

- Time to relapse, progression free, event free and overall survivals - Transplant related mortality at 100 days and 1, 3, and 5 years

Secondary outcomes will include: - Time to neutrophil or platelet engraftment - Incidence of organ toxicity (pneumonitis/VOD) - Incidence and severity of graft versus host disease (GVHD) - Incidence of secondary malignancies - Cause of death

Scientific Justification: Marginal zone lymphomas (MZL) are a group of mature B-cell neoplasms including splenic B-cell marginal zone lymphoma (SMZL), nodal marginal zone lymphoma (NMZL), and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (1). Marginal zone lymphomas are so named because the tumor cells share a characteristic immunotype with B-lymphocytes occupying the marginal zone of normal lymph node follicles. The first entity recognized in this group was MALT lymphoma (2) which comprises approximately 9% of all B-cell lymphoma in adults (3) and up to 50% of primary gastric lymphomas (4). MALT lymphomas represent small B-cell lymphomas that can originate at any epithelial site but are most frequent in the stomach where they are frequently associated with infection by Helicobacter pylori. MALT lymphomas are usually, but not always, localized, and durable remissions in stage I MALT lymphomas can be achieved with surgery, radiotherapy or Helicobacter pylori irradication in some gastric MALT lymphomas (5). NMZL, formerly known as monocytoid B-cell lymphoma, usually presents with widespread lymphadenopathy (6). SMZL is a rare subtype that typically presents with splenomegaly, bone marrow involvement, and circulating tumor cells, but no lymphadenopathy (7). All subtypes are highly responsive to rituximab (8-12) but cure of patients with widespread disease is uncertain (13). A recent subgroup analysis of Eastern Cooperative Oncology Group protocol E4402 (RESORT) showed that maintenance rituximab improves time to treatment failure and time to first cytotoxic therapy but it is likely that more time is needed to demonstrate survival benefit (14). Prognosis and prognostic factors remain poorly defined and most data is from small institutional retrospective series and from extrapolation from large NHL trial where a minority of patients with MZL were enrolled. For NMZL, five-year overall survival in various series has ranged from 55 to 79%(15-19). Prognostic factors are not well defined either. In one study, a higher FLIPI (Follicular lymphoma international prognostic index) score predicted a worse overall survival (15, 20). The optimal therapy for patients who have relapsed/refractory marginal zone lymphoma has not been defined. Like follicular lymphomas, patients who progressed after induction therapy and have aggressive

43


behaving disease are considered for HCT (21). The benefit of high-dose therapy followed autologous stem cell transplant (autoSCT) for patients who have relapsed/refractory follicular lymphoma has been shown in the randomized CUP trial (22). The results of studies such as this are often extrapolated to other types of indolent lymphomas without clear data from specific disease entities. The role of autoSCT for patients who have marginal zone lymphoma is unclear based primarily on paucity of data. Only 2 small single-institution case series reports were published: Brown and colleagues at Dana Farber Cancer Institute (23) retrospectively analyzed the outcomes of 11 patients with chemosensitive but disseminated marginal zone lymphomas who underwent uniform conditioning with cyclophosphamide and total body irradiation followed by transplantation with anti-B cell monoclonal antibody-purged autologous bone marrow (auto BMT) from 1994-1999. All patients had stage IV disease and received multiple chemotherapy regimens prior to autologous BMT. Only 36% were in complete remission at the time of bone marrow harvest, and 36% had overt bone marrow infiltration at that time. Two treatment-related deaths occurred between 100 days and 6 months. Three patients relapsed and died of disease. One patient developed and died of myelodysplasia. Five patients remain in continuous complete remission at a median follow-up of 52 months (45%). The median PFS for these patients was 56 months, with median OS of 58 months. The only significant predictor of disease-free and OS was age at the time of transplant (23). Subsequently, Li and colleagues at the University of Nebraska Medical Center analyzed the clinical outcomes of 14 patients who had relapsed or refractory MZL and underwent autoSCT from 1992-2008 (24). The median age was 48 years (29-62 years). Five patients had NMZL, two had SMZL, and seven had MALT lymphoma. Four patients had early-stage disease at diagnosis and the remainder had advanced-stage disease. All had relapsed or progressed before beginning the transplantation process. The median number of previous chemotherapy regimens was 2 (1-4). Thirteen patients received mobilized peripheral blood as their source of hematopoietic cells and one patient received marrow. Seven patients were sensitive to initial standard chemotherapy but subsequently relapsed, whereas the other seven patients did not achieve a complete response to initial therapy. However, all patients were sensitive to salvage chemotherapy immediately before transplantation. The preparative regimens included CY/TBI (n = 4), BEAC (n = 6), or BEAM (n = 4). With a median duration of follow-up for surviving patients of 138 months, median PFS and OS were 108 and 120 months respectively. Three treatment-related deaths were seen in the first 100 days posttransplantation. Only two patients have relapsed. Secondary malignancies were seen in three patients (myelodysplastic syndrome, n = 2; gastric carcinoma. n = 1). Beyond few case reports, there is virtually no data on outcomes of alloSCT for MZL (25-27). This study will investigate the outcomes of patients who received autologous and/or allogeneic HCT for relapsed or refractory marginal zone lymphomas. We attempt to define disease, treatment, and transplant-related factors that result in poor outcomes. Patient Eligibility: The study will include patients with the following:

Diagnosis of marginal zone lymphoma (MALT, NMZL, or SMZL)

Age of 18 years or older

Autologous or allogeneic HCT for MZL

Patients who have had CNS lymphomatous involvement are eligible

Excluded are:

Patients with the diagnosis of other B-cell or T-cell lymphomas, or more than 1 lymphoma diagnosis

44


Patients who transformed to diffuse large B-cell or other aggressive lymphomas Outcome definitions:

Time to engraftment: Defined as time between day of transplantation and recovery of neutrophils and/or platelets.

Time to progression: Defined as time between day of transplantation and documentation of disease recurrence/progression. Patients alive and disease free will be censored at last follow up.

Event free survival: an event is defined as progression/recurrence or death.

Transplant Related Mortality: Defined as death within 28 days of transplantation or time to death without recurrence of disease.

Overall survival: time to death. Patients are censored at last follow-up.

Causes of death: as defined by Copeland et al (32) Variables to be analyzed : Patient Related:

- Age at transplantation (≤60 vs. >60) - Karnofsky performance status (<70 vs. ≥70) - Gender (male vs. female) - CMV status in donor and recipient - Hepatitis C virus seropositivity

Disease related at diagnosis: - Histology (MALT, NMZL, SMZL) - Stage at diagnosis (I/II vs. III/IV) - Age adjusted IPI - B-symptoms (yes/no) - Bone marrow involvement (yes/no) - Extranodal/splenic involvement (yes/no)

Disease related at transplant: - Type of lymphoma (relapsed or refractory) - B-symptoms (yes/no) - Extranodal/splenic involvement (yes/no) - Bone marrow involvement (yes/no) - Time from diagnosis to transplant - Number of lines of therapy - Prior autologous transplant (yes/no) - Disease status

o 2nd vs. 3rd or greater CR/PR o Duration of 1st CR

- Disease sensitivity (sensitive vs. resistant vs. untreated) Peri-transplant therapy:

- Pre-transplant o Rituximab exposure (yes/no) o Prior involved field radiotherapy (yes/no)

Lung shielding (yes/no) o Other prior radiotherapy

- Post- transplant o Involved field radiotherapy (yes/no)

45


o Rituximab (yes/no) o Chemotherapy (yes/no) o Other

Post-transplant outcomes: - Peri-transplant performance status

o Pre-transplant organ dysfunction o Post-transplant organ dysfunction (pneumonitis, VOD)

- Post-transplant outcomes o PFS o OS o Cumulative incidence of relapse o Sites of relapse

- Graft versus host disease (GVHD) o Acute (site, grade) o Chronic (site, grade)

- CMV reactivation o CMV viremia o Invasive CMV disease

- Long term outcomes o Secondary malignancies o Organ dysfunction

Transplant related: - Conditioning regimen

o AutoSCT conditioning regimen o Myeloablative vs reduced-intensity conditioning o Type of conditioning regimen o Dose of TBI (<4 Gy, 4-13 Gy, ≥13Gy) and number of fractions o T-cell depletion (antithymocyte globulin or alemtuzumab) o Graft source (MRD, MUD, umbilical cord blood) o Number of HLA mismtaches

- Year of transplant - Stem cell source (bone marrow vs peripheral blood stem cells) - Time to neutrophil/platelet engraftment

Data Requirements: Patients, disease and transplant related characteristics will be obtained from the CIBMTR database. No additional supplemental data collection is anticipated. Study Design (Scientific Plan): This study will determine trends in utilization and outcomes of autoSCT and/on alloSCT for MZL including PFS, OS, relapse, and long term complications after transplant. All patients with the diagnosis of MZL who underwent autoSCT and/or alloSCT who meet the eligibility criteria will be enrolled. We also aim to define disease, treatment, and transplant related characteristics that result in poor outcomes. As most of these patients had an alloSCT after failure of autoSCT; will analyze those groups separately and correct for the confounding effect of disease-related characteristics for the difference in outcomes between both groups.

46


Patient-, disease-, and transplantation-related variables and outcomes will be described in three cohorts: recipients of (1) autoSCT or (2) alloSCT from MRD (3) MUD/mismatched related donors. Univariate probabilities of developing acute or chronic GVHD, TRM, and lymphoma progression will calculated using cumulative incidence curves to accommodate competing risks. Probabilities of OS and PFS will be calculated using Kaplan-Meier estimator. Confidence intervals (CIs) will calculated with a log transformation. Multivariate analyses were not performed because of the imbalance in baseline characteristics of the cohorts and the changes in MZL management over the period studied. The propensity score will be calculated using a logistic-regression model using the following factors: age, gender, Karnofsky performance status pre-transplant, disease stage, B-symptoms, extranodal involvement, bone marrow involvement at diagnosis, number of regimens prior to transplant, disease sensitivity prior to transplant, time from diagnosis to transplant, graft source, year of transplant, and transplant center. The Center of International Bone Marrow Transplant Research (CIBMTR) has registered 451 transplants for patients with MZL (please see table below for details).

AutoSCT AlloSCT Total

Extranodal marginal zone B-cell 144 40 184 Nodal marginal zone B-cell 106 84 190 Splenic marginal zone B-cell 43 34 77

Total 293 158 451

We are also planning to compare outcomes of MZL who were transplanted to a comparator cohort of MZL who had not been transplanted from University Hospitals Case Medical Center (UHCMC), Cleveland Clinic Foundation, and University of Nebraska Medical Center (please see table below for details). We have currently reviewed 141 cases with histologically confirmed diagnosis of MZL at UHCMC and are currently reviewing 218 cases of MZL at CCF.

University

Hospitals Case

Medical Ctr

Cleveland

Clinic

Foundation

University of

Nebraska

Medical Ctr

Total

Extranodal marginal zone B-

cell

54 160 66 280

Nodal marginal zone B-cell 28 33 23 84

Splenic marginal zone B-cell 17 25 7 49

Total 99 218 96 413

References: 1. Swerdlow S. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon,

France: International Agency for Research on Cancer; 2008. 2. Isaacson PG. Mucosa-associated lymphoid tissue lymphoma. Seminars in hematology. 1999

Apr;36(2):139-47. PubMed PMID: 10319382. 3. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's

lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 1997 Jun 1;89(11):3909-18. PubMed PMID: 9166827. Epub 1997/06/01. eng.

47


4. Doglioni C, Wotherspoon AC, Moschini A, de Boni M, Isaacson PG. High incidence of primary gastric lymphoma in northeastern Italy. Lancet. 1992 Apr 4;339(8797):834-5. PubMed PMID: 1347858.

5. Tsang RW, Gospodarowicz MK, Pintilie M, Wells W, Hodgson DC, Sun A, et al. Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003 Nov 15;21(22):4157-64. PubMed PMID: 14615444.

6. Berger F, Felman P, Thieblemont C, Pradier T, Baseggio L, Bryon PA, et al. Non-MALT marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients. Blood. 2000 Mar 15;95(6):1950-6. PubMed PMID: 10706860.

7. Catovsky D, Matutes E. Splenic lymphoma with circulating villous lymphocytes/splenic marginal-zone lymphoma. Seminars in hematology. 1999 Apr;36(2):148-54. PubMed PMID: 10319383.

8. Conconi A, Martinelli G, Thieblemont C, Ferreri AJ, Devizzi L, Peccatori F, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003 Oct 15;102(8):2741-5. PubMed PMID: 12842999.

9. Jager G, Neumeister P, Brezinschek R, Hinterleitner T, Fiebiger W, Penz M, et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with cladribine: a phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002 Sep 15;20(18):3872-7. PubMed PMID: 12228207.

10. Kalpadakis C, Pangalis GA, Dimopoulou MN, Vassilakopoulos TP, Kyrtsonis MC, Korkolopoulou P, et al. Rituximab monotherapy is highly effective in splenic marginal zone lymphoma. Hematological oncology. 2007 Sep;25(3):127-31. PubMed PMID: 17514771.

11. Leahy MF, Seymour JF, Hicks RJ, Turner JH. Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006 Sep 20;24(27):4418-25. PubMed PMID: 16940276.

12. Witzig TE, Geyer SM, Kurtin PJ, Colgan JP, Inwards DJ, Micallef IN, et al. Salvage chemotherapy with rituximab DHAP for relapsed non-Hodgkin lymphoma: a phase II trial in the North Central Cancer Treatment Group. Leukemia & lymphoma. 2008 Jun;49(6):1074-80. PubMed PMID: 18569634.

13. Raderer M, Streubel B, Woehrer S, Puespoek A, Jaeger U, Formanek M, et al. High relapse rate in patients with MALT lymphoma warrants lifelong follow-up. Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 May 1;11(9):3349-52. PubMed PMID: 15867234.

14. Williams ME, Hong F, Kahl BS, Gascoyne RD, Wagner LI, Krauss JC, et al. A subgroup analysis of small lymphocytic and marginal zone lymphomas in the Eastern Cooperative Oncology Group protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden indolent non-Hodgkin lymphoma. ASCO Meeting Abstracts. 2012 May 30, 2012;30(15_suppl):8007.

15. Arcaini L, Paulli M, Burcheri S, Rossi A, Spina M, Passamonti F, et al. Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease. British journal of haematology. 2007 Jan;136(2):301-4. PubMed PMID: 17233821.

16. Camacho FI, Algara P, Mollejo M, Garcia JF, Montalban C, Martinez N, et al. Nodal marginal zone lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases. The American journal of surgical pathology. 2003 Jun;27(6):762-71. PubMed PMID: 12766579. Epub 2003/05/27. eng.

17. Nathwani BN, Anderson JR, Armitage JO, Cavalli F, Diebold J, Drachenberg MR, et al. Marginal zone B-cell lymphoma: A clinical comparison of nodal and mucosa-associated lymphoid tissue

48


types. Non-Hodgkin's Lymphoma Classification Project. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999 Aug;17(8):2486-92. PubMed PMID: 10561313.

18. Nathwani BN, Drachenberg MR, Hernandez AM, Levine AM, Sheibani K. Nodal monocytoid B-cell lymphoma (nodal marginal-zone B-cell lymphoma). Seminars in hematology. 1999 Apr;36(2):128-38. PubMed PMID: 10319381. Epub 1999/05/13. eng.

19. Traverse-Glehen A, Felman P, Callet-Bauchu E, Gazzo S, Baseggio L, Bryon PA, et al. A clinicopathological study of nodal marginal zone B-cell lymphoma. A report on 21 cases. Histopathology. 2006 Jan;48(2):162-73. PubMed PMID: 16405665. Epub 2006/01/13. eng.

20. Heilgeist A, McClanahan F, Ho AD, Witzens-Harig M. Prognostic value of the Follicular Lymphoma International Prognostic Index score in marginal zone lymphoma: an analysis of clinical presentation and outcome in 144 patients. Cancer. 2013 Jan 1;119(1):99-106. PubMed PMID: 22736411. Epub 2012/06/28. eng.

21. Zinzani PL. The many faces of marginal zone lymphoma. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program. 2012;2012:426-32. PubMed PMID: 23233614.

22. 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003 Nov 1;21(21):3918-27. PubMed PMID: 14517188.

23. Brown JR, Gaudet G, Friedberg JW, Neuberg D, Mauch P, Kutok JL, et al. Autologous bone marrow transplantation for marginal zone non-Hodgkin's lymphoma. Leukemia & lymphoma. 2004 Feb;45(2):315-20. PubMed PMID: 15101717. Epub 2004/04/23. eng.

24. Li L, Bierman P, Vose J, Loberiza F, Armitage JO, Bociek RG. High-dose therapy/autologous hematopoietic stem cell transplantation in relapsed or refractory marginal zone non-Hodgkin lymphoma. Clinical lymphoma, myeloma & leukemia. 2011 Jun;11(3):253-6. PubMed PMID: 21658651. Epub 2011/06/11. eng.

25. Busemann C, Gudzuhn A, Hirt C, Kirsch M, Vogelgesang S, Schmidt CA, et al. Treatment of splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell transplantation. Experimental hematology & oncology. 2012;1(1):32. PubMed PMID: 23210733. Pubmed Central PMCID: PMC3515347. Epub 2012/12/06. eng.

26. Lee L, Lipton JH, Bailey D, Kukreti V. Tale of two lymphomas: peripheral T-cell lymphoma after allogeneic stem-cell transplantation for marginal zone lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 Nov 1;30(31):e309-11. PubMed PMID: 22965958. Epub 2012/09/12. eng.

27. Ferraccioli G, Damato R, De Vita S, Fanin R, Damiani D, Baccarani M. Haematopoietic stem cell transplantation (HSCT) in a patient with Sjogren's syndrome and lung malt lymphoma cured lymphoma not the autoimmune disease. Annals of the rheumatic diseases. 2001 Feb;60(2):174-6. PubMed PMID: 11203719. Pubmed Central PMCID: PMC1753470. Epub 2001/02/24. eng.

28. Gutierrez-Delgado F, Holmberg L, Hooper H, Petersdorf S, Press O, Maziarz R, et al. Autologous stem cell transplantation for Hodgkin's disease: busulfan, melphalan and thiotepa compared to a radiation-based regimen. Bone Marrow Transplant. 2003 08//;32(3):279-85.

29. Salar A, Sierra J, Gandarillas M, Caballero MD, Marín J, Lahuerta JJ, et al. Autologous stem cell transplantation for clinically aggressive non-Hodgkin's lymphoma: the role of preparative regimens. Bone Marrow Transplant. 2001 02//;27(4):405-12.

30. Liu HW, Seftel MD, Rubinger M, Szwajcer D, Demers A, Nugent Z, et al. Total body irradiation compared with BEAM: Long-term outcomes of peripheral blood autologous stem cell

49


transplantation for non-Hodgkin's lymphoma. International journal of radiation oncology, biology, physics. 2010 Oct 1;78(2):513-20. PubMed PMID: 20137862. Epub 2010/02/09. eng.

31. 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(5):294-301.

32. Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM, et al. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007 Dec;13(12):1469-76. PubMed PMID: 18022577. Epub 2007/11/21. eng.

50


Characteristics of ≥18 year old patients who underwent HCT for marginal zone lymphoma registered to the CIBMTR from 2000-2013

Variable

AlloHCT

Registration

only

AutoHCT

Registration

only

AlloHCT

Research

AutoHCT

Research

Number of patients 109 259 50 29

Number of centers 71 128 39 23


Median 56 (23-68) 57 (23-75) 53 (31-67) 57 (23-72)

20-29 3 ( 3) 2 ( 1) 0 1 ( 3)

30-39 7 ( 6) 25 (10) 3 ( 6) 1 ( 3)

40-49 22 (20) 44 (17) 15 (30) 7 (24)

50-59 49 (45) 92 (36) 23 (46) 6 (21)

≥60 28 (26) 96 (37) 9 (18) 14 (48)

Subdisease

Extranodal marginal zone B-cell of MALT 30 (28) 124 (48) 11 (22) 10 (34)

Nodal marginal zone B-cell 56 (51) 94 (36) 28 (56) 12 (41)

Splenic marginal zone B-cell 23 (21) 41 (16) 11 (22) 7 (24)

Sex

Male 65 (60) 154 (59) 28 (56) 14 (48)

Female 44 (40) 105 (41) 22 (44) 15 (52)

Karnofsky score

<90% 48 (44) 125 (48) 19 (38) 15 (52)

90-100% 42 (39) 88 (34) 19 (38) 7 (24)

Missing 19 (17) 46 (18) 12 (24) 7 (24)

Conditioning regimen N/A N/A

RIC/NST 71 (65) 28 (56)

Myeloablative 36 (33) 18 (36)

Missing 2 ( 2) 4 ( 8)

Donor type

HLA-identical siblings 64 (59) 0 24 (48) 0

Other relative 8 ( 7) 0 2 ( 4) 0

Unrelated donor 37 (34) 0 24 (48) 0

Autologous 0 259 0 29

51


Variable

AlloHCT

Registration

only

AutoHCT

Registration

only

AlloHCT

Research

AutoHCT

Research

Number of patients 109 259 50 29

Graft type

Bone marrow 12 (11) 0 6 (12) 1 ( 3)

Peripheral blood 95 (87) 259 41 (82) 28 (97)

Cord blood 2 ( 2) 0 3 ( 6) 0

Year of HCT

2000-2005 32 (30) 106 (41) 27 (54) 15 (52)

2006-2013 77 (70) 153 (59) 23 (46) 14 (48)

Follow up of survivors, median (range) 26 (4-144) 30 (2-148) 64 (3-144) 84 (3-139)

52


Study Proposal 1411-83 Study Title: A retrospective review of outcomes with allogeneic transplant for gamma-delta T cell lymphoma James Leonard Gajewski, MD, Oregon Health Science University, [email protected] Richard Thomas Maziarz, MD, Oregon Health Science University, [email protected] Hypothesis: Allogeneic transplantation can provide durable disease control in gamma-delta T-cell lymphomas. Specific Aims: Descriptive review of transplant outcomes with 3 year post transplant overall survival, progression free survival, treatment related mortality and relapse rate. Scientific Justification: Non-transplant therapies published have had very short followup only 3-6 months. These diseases have much longer survival. Non transplant therapies at some point fail. There has been no published study on transplant outcomes. A preliminary review of CIBMTR data base for these diseases show: 3 year Kaplan Meier overall survival of:

Allogeneic HCT for gamma delta t-cell lymphoma-40% Patient Eligibility Population: Patients reported to CIBMTR between 1999 and 2013 with gamma-delta t cell lymphoma undergoing

first allogeneic transplantation. All graft and donor sources are eligible. Data Requirements: None Sample Requirements: None Study Design: Retrospective review of patients treated with autologous transplants for gamma-delta t cell lymphoma

Descriptive analysis of date of transplant, age at transplant, gender, graft source, donor and Kaplan Meier survival, progression free survival, treatment related mortality and relapse

References: 1. Hosing C, Champlin RE Stem Cell Transplantation in T cell Non Hodgkin’s Lymphoma Ann Oncol

2011:22, 1471 2. Lamy T, Loughran TP, Jr. clinical features of large granular lymphocytic lymphoma. Semin

Hematology 2003:40, 185

53


Characteristics of patients who received an allogeneic transplantation for Hepatosplenic gamma-delta

T-cell registered to the CIBMTR from 1999-2013*




Median 29 (9-64) 33 (3-70)

<10 1 ( 2) 1 ( 4)

10-19 14 (22) 3 (12)

20-29 20 (31) 6 (23)

30-39 12 (18) 6 (23)

40-49 11 (17) 6 (23)

50-59 6 ( 9) 2 ( 8)

≥60 1 ( 2) 2 ( 8)

Sex

Male 42 (65) 24 (92)

Female 23 (35) 2 ( 8)

Karnofsky score

<90% 27 (42) 11 (42)

90-100% 26 (40) 13 (50)

Missing 12 (18) 2 ( 8)

Donor type

HLA-identical siblings 38 (59) 12 (44)

Other relative 8 (12) 4 (15)

Unrelated donor 19 (29) 10 (38)

Conditioning regimen

RIC/NST 13 (20) 7 (27)

Myeloablative 50 (77) 16 (62)

Missing 2 ( 3) 3 (12)

Graft type

Bone marrow 16 (25) 3 (12)

Peripheral blood 42 (65) 19 (73)

Cord blood 7 (11) 4 (15)

54




Year of transplant

1999 1 ( 2)

2000 1 ( 2) 0

2001 3 ( 5) 0

2002 2 ( 3) 0

2003 1 ( 2) 1 ( 4)

2004 3 ( 5) 1 ( 4)

2005 5 ( 8) 3 (12)

2006 7 (11) 0

2007 5 ( 8) 1 ( 4)

2008 6 ( 9) 4 (15)

2009 4 ( 6) 2 ( 8)

2010 7 (11) 0

2011 5 ( 8) 4 (15)

2012 8 (12) 3 (12)

2013 7 (11) 7 (27)

Median follow up of survivors (range) 26 (3-166) 23 (3-100)

*No cases registered prior 1999.

55


Study Proposal 1408-02/1411-27 Study Title: Alternative Donor Allogeneic Hematopoietic Transplantation Strategies for Lymphoid Malignancies in Adult Patients: Comparing Matched Unrelated versus Haploidentical Related Donor Transplantation Abraham S. Kanate, MD, Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia

University, [email protected] Alberto Mussetti, MD, Department of Hematology and Bone Marrrow Transplantation, Istituto

Nazionale dei Tumori di Milano, Università degli Studi di Milano, [email protected]

Mohamed A. Kharfan-Dabaja, MD, Department of Blood and Marrow Transplantation, Department of Oncologic Sciences, H. Lee Moffitt Cancer Center/University of South Florida College of Medicine, Tampa, FL, USA, [email protected]

Objectives: The primary objective is to compare the one-year overall survival (OS) for 8/8 HLA-matched unrelated donor (URD) hematopoietic cell transplantation (HCT) versus T-cell replete haploidentical related donor HCT using post-transplant cyclophosphamide (PT-Cy) in patients with lymphomas (Hodgkin and non-Hodgkin lymphoma).

The secondary objective is to compare graft failure, incidence of acute and chronic graft-versus-host disease (GVHD) relapse rate, progression-free survival (PFS) and non-relapse mortality (NRM) for 8/8 HLA matched URD transplantation versus T-cell replete haploidentical related donor HCT using PT-Cy in patients with various subtypes of lymphomas. Diseases will be stratified by disease type – Hodgkin Lymphoma (HL) vs. non-Hodgkin Lymphoma (NHL). Scientific Justification: Allogeneic HCT (allo-HCT) remains a potentially curative strategy in patients with various subtypes of lymphomas. Myeloablative conditioning (MAC) while considered in selected patients is often contraindicated due to advanced age, existing co-morbidities, or in some cases prior high-dose therapy and autologous HCT leading to high NRM (1-5). With the increasing utilization of reduced intensity/non-myeloablative conditioning (RIC/NMA) allo-HCT regimens more patients are now eligible for allo-HCT (6-9); however, lowering the intensity of the preparative regimen might be associated with increased risk of disease relapse (2, 3, 10).

Advances in HLA-typing coupled with better supportive care have improved procedure related complications after URD allo-HCT. Unrelated donor searches can be time consuming and often fail to identify a suitable HLA-matched donor especially for minority populations. Haploidentical related donors are a more readily available donor source for most patients and are currently being utilized when suitable HLA-matched sibling or unrelated donors are unavailable (11, 12). Initial studies evaluating haploidentical allo-HCT were associated with prohibitive GVHD and NRM. To circumvent this, T-cell depleted grafts were utilized (with high CD34+ cell doses in some studies) but this approach was associated with graft failure, delayed immune reconstitution and infectious complications. Recently T-cell replete haploidentical allo-HCT followed by post transplant cyclophosphamide (PT-Cy) to mitigate donor T-cells alloreactivity has yielded promising results in several studies (13-15). Retrospective studies have reported comparable survival rates to URD allo-HCT and low chronic GVHD, ranging between 5 -15% at 2 years post-HCT (17-18).

56


We hypothesize that haploidentical allo-HCT with PT-Cy would decrease relapse risk due to a higher degree of HLA disparity between donor and recipient and graft-versus-lymphoma effect without significantly increasing GVHD compared to URD allo-HCT, thereby ultimately improving survival.

A large majority of the lymphoma patients being considered for an allo-HCT are likely to have received salvage therapy for relapsed/progressive disease and durability of achieved responses is always a concern. Accordingly, timely intervention is of paramount importance. Prospective studies comparing post-transplant outcomes with URD or haploidentical related donor (with PT-Cy) allo-HCT in lymphoma patients are lacking. Considering the low likelihood of a prospective randomized controlled study, performing a non-randomized comparison using registry data from the Center for International Bone Marrow Transplantation Research (CIBMTR) would be the most desirable approach to answer such question at present. Duly noting the limitations of a retrospective (registry) analysis, this study may support the use of haploidentical related donor allo-HCT as an alternative to URD allografts. This in turn can potentially justify the use of readily available donor. Since NHL and HL have differing disease presentations and clinical courses and taking into account recent reports suggesting improved outcomes with haploidentical donor allo-HCT in HL (16), evaluating outcomes stratified by disease status is necessary. If the sample size is adequate, a multivariate analysis, stratifying NHL subtypes (indolent vs. aggressive) and conditioning regimens (MAC vs. RIC/NMA) will be considered. Study Population: Patients aged ≥18 years who received their first allo-HCT an 8/8 HLA matched URD or haploidentical related donor (defined as > 2 antigen level mismatches) for a diagnosis of lymphoma (HL or NHL) from 2007 to 2013. The URD group must be 8/8 HLA matched at HLA -A, -B, -C and -DRB1 using bone marrow or peripheral blood grafts. The haploidentical related donor group is to be limited to only those receiving post-transplantation cyclophosphamide using bone marrow or peripheral blood grafts. Outcomes:

Hematopoietic recovery: time to neutrophil (ANC) recovery >0.5×109/L; time to platelet recovery ≥20×109/L.

Acute graft-versus-host disease: maximum overall grade of grade II-IV and grade III-IV acute GVHD, we do not collect date of onset of acute GVHD.

Chronic graft-versus-host disease: maximum extent of chronic GVHD, and time to chronic GVHD.

Relapse/progression: Time of relapse or progression of the original malignancy post-HCT.

Non-relapse mortality: time to death without disease relapse.

Disease-free survival: survival without relapse. Patients are censored at time of last contact.

Overall survival: Events are death from any cause. Surviving patients are censored at time of last contact.

Primary cause of death: according to the Copelan algorithm, descriptive only. Variables to be analyzed: Patient-related:

Age: continuous to find the appropriate cut point for the survival model

Gender: male vs. female

Karnofsky performance score: <90% vs. ≥90%

Co-morbidity index: 0 vs. 1-2 vs. 3

CMV status: recipient positive vs. recipient negative vs. unknown

57


Disease-related:

Disease subtype: NHL vs. HL

NHL subtype: indolent vs. aggressive

Disease status at time of transplant: sensitive vs. resistant

Disease stage at diagnosis: I/II vs. III/IV Transplant-related:

Prior autologous HCT: Yes vs. No

Prior radiation therapy: Yes vs. No

Interval from diagnosis to transplant: <12m vs. ≥ 12m

Main effect: Haploidentical HCT vs. HLA 8/8 URD

Conditioning: MAC vs. RIC/NMA

ATG use: Yes vs. No Study Design: A retrospective multicenter study will be conducted utilizing CIBMTR data. Patients will be eligible if they satisfied the criteria detailed in the “Patient eligibility population” section. Patients will then be stratified according to URD or haploidentical PT-Cy. The objective of this analysis is to compare these two approaches and their effects on allo-HCT outcomes.

Chi-square or the Wilcoxon statistic will be used to compare patient, disease and transplantation characteristics between the 2 groups for categorical or continuous variables respectively. The probabilities of neutrophils and platelets recovery, acute GVHD, chronic GVHD, NRM, relapse rate will be calculated using the cumulative incidence estimator. PFS and OS will be calculated using the Kaplan-Meier estimator. For neutrophil and platelet recovery, acute GVHD and chronic GVHD, death without the event will be the competing event. For NRM, relapse/progression will be the competing event. For relapse rate, NRM will be the competing event. Data on patients without an event will be censored at last follow up. For univariate analysis, Gray test and log-rank test will be used to identify factors influencing cumulative incidence and survival respectively. The association between treatment groups and outcomes will be studied with multivariate Cox regression models. P values are 2 sided and values < 0.05 will be considered significant. The treatment group will be included in all steps of model building regardless of level of significance. The other variables tested will be retained in the final multivariate model if the variable will attain the level of significance set for these analyses. Results will be expressed as hazard ratio (HR) with 95% confidence intervals (CI). Possible interactions within the treatment groups and other variables will be tested. All models will be tested regarding proportional hazard of assumptions (PHA). If the assumption will be violated, time dependent covariates will be constructed.

Potential Pitfalls:

Even with the increasing utilization of haploidentical allo-HCT with PT-Cy, the sample size may be small to perform meaningful statistical analysis. If so additional data could be requested from European Bone Marrow transplantation (EBMT) registry or from the Gruppo Italinao Midollo Osseo (GITMO) registry.

58


References: 1. 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. Biology of Blood and Marrow Transplantation. 2010;16(1):35–45.

2. Bacher U, Klyuchnikov E, Le-Rademacher J, et al. Conditioning regimens for allotransplants for diffuse large B-cell lymphoma: myeloablative or reduced intensity? Blood. 2012.

3. van Kampen RJW, Canals C, Schouten HC, et al. Allogeneic Stem-Cell Transplantation As Salvage Therapy for Patients With Diffuse Large B-Cell Non-Hodgkin’s Lymphoma Relapsing After an Autologous Stem-Cell Transplantation: An Analysis of the European Group for Blood and Marrow Transplantation Registry. Journal of Clinical Oncology. 2011;29(10):1342–1348.

4. van Besien K, Loberiza FR, Bajorunaite R, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood. 2003;102(10):3521 –3529.

5. Gajewski JL, Phillips GL, Sobocinski KA, et al. Bone marrow transplants from HLA-identical siblings in advanced Hodgkin’s disease. Journal of Clinical Oncology. 1996;14(2):572–578.

6. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97(11):3390 –3400.

7. Morris E, Thomson K, Craddock C, et al. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood. 2004;104(13):3865–3871.

8. Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood. 2001;98(13):3595 –3599.

9. Sorror ML, Storer BE, Maloney DG, et al. Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood. 2008;111(1):446–452

10. Rodriguez R, Nademanee A, Ruel N, et al. Comparison of Reduced-Intensity and Conventional Myeloablative Regimens for Allogeneic Transplantation in Non-Hodgkin’s Lymphoma. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2006;12(12):1326–1334.

11. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23(15): 3447-54.

12. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295(5562): 2097-100.

13. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14(6): 641-50.

14. Tuve S, Gayoso J, Scheid C, Radke J, Kiani A, Serrano D et al. Haploidentical bone marrow transplantation with post-grafting cyclophosphamide: multicenter experience with an alternative salvage strategy. Leukemia 2011; 25(5): 880-3.

15. Bacigalupo A, Dominietto A, Di Grazia C, Tamparelli T, Gualandi F, Ibatici A et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts: a single center experience in 488 patients (abstract). Bone Marrow Transplant 2013; 48(suppl 2): S63.

16. Raiola A, Dominietto A, Varaldo R, et al. Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin's lymphoma.

59


17. Bone Marrow Transplant. 2014 Feb;49(2):190-4. 18. Castagna L, Bramanti S, Furst S, et al. Nonmyeloablative conditioning, unmanipulated haploidentical

SCT and post-infusion CY for advanced lymphomas. Bone Marrow Transplant. 2014 Sep 15. 19. Bashey A, Zhang X, Sizemore CA, et al. T-Cell-Replete HLA-Haploidentical Hematopoietic

Transplantation for Hematologic Malignancies Using Post-Transplantation Cyclophosphamide Results in Outcomes Equivalent to Those of Contemporaneous HLA-Matched Related and Unrelated Donor Transplantation. J. Clin. Oncol. 31, 1310–1316 (2013).

60


Characteristics of patients who underwent a RIC/NST allogeneic HCT for NHL or HD registered to the

CIBMTR from 2007-2013*

Variable Haplo-identical Matched unrelated


Number of centers 14 103

Research cases 39 (29) 143 (26)

Age at transplant, years 58 (15-75) 57 (7-75)

Median (range)

<10 0 1 (<1)

10-19 3 ( 2) 5 ( 1)

20-29 6 ( 4) 25 ( 5)

30-39 9 ( 7) 34 ( 6)

40-49 18 (13) 81 (15)

50-59 41 (30) 191 (35)

≥60 59 (43) 216 (39)

Sex

Male 86 (63) 342 (62)

Female 50 (37) 211 (38)

Karnofsky score

<90% 19 (14) 189 (34)

90-100% 105 (77) 310 (56)

Missing 12 ( 9) 54 (10)

Disease

Non-Hodgkin 119 (88) 524 (95)

Hodgkin 17 (13) 29 ( 5)

Graft type

Bone marrow 132 (97) 44 ( 8)

Peripheral blood 4 ( 3) 509 (92)

61


Continued.

Variable Haplo-identical Matched unrelated

Year of transplant

2007 1 ( 1) 71 (13)

2008 18 (13) 57 (10)

2009 17 (13) 100 (18)

2010 26 (19) 83 (15)

2011 26 (19) 72 (13)

2012 29 (21) 86 (16)

2013 19 (14) 84 (15)

GVHD prophylaxis

T-cell depletion ± other 0 1 (<1)

CD34 select ± other 0 3 ( 1)

Cyclophosphamide alone 0 1 (<1)

Cyclophosphamide ± others 136 2 (<1)

Tacrolimus + MMF 0 90 (16)

Tacrolimus + MTX 0 248 (45)

Tacrolimus alone 0 73 (13)

CSA + MMF 0 82 (15)

CSA + MTX 0 13 ( 2)

CSA alone 0 23 ( 4)

Other /Missing 0 17 ( 2)


*4 cord blood grafts were excluded. Myeloablative was excluded (52 haplos and 509 MUD). Post HCT

Cy was selected for haplo-identical group.

62


Study Proposal 1411-06/1411-36/1412-13 Study Title: Comparing Outcomes between Haploidentical and HLA Matched Related Donor Transplants for Patients with Lymphoid Malignancies Vanderson Rocha, MD, PhD, Oxford University Hospitals NHS Trust, Churchill Hospital,

[email protected] Nilanjan Ghosh, MD, PhD, Levine Cancer Institute/Carolinas Health Care System,

[email protected] Reem Karmali, MD, MS, Rush University Medical Center, [email protected] Objectives: The primary objective is to compare the one-year overall survival (OS) for HLA-matched sibling donor versus haploidentical hematopoietic stem cell transplantation (haploSCT) with post-transplant cyclophosphamide in patients with lymphomas (Hodgkin and non-Hodgkin).

The secondary objective is to compare graft failure, incidence of acute and chronic graft-versus-host disease (GVHD) relapse incidence, disease-free survival (DFS) and non-relapse mortality (NRM) for matched sibling donor versus haploSCT with post-transplant cyclophosphamide in patients with lymphoid malignancies. We will also identify patient, disease and transplant related factors that are predictive of OS, NRM, PFS after haploSCT. Diseases will be stratified by disease type – Hodgkin Lymphoma (HL) vs. non-Hodgkin Lymphoma (NHL).

Scientific Justification: Allo SCT has been used effectively in advanced hematologic malignancies (Copelan 2006). Conventionally, the best donor for allo SCT is a HLA matched sibling. Unfortunately, a number of limitations exist to this approach including high transplant related mortality associated with myeloablative preparative regimens, suboptimal disease control with reduced intensity conditioning (RIC; Robinson 2002; Corradini 2007), and the limited availability of HLA matched donors. HaploSCT followed by post-transplant cyclophosphamide is emerging as an approach that may have the potential to circumvent these aforementioned limitations in lymphoid malignancies (Luznik 2008).

Though limited, data looking at the feasibility and toxicity of this approach have been encouraging: Castagna et al reported that haploidentical SCT with RIC and post-infusion cytoxan (n=49) could achieve reasonable projected 2-year overall and progression free survival (71 and 63% respectively) with a low cumulative non-relapse mortality (16.3%; 95% CI: 5.9-26.8%) comparable to related and unrelated donor transplants. Additionally, rates of acute and chronic graft versus host disease were acceptable (25.6%; 95% CI: 12.9-38.3% and 5.2%; 95% CI: 0-12.4%, respectively) as was time to engraftment. The same group reported improved outcomes with 3 year PFS and OS of 63% and 77% respectively, using halpoSCT in advanced Hodgkins lymphoma (Raiola 2014). These evolving trends of improved progression free survival and lower NRM suggest that haploSCT can be useful in the treatment of high risk lymphomas. Nonetheless, whether outcomes after haploSCT with post-infusion cytoxan for patients with lymphoid malignancies are comparable to other strategies are still not known.

A retrospective comparison using registry data from the Center for International Bone Marrow Transplantation Research (CIBMTR) might be the most desirable approach to answer such a question.

63


This study may identify haploSCT as a feasible alternative to matched sibling allografts that provides the advantage of superior control given greater HLA disparity. In our deeper analysis of data, we expect to identify patient, disease and treatment related factors that predict for the greatest benefit with a haploSCT approach to potentially justify the use of these readily available donors in subset patient populations. Study Population: Patients aged ≥18 years who received their first allo-SCT after either myeloablative (MA) conditioning or RIC from an HLA matched sibling or a haploidentical related donor (defined as > 2 antigen level mismatches) for a diagnosis of lymphoma (HL or NHL) from 2007 to 2013, will be included. Graft source will include marrow or PBSC donors in either group. The haploidentical related donor group will be limited to only those who received post-transplantation cyclophosphamide. Patients who underwent T cell depletion will be excluded from the study. Outcomes:

Hematopoietic recovery: time to neutrophil (ANC) recovery >0.5×109/L; time to platelet recovery ≥20×109/L.

Acute and chronic graft-versus-host disease (GVHD): Acute GVHD is graded according to the modified Glucksberg criteria from the Consensus Conference Classification and chronic GVHD is assessed according to the Seattle criteria. We will collect information on incidence of Day 100 acute GVHD (grade II-IV), and incidence of chronic GVHD at years 1 and 2

Graft failure: Incidence of primary and secondary graft failure.

Relapse incidence: defined as hematologic disease recurrence by the transplant center.

Non-relapse mortality: time to death without disease relapse.

Disease-free survival: survival without relapse. Patients are censored at time of last contact.

Overall survival: Events are death from any cause. Surviving patients are censored at time of last contact.

Variables to be analyzed: Patient-related:

Age: continuous or in groups

Gender: male vs. female

Karnofsky performance score: <90% vs. ≥90%

Co-morbidity index: 0 vs. 1-2 vs. 3

CMV status: recipient positive vs. recipient negative vs. unknown

Ethnicity and race: Caucasian, African-American, other Donor-related:

Donor age: continuous or in groups

Donor-recipient sex match: M/M, M/F, F/M, F/F, missing

Donor-recipient CMV status match: +/+, +/-, -/+, -/-, missing Disease-related:

Disease subtype: NHL vs. HL (and specific histology)

Disease status at time of transplant: CR1 or > CR2, CRu, PR, SD, PD

Disease stage at diagnosis: I/II vs. III/IV

Extranodal involvement (including CNS and bone marrow involvement) Transplant-related:

Graft source: marrow vs PBSC

64


Preparative regimen: MA vs RIC

Prior autologous SCT: Yes vs. No; duration between auto SCT and allo-SCT

Number of prior therapies: 1, 2 vs ≥3

Prior radiation therapy: Yes vs. No

Interval from diagnosis to transplant: <3, 3-6, 6-12, 12-24, vs. ≥ 24 months, missing

Main effects: HaploSCT vs. matched sibling donor (including MA and RIC groups combined); RIC haploSCT vs. RIC matched sibling donor; if numbers permit, analysis of MA haploSCT vs. MA matched sibling donor

Study Design: Retrospective Comparison of Outcomes for HaploSCT vs Matched Sibling Donor

Median values and ranges will be used for continuous variables and percentages for categorical variables. For each continuous variable, the study population will be initially split into quartiles and in two groups by the median. Patient, disease, and transplant related variables of the groups will be compared using Chi-square or Fischer exact test for categorical variables, and Mann-Whitney test for continuous variables. The probabilities of OS and DFS will be calculated using the Kaplan-Meier method and log-rank test for univariate comparisons. Probabilities of relapse, NRM, acute and chronic GVHD and engraftment will calculated using cumulative incidence curves to accommodate for competing risk (Prentice 1978). The cumulative incidence of grade II‐IV acute GVDH and chronic GVHD (limited and extensive) will also be determined using the competing risks method. The competing risks include disease progression and death. Patients who do not experience GVHD or progression of disease and alive at the last follow‐up will be censored. Associations among patient, disease, and transplant related variables and outcomes will be evaluated using a multivariate Cox proportional hazards regression. A stepwise selection multivariate model will be built to identify covariates that influence outcomes. Covariates with a p<0.05 will be considered significant. Taking into account recent reports suggesting improved outcomes with haploidentical donor allo-SCT in HL (Raiola 2014), evaluating outcomes stratified by disease status (i.e. NHL vs HL) will be necessary. References:

1. Copelan, E.A., Hematopoietic stem-cell transplantation. N Engl J Med, 2006. 354(17): p. 1813-26. 2. Corradini P, Dodero A, Farina L, Fanin R, Patriarca F, Miceli R et al Allogeneic SCT following

reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome. Leukemia 2007; 21: 2316–2323.

3. Castagna L, Bramanti S, Furst S, Giordano L, Crocchiolo R, Sarina B, Mauro E, Morabito L, Bouabdallah R, Coso D, Balzarotti M, Broussais F, Cheick JE, Stella CC, Brusamolino E, Blaise D, Santoro A. Nonmyeloablative conditioning, unmanipulated haploidentical SCT and post-infusion CY for advanced lymphomas. Bone Marrow Transplant. 2014 Sep 15. [Epub ahead of print]

4. Luznik, L., et al., HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant, 2008. 14(6): p. 641-50.

5. Prentice, R.L., et al., The analysis of failure times in the presence of competing risks. Biometrics, 1978. 34(4): p. 541-54.

6. Raiola A, Dominietto A, Varaldo R, et al. Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin's lymphoma. Bone Marrow Transplant. 2014 Feb;49(2):190-4.

65

http://www.ncbi.nlm.nih.gov/pubmed/25222502


7. Robinson SP., Goldstone AH, Mackinnon S, Carella A, Russell N, Ruiz de Elvira C et al Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the lymphoma working party of the european group for blood and bone marrow transplantation. Blood 2002; 100: 4310–4316.

66


Characteristics of patients who underwent a RIC/NST allogeneic HCT for NHL or HD registered to the

CIBMTR from 2007-2013*

Variable Haplo-identical HLA-identical siblings


Research cases 39 (29) 201 (18)

Age at transplant, years 58 (15-75) 55 (5-77)

Median (range)

<10 0 1 (<1)

10-19 3 ( 2) 23 ( 2)

20-29 6 ( 4) 42 ( 4)

30-39 9 ( 7) 86 ( 8)

40-49 18 (13) 208 (18)

50-59 41 (30) 474 (42)

≥60 59 (43) 307 (27)

Sex

Male 86 (63) 709 (62)

Female 50 (37) 432 (38)

Karnofsky score

<90% 19 (14) 318 (28)

90-100% 105 (77) 694 (61)

Missing 12 ( 9) 129 (11)

Disease

Non-Hodgkin 119 (88) 1068 (94)

Hodgkin 17 (13) 73 ( 6)

Graft type

Bone marrow 132 (97) 62 ( 5)

Peripheral blood 4 ( 3) 1079 (95)

67


Continued.

Variable Haplo-identical HLA-identical siblings

Year of transplant

2007 1 ( 1) 155 (14)

2008 18 (13) 175 (15)

2009 17 (13) 184 (16)

2010 26 (19) 160 (14)

2011 26 (19) 160 (14)

2012 29 (21) 157 (14)

2013 19 (14) 150 (13)

GVHD prophylaxis

T-cell depletion ± other 0 6 (<1)

CD34 select ± other 0 26 ( 2)

Cyclophosphamide alone 0 3 (<1)

Cyclophosphamide ± others 136 21 ( 2)

Tacrolimus + MMF 0 140 (12)

Tacrolimus + MTX 0 348 (30)

Tacrolimus alone 0 104 ( 9)

CSA + MMF 0 179 (16)

CSA + MTX 0 132 (12)

CSA alone 0 120 (11)

Other /Missing 0 53 ( 5)


*Myeloablative was excluded (22 haplos and 1203 HLA identical siblings). Post HCT Cy was selected for

haplo-identical group.

68

not for publication or presentation...not for publication or presentation c. ly13-01 hamadani m,...

Documents