A G E N D A CIBMTR WORKING COMMITTEE FOR … · M, Klein A, Lazarus H, Mei M, Mussetti A, Nishihori...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR LYMPHOMA Salt Lake City, Utah Wednesday, February 21, 2018, 2:45 – 4:45 pm

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

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

Co-Chair: Timothy Fenske, MD, Medical College of Wisconsin, Milwaukee, WI; Telephone: 414-805-4633; E-mail: [email protected]

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

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

Statistician: Carlos Litovich, MPH, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0660; E-mail: [email protected]

1. Introductiona. Minutes and Overview Plan from February 2017 meeting (Attachment 1)

2. Accrual summary (Attachment 2)

3. Presentations, published or submitted papers

a. LY06-03 Sureda A, Zhang M-J, Dreger P, Carreras J, Fenske T, Finel H, Schouten H, Montoto S, Robinson S, Smith S, Boumedil A, Hamadani M, Pasquini M. HLA identical sibling allogeneic stem cell transplantation versus HLA matched unrelated donor allogeneic stem cell transplantation in patients with follicular lymphoma. Cancer (In Press).

b. LY15-03 Casulo C, Friedberg JW, Ahn KW, Flowers C, DiGilio A, Smith SM, Ahmed S, Inwards D, Aljurf M, Chen AI, Choe H, Cohen J, Copelan E, Farooq U, Fenske TS, Freytes C, Gaballa S, Ganguly S, Jethava Y, Kamble RT, Kenkre VP, Lazarus H, Lazaryan A, Olsson RF, Rezvani AR, Rizzieri D, Seo S, Shah GL, Shah N, Solh M, Sureda A, William B, Cumpston A, Zelenetz AD, Link BK, Hamadani M. Autologous transplantation in follicular lymphoma with early therapy failure: A NLCS and CIBMTR analysis. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. doi:10.1016/j.bbmt.2017.12.771. Epub 2017 Dec 11.

c. LY16-01a Kanate AS, DiGilio A, Ahn KW, Al Malki M, Jacobsen E, Steinberg A, Hammerschlak N, Kharfan-Dabaja M, Salit R, Ball E, Bashir Q, Cashen A, Couriel D, Diez-Martin J, Katsanis E, Linhares Y, Mori S, Nash R, Pawarode A, Perales M-A, Phipps CD, Richman C, Savani BN, Shapira MY, Stiff P, Strair R, Fenske TS, Smith SM, Sureda A, Olteanu H, Hamadani M. Allogeneic haematopoietic cell transplantation for extranodal natural killer/T-cell lymphoma, nasal type: A CIBMTR analysis. British Journal of Haematology. doi:10.1111/bjh.14879. Epub 2017 Aug 2.

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d. LY16-01b Hamadani M, Kanate AS, DiGilio A, Ahn KW, Smith SM, Lee JW, Ayala E, Chao N, Hari P,Bolaños-Meade J, Gress R, Smedegaard Anderson N, Chen Y-B, Farooq U, Schiller G, Yared J,Sureda A, Fenske TS, Olteanu H. Allogeneic hematopoietic cell transplantation for aggressive NKcell leukemia. A Center for International Blood and Marrow Transplant Research analysis.Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood andMarrow Transplantation. 2017 May 1; 23(5):853-856. doi:10.1016/j.bbmt.2017.01.082. Epub2017 Feb 1. PMC5410937.

e. LY16-04 Smith S, Godfrey J, Ahn KW, DiGilio A, Ahmed S, Agrawal V, Bachanova V, Bacher U,Bashey A, Bolaños-Meade J, Cairo M, Chen A, Chhabra S, Copelan E, Dahi P, Aljurf M, Farooq U,Ganguly S, Hertzberg M, Holmberg L, Inwards D, Kanate A, Karmali R, Kenkre V, Kharfan-DabajaM, Klein A, Lazarus H, Mei M, Mussetti A, Nishihori T, Ramakrishnan Geethakumari P, Saad A,Savani B, Schouten H, Shah N, Urbano-Ispizua A, Vij R, Vose J, Sureda A, Hamadani M. Utility ofautologous vs allogeneic transplant as the first transplantation approach in follicular lymphomapatients with early chemoimmunotherapy failure. Cancer (In Press).

f. LY16-05a Epperla N, Ahn KW, Ahmed S, Jagasia M, DiGilio A, Devine SM, Jaglowski S, Kennedy V,Rezvani AR, Smith SM, Sureda A, Fenske TS, Kharfan-Dabaja MA, Armand P, Hamadani M.Rituximab-containing reduced-intensity conditioning improves progression-free survivalfollowing allogeneic transplantation in B cell non-Hodgkin lymphoma. Journal of Hematology &Oncology. 2017 Jun 12; 10(1):117. doi:10.1186/s13045-017-0487-y. Epub 2017 Jun 12.PMC5469142.

g. LY16-05b Epperla N, Ahn KW, Armand P, Jaglowski S, Ahmed S, Kenkre VP, Savani B, Jagasia M,Shah NN, Fenske TS, Sureda A, Smith SM, Hamadani M. Fludarabine and Busulfan versusFludarabine, Cyclophosphamide, and Rituximab as Reduced-Intensity Conditioning forAllogeneic Transplantation in Follicular Lymphoma. Biol Blood Marrow Transplant. 2018 Jan;24(1):78-85. doi: 10.1016/j.bbmt.2017.10.011. Epub 2017 Oct 13. PMID: 29032272.

h. LY17-01 Allogeneic hematopoietic cell transplantation for Non-Hodgkin lymphoma patients age65 or older compared to patients age 55-64 (N Shah) Accepted for oral presentation at the 2018BMT Tandem Meetings in Salt Lake City, February 2018.

4. Studies in progress (Attachment 3)a. LY16-02 Comparison of alternative donor source stem cell transplant versus matched related

donor stem cell transplant for Hodgkin Lymphoma (S Ahmed/J Kanakry) Deferredb. LY16-03 Outcome of patients who have undergone haploidentical stem cell transplantation for

diffuse large B cell lymphoma: A retrospective study of the CIBMTR Lymphoma WC and the EBMT Lymphoma WP (P Dreger/A Sureda) Manuscript Preparation

c. LY17-01 Allogeneic hematopoietic cell transplantation for Non-Hodgkin lymphoma patients age 65 or older compared to patients age 55-64 (N Shah) Manuscript Preparation. Accepted for oral presentation at the 2018 BMT Tandem Meetings in Salt Lake City, February 2018.

d. LY17-02 Allografts in lymphoma following reduced intensity conditioning (N Ghosh/S Ahmed) Protocol Development

e. LY17-03 Impact of allogeneic hematopoietic cell transplantation on the outcomes of Angioimmunoblastic T-cell lymphoma (N Epperla) Datafile Preparation

5. Introduction to TED (Transplant Essential Data) vs CRF (Comprehensive Report Form)(M Hamadani)

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6. Future/proposed studies

a. PROP 1711-13/123 Outcomes of hematopoietic stem cell transplantation (HSCT) in rare T Cell lymphoma (TCL) subtypes – Hepatosplenic TCL (HSTCL) and Enteropathy Associated TCL (EATL)(Koshy, Jagadeesh, and Majhail) (Attachment 4)

b. PROP 1711-19 Outcomes of elderly patients undergoing high-dose therapy and autologous stem cell transplantation for non-Hodgkin lymphoma (Murthy, Ayala, and Kharfan-Dabaja)(Attachment 5)

c. PROP 1711-52 Does outcome after allogeneic hematopoietic cell transplantation differ between patients with de novo diffuse large B-cell lymphoma (DLBCL) and transformed DLBCL arising in the setting of indolent lymphoma? (Herrera) (Attachment 6)

d. PROP 1711-67 Allogeneic hematopoietic transplantation strategies for anaplastic large cell lymphoma in adult patients: current trends and impact of pre-transplant targeted therapy(Brentuximab, Vedotin, and Crizotinib) (Mussetti, Kanate, and Corradini) (Attachment 7)

e. PROP 1711-69 Outcomes in B cell Non-Hodgkin’s Lymphoma (NHL) patients who underwent autologous stem cell transplantation following Rituximab containing conditioning regimens(Jagadeesh, Majhail, and Hill) (Attachment 8)

f. PROP 1711-102 Effect of time to relapse on overall survival in Mantle Cell lymphoma patients following frontline autologous stem cell transplant (Ridell and Smith) (Attachment 9)

g. PROP 1711-127 Outcomes of consolidation autologous hematopoietic cell transplantation in patients with Plasmablastic lymphoma (Mukherjee, Pingali, and Veeraputhiran) (Attachment 10)

h. PROP 1711-156 Role of autologous hematopoietic cell transplantation in NK/T-Cell lymphomas (Badar) (Attachment 11)

Dropped proposed studies

a. PROP 1710-12 Impact of auto SCT vs RIC allo SCT in mature T-NHL in CR1 in the most recent era.Dropped due to committee scientific priority.

b. PROP 1710-18 Outcomes of allogeneic hematopoietic stem cell transplantation for marginalzone non-Hodgkin lymphoma. Dropped due to feasibility.

c. PROP 1711-39 Autologous hematopoietic cell transplantation versus allogeneic hematopoieticcell transplantation in mantle cell lymphoma harboring 17p deletion or TP53 mutation. Droppeddue to feasibility.

d. PROP 1711-66 Outcomes after allogeneic hematopoietic cell transplantation in patients withaggressive B-cell non-Hodgkin lymphoma who previously received chimeric antigen receptormodified T-cells. Dropped due to feasibility.

e. PROP 1711-70 Allogeneic transplant versus autologous transplant as first-line consolidation forpatients with peripheral T-cell lymphoma. Dropped due to committee scientific priority.

f. PROP 1711-81 Comparison of outcomes in first stem cell transplantation for DLBCL in CR2 orgreater; autologous vs reduced intensity conditioning allogeneic stem cell transplantation.Dropped due to committee scientific priority.

g. PROP 1711-93 Outcomes of allogeneic stem cell transplantation compared to autologous stemcell transplantation in patients with non-Hodgkin’s lymphoma with central nervous systeminvolvement. Dropped due to feasibility.

h. PROP 1711-100 Outcomes with allogeneic transplantation in an era of novel therapies inHodgkin lymphoma. Dropped due to overlap with ongoing CIBMTR & EBMT study.

i. PROP 1711-101 Allogeneic Transplant Outcomes for Patients with Mature T-cell MalignanciesRelapsed post-Autologous Transplant. Dropped due to committee scientific priority.

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j. PROP 1711-119 Outcomes of autologous hematopoietic cell transplantation (autoHCT) in CNS lymphoma (CNSL). Dropped due to committee scientific priority.

k. PROP 1711-129 Outcomes of allogeneic stem cell transplantation compared to autologous stem cell transplant in patients with non-Hodgkin’s lymphoma with central nervous system involvement. Dropped due to feasibility.

7. Other Business

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Not for publication or presentation Attachment 1

MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR LYMPHOMA Orlando, Florida Thursday, February 23, 2017, 2:45 – 4:45 pm

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

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

Co-Chair: Timothy Fenske, MD, Medical College of Wisconsin, Milwaukee, WI; Telephone: 414-805-4633; E-mail: [email protected]

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

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

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

1. IntroductionThe CIBMTR Hodgkin and Non-Hodgkin Lymphoma Working Committee was called to order at 2:45pm on Thursday, February 23, 2017 by Dr. Mehdi Hamadani. Dr. Tim Fenske introduced the workingcommittee leadership as well as the EBMT representative, Dr. Peter Dreger. Dr. Fenske alsooutlined the Working Committee goals, expectations, and limitations and provided an update on theWorking Committee productivity including 3 publications, and 3 abstracts at the 2017 BMT Tandemmeetings. Dr. Anna Sureda went over the four submitted manuscripts and reviewed the votingguidelines. The guidelines are based on a scale from 1 to 9; 1=high scientific impact, 9=lowscientific impact. Alyssa DiGilio explained the difference between the TED and CRF data collectionforms, the study life cycle, and the rules for authorship: 1) substantial and timely contributions toconception and design, or acquisition of data, or analysis and interpretation of data; 2) drafting thearticle or revising it critically for important intellectual content; 3) final approval for the version tobe published.

2. Accrual summaryDr. Anna Sureda presented a slide with the accruals on it. Due to the full agenda, there was notmuch discussion on the numbers, but it was mentioned that the committee has them in attachment2.

3. Presentations, published or submitted papersDue to the full agenda, the 2016 presentations, published papers, and submitted papers werementioned by Dr. Fenske and Dr. Sureda but were not presented.

a. LY14-02 Fenske TS, Ahn KW, Graff TM, DiGilio A, Bashir Q, Kamble RT, Ayala E, Bacher U,Brammer JE, Cairo M, Chen A, Chen YB, Chhabra S, D’Souza AD, Farooq U, Freytes C, Ganguly S,Hertzberg M, Inwards D, Jaglowski S, Kharfan-Dabaja MA, Lazarus HM, Nathan S, Pawarode A,

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Perales MA, Reddy N, Seo S, Sureda A, Smith SM, Hamadani M. Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation. Br J Haematol. 2016 Jul; 174(2):235-48: doi: 10.1111/bjh. 14046. PMID: 27269951

b. LY15-02 Ghosh N, Karmali R, Rocha V, Ahn KW, DiGilio A, Hari P, Bachanova V, Bacher U, Dahi P, deLima M, D’Souza A, Fenske TS, Ganguly S, Kharfan-Dabaja MA, Prestidge TD, Savani BN, Smith SM, Sureda AM, Waller EK, Jaglowski S, Herrera AF, Armand P, Salit RB, Wagner-Johnston ND, Bolanos-Meade J, Hamadani M. Reduced-intensity transplantation for lymphomas using haploidentical related donors versus HLA-matched sibling donors. J Clin Oncol. 2016 Sep 10;34(26): 3141-9. doi: 10.1200/JCO.2015.66.3476. PMID: 27269951. Oral presentation at the 2016 BMT Tandem Meetings in Honolulu, HI, February 2016. https://www.cibmtr.org/ReferenceCenter/Patient/PatientSummaries/Documents/2016.10.21 Ghosh.pdf

c. LY16-01b Hamadani M, Kanate A, DiGilio A, Ahn KW, Smith SM, Lee JW, Ayala E, Chao N, Hari P, Bolaños-Meade J, Gress R, Smedegaard Anderson N, Chen Y, Farooq U, Schiller G, Yared J, Sureda A, Fenske TS, Olteanu H. Allogeneic Hematopoietic Cell Transplantation for Aggressive NK-cell Leukemia. A CIBMTR Analysis. Biol Blood Marrow Transplant. 2017 Feb 1. pii: S1083-8791(17)30237-9. doi: 10.1016/j.bbmt.2017.01.082. [Epub ahead of print]

d. LY16-01a Kanate AS, Olteanu H, Ahn KW, DiGilio A, Sureda A, Fenske TS, Smith SM, Hamadani M. Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Extranodal Natural Killer (NK)/T-cell Lymphoma, Nasal Type (ENKL): A CIBMTR Analysis. Submitted to Haematologica. Oral presentation at the 2017 BMT Tandem Meetings in Orlando, FL, February 2017.

e. LY15-03 Casulo C, Friedberg JW, Ahn KW, DiGilio A, Sureda A, Fenske TS, Smith SM, Hamadani M. Autologous Hematopoietic Cell Transplant (autoHCT) is Associated with Improved Overall Survival (OS) of Follicular Lymphoma (FL) Patients (pts) Experiencing Early Therapy Failure after First line Chemo-immunotherapy: A National Lymphocare study (NLCS) and CIBMTR Analysis. Submitted to JCO. Oral presentation at the 2017 BMT Tandem Meetings in Orlando, FL, February 2017.

f. LY16-05 Epperla N, Ahn KW, DiGilio A, Jagasia M, Armand P, Ahmed S, Devine S, Jaglowski S, Kharfan-Dabaja MA, Kennedy V, Rezvani A, Smith SM, Sureda A, Fenske TS, Hamadani M. Rituximab (R) versus Non-Rituximab (NR) containing Reduced Intensity Conditioning (RIC) Regimens for Allogeneic Hematopoietic Cell Transplantation (alloHCT) in B-cell Non-Hodgkin Lymphomas (B-NHL): A CIBMTR Analysis. Submitted to Lancet Haematology. Oral presentation at the 2017 BMT Tandem Meetings in Orlando, FL, February 2017.

4. Studies in progress (Attachment 3) a. LY16-03 Outcome of patients who have undergone haploidentical stem cell transplantation for

diffuse large B cell lymphoma: A retrospective study of the CIBMTR Lymphoma WC and the EBMT Lymphoma WP (P Dreger/A Sureda) Protocol Development Dr. Peter Dreger gave an update on LY16-03. He described the point of the study: to compare haploidentical transplants with HLA identical siblings, 8/8 unrelated donors, and 7/8 unrelated donors. The EBMT numbers for this were presented: 671 HLA identical siblings, 553 8/8 URD, 129 7/8 URD, and 82 haploidentical transplants (49 of whom received post-transplant cyclophosphamide).

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https://www.cibmtr.org/ReferenceCenter/Patient/PatientSummaries/Documents/2016.10.21%20Ghosh.pdf

https://www.cibmtr.org/ReferenceCenter/Patient/PatientSummaries/Documents/2016.10.21%20Ghosh.pdf


b. LY16-04 Utility of autologous vs allogeneic transplant as the first transplantation approach in follicular lymphoma patients with early chemoimmunotherapy failure (J Godfrey/S Smith) Analysis Dr. Sonali Smith provided an update on this study. She said the main point was to compare autologous versus allogeneic transplantation for patients experiencing early chemo-immunotherapy failure in Follicular Lymphoma. The baseline characteristics table of the patients was shown, which highlighted the three groups that will be compared in the study: autoHCT (n=240), HLA identical sibling alloHCT (n=105), and 8/8 unrelated donors (n=95).

c. LY06-03 HLA identical sibling allogeneic stem cell transplantation versus HLA matched unrelated donor allogeneic stem cell transplantation in patients with follicular lymphoma (A Sureda/H Schouten) Manuscript Preparation

d. LY14-03 Multi-center retrospective study of outcomes of autologous hematopoietic cell transplantation for patients with EBER-ISH/LMP positive relapsed/refractory Hodgkin lymphoma (P Satwani) Deferred currently collecting data from centers

e. LY16-02 Comparison of alternative donor source stem cell transplant versus matched related donor stem cell transplant for Hodgkin Lymphoma (S Ahmed/J Kanakry) Deferred

5. Introduction to TED (Transplant Essential Data) vs CRF (Comprehensive Report Form) (A DiGilio) Alyssa DiGilio emphasized the difference between the TED and CRF databases. It was emphasized that CRF is a subset of the TED database, and that the CRF forms collect all disease specific information such as lines of therapy, extranodal involvement, and prior radiation. If a study needs any of these information, they will have to be a CRF study.

6. Future/proposed studies a. PROP 1610-12/1611-92 Allografts in lymphoma following reduced intensity conditioning (N

Ghosh/S Ahmed) (Attachment 4) Dr. Ghosh presented this study. This study will look at five of the most reduced intensity conditioning regimens for lymphoma in order to determine which, if any, have survival benefits for transplant. There are five different regimens being compared: Flu/Bu (N=860), Flu/Mel (N=1113), Flu/Cy/TBI (N=169), 2 Gy TBI +/- Flu (N=334), and Flu/Cy (N=540). The Working Committee asked if Rituxan vs non-Rituxan in conditioning regimen would be tested. Dr. Hamadani specified that there was just an abstract presented by Dr. Epperla that looked at this exact question, but this will be added as a covariate in the model. It was also asked if the three NMA conditioning regimens would be combined into one. Dr. Hamadani said that if they were found to be statistically similar to each other, they could be combined but until we know that we cannot combine them.

b. PROP 1611-52 Clinical outcomes of Medicare eligible patients (age ≥ 65) undergoing allogeneic hematopoietic cell transplant for relapsed/refractory Non-Hodgkin’s lymphoma (N Shah) (Attachment 5) Dr. Shah presented this study. This study plans to look at outcomes of elderly patients undergoing allogeneic stem cell transplantation for Non-Hodgkin lymphoma to see if these patients should be eligible for Medicare coverage. There are 946 patients who meet these criteria. One member of the committee asked if this proposal could be combined with the previous one, but Dr. Hamadani said that these are two different populations that are looking at a different question, so this cannot be done. Another committee member asked if maintenance therapy information would be available, to which Dr. Hamadani said we have this on a subset of

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patients. It was also noted that the year of transplant would be a covariate in the model to account for variability in treatments over time.

c. PROP 1611-97 A comparison of consolidative autologous stem cell transplantation vs non-transplant consolidation in elderly patients with mantle cell lymphoma (J Cohen/I Greenwell) (Attachment 6) Dr. Greenwell presented this study. This study looks to use the LEO/MER database as a control non-transplant arm to be compared with the CIBMTR transplant cohort for elderly patients with mantle cell lymphoma. In the CIBMTR database, there are 532 patients undergoing first autologous transplant over age 55 with mantle cell lymphoma, but the exact number of patients in the LEO/MER database was unknown (it was estimated to be roughly 220). There were some concerns about overlap between the two datasets, which could be solved by using some identifying information to try to link patients to ensure that the non-transplant cohort truly did not get a transplant. A member of the Working Committee also suggested to do propensity matching on the two cohorts to adjust for potential differences, but because multivariate analyses do just as well as propensity score matching without losing patients from matching it was decided to not do this.

d. PROP 1611-63 Efficacy and safety of hematopoietic cell transplantation for intravascular large B-cell lymphoma (A Kanate/ N El Jurdi) (Attachment 7) Dr. Kanate presented this study. This study aims to look at the outcomes of autologous transplantation for intravascular large B-cell lymphoma. There were 257 patients in the CIBMTR database that met these criteria. One member of the committee asked if the number of intravascular B cell patients for pediatrics was known, but it was not. It was noted that the pathology reports will have to be checked for these cases to ensure that they are truly intravascular large B-cell cases. It was also mentioned whether the CIBMTR should add this disease to be selected more frequently for CRF track as only 43 of these patients are on the CRF track.

e. PROP 1611-103 Effect of time to relapse on overall survival in mantle cell lymphoma patients following frontline autologous stem cell transplant (M Tallarico/S Smith) (Attachment 8) Dr. Smith presented this study. This study plans to look and compare the outcomes of mantle cell lymphoma patients who had relapsed after autologous transplantation. There are 172 patients who had relapsed within 2 years post autoHCT and 174 who had relapsed after 2 years post autoHCT. One member of the committee asked if the proportion of the patients who relapsed versus those who hadn’t relapsed was looked at. Another recommended censoring patients who ended up getting an allogeneic transplant at the time of their alloHCT. It was also recommended that instead of using 2 years as the cut-off to look at the data to find an appropriate cut point.

f. PROP 1612-01 Hematopoietic stem cell transplantation for mature T- and NK- cell malignancies in children, adolescents, and young adults (A Xavier/A Flowers/M Cairo) (Attachment 9) Dr. Cairo presented this study. This study plans to look and compare the outcomes of alloHCT vs autoHCT in CAYA patients with T- and NK- cell malignancies. There are 851 alloHCT patients and 731 autoHCT patients in the population. One member of the committee asked if we would have EBV data on these patients, but it was noted that this is not collected on the CIBMTR forms.

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g. PROP 1611-09 Impact of allogeneic hematopoietic cell transplantation on the outcomes of angioimmunoblastic T-cell lymphoma (N Epperla) (Attachment 10) Dr. Epperla presented this study, which will look at the outcomes of alloHCT for angioimmunoblastic T-cell lymphoma. There are 329 patients in the CIBMTR database with this disease, which would be the largest study population for this group to date. It was noted by the committee that this is a very important study. Another member of the committee asked about doing an auto vs alloHCT study for this, but it was noted that these comparisons are generally tough to do, but we could describe the characteristics of patients getting each type.

h. PROP 1611-98 Allogeneic versus autologous hematopoietic cell transplantation in patients who achieve only partial remission to salvage therapy in relapsed/refractory classical Hodgkin lymphoma (V Kenkre/M Juckett/W Longo) (Attachment 11) Dr. Kenkre presented this study, which aims to look at alloHCT vs autoHCT for patients not in complete remission for Hodgkin lymphoma at the time of transplant. There are 695 patients receiving alloHCT and 8864 receiving autoHCT. It was noted by the committee that PET data will be essential for completing this study, and it is currently only available for 1% of the population.

Fifteen additional proposals were submitted to the committee but were not presented due to the following reasons: a. PROP 1606-01 Outcomes of autologous hematopoietic transplants in elderly patients with Non-

Hodgkin’s lymphoma: A CIBMTR analysis. Dropped due to feasibility b. PROP 1610-13 Comparison of autologous versus allogeneic hematopoietic cell transplantation

for patients with HIV-associated lymphomas. Dropped due to feasibility-low number of patients (N=10 alloHCT HIV-lymphomas)

c. PROP 1610-16 Predictors of successful autologous stem cell transplantation for the treatment of primary CNS lymphoma. Dropped due to feasibility-low number of patients (N=45)

d. PROP 1611-11 Outcomes of mantle cell lymphoma patients receiving allogeneic hematopoietic transplantation after autologous transplantation failure. Dropped due to feasibility

e. PROP 1611-17 Clinical outcomes of patients with relapsed or refractory nodular lymphocyte predominant Hodgkin Lymphoma after autologous transplant. Dropped due to feasibility-low number of patients (N=31)

f. PROP 1611-43 Allogeneic hematopoietic cell therapy for central nervous system lymphoma. Dropped due to feasibility-low number of patients (N=5)

g. PROP 1611-55 Impact of autologous transplantation on outcomes for MYC+ diffuse large B cell lymphomas. Dropped due to feasibility

h. PROP 1611-56 Long term effects of matched and alternative donor hematopoietic cell transplantation with or without total body skin electron beam therapy in patients with MF/SS. Dropped due to feasibility

i. PROP 1611-57 Conditioning regimens for autologous transplantation in relapsed/refractory Hodgkin lymphoma: is total lymphoid irradiation (TLI) comparable to a non-TLI approach with or without brentuximab maintenance? Dropped due to feasibility-low number of patients (N=88)

j. PROP 1611-75 Impact of concurrent overexpression of MYC and BCL2 in patients with diffuse large B cell lymphoma treated with allogeneic or autologous SCT. Dropped due to feasibility

k. PROP 1611-83 Outcomes of allogeneic compared with autologous stem cell transplantation as consolidative therapy for high risk lymphomas. Dropped due to feasibility

l. PROP 1611-93 Impact of Brentuximab vedotin salvage therapy on transplant outcomes in relapsed or refractory Hodgkin’s lymphoma. Dropped due to feasibility-low number of patients (N=115)

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m. PROP 1611-94 Donor lymphocyte infusion for the prevention and treatment of relapse in patients undergoing reduced-intensity allogeneic transplantation in lymphoma. Dropped due to feasibility

n. PROP 1611-146 The role of consolidative hematopoietic cell transplantation in first complete remission of patients with lymphoblastic lymphoma treated with ALL-type induction. Dropped due to feasibility

o. PROP 1612-02 Outcomes of allogeneic hematopoietic transplantation for large granular lymphocyte (LGL) leukemia: A CIBMTR Analysis. Dropped due to feasibility

7. Other Business After the new proposals were presented, the voting process was reiterated, and each participant had the opportunity to rate each new proposal using paper ballots. Without additional comments, the meeting was adjourned at 4:31 pm.

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Working Committee Overview Plan for 2017-2018

a. LY06-03 Sib vs MUD for follicular NHL/EBMT with CIBMTR. We anticipate the final analysis to be done by July 1, 2015. We anticipate that the manuscript will be submitted by the end of March 2017 and published by July 1, 2017.

b. LY14-03 Multi-center retrospective study of outcomes of autologous hematopoietic cell transplantation for patients with EBER-ISH/LMP positive relapsed/refractory Hodgkin lymphoma. This study is currently deferred and will be deferred until July 1, 2018.

c. LY16-02 Alternative donor source stem cell transplant vs matched donor stem cell transplant for Hodgkin lymphoma. This study is currently deferred and will be deferred until July 1, 2018.

d. LY16-03 Outcomes of patients who have undergone a haploHCT for DLBCL. We anticipate having this study in data file preparation by July 1, 2017 and in manuscript preparation by July 1, 2018.

e. LY16-04 Utility of autologous vs. allogeneic transplant as first transplantation approach in follicular lymphoma patients with early chemoimmunotherapy failure. We anticipate having this study submitted by July 1, 2017 and published by July 1, 2018. We are targeting this paper to be submitted to JCO.

f. LY17-01 (Prop 1611-52) Clinical outcomes of medicare eligible patients undergoing allogeneic hematopoietic cell transplant for relapsed/refractory Non-Hodgkin’s lymphoma. We anticipate having this study in manuscript preparation by July 1, 2018.

g. LY17-02 (Prop 1610-12/1611-92) Allografts in lymphoma following reduced intensity conditioning. We anticipate having this study in manuscript preparation by July 1, 2018.

h. LY17-03 (Prop 1611-09) Impact of allogeneic hematopoietic cell transplantation on the outcomes of angioimmunoblastic T-cell lymphoma. We anticipate having this study in analysis by July 1, 2018.

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Oversight Assignments for Working Committee Leadership (March 2017)

Tim Fenske LY17-01 Clinical outcomes of medicare eligible patients undergoing allogeneic hematopoietic cell transplant for relapsed/refractory Non-Hodgkin’s lymphoma

Anna Sureda LY16-03 Outcomes of patients who have undergone haploHCT for DLBCL LY17-02 Allografts in lymphoma following reduced intensity conditioning

Sonali Smith LY16-04 Utility of autologous vs allogeneic transplant as first transplantation approach in follicular lymphoma patients with early chemoimmunotherapy failure LY17-03 Impact of allogeneic hematopoietic cell transplantation on the outcomes of angioimmunoblastic T-cell lymphoma

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Accrual Summary for Hodgkin and Non-Hodgkin Lymphoma Working Committee: 2000-2017

HLA-Identical Sibling Alternative Donor Autologous TED only Research TED only Research TED only Research

N (%) N (%) N (%) N (%) N (%) N (%) Anaplastic large cell 275 43 311 125 1498 135

PIF 34 (12) 8 (19) 34 (11) 17 (14) 138 (9) 8 (6) CR1 38 (14) 6 (14) 42 (14) 20 (16) 535 (36) 52 (39) Rel 1 28 (10) 6 (14) 22 (7) 9 (7) 159 (11) 17 (13) CR2 72 (26) 15 (35) 81 (26) 36 (29) 363 (24) 32 (24) Other/Unknown 103 (37) 8 (19) 132 (42) 43 (34) 303 (20) 26 (19)

Burkitt/small noncleaved 164 45 96 86 535 103 PIF 19 (12) 5 (11) 8 (8) 17 (20) 53 (10) 18 (17) CR1 35 (21) 11 (24) 17 (18) 14 (16) 185 (35) 41 (40) Rel 1 23 (14) 6 (13) 8 (8) 13 (15) 49 (9) 9 (9) CR2 40 (24) 18 (40) 31 (32) 31 (36) 126 (24) 27 (26) Other/Unknown 47 (29) 5 (11) 32 (33) 11 (13) 122 (23) 8 (8)

Diffuse large cell/Immunoblastic

1751 298 1887 631 19909 2213

PIF 306 (17) 77 (26) 289 (15) 179 (28) 2326 (12) 294 (13) CR1 160 (9) 45 (15) 182 (10) 75 (12) 3501 (18) 435 (20) Rel 1 274 (16) 41 (14) 201 (11) 73 (12) 3373 (17) 401 (18) CR2 240 (14) 28 (9) 305 (16) 89 (14) 5495 (28) 621 (28) Other/Unknown 771 (44) 107 (36) 910 (48) 215 (34) 5214 (26) 462 (21)

Follicular 1436 494 1231 614 4561 781 PIF 163 (11) 64 (13) 118 (10) 102 (17) 423 (9) 60 (8) CR1 97 (7) 37 (7) 77 (6) 34 (6) 496 (11) 98 (13) Rel 1 196 (14) 100 (20) 143 (12) 91 (15) 790 (17) 152 (19) CR2 173 (12) 73 (15) 157 (13) 73 (12) 1057 (23) 178 (23) Other/Unknown 807 (56) 220 (45) 736 (60) 314 (51) 1795 (39) 293 (38)

Lymphoblastic 172 49 132 99 281 31 PIF 18 (10) 7 (14) 8 (6) 12 (12) 14 (5) 2 (6) CR1 50 (29) 11 (22) 21 (16) 18 (18) 124 (44) 17 (55) Rel 1 28 (16) 8 (16) 9 (7) 17 (17) 24 (9) 0 CR2 32 (19) 12 (24) 36 (27) 33 (33) 35 (12) 5 (16) Other/Unknown 44 (26) 11 (22) 58 (44) 19 (19) 84 (30) 7 (23)

Mantle 879 198 1008 379 6757 761 PIF 111 (13) 38 (19) 90 (9) 61 (16) 485 (7) 66 (9) CR1 176 (20) 38 (19) 146 (14) 68 (18) 4349 (64) 507 (67)

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HLA-Identical Sibling Alternative Donor Autologous

TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%) Rel 1 135 (15) 34 (17) 153 (15) 63 (17) 223 (3) 27 (4) CR2 163 (19) 28 (14) 291 (29) 78 (21) 386 (6) 50 (7) Other/Unknown 294 (33) 60 (30) 328 (33) 109 (29) 1314 (19) 111 (15) Marginal 85 27 91 34 334 39 PIF 11 (13) 8 (30) 10 (11) 8 (24) 34 (10) 8 (21) CR1 7 (8) 3 (11) 13 (14) 5 (15) 55 (16) 4 (10) Rel 1 9 (11) 1 (4) 10 (11) 5 (15) 42 (13) 3 (8) CR2 11 (13) 3 (11) 9 (10) 3 (9) 64 (19) 9 (23) Other/Unknown 47 (55) 12 (44) 49 (54) 13 (38) 139 (42) 15 (38) NK T cell 234 49 251 86 664 64 PIF 35 (15) 7 (14) 46 (18) 19 (22) 69 (10) 10 (16) CR1 57 (24) 13 (27) 66 (26) 29 (34) 269 (41) 28 (44) Rel 1 23 (10) 5 (10) 14 (6) 7 (8) 51 (8) 4 (6) CR2 44 (19) 3 (6) 48 (19) 17 (20) 115 (17) 11 (17) Other/Unknown 75 (32) 21 (43) 77 (31) 14 (16) 160 (24) 11 (17) T cell 822 170 940 342 2764 295 PIF 186 (23) 53 (31) 201 (21) 122 (36) 271 (10) 33 (11) CR1 149 (18) 31 (18) 162 (17) 63 (18) 1405 (51) 141 (48) Rel 1 89 (11) 14 (8) 82 (9) 31 (9) 223 (8) 30 (10) CR2 114 (14) 23 (14) 157 (17) 37 (11) 307 (11) 41 (14) Other/Unknown 284 (35) 49 (29) 338 (36) 89 (26) 558 (20) 50 (17) NHL Not specified 180 24 123 99 888 26 PIF 15 (8) 4 (17) 8 (7) 30 (30) 94 (11) 7 (27) CR1 13 (7) 0 5 (4) 13 (13) 112 (13) 6 (23) Rel 1 28 (16) 2 (8) 12 (10) 13 (13) 64 (7) 5 (19) CR2 15 (8) 2 (8) 23 (19) 14 (14) 114 (13) 2 (8) Other/Unknown 109 (61) 16 (67) 75 (61) 29 (29) 504 (57) 6 (23) Other 517 160 495 230 3350 421 PIF 95 (18) 46 (29) 96 (19) 56 (24) 504 (15) 68 (16) CR1 89 (17) 24 (15) 81 (16) 55 (24) 992 (30) 123 (29) Rel 1 49 (9) 17 (11) 49 (10) 26 (11) 388 (12) 46 (11) CR2 59 (11) 5 (3) 84 (17) 26 (11) 617 (18) 78 (19) Other/Unknown 225 (44) 68 (43) 185 (37) 67 (29) 849 (25) 106 (25)

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HLA-Identical Sibling Alternative Donor Autologous

TED only Research TED only Research TED only Research N (%) N (%) N (%) N (%) N (%) N (%) Hodgkin 1341 171 1869 363 15712 1466 PIF 200 (15) 27 (16) 224 (12) 69 (19) 2149 (14) 228 (16) CR1 67 (5) 8 (5) 97 (5) 32 (9) 1599 (10) 162 (11) Rel 1 156 (12) 36 (21) 212 (11) 53 (15) 3048 (19) 278 (19) CR2 143 (11) 17 (10) 224 (12) 38 (10) 4317 (27) 432 (29) Other/Unknown 775 (58) 83 (49) 1112 (59) 171 (47) 4599 (29) 366 (25) Graft type 7856 1728 8434 3088 57253 6335 BM 806 (10) 157 (9) 1470 (17) 702 (23) 683 (1) 50 (<1) PBSC 6990 (89) 1566 (91) 6311 (75) 1915 (62) 55539 (97) 6232 (98) Other/Unknown 60 (<1) 5 (<1) 653 (8) 471 (15) 1031 (2) 53 (<1)

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TO: Lymphoma Working Committee Members

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

RE: Studies in Progress Summary

LY16-03: Outcome of patients who have undergone haploidentical stem cell transplantation for diffuse large B cell lymphoma: A retrospective study of the CIBMTR Lymphoma WC and the EBMT Lymphoma WP (P Dreger/ A Sureda) This study combines data from the CIBMTR and EBMT to look at haploidentical transplants against other donor options for diffuse large B cell lymphoma. This study is currently in manuscript preparation. The goal of this study is to submit the study for publication by June 2018.

LY16-02: Comparison of alternative donor source stem cell transplant versus matched related donor stem cell transplant for Hodgkin Lymphoma (S Ahmed/J Kanakry) This study looks to compare haploidentical, cord blood, 8/8 unrelated donors, 7/8 unrelated donors, and HLA identical sibling donors in patients with Hodgkin Lymphoma. This study is currently deferred to increase the numbers in the study population. The goal of this study is to start protocol development in July 2018.

LY17-01: Allogeneic hematopoietic cell transplantation for Non-Hodgkin lymphoma patients age 65 or older compared to patients age 55-64 (N Shah) This study looks to compare patients with Non-Hodgkin lymphoma age 55-64 to 65 or older and examine their outcomes. This study’s manuscript is currently being evaluated by the writing committee. The goal of this study is to submit the study for publication by June 2018.

LY17-02: Allografts in lymphoma following reduced intensity conditioning (N Ghosh/S Ahmed) This study looks to describe post-allogeneic transplant outcomes in Hodgkin’s disease and Non-Hodgkin lymphoma patients following reduced intensity or non-myeloablative conditioning. This study is currently under protocol development. The goal of this study is to present at ASH 2018 or BMT Tandem Meeting 2019.

LY17-03: Impact of allogeneic hematopoietic cell transplantation on the outcomes of Angioimmunoblastic T-cell lymphoma (N Epperla) This study looks to describe the post-allogeneic transplant outcomes of Angioimmunoblastic T-cell lymphoma patients age 18 or older. This study is currently under data file preparation. The goal of this study is to present at ASH 2018 or BMT Tandem Meeting 2019.

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Proposal: 1711-13/123

Title: Outcomes of Hematopoietic Stem Cell Transplantation (HSCT) in Rare T Cell Lymphoma (TCL) Subtypes – Hepatosplenic TCL (HSTCL) and Enteropathy Associated TCL (EATL).

Nebu Koshy, MD, [email protected], Louisiana State University Health Sciences Center Deepa Jagadeesh, MD, MPH, [email protected], Cleveland Clinic Navneet Majhail, MD, MS, [email protected], Cleveland Clinic

Hypothesis: T cell lymphomas are rare and aggressive disease accounting for only 10-15% of all NHL. The rare subtypes of TCL like enteropathy associated TCL (EATL) and hepatosplenic TCL (HSTCL) have very poor prognosis due to lack of effective treatment regimens. Our hypothesis is as follows:

1. Hematopoietic cell transplantation (both auto and allo) may provide durable remission forpatients with enteropathy associated T cell lymphoma (EATL) and hepatosplenic T celllymphoma (HSTCL).

2. Autologous HSCT may result in improved outcome when performed as consolidation in firstcomplete or partial remission.

3. Allogeneic HSCT may result in improved outcome when performed as salvage at the time ofrelapse.

Specific aims: • Primary aim

1. Evaluate the outcomes of both autologous and allogeneic HSCT in both HSTCL and EATL byestimating progression free survival (PFS), overall survival (OS) and non-relapse mortality

• Secondary aims1. Estimate the rate of acute and chronic GVHD following allogeneic HSCT in HSTCL and EATL

patients2. To identify prognostic markers for transplant outcomes in HSTCL and EATL patients3. To identify if pretransplant regimens have an impact on outcome4. To evaluate the cause of death post transplant in HSTCL and EATL patients5. To estimate the time to neutrophil and platelet engraftment, incidence of relapse rate

Scientific impact: If improved outcomes are observed with HSCT in these rare subtypes, it could impact treatment paradigm and have practice changing implications.

Scientific justification: T cell lymphomas are rare and aggressive disease accounting for only 10-15% of all NHL. The rarity of the disease is a major barrier in conducting clinical trials to identify effective treatment regimens thus resulting in poor outcomes. The 5-year overall survival (OS) in most TCL subtypes is approximately 30- 35% [1]. Some of the rarer subtypes like EATL and HSTCL have a much lower incidence rate making it even more cumbersome to conduct both epidemiological studies and clinical trials. HSTCL represent 2- 3% of all TCL, while EATL is around 3-8%. These entities tend to have a lower response rate to upfront anthracycline containing regimens, higher relapse rate and inferior outcomes. The 5 year OS in HSTCL

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and EATL are 7% and 20% respectively [1]. There is ambiguity about the best treatment option in newly diagnosed patients and the role of HSCT is not well defined. In most eligible patients, the mainstay of treatment includes anthracycline based combination induction chemotherapy. Both autologous and allogeneic stem cell transplantation are frequently used in suitable patients either as a consolidative therapy or at the time of relapse with expectation to improve outcomes. Unfortunately, there is very limited data on transplant outcomes in these rare TCL subtypes. The largest series published is the retrospective data from European Bone marrow transplant (EBMT) registry that included 25 HSTCL patients who underwent autologous (n=7) and allogeneic (n=18) HSCT [2]. There was a suggestion of improved outcomes with allogeneic HSCT with 3 year PFS and OS of 48% and 54% respectively. Unfortunately the 3 year NRM in this small cohort was significant at 40%. Of the seven patients who underwent ASCT, 5 relapsed and died. EBMT also published their data on 44 EATL patients who underwent autologous HSCT [3]. The four year PFS and OS were 54% and 59% respectively with trend for improved outcomes in patients transplanted in their first remission CR1/PR1 compared to others, 66% vs 36% (p=.062). The optimal way to evaluate transplant outcomes in these rare subtypes is using registry based data as it will be the best source for large sample size as single or even multi-institutional census will be too small to draw any meaningful conclusion. Patient eligibility population: Adult patients aged ≥18 years with either EATL or HSTCL who underwent HSCT, either autologous or allogeneic, from 2000 to 2015 Data requirements:

• Pre-transplant Essential Data: Form 2400 • Hodgkin and Non-Hodgkin lymphoma Post HSCT data: Form 2118 • Recipient Death data: Form 2900

Variables: Allogeneic and autologous HCT patients

• Date of transplant • Age • Gender • KPS • HCT-CI • Race • B symptoms • Stage at diagnosis • LDH • IPI • PIT score at transplantation • Bone marrow involvement at diagnosis and transplant • CNS involvement at diagnosis and transplant • Extranodal involvement at diagnosis and transplant

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• Interval from diagnosis to HCT • First line of therapy • Response to first line of therapy • PET scan results prior to transplant if available • Lines of therapy before HCT • Radiation therapy • Year of transplant • Timing of HCT

- Upfront - Late (>1 line of therapy) - Unknown

• Remission status prior to HCT • Disease risk index at transplant • Mobilization regimen for auto HCT • Graft source – PB vs BM • Conditioning regimens • Days to neutrophil engraftment • Days to platelet engraftment • Follow up of survivors in months to calculate median • Response to transplant • 100 day disease status • PET scan results after transplant if available • 30 and 100 day mortality • Date of relapse post-transplant • Date and cause of death

Allogeneic HCT specific variables:

• H/o prior auto HCT • Interval from auto to allogeneic HCT • Donor type • Donor recipient sex match • Donor recipient CMV status • Conditioning intensity and regimens

a. TBI +/- b. ATG +/-

• GVHD prophylaxis • Incidence of acute and chronic GVHD

Study design: This is a retrospective registry based analysis evaluating outcomes of HSCT in EATL and HSTCL patients.

The main outcomes that will be analyzed are OS, PFS and NRM. All outcomes will be calculated relative to the transplant date. Cumulative incidence method will be used to estimate relapse and NRM. Kaplan-Meier analysis will be used to estimate PFS and OS. Cox proportional hazard analysis will be used for univariate analysis to identify prognostic factors for PFS and OS. Multivariable analysis will be done using

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stepwise selection. Results will be reported as hazard ration (HR), 95% confidence interval for HR and p value.

Data source: CIBMTR Research Database. References: 1. Vose, J., et al., International peripheral T-cell and natural killer/T-cell lymphoma study: pathology

findings and clinical outcomes. J Clin Oncol, 2008. 26(25): p. 4124-30. 2. Rashidi, A. and A.F. Cashen, Outcomes of allogeneic stem cell transplantation in hepatosplenic T-cell

lymphoma. Blood Cancer Journal, 2015. 5: p. e318. 3. Jantunen, E., et al., Autologous stem cell transplantation for enteropathy-associated T-cell

lymphoma: a retrospective study by the EBMT. Blood, 2013. 121(13): p. 2529-32.

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Characteristics of first alloHCT or autoHCT for hepatosplenic TCL or enteropathy associated TCL from 2000-2015

Enteropathy-type T-cell lymphoma

Hepatosplenic gamma-delta T-cell

Number of patients 129 196 Research level data 15 48 Number of centers 80 103 Patient age at transplant

Median (range) 57 (10-76) 35 (3-75) 0-18 1 (<1) 22 (11) 18-29 5 (4) 57 (29) 30-39 12 (9) 39 (20) 40-49 15 (12) 38 (19) 50-59 46 (36) 27 (14) ≥ 60 50 (39) 13 (7) Patient sex Male 83 (64) 126 (64) Female 45 (35) 70 (36) Missing 1 (<1) 0 Karnofsky performance score ≥90 66 (51) 91 (46) <90 51 (40) 82 (42) Missing 12 (9) 23 (12) Patient race Caucasian 87 (67) 125 (64) African-American 2 (2) 35 (18) Asian 16 (12) 14 (7) Pacific islander 0 1 (<1) Other 1 (<1) 4 (2) Missing 23 (18) 17 (9) Graft type Bone marrow 7 (5) 32 (16) Peripheral blood 119 (92) 147 (75) Umbilical cord blood 1 (<1) 17 (9) Missing 2 (2) 0

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Number of patients 129 196 Type of transplant Allogeneic HCT 32 (25) 147 (75) Autologous HCT 97 (75) 49 (25) Type of transplant, research level data Allogeneic HCT 6 (40) 42 (88) Autologous HCT 9 (60) 6 (13) Disease status Sensitive 119 (92) 170 (87) Resistant 7 (5) 18 (9) Unknown 3 (2) 8 (4) Donor type Autologous HSCT 97 (75) 49 (25) HLA-identical sibling 12 (9) 72 (37) Syngeneic twin 0 1 (<1) Unrelated donor, HLA unknown 10 (8) 48 (24) HLA-matched other relative 2 (2) 5 (3) HLA-mismatched relative 5 (4) 11 (6) HLA-matched unrelated 3 (2) 2 (1) HLA-mismatched unrelated 0 3 (2) Multiple donor 0 1 (<1) Missing 0 4 (2) Year of transplant 2000 2 (2) 2 (1) 2001 3 (2) 3 (2) 2002 4 (3) 4 (2) 2003 7 (5) 3 (2) 2004 4 (3) 5 (3) 2005 3 (2) 12 (6) 2006 11 (9) 12 (6) 2007 4 (3) 8 (4) 2008 5 (4) 19 (10) 2009 10 (8) 12 (6) 2010 10 (8) 14 (7) 2011 8 (6) 16 (8) 2012 16 (12) 17 (9)

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Number of patients 129 196 2013 19 (15) 21 (11) 2014 10 (8) 24 (12) 2015 13 (10) 24 (12) Median follow-up of survivors (range), months 44 (1-169) 54 (3-169)

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Proposal: 1711-19

Title: Outcomes of elderly patients Undergoing High-Dose Therapy and Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma

Hemant Murthy ,MD, [email protected], University of Florida Ernesto Ayala, MD, [email protected], Moffitt Cancer Center Mohamed A. Kharfan-Dabaja, [email protected], Moffitt Cancer Center

Hypothesis: Hematopoietic cell therapy-comorbidity index (HCT-CI) is predictive of treatment related mortality and length of stay (LOS) in elderly patients (age 55 and older) undergoing autologous stem cell transplantation in Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL)

Specific aims: • To assess HCT-CI impact on treatment related mortality in patients age 55 and older with HL and

NHL undergoing AutoHCT• To assess HCT-CI impact on Length of stay and readmission rate in patients age 55 and older

with NHL undergoing AutoHCT• To assess the overall outcomes (OS, PFS, Relapse rate) after autoHCT in patients age 55 and

older with NHL undergoing AutoHCT• Assess impact of HCT-CI on time to neutrophil and platelet engraftment

Scientific justification: High Dose therapy followed by autologous stem cell transplantation (HDT-ASCT) represents one of the most widely used therapies in the treatment of lymphomas, and has long been shown to improve both progression free survival and overall survival in chemosensitive non-Hodgkin lymphoma in second remission1,2. The benefit of HDT-AHCT have been demonstrated over various non-Hodgkin lymphoma subtypes including the Parma study for relapse or primary refractory intermediate to high grade NHL and the Nordic MCL2 and European MCL Network study for mantle cell lymphoma in first remission. Upfront HDT-ASCT for peripheral t cell lymphoma has shown 3-5 year PFS ranging from 36% to 61%3-5.

The hematopoietic cell transplant comorbidity index (HCT-CI) scoring system developed by Sorror et al. has been shown to be predictive of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplants in patients with hematologic malignancies6. Recently, studies have been conducted in an effort to validate the HCT-CI in AHCT. A CIBMTR study presented at ASH in 2012 by Pasquini and colleagues validated the HCT-CI in patients who underwent AHCT between 2007 and 2009, accounting for both myeloma and lymphoma patients, demonstrating increase TRM and decrease overall survival in those with higher HCT-CI scores7. Higher HCT-CI scores also have been reported to predict for 30 day readmission rates in lymphoma and myeloma patients8. Saad and colleagues with the CIBMTR reported HCT-CI to be predictive of survival in multiple myeloma, although not for non-relapse mortality9.

With improvement in supportive and transplant related care, the number of AHCT performed, as well as the average age of patients undergoing AHCT continues to rise, with nearly 40% of all AHCT performed in patients 60 years and older10. The role of comorbidity assessment, particularly the HCT-CI in elderly patients with NHL is less clear. Dahi and colleagues at MSKCC reported favorable outcomes in patients age 60 and older, and found neither age nor HCT-CI correlated with treatment related mortality or

24


outcomes11. Hermet et al reported patients age 70 and older undergoing AHCT for NHL with 1 year non-relapse mortality of 8.5%, although over 70% of patients had HCT-CI of 012. More recently, a high HCT-CI score was predictive of non-relapse mortality and morbidity as was advance age, >55 years, in autologous stem cell transplantation with half of the patients reported with Hodgkin and non-Hodgkin lymphoma13. Another group reported comorbidities, independent of age, were predictive of overall and progressive free survival in patients age 50 or older undergoing AHCT for Hodgkin lymphoma14. In addition, a large study of over 700 patients found hct-ci >3 and age >50 to be predictive of increase NRM in AHCT for lymphoma15. We seek to utilize the CIBMTR database to evaluate outcomes of elderly patients who received an AHCT for NHL, and whether HCT-CI correlates with TRM, length of stay and readmission rates, or other outcomes such as PFS and OS. The scientific impact of such a study is based on the fact that there is no accepted consensus about proper risk stratification of patients undergoing AHCT for lymphoma, particularly elderly ones. Numerous smaller studies have reported conflicting data and a large registry study may provide clarity and guidance for risk stratification and impact of pre-transplant comorbidities on significant outcomes following AHCT for lymphoma. Patient eligibility population: All patients age 55 and older who have underwent AHCT for NHL between 2008-2016 Variables: Patient-related:

• Age at HCT, years (stratified by decade: 55-59, 60-64, 65-69, 70 or older) • Sex: male vs female • Race: Caucasian vs African American vs others • Karnofsky performance score: ≥90% vs. <90% vs. missing • HCT-CI (0-1 vs 2 vs 3 vs >3) • Specific pre-transplant comorbidities:

o Arrhythmia: (atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmias)

o Cardiac disease (coronary artery disease, congestive heart failure, myocardial infarction, or EF ≤ 50%)

o Cerebrovascular disease (transient ischemic attack or cerebrovascular accident) o Diabetes: requiring treatment with insulin or oral hypoglycemics but not diet alone o Heart valve disease (except mitral valve prolapsed) o Hepatic dysfunction: bilirubin > ULN to 1.5 × ULN, or AST/ALT > ULN to 2.5 × ULN o Infection: active infection requiring continuation of antimicrobial treatment after

day 0, HIV test, and CMV status. o Inflammatory bowel disease (Crohn's disease or ulcerative colitis) o Obesity: body mass index > 35 o Peptic ulcer (requiring treatment) o Psychiatric disturbance (depression or anxiety requiring psychiatric consult or

treatment) o Pulmonary dysfunction: mild (DLco and/or FEV1 < normal but > 80% or no dyspnea

on activity), moderate (DLco and/or FEV1 66-80% or dyspnea on slight activity), severe (DLco and/or FEV1 ≤ 65% or dyspnea at rest or requiring oxygen).

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o Renal dysfunction: serum creatinine > 2 mg/dL or >177 μmol/L, on dialysis, or prior renal transplantation

o Rheumatologic disease (SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatic).

o Solid tumor: diagnosed prior to transplant. Disease-related:

• Disease diagnosis: Hodgkin lymphoma vs NHL (B cell vs T cell lymphoma vs other) • B symptoms at diagnosis • Bone marrow involvement at diagnosis (yes vs no) • IPI score at diagnosis • Disease stage at diagnosis • Disease risk Index (DRI) • Chemosensitive vs. chemorefractory at time of transplant • State of disease at time of transplant: CR1 vs CR2 vs CR3 or higher CR vs PR vs SD • Interval from diagnosis to transplant • Prior therapies received prior to stem cell transplantation • LDH at transplant: normal vs high vs missing • Post transplant maintenance therapy: Yes/no

Transplant-related: • Stem cell source: bone marrow vs. peripheral blood • Year of transplant: 2008- 2012 vs. after 2012 • Conditioning regimen (BEAM vs CBV vs other) • Length of Stay (captured between day 0 and 100 post transplant)

o Total number of hospital days (initial admission and any readmission) o Rate of readmission

Data requirements: Recipient baseline data, pre-HCT data, 100 day post-HCT data, six months to two year post-HCT data, recipient death data. Post-transplant complications and toxicities, Study design: This study will investigate the impact of pre-transplant co-morbid conditions, as measured by the HCT-CI on treatment related mortality, length of hospitalization/readmission, progression free survival and overall survival in elderly patients undergoing autologous stem cell transplantation for Hodgkin and non-Hodgkin lymphoma. Descriptive tables of patient, disease-, and transplant-related factors will be created. The tables will list median and range for continuous variables and percent of total for categorical variables. Probabilities of OS will be calculated using the Kaplan-Meier estimator. LOS will be calculated as the mean number of days patients were alive and out of the hospital within the first 100 days after transplant16. Cumulative incidence of NRM will be estimated by standard methods, with relapse of lymphoma treated as a competing risk. Progression free survival and Overall survival (OS) will calculated from the date of autologous HCT using Kaplan-Meier estimates. Multivariate analysis will be performed using Cox proportional hazards models for various outcomes. A stepwise model building approach will then be used to identify the significant risk factors associated

26


with the outcomes. Factors, which are significant at a 5% level, will be kept in the final model. The potential interactions between main effect and all significant risk factors will be tested.

References:

1. Maziarz RT, Wang Z, Zhang MJ, et al. Autologous haematopoietic cell transplantation for non-Hodgkin lymphoma with secondary CNS involvement. Br J Haematol. 2013;162(5):648-656.

2. Philip T, Armitage JO, Spitzer G, et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med. 1987;316(24):1493-1498.

3. Beitinjaneh A, Saliba RM, Medeiros LJ, et al. Comparison of survival in patients with T cell lymphoma after autologous and allogeneic stem cell transplantation as a frontline strategy or in relapsed disease. Biol Blood Marrow Transplant. 2015;21(5):855-859.

4. d'Amore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093-3099.

5. Reimer P, Rudiger T, Geissinger E, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27(1):106-113.

6. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912-2919.

7. Pasquini MC, logan, B.R., Ho, V.T., McCarthy, P.L., Cooke, K.R., Rizzo, J.D., Zhu, X., Sorror, M.L. Comorbidity Index (CI) in Autologous Hematopoietic Cell Transplantation (HCT) for Malignant Diseases: Validation of the HCT-CI. 54th ASH Annual Meeting and Exposition. Atlanta, GA; 2012.

8. Jaglowski SM, Ruppert AS, Hofmeister CC, et al. The hematopoietic stem cell transplant comorbidity index can predict for 30-day readmission following autologous stem cell transplant for lymphoma and multiple myeloma. Bone Marrow Transplant. 2014;49(10):1323-1329.

9. Saad A, Mahindra A, Zhang MJ, et al. Hematopoietic cell transplant comorbidity index is predictive of survival after autologous hematopoietic cell transplantation in multiple myeloma. Biol Blood Marrow Transplant. 2014;20(3):402-408 e401.

10. Pasquini MC ZX. 2014 CIBMTR Summary Slides. Available at: http://wwwcibmtrorg. 2014. 11. Dahi PB, Tamari R, Devlin SM, et al. Favorable outcomes in elderly patients undergoing high-

dose therapy and autologous stem cell transplantation for non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2014;20(12):2004-2009.

12. Hermet E, Cabrespine A, Guieze R, et al. Autologous hematopoietic stem cell transplantation in elderly patients (>/=70years) with non-Hodgkin's lymphoma: A French Society of Bone Marrow Transplantation and Cellular Therapy retrospective study. J Geriatr Oncol. 2015;6(5):346-352.

13. Berro M, Arbelbide JA, Rivas MM, et al. Hematopoietic Cell Transplantation-Specific Comorbidity Index Predicts Morbidity and Mortality in Autologous Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017;23(10):1646-1650.

14. Martinez C, Jorge AS, Pereira A, et al. Comorbidities, not age, are predictive of survival after autologous hematopoietic cell transplantation for relapsed/refractory Hodgkin's lymphoma in patients older than 50 years. Ann Hematol. 2017;96(1):9-16.

15. Graf SA, Vaughn JE, Chauncey TR, et al. Comorbidities, Alcohol Use Disorder, and Age Predict Outcomes after Autologous Hematopoietic Cell Transplantation for Lymphoma. Biol Blood Marrow Transplant. 2016;22(9):1582-1587.

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http://wwwcibmtrorg/


16. Ballen KK, Joffe S, Brazauskas R, et al. Hospital length of stay in the first 100 days after allogeneic hematopoietic cell transplantation for acute leukemia in remission: comparison among alternative graft sources. Biol Blood Marrow Transplant. 2014;20(11):1819-1827.

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Characteristics of patients age 65 or older undergoing first autologous HCT for NHL during 2008-2016

N (%)

Number of patients 3942 Research level data 435 Number of centers 218 Patient age at transplant

Median (range) 69 (65-84) 65 - 69 2478 (63) 70 - 79 1451 (37) ≥ 80 13 (<1) Patient sex Male 2377 (60) Female 1565 (40) Karnofsky performance score ≥ 90 2160 (55) < 90 1681 (43) Missing 101 (3) HCT-CI 0 1140 (29) 1-2 1093 (28) ≥ 3 1709 (43) Patient race Caucasian 3465 (88) African-American 105 (3) Asian 114 (3) Pacific islander 8 (<1) Native American 9 (<1) More than one race 3 (<1) Missing 238 (6) Subtype of lymphoma NHL follicular, predominantly small cleaved cell 79 (2) NHL follicular, mixed,small cleaved and large cell 135 (3) NHL follicular, predominantly large cell 122 (3) NHL diffuse, large B-cell 3459 (88) Follicular, predominantly large cell Grade IIIA 49 (1) Follicular, predominantly large cell Grade IIIB 21 (<1) Follicular, unknown grade 77 (2)

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N (%) Number of patients 3942 Disease status Sensitive 3700 (94) Resistant 207 (5) Untreated 5 (<1) Missing 30 (<1) Graft type Bone marrow 10 (<1) Peripheral blood 3925 Missing 7 (<1) Year of transplant 2008 281 (7) 2009 326 (8) 2010 362 (9) 2011 418 (11) 2012 472 (12) 2013 493 (13) 2014 492 (12) 2015 541 (14) 2016 557 (14) Median follow-up of survivors (range), months 37 (<1-108)

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Proposal: 1711-52

Title: Does outcome after allogeneic hematopoietic cell transplantation differ between patients with de novo diffuse large B-cell lymphoma (DLBCL) and transformed DLBCL arising in the setting of indolent lymphoma?

Alex Francisco Herrera, MD, [email protected], City of Hope

Hypothesis: Patients who have transformed indolent lymphoma (TIL) have improved progression-free survival (PFS) after allogeneic hematopoietic cell transplantation (alloHCT) compared to patients with de novo DLBCL.

Specific aims: • Evaluate whether there is a difference in post-alloHCT PFS among patients with TIL as compared

to patients with de novo DLBCL.• Evaluate whether there is a difference in post-alloHCT overall survival and cumulative incidence

of relapse among patients with TIL as compared to patients with de novo DLBCL.

Scientific impact: Outcomes after alloHCT for DLBCL are suboptimal, with relatively high rates of relapse and disappointing PFS. Especially in the setting of an ever-expanding arsenal of novel agents and powerful immunotherapeutic agents (i.e. CAR T-cells), this may lead to reluctance to pursue alloHCT in patients with multiply relapsed or refractory DLBCL. However, if it were determined that patients with transformed lymphoma have more favorable disease-related outcomes relative to patients with de novo DLBCL, it could impact practice, making alloHCT a more attractive strategy in this subgroup of aggressive lymphomas.

Scientific justification: Transformed indolent lymphomas (TIL) are a diverse subset of aggressive non-Hodgkin lymphomas (NHL) that develop through histologic transformation of an underlying indolent NHL, such as follicular lymphoma (FL). Patients with TIL are generally managed like patients with de novo diffuse large B-cell lymphoma (DLBCL); and, similar to DLBCL, outcomes in these patients have improved in the rituximab era.1 However, patients with relapsed or refractory (rel/ref) TIL have a poor prognosis, with a 4-year PFS and OS of 27% and 39%, respectively.2 3 Standard therapy for patients with rel/ref TIL (after failure of initial anthracycline-based chemoimmunotherapy) is salvage chemoimmunotherapy followed by autologous hematopoietic cell transplantation (autoHCT) in chemosensitive patients who are transplant candidates, or palliative therapies (e.g. chemoimmunotherapy, radioimmunotherapy, lenalidomide) in patients who are not candidates for transplantation.1 However, even in transplanted transformed DLBCL patients, outcomes are poor, with varying retrospective studies reporting 5 year PFS ranging from 25-57%,1 and the prospective NCIC CTG LY12 study demonstrating a 4-year event-free survival of 45% in transplanted patients.2

Allogeneic stem cell transplantation (alloHCT) can produce durable remissions in a subset of patients with rel/ref aggressive B-NHL even after failure of autoHCT.4,5 Data on outcomes of alloHCT in patients with TIL are limited, and survival estimates vary widely in the various small, restrospective studies that are available, ranging from as low as 5-year PFS/OS of 18% and 22%, respectively, to 4-year PFS/OS of 56% and 66%, respectively.6-9 The study populations in these analyses have been heterogeneous across

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studies, with some studies limiting eligibility to transformed follicular lymphoma and others including patients with TIL who had a wide range of underlying indolent lymphomas, including CLL/SLL (Richter transformation, RT). However, RT has a particular biology that is distinct from other TILs and it may have a particularly poor prognosis among transformed subtypes.3 There have been a number of studies performed that compare autoHCT versus alloHCT outcomes in patients with TIL, with the studies generally favoring autoHCT due to similar incidence of relapse but lower non-relapse mortality as compared to alloHCT.10-12 However, few studies have evaluated whether outcomes after alloHCT differ in patients with TIL as compared to de novo DLBCL. One study from Japan by Tada and colleagues, compared alloHCT outcomes in patients with FL, patients with DLBCL transformed from FL, and patients with de novo DLBCL. The authors determined that the PFS and OS in patients with DLBCL transformed from FL were significantly better as compared to de novo DLBCL and similar to patients with FL.13 The provocative findings from this small study (n=97 and only n=22 with DLBCL transformed from FL) were independently duplicated in another small, retrospective, multicenter study evaluating outcomes of patients with aggressive B-cell NHL (n=78 and n=25 with TIL), as a diagnosis of TIL was associated with better PFS (HR 0.48, p=0.024) and OS (0.48, p=0.03), and a lower incidence of relapse (HR 0.34), p=0.013) as compared to patients with DLBCL.14 Another study of RIC alloHCT for aggressive B-NHL showed a trend towards improved survival among patients with transformed FL compared to de novo DLBCL.9 We aim to confirm these findings in the larger CIBMTR cohort and propose to evaluate alloHCT outcomes in patients with DLBCL in the CIBMTR database excluding patients with RT and compare outcomes among patients with TIL and de novo DLBCL. Patient eligibility population: Adult (18 years or older) DLBCL patients who have undergone alloHCT (MAC or RIC) between the years 2003-2015, excluding:

• Richter transformation of CLL/SLL • Primary mediastinal large B-cell lymphoma • Primary CNS lymphoma • Patients with a prior history of transformed DLBCL but who only have indolent lymphoma at the

time of transplantation • Grade 3 follicular lymphoma without transformation to DLBCL • Patients with history of DLBCL undergoing alloHCT for MDS or acute leukemia

Data requirements: If supplemental data is required, please review data collection forms at: http://www.cibmtr.org/DataManagement/DataCollectionForms/Pages/index.aspx Variables: Patient related:

• Age at diagnosis • Age at alloHCT • Gender: male vs. female • Karnofsky performance score at alloHCT • HCT-CI • Race/Ethnicity

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http://www.cibmtr.org/DataManagement/DataCollectionForms/Pages/index.aspx


Disease related: • Disease stage at diagnosis: early vs advanced • Underlying indolent lymphoma subtype: FL vs MZL vs LPL • If underlying lymphoma is FL, FL grade: grade I vs grade II vs grade III • Bone marrow involvement at diagnosis: yes vs no vs. missing • Extranodal involvements at diagnosis: yes vs no vs. missing • LDH at diagnosis: Normal vs. High vs. missing • Response to 1st line therapy: CR vs. PR vs. SD vs. Progression vs. unknown • Time from diagnosis to 1st therapy failure • Prior autoHCT: yes vs no vs unknown

Transplant related: • Time from diagnosis to alloHCT • Chemosensitivity at HCT: CR vs. PR vs. chemorefractory vs. Untreated vs. missing/unkown • Bone marrow involvement at HCT: yes vs no vs missing • Elevated LDH at HCT: yes vs no vs. missing • Extranodal involvement at HCT: yes vs no vs. missing • Bulky disease at HCT: yes vs no vs missing • Number of lines of chemotherapies prior to transplantation: continuous; 1 vs. 2 vs. 3 vs. 4 or

more • Donor source: Bone marrow vs. Peripheral Blood vs. Cord • Donor gender • Conditioning regimen intensity: MAC vs RIC • Conditioning regimen type (e.g. Flu/melphalan) • GVHD prophylaxis regimen • Year of transplantation • Incidence of acute GVHD (yes/no, date, grade) • Incidence of chronic GVHD (yes/no, date, limited/extensive) • Donor Type: matched sibling vs matched unrelated vs mismatched unrelated vs haplo vs cord • Vital status: Alive v dead • Relapse status: Yes v No • Time from alloHCT to relapse (to calculate PFS)

Study design: The objective of this study is to compare the post-alloHCT PFS and OS of patients with TIL compared to patients with de novo DLBCL. The goal is to determine whether patients with TIL have more favorable outcome after alloHCT than patients with de novo DLBCL and thus, whether alloHCT should feature more prominently in the care of patients with TIL. Patient-, disease- and transplant- related factors will be compared between groups (TIL vs de novo) using the Chi-square test for categorical variables and the Wilcoxon two sample test for continuous variables. PFS and OS will be estimated using the Kaplan-Meier method. Cumulative incidence of non-relapse mortality (NRM) and relapse/progression (CIR) will be calculated reflecting time to non-relapse death and time to relapse, respectively, as competing risks. The log-rank test will be used to compare OS and PFS between the study groups (TIL vs de novo DLBCL), while the Gray test will be used to compare NRM and CIR incidences. Multivariable analysis using Cox models for PFS and OS with stepwise variable selection will be performed using the patient-, disease- and transplant-related variables described above.

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References: 1. Casulo C, Burack WR, Friedberg JW. Transformed follicular non-Hodgkin lymphoma. Blood.

2015;125(1):40-47. 2. Kuruvilla J, MacDonald DA, Kouroukis CT, et al. Salvage chemotherapy and autologous stem cell

transplantation for transformed indolent lymphoma: a subset analysis of NCIC CTG LY12. Blood. 2015;126(6):733-738.

3. Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome. Blood. 2014;123(11):1647-1657. 4. 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;120(20):4256-4262. 5. Fenske TS, Ahn KW, Graff TM, et al. Allogeneic transplantation provides durable remission in a

subset of DLBCL patients relapsing after autologous transplantation. Br J Haematol. 2016;174(2):235-248.

6. Hamadani M, Awan FT, Elder P, et al. Feasibility of allogeneic hematopoietic stem cell transplantation for follicular lymphoma undergoing transformation to diffuse large B-cell lymphoma. Leuk Lymphoma. 2008;49(10):1893-1898.

7. Rezvani AR, Storer B, Maris M, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin's lymphoma. J Clin Oncol. 2008;26(2):211-217.

8. Clavert A, Le Gouill S, Brissot E, et al. Reduced-intensity conditioning allogeneic stem cell transplant for relapsed or transformed aggressive B-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2010;51(8):1502-1508.

9. Thomson KJ, Morris EC, Bloor A, 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):426-432.

10. Villa D, Crump M, Panzarella T, et al. Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow transplant group. J Clin Oncol. 2013;31(9):1164-1171.

11. Villa D, George A, Seymour JF, et al. Favorable outcomes from allogeneic and autologous stem cell transplantation for patients with transformed nonfollicular indolent lymphoma. Biol Blood Marrow Transplant. 2014;20(11):1813-1818.

12. Wirk B, Fenske TS, Hamadani M, et al. Outcomes of hematopoietic cell transplantation for diffuse large B cell lymphoma transformed from follicular lymphoma. Biol Blood Marrow Transplant. 2014;20(7):951-959.

13. Tada K, Kim SW, Asakura Y, et al. Comparison of outcomes after allogeneic hematopoietic stem cell transplantation in patients with follicular lymphoma, diffuse large B-cell lymphoma associated with follicular lymphoma, or de novo diffuse large B-cell lymphoma. Am J Hematol. 2012;87(8):770-775.

14. Herrera AF, Song, J. Y., Griffin, G. K., et al. Double-Hit and Double-Expressor Lymphomas Are Not Associated with an Adverse Outcome after Allogeneic Stem Cell Transplantation. Blood 128 (22), 830-830.; 2016.

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Baseline characteristics of DLBCL patients registered in the CIBMTR from 2003-2016

N (%)


Median (range) 55 (<1-75) 18-29 30 (2) 30-39 101 (6) 40-49 179 (10) 50-59 301 (17) 60-69 629 (36) ≥ 70 495 (29) Transformed DLBCL No 1323 (76) Yes 412 (24) Patient sex Male 1068 (62) Female 667 (38) Karnofsky performance score ≥ 90 999 (58) < 90 679 (39) Missing 57 (3) Graft type Bone marrow 215 (12) Peripheral blood 1404 (81) Umbilical cord blood 116 (6) Donor type HLA-identical sibling 538 (31) Identical twin 19 (1) HLA-matched other relative 36 (2) HLA-mismatched relative 177 (10) Other relative, HLA TBD 3 (<1) HLA-matched unrelated 166 (10) HLA-mismatched unrelated 49 (3) Unrelated donor, HLA TBD 745 (43) Multiple donor 2 (<1)

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N (%)

Number of patients 1735 Year of transplant 2003 68 (4) 2004 63 (4) 2005 72 (4) 2006 92 (5) 2007 81 (5) 2008 60 (3) 2009 65 (4) 2010 34 (2) 2011 23 (1) 2012 29 (2) 2013 331 (19) 2014 292 (17) 2015 279 (16) 2016 246 (14) Median follow-up of survivors (range), months 35 (<1-175)

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Baseline characteristics of transformed DLBCL patients registered in the CIBMTR from 2003-2016

N (%)

Number of patients 412 Research level data 250 Number of centers 107 Patient age at transplant Median (range) 57 (11-75) 18-29 1 (<1) 30-39 6 (1) 40-49 24 (6) 50-59 56 (14) 60-69 169 (41) ≥ 70 156 (38) Patient sex Male 263 (64) Female 149 (36) Karnofsky performance score ≥ 90 255 (62) < 90 145 (35) Missing 12 (3) Graft type Bone marrow 40 (10) Peripheral blood 346 (84) Umbilical cord blood 26 (6) Donor type HLA-identical sibling 114 (28) Identical twin 5 (1) HLA-matched other relative 8 (2) HLA-mismatched relative 42 (10) HLA-matched unrelated 43 (10) HLA-mismatched unrelated 8 (2) Unrelated donor, HLA TBD 192 (47)

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N (%)

Number of patients 412 Year of transplant 2003 17 (4) 2004 15 (4) 2005 19 (5) 2006 17 (4) 2007 21 (5) 2008 9 (2) 2009 19 (5) 2010 9 (2) 2011 5 (1) 2012 6 (1) 2013 43 (10) 2014 81 (20) 2015 83 (20) 2016 68 (17) Median follow-up of survivors (range), months 25 (3-175)

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Proposal: 1711-67

Title: Allogeneic hematopoietic transplantation strategies for anaplastic large cell lymphoma in adult patients: current trends and impact of pre-transplant targeted therapy (Brentuximab Vedotin and Crizotinib)

Alberto Mussetti, MD, [email protected], Istituto Nazionale dei Tumori di Milano Abraham S. Kanate, MD, [email protected], West Virginia University Paolo Corradini, MD, [email protected], Istituto Nazionale dei Tumori di Milano

Hypothesis: In the current era, the advent of targeted therapies such as anti-CD30 antibody-drug conjugate brentuximab vedontin (BV) and anaplastic lymphoma kinase inhibitors (crizotinib) may improve survival outcomes in anaplastic large cell lymphoma (ALCL) patients undergoing allogeneic hematopoietic cell transplantation (alloHCT).

Objectives: • Primary objective: Overall Survival (OS) after alloHCT for ALCL patients• Secondary objectives:

o Progression Free Survival (PFS), Toxicity Related Mortality (TRM), neutrophil engraftment,platelets engraftment, Relapse Incidence/Progression of Disease (RI/POD), acute Graftversus Host Disease (aGVHD), chronic Graft versus Host Disease (cGVHD), following allo HCTfor ALCL

o Primary cause of death: according to the Capelan algorithm, descriptive only

Scientific justification: Anaplastic Large Cell Lymphoma (ALCL) accounts for 5% of non-Hodgkin lymphomas and almost 15% of peripheral T-cell lymphomas.1

ALK-positive and ALK-negative ALCL are two very different entities. While ALK-positive ALCL is more common in younger patients and has a better overall survival (5-year OS 60%), ALK-negative ALCL usually affects older patients and has a worse prognosis (5-year OS 49%). At diagnosis, CHOP-based chemotherapy is the most commonly used induction treatment for ALCL. ALK + ALCL may have complete remission (CR) rate of almost 90% while in ALK – ALCL CR is seen in only 50%,in line with other PTCLs histologies.2 For this reason, consolidation therapy is not suggested by currentguidelines for ALK + ALCL while autologous transplant is the preferred first-line consolidation strategyfor ALK – ALCL with a 3-year overall survival of 71%.3 However, failure-free survival (FFS) at relapse is notdifferent between the two entities with a median progression-free survival of 5.2 months and 3.0months between ALK + ALCL and ALK – ALCL.4

While common second-line chemotherapies (e.g. ICE, DHAP, GemOx) have usually an overall response rate (ORR) of 35-40%,5 brentuximab vedotin has shown a very promising efficacy for ALCL with an ORR of 86% and CR of 57%.6 Moreover, for ALK+ ALCL, the ALK inhibitor crizotinib showed a promising activity in both pediatric and adult relapsed/refractory lymphoma with a CR rate of 76% and 100% respectively.7,8 Considering the high response rate, most of these patients will likely be eligible for a potentially curative alloHCT. Subgroup analysis of PTCL patients who received alloHCT have shown that this procedure is feasible for ALCL patients. The French group reported the outcome of 27 ALCL patients

39


from a cohort of 77 PTCLs with a 5-year OS of 55%. CIBMTR reported a possible role for autologous transplant for selected ALCL patients after first relapse.9

Currently, there are no studies regarding the role of alloHCT on a homogeneous cohort of ALCL, especially after a few years from the introduction of brentuximab and crizotinib into the clinical practice. Moreover, there are no studies reporting the optimal dosage/timing/suspension and possible restart of brentuximab and crizotinib for ALCL patients undergoing alloHCT.

We consider a registry study as the appropriate typology of study to address these questions considering the rare use of alloHCT for ALCL.

The innovation of this study relies on reporting for the first time the results of alloHCT in ALCL patients in the brentuximab vedotin and crizotinib era.

The clinical significance of this study consists in furnishing more consistent data regarding the use of alloHCT in ALCL patients. A comparison between those patients who used novel treatments before transplant and standard chemotherapy could give useful clinical informations regarding which salvage therapy should be preferred at relapse. Moreover, a subset analysis on those ALK+ patients who received ALK-inhibitors (e.g. crizotinib) pre alloHCT could help in finding which is the best way to administer this recent class of drugs in transplant-eligible patients.

Study Population: Inclusion Criteria:

• Relapsed/refractory ALCL patients (ALK + and ALK -)• Age ≥18 years, undergoing first allogeneic HCT between 2008-2016, reported to the CIBMTR.• HLA-matched related or unrelated donor• HLA-haploidentical donor (only with PT-Cy)• Any conditioning regimen will be permitted.• Bone marrow and/or peripheral blood as graft source.

Outcomes: Hematopoietic recovery: The primary measures for hematopoietic recovery will be:

• Time to neutrophils (ANC) > 0.5 x109/L sustained for three consecutive days. This endpoint willbe evaluated at 28-day and 100-day after HCT.

• Time to achieve a platelet count of (a) >20 x 109/L independent of platelet transfusions for 3consecutive days, and (b) >50 x 109/L independent of platelet transfusions for 3 consecutivedays within 28 and 100 days post-transplant.This endpoint will be evaluated at 28-day and 100-day after HCT.

TRM: Cumulative incidence of TRM at day +100 and 1, 3, and 5 year. TRM is defined as death without preceding disease relapse/progression. Relapse/progression are competing events. RI/POD: Cumulative incidence of disease relapse/progression at 1, 3, and 5 years, with TRM as competing event. PFS: Survival without relapse/progression or death at 1,3 and 5 years. Relapse or progression of disease and death are events. Those who survive without recurrence or progression are censored at last contact. OS: Time to death at 1,3 and 5 years. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up.

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Acute GVHD: Cumulative incidence of grade II-IV acute GVHD per consensus criteria at day +100 and +180, with death as competing risk. Chronic GVHD: Cumulative incidence of limited and extensive chronic GVHD at 1 and 3 years, with death as competing risk. Data Requirements: Utilizing data collected by CIBMTR from pre and post HCT, which includes pre-transplant essential data form #2400, post-transplant essential data form #2450, selective post-transplant selective data form #2455 and 100 day post-HCT data form #2100, Six Months to Two Years Post-HCT Data #2200. The parameters to be assessed are outlined in table 1 below.

Table. 1 Data Requirements

Type of data Data point Specific data Patient Specific

Patient specific characteristics

• Age at transplant (Date of birth) • Gender • Race • Significant comorbidities • Primary disease type (ALCL) • Disease risk (high risk or standard) • Status of disease at transplantation • Remission status (CR1, CR2, etc) • Use of brentuximab • Use of crizotinib

Transplant Specific

Transplant date • Transplant date Transplant information • HLA-matched related or unrelated donors,

haploidentical Preparative regimen used

• Myeloablative or reduced-intensity

GVHD prophylaxis • Cyclosporine/tacrolimus + MTX or PT-Cy based in case of haploidentical donor

Graft characteristic • Stem cell source (BM or PBSC) 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

• Graft failure (primary and secondary) GVHD • Acute GVHD (aGVHD)

o Incidence of grade II-IV acute GVHD (aGVHD) (subset evaluating grade III-IV aGVHD)

o Time to aGVHD • Chronic GVHD

o Incidence of chronic GVHD at 2 years (cGVHD) o Severity of GVHD after day 100

Mortality • Time to mortality • Day 100, 6 months and 2 year mortality

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• Treatment related mortality at 6 months and 1 year • Cause of mortality

Infection • Incidence of viral, fungal, bacterial infection Disease relapse • Incidence of disease relapse

• Time to disease relapse Variables: Patient-related:

• Age at HCT, years: 18-29; 30-39; 40-49, 50-59, ≥60 years and continuous • Sex: male vs female • Karnofsky performance score: ≥90% vs. <90% • Sorror Co-morbidity index: 0 vs. 1-2 vs. 3 • Race: White vs. Afroamerican vs. Asian/pacific islander vs. Hispanic vs. others

Disease-related: • Elevated LDH at diagnosis: yes vs no • Time from diagnosis to HCT: <1year vs. ≥1 year and continuous • Number of prior chemotherapy regimens received: continuous (for CRF cases) • Chemosensitivity at HCT: chemosensitive vs chemoresistant • Crizotinib or other ALK-inhibitors use previous to alloHCT (only ALK+ ALCL) • Brentuximab use previous to alloHCT

Transplant-related: • Conditioning regimen: TBI-based vs no TBI • Graft type: bone marrow vs peripheral blood • GVHD prophylaxis • Year of HCT: Continuous • Female donor/Male recipient: yes vs no • Negative donor/Positive recipient CMV status: yes vs no

Study design: The aim of this study is to describe the clinical outcomes of alloHCT in patients affected by ALCL.

OS and PFS probabilities will be calculated using Kaplan-Meier estimator. Neutrophil engraftment, platelets engraftment, acute GVHD, chronic GVHD, TRM, RI/POD will be calculated using cumulative incidence estimates to account for competing risks. Cox proportional hazards regression will be used to compare the two HCT types for, NRM, relapse/progression, PFS, and OS. The assumption of proportional hazards for each factor in the Cox model will be tested using time-dependent covariates. When the test indicated differential effects over time (non-proportional hazards), models will be constructed breaking the post transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. The proportionality assumptions will be further tested. A backward stepwise model selection approach will be used to identify all significant risk factors. Each step of model building contained the main effect for conditioning regime. Factors which are significant at a 5% level will be kept in the final model. The potential interactions between main effect and all significant risk factors will be tested.

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Potential Pitfalls: AlloHCT cohort with previous use of ALK-inhibitors may be too small to perform meaningful statistical analysis. In this scenario additional data could be requested from European Bone Marrow Transplantation (EBMT) registry. However, also a comprehensive analysis of a large cohort of ALCL patients undergoing alloHCT will be new and of clinical interest.

References: 1. International T-Cell Lymphoma Project. International Peripheral T-Cell and Natural Killer/T-Cell

Lymphoma Study: Pathology Findings and Clinical Outcomes. J. Clin. Oncol. 26, 4124–4130 (2008). 2. Savage, K. J. et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically

different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111, 5496–5504 (2008).

3. Reimer, P. et al. Autologous Stem-Cell Transplantation As First-Line Therapy in Peripheral T-Cell Lymphomas: Results of a Prospective Multicenter Study. J. Clin. Oncol. 27, 106–113 (2009).

4. Chihara D. The survival outcome of the patients with relapsed/refractory anaplastic large-cell lymphoma. in (2015).

5. Zelenetz, A. D. et al. Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin’s lymphoma. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 14 Suppl 1, i5-10 (2003).

6. Pro, B. et al. Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study. J. Clin. Oncol. 30, 2190–2196 (2012).

7. Mossé, Y. P. et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 14, 472–480 (2013).

8. Gambacorti Passerini, C. et al. Crizotinib in Advanced, Chemoresistant Anaplastic Lymphoma Kinase–Positive Lymphoma Patients. JNCI J. Natl. Cancer Inst. 106, (2014).

9. Smith, S. M. et al. Hematopoietic Cell Transplantation for Systemic Mature T-Cell Non-Hodgkin Lymphoma. J. Clin. Oncol. 31, 3100–3109 (2013).

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Characteristics of anaplastic large cell lymophoma patients who received an allogeneic HCT or autologous HCT from 2013-2016

Allogeneic HCT Autologous HCT

Number of patients 62 38 Number of centers 44 31 Patient age at transplant

Median (range) 39 (5-72) 58 (19-73) 0-18 18 (29) 0 18-29 4 (6) 3 (8) 30-39 10 (16) 4 (11) 40-49 6 (10) 3 (8) 50-59 12 (19) 11 (29) ≥ 60 12 (19) 17 (45) Patient sex Male 38 (61) 26 (68) Female 24 (39) 12 (32) Karnofsky performance score ≥ 90 37 (60) 24 (63) <90 23 (37) 14 (37) Missing 2 (3) 0 Subtype of lymphoma Anaplastic large-cell lymphoma (ALCL), ALK+ 26 (42) 4 (11) Anaplastic large-cell lymphoma (ALCL), ALK- 17 (27) 28 (74) Anaplastic LC,T/N cell, cutaneous 15 (24) 2 (5) Anaplastic LC,T/N cell, systemic 4 (6) 4 (11) Graft type Bone marrow 22 (35) 0 Peripheral blood 22 (35) 38 Umbilical cord blood 18 (29) 0 Donor type Autologous HSCT NA 38 (100) HLA-identical sibling 12 (19) NA Sysgeneic twin 2 (3) NA Unrelated donor 33 (53) NA HLA-matched other relative 2 (3) NA HLA-mismatched relative 12 (19) NA Missing 1 (2) NA

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Allogeneic HCT Autologous HCT

Number of patients 62 38 Brentuximab No 30 (48) 29 (76) Yes 32 (52) 9 (24) Crizotinib No 55 (89) 38 Yes 7 (11) 0 Year of transplant 2013 13 (21) 7 (18) 2014 17 (27) 8 (21) 2015 20 (32) 14 (37) 2016 12 (19) 9 (24) Median follow-up of survivors (range), months 24 (3-38) 16 (5-50)

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Proposal: 1711-69

Title: Outcomes in B cell Non-Hodgkin’s Lymphoma (NHL) Patients Who Underwent Autologous Stem Cell Transplantation Following Rituximab Containing Conditioning Regimens

Deepa Jagadeesh, MD, MPH, [email protected], Cleveland Clinic, Navneet Majhail, MD, MS, [email protected], Cleveland Clinic, Brian T Hill, MD, PhD, [email protected], Cleveland Clinic

Hypothesis: Rituximab containing condition regimen may improve outcomes in B cell non Hodgkin lymphoma (NHL) like diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) patients undergoing autologous stem cell transplantation (ASCT) compared to non-rituximab containing condition regimens

Specific aims • To evaluate the impact of rituximab containing conditioning regimen for in DLBCL and FL

patients undergoing ASCT compared to non-rituximab conditioning regimen. The outcomes willbe evaluated in terms of non relapse mortality (NRM), progression free survival (PFS) and overallsurvival (OS)

• Secondary objectives include time to neutrophil and platelet engraftment, incidence ofinfections post-transplant and relapse rate.

Scientific impact: If improved outcomes are observed with rituximab containing preparative regimens, this could provide sound rationale for future clinical trial design to validate these results prospectively.

Scientific justification: The advent of monoclonal antibody rituximab has revolutionized the treatment of B cell non-Hodgkin lymphoma (NHL) with superior outcomes. The impact of rituximab when combined with conditioning regimens is not well defined as there are very few trials exploring this. A few studies have evaluated the outcomes integrating rituximab during stem cell mobilization for purging. These early studies showed that purging using rituximab was safe and feasible in both low and high grade B cell NHL ([1, 2]. Khouri et al demonstrated better 2 year OS (80% vs 53%; p=.002) and disease free survival (67% vs 43%; p=.004) with pre and post-transplant administration of rituximab in aggressive B cell NHL compared to matched historical controls [3]. However, infection rates were higher in the rituximab group. An Italian retrospective multicenter study revealed the addition of rituximab during mobilization resulted in improved outcomes in DLBCL and FL patients undergoing salvage ASCT with superior 5 year OS (69% vs 60%) and event free survival (61% vs 51%) compared to no rituximab [4]. The BMT CTN 0410 phase III trial randomized relapsed/refractory DLBCL patients with chemo sensitive disease to either rituximab/BEAM (carmustine, etoposide, cytarabine and melphalan) or radioimmunotherapy iodine-131 tositumomab with BEAM (B-BEAM) [5]. Comparable outcomes were observed in both arms with 2 year OS and progression free survival (PFS) of 67% vs 61% (p=.38) and 49% vs 48% (p=.94) in R-BEAM and B-BEAM respectively. Recently published CIBMTR analysis revealed superior PFS with rituximab containing reduced intensity regimens (R-RIC) compared to nonR-RIC regimes in both aggressive and low grade B cell NHL following allogeneic stem cell transplantation [6]. Although the role of rituximab in B cell NHL treatment is well defined, its impact when incorporated during peritransplant period remains

46


indeterminate. It is important to know if integration of rituximab in pre-ASCT conditioning regimens influences outcomes in B cell NHL. A large registry based study will be ideal to explore this hypothesis. Patient eligibility population: Adult patients aged ≥18 years with DLBCL and FL who underwent ASCT between 2000-2015 using either BEAM or busulfan based conditioning regimen with or without rituximab Data collection forms: Hodgkin and Non-Hodgkin’s lymphoma pre-HSCT data and Hodgkin and Non-Hodgkin’s lymphoma post-HSCT data forms Variables: Age at diagnosis and transplant, gender, race, KPS score, lymphoma subtype, B symptoms at diagnosis, stage at diagnosis, LDH, IPI, FLIPI, number of prior therapies, BM involvement at diagnosis and transplant, CNS involvement at diagnosis, extranodal involvement, time from diagnosis to transplant, number of prior therapy, chemotherapy regimen, radiation therapy, disease status at transplant, PET scan results prior to transplant if available, mobilization regimen, conditioning regimen, TBI based regimens, disease risk index at transplant, days to neutrophil and platelet engraftment, response to transplant, 100 day disease status, PET scan results post-transplant if available, 100 day mortality, median follow up, alive/dead, cause of death Study design: This is a retrospective registry based analysis evaluating outcomes of rituximab containing condition regimen to non-rituximab condition regimen in DLBCL and FL patients who underwent ASCT The outcomes will be analyzed based on 5 year NRM, PFS and OS. All outcomes will be calculated relative to the transplant date. Cumulative incidence method will be used to estimate relapse and NRM. Kaplan-Meier analysis will be used to estimate PFS and OS. Cox proportional hazard analysis will be used for univariate analysis to identify prognostic factors for PFS and OS. Multivariable analysis will be done using stepwise selection. Results will be reported as hazard ration (HR), 95% confidence interval for HR and p value. Data source: CIBMTR Research Database.

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References: 1. Flinn, I.W., et al., Immunotherapy with rituximab during peripheral blood stem cell transplantation

for non-Hodgkin's lymphoma. Biol Blood Marrow Transplant, 2000. 6(6): p. 628-32. 2. Flohr, T., et al., Rituximab in vivo purging is safe and effective in combination with CD34-positive

selected autologous stem cell transplantation for salvage therapy in B-NHL. Bone Marrow Transplantation, 2002. 29: p. 769.

3. Khouri, I.F., et al., Concurrent Administration of High-Dose Rituximab Before and After Autologous Stem-Cell Transplantation for Relapsed Aggressive B-Cell Non-Hodgkin’s Lymphomas. Journal of Clinical Oncology, 2005. 23(10): p. 2240-2247.

4. Tarella, C., et al., Rituximab Improves the Efficacy of High-Dose Chemotherapy With Autograft for High-Risk Follicular and Diffuse Large B-Cell Lymphoma: A Multicenter Gruppo Italiano Terapie Innnovative nei Linfomi Survey. Journal of Clinical Oncology, 2008. 26(19): p. 3166-3175.

5. Vose, J.M., et al., Phase III Randomized Study of Rituximab/Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) Compared With Iodine-131 Tositumomab/BEAM With Autologous Hematopoietic Cell Transplantation for Relapsed Diffuse Large B-Cell Lymphoma: Results From the BMT CTN 0401 Trial. Journal of Clinical Oncology, 2013. 31(13): p. 1662-1668.

6. Epperla, N., et al., Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma. Journal of Hematology & Oncology, 2017. 10(1): p. 117.

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Characteristics of first autologous HCT for diffuse large B-cell lymphoma or follicular lymphoma patients from 2000-2015

DLBCL FL


Median (range) 57 (<1-86) 55 (<1-80) 0-18 121 (<1) 6 (<1) 18-29 1049 (5) 39 (<1) 30-39 1636 (8) 253 (6) 40-49 3091 (16) 933 (24) 50-59 5891 (30) 1539 (39) ≥ 60 7596 (39) 1192 (30) Patient sex Male 11600 (60) 2291 (58) Female 7764 (40) 1664 (42) Missing 20 (<1) 7 (<1) Karnofsky performance score ≥90 7163 (37) 1367 (35) <90 9283 (48) 1839 (46) Missing 2938 (15) 756 (19) Graft type Bone marrow 226 (1) 50 (1) Peripheral blood 18887 (97) 3814 (96) Missing 271 (1) 98 (2) Rituximab use in conditioning No 16816 (87) 3475 (88) Yes 2568 (13) 487 (12) Year of transplant 2000 958 (5) 269 (7) 2001 1083 (6) 280 (7) 2002 1041 (5) 281 (7) 2003 955 (5) 264 (7) 2004 1168 (6) 272 (7) 2005 1161 (6) 287 (7) 2006 1175 (6) 307 (8) 2007 984 (5) 271 (7) 2008 1111 (6) 251 (6)

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DLBCL FL

Number of patients 19384 3962 2009 1245 (6) 285 (7) 2010 1279 (7) 293 (7) 2011 1434 (7) 228 (6) 2012 1450 (7) 265 (7) 2013 1431 (7) 185 (5) 2014 1388 (7) 114 (3) 2015 1521 (8) 110 (3) Year of transplant, rituximab used in conditioning 2000 4 (<1) 6 (1) 2001 4 (<1) 1 (<1) 2002 3 (<1) 1 (<1) 2003 30 (1) 5 (1) 2004 30 (1) 2 (<1) 2005 22 (<1) 9 (2) 2006 41 (2) 15 (3) 2007 124 (5) 33 (7) 2008 439 (17) 91 (19) 2009 296 (12) 113 (23) 2010 244 (10) 32 (7) 2011 269 (10) 33 (7) 2012 253 (10) 48 (10) 2013 306 (12) 39 (8) 2014 232 (9) 27 (6) 2015 271 (11) 32 (7) Median follow-up of survivors (range), months 59 (<1-199) 72 (<1-205)

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Proposal: 1711-102

Title: Effect of Time to Relapse on Overall Survival in Mantle Cell Lymphoma Patients Following Frontline Autologous Stem Cell Transplant

Peter Riedell, MD, [email protected], The University of Chicago Sonali Smith, MD, [email protected], The University of Chicago

Hypothesis: We hypothesize that early relapse of disease (<2 years) following autologous transplantation in mantle cell lymphoma is predictive of a high-risk group with inferior overall survival.

Specific aims: • Objective 1: To compare post-relapse survival among patients relapsing <2 years and ≥2

years following frontline autologous stem cell transplant for mantle cell lymphoma.

• Objective 2: To determine factors predicting early relapse after autologous stem celltransplantation for mantle cell lymphoma between January 2001 and December 2016

Scientific impact: Time to relapse has been prognostic in other lymphoma subtypes, but has not been fully evaluated in mantle cell lymphoma. Such analysis may help to more accurately identify high-risk subgroups and aid in therapeutic decision making.

Scientific justification: Mantle cell lymphoma (MCL) is an aggressive subtype of Non-Hodgkin lymphoma (NHL) and is characterized by the t(11:14) chromosomal translocation which results in dysregulation and overexpression of the cell cycle protein cyclin D1.(1, 2) MCL accounts for approximately 5-10% of NHL cases and has been increasing in incidence in the past two decades.(3)

The treatment landscape in MCL has evolved through a better understanding of optimal treatment strategies, disease biology, and patient selection. Initial experience with anthracycline based regimens and rituximab elicited a high response rate, though yielded a poor median progression-free survival (PFS) and overall survival (OS) (1.5 and 3 years, respectively).(4) Consequently, novel treatment combinations have been explored in an effort to attain deeper and more durable remissions. The role of multi-agent chemotherapy followed by conditioning therapy and autologous stem cell transplant (ASCT) has been evaluated in a number of studies, consistently yielding high response rates and prolonged PFS.(5-7) Based on these findings, induction therapy followed by autologous transplantation has become a common practice in the treatment of fit patients with MCL.

Despite this aggressive treatment approach, MCL continues to have a less favorable prognosis when compared to other B-cell NHL subtypes, and remains incurable with conventional therapy.(8) When evaluating outcomes in MCL, it is evident that there is significant heterogeneity. A retrospective study by Fenske et al. revealed that nearly 20% of patients who underwent early ASCT for chemotherapy-sensitive MCL relapsed at 2-years.(9) Though recent prospective trials have demonstrated a median event-free survival (EFS) of approximately 7 years with intensive treatment, nearly 20% of patients were noted to suffer disease progression or death at 2 years.(5, 7) This subset of early relapsing

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patients is suggestive of a more aggressive disease phenotype, and consequently, these patients may benefit from novel therapeutic approaches in either the upfront or relapsed setting. Multiple studies have attempted to predict prognosis based on baseline characteristics, including the mantle cell lymphoma international prognostic index (MIPI). The MIPI score was derived from a cohort of 455 patients with advanced stage MCL and is used to predict overall survival. The index stratifies patients into three risk groups; low-risk with a 5-year median OS of 60%, and intermediate-, and high-risk with a 5-year median OS of 35%, and 20%, respectively.(10, 11) Though the MIPI score is highly applicable in untreated patients, it has not been validated for risk-stratification in the setting of disease progression. More recent efforts evaluating clinical outcomes in lymphoma have explored the impact of early disease progression on OS. In follicular lymphoma, the National Lymphocare study revealed a significantly decreased OS in patients relapsing within 24 months of R-CHOP chemotherapy.(12) Similarly, in DLBCL, patients without relapse at 24 months achieved an equivalent OS to that of the age- and sex-matched general population.(13) Based on this data, time to event analysis has recently emerged as a robust risk-defining tool. The clinical significance of early relapse and its impact on OS is currently unknown in MCL. As such, we seek to investigate whether time to progression following ASCT may affect overall survival outcomes in MCL. We propose to use the CIBMTR database to compare the outcomes of patients relapsing <2 and ≥2 years following frontline ASCT for MCL. We hypothesize that early relapse (<2 years) following ASCT is predictive of a high-risk group with inferior OS in MCL. Identification of baseline characteristics and survival outcomes of patients with early relapse may prove useful in determining if this population should be considered for alternative treatment strategies. Patient eligibility population: Inclusion criteria:

1. Adults (age ≥ 18) with a diagnosis of mantle cell lymphoma who underwent a first ASCT between 2000-2016

2. Patients who received transplant within 12 months of diagnosis of MCL 3. Patients must have received frontline treatment with rituximab-containing

chemoimmunotherapy 4. Patients must have received an ASCT in first partial remission (PR1) or first complete remission

(CR1) 5. Patients must have documented relapse of MCL

Exclusion criteria: 1. Patient not transplanted in PR1/CR1 2. Patients receiving induction therapy with single agent rituximab or chemotherapy without

rituximab

Data requirements: We will utilize the following CIBMTR data forms:

• 2400: Pre-Transplant Essential Data • 2018: Hodgkin and Non-Hodgkin Lymphoma Pre-HCT Data • 2118: Hodgkin and Non-Hodgkin Lymphoma Post-HCT Data

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Outcomes: • Relapse/Progression: Cumulative incidence of disease relapse/progression • Progression-free survival (PFS): survival without relapse/progression or death. Relapse or

progression of disease and death are events. Patients surviving without recurrence or progression will be censored at time of last follow-up.

• Time to death from relapse in years: Death from any cause will be considered an event. Surviving patients will be censored if they were lost to follow-up, drop out, or were alive at the end of the study period.

• Time to relapse from transplant in years: Relapsed MCL will be considered an event. Patients will be censored if they were lost to follow-up, drop out, or did not relapse at the end of the study period.

Variables: Main effect: Relapse <2, ≥2 years after transplantation Patient-related:

• Age at HCT, years: <60 vs ≥60 years; and continuous • Gender: male vs female • Karnofsky score at transplant: ≥90% vs <90% vs unknown • Race: White vs African American vs others vs unknown

Disease-related:

• Disease stage at transplant: I/II vs III/IV vs unknown • Bone marrow involvement at transplantation: yes vs no • Ki67: >33% vs ≤33%

Transplant-related:

• Number of lines of chemotherapy prior to transplant: 1 vs >1; and continuous • Transplantation conditioning therapy: BEAM vs BEC +/- cytarabine vs others • Disease status at transplant: CR vs PR • Total number of CD34+ cells infused, x106/kg: continuous • Year transplanted: continuous

Post-transplant related:

• Post-transplant therapy: Allogeneic transplant vs non-transplant therapy • Maintenance rituximab: yes vs no • Number of treatments following relapse: continuous

Study design: This will be a retrospective analysis of the CIBMTR database. The goal of this study is to identify baseline characteristics and survival outcomes of patients with early progression (relapse <2 years following ASCT) in order to determine if this population should be considered for alternative treatment strategies. We specifically seek to compare outcomes of MCL patients relapsing <2 years, >2 years following ASCT, while adjusting for significant patient- and disease-related variables. Patient- and disease-related factors will be compared between treatment groups using logistic regression for the covariates listed above with backwards selection (factors removed in <5% significant) to find factors associated with progression of disease. Univariable associations between factors and relapse will also be calculated by

53


the Pearson X2 test. Adjusted probabilities of progression free survival (PFS) and overall survival will be generated from the final models stratified by weighted averages of covariate values using the pooled sample proportion as the weight function. These adjusted probabilities estimate likelihood of outcomes in populations with similar prognostic factors. Data source: For this study, we will utilize the CIBMTR Research Database. No external data sources will be employed. References: 1. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical

features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol. 1998;16(8):2780-95.

2. McKay P, Leach M, Jackson R, Cook G, Rule S. Guidelines for the investigation and management of mantle cell lymphoma. Br J Haematol. 2012;159(4):405-26.

3. Zhou Y, Wang H, Fang W, Romaguer JE, Zhang Y, Delasalle KB, et al. Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004. Cancer. 2008;113(4):791-8.

4. Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23(9):1984-92.

5. Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112(7):2687-93.

6. Damon LE, Johnson JL, Niedzwiecki D, Cheson BD, Hurd DD, Bartlett NL, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27(36):6101-8.

7. Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013;121(1):48-53.

8. Herrmann A, Hoster E, Zwingers T, Brittinger G, Engelhard M, Meusers P, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27(4):511-8.

9. Fenske TS, Zhang MJ, Carreras J, Ayala E, Burns LJ, Cashen A, et al. Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality. J Clin Oncol. 2014;32(4):273-81.

10. Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, Kluin-Nelemans HC, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558-65.

11. Hoster E, Klapper W, Hermine O, Kluin-Nelemans HC, Walewski J, van Hoof A, et al. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014;32(13):1338-46.

12. Casulo C, Byrtek M, Dawson KL, Zhou X, Farber CM, Flowers CR, et al. Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516-22.

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13. Maurer MJ, Ghesquieres H, Jais JP, Witzig TE, Haioun C, Thompson CA, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014;32(10):1066-73.

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Characteristics of autologous HCT of MCL patients with time from diagnosis to transplant < 1 year reported to CIBMTR during 2000-2015

N (%)

Number of patients (research level data) 610 Number of centers 123 Patient age, years

Median (range) 59 (29-78) 18-29 1 (<1) 30-39 13 (2) 40-49 77 (13) 50-59 237 (39) ≥ 60 282 (46) Patient sex Male 468 (77) Female 142 (23) Karnofsky performance score ≥90 295 (48) <90 277 (45) Missing 38 (6) Patient race Caucasian 557 (91) African-American 21 (3) Asian 9 (1) Native American 1 (<1) Other 7 (1) More than one race 2 (<1) Missing 13 (2) Disease status Sensitive 590 (97) Resistant 7 (1) Unknown 13 (2) Graft type Bone marrow 1 (<1) Peripheral blood 606 (99) Missing 3 (<1)

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N (%) Number of patients (research level data) 610 Year of HCT 2000 30 (5) 2001 28 (5) 2002 39 (6) 2003 29 (5) 2004 21 (3) 2005 27 (4) 2006 38 (6) 2007 30 (5) 2008 93 (15) 2009 31 (5) 2010 15 (2) 2011 30 (5) 2012 22 (4) 2013 87 (14) 2014 51 (8) 2015 39 (6) Median follow-up of survivors (range), months 74 (1-193)

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Proposal: 1711-127

Title: Outcomes of consolidation autologous hematopoietic cell transplantation in patients with Plasmablastic lymphoma.

Akash Mukherjee, MD, [email protected], Houston Methodist Hospital Sai Ravi Pingali, MD, [email protected], Houston Methodist Hospital Muthu Veeraputhiran, MD, [email protected], University of Arkansas Medical Center

Hypothesis: Consolidation autologous hematopoietic cell transplantation (auto-HCT) is safe and improves outcome of patients with plasmablastic lymphoma.

Specific aims: • Primary aim:

To evaluate non-relapse mortality (NRM), overall survival (OS), progression free survival (PFS), ofstudy cohort at day 100, 1, 3 and 5 years.

• Secondary aim:To evaluate rate of engraftment and incidence of secondary malignancies.

Scientific impact: There are no large studies evaluating outcomes of auto-HCT in PBL patients. This study is only feasible with large data sets like CIBMTR data-base. Evaluating outcomes of auto-HCT in HIV positive vs HIV negative PBL patients would be very helpful in clinical practice. This study would allow us to effectively compare the outcomes while adjusting for the patient and disease related factors, thereby giving us a better understanding of auto-HCT outcomes in PBL patients.

Scientific justification: Plasmablastic lymphoma (PBL) accounts for 2% to 3% of all HIV associated lymphomas but can also be seen in HIV negative patients. In HIV negative patients, one third of patients have an underlying immunosuppressive status due to solid organ transplant or allogeneic hematopoietic stem cell transplantation. 1,2. PBL carries poor prognosis with a median PFS and median OS of 6 months and 11 months respectively regardless of the intensity of induction therapy.1,3. A retrospective review of 70 HIV positive relapsed/refractory PBL patients between 1997 to 2009 showed a median OS of only 3.5 months.1,4. Consolidation auto-HCT with high dose chemotherapy is a standard practice for patients with relapsed/refractory chemosensitive lymphomas. Several studies showed safety and efficacy of auto-HCT in HIV positive lymphoma patients on highly active anti-retroviral therapy (HAART) with treatment related mortality in range of 5%-10%.5-8. HIV status did not influence the outcome of auto-HCT in NHL patients and showed similar DFS and OS when compared to HIV negative patients.6.

Another study by Liu et al. on 9 HIV negative patients with PBL who underwent auto-HCT after receiving induction with CHOP or hyperCVAD. Responses were observed in 8 cases (7 complete, 1 partial response). Four patients underwent consolidation with autologous hematopoietic stem cell transplant (HSCT) in first complete remission (CR1). At median follow-up of 23.9 months, 7 patients were alive and 5 were disease-free. This study did show a role for aggressive induction chemotherapy followed by consolidation with autologous HSCT in CR1 for patients with HIV-negative PBL.9.

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Given higher risk of relapse and poor OS in R/R PBL, considering auto-HCT in CR1 seems logical approach. EBMT registry study reported outcomes of 24 patients who underwent auto-HCT for PBL between 2001-2011 and showed its potential benefit in both salvage setting as well as consolidative therapy after first line induction chemotherapy.10. Majority of patients received auto-HCT consolidation in first complete remission (50%) or partial remission (17%) and vast majority (71%) of patients received BEAM conditioning regimen. Relapse rate and overall survival rate at 2 years were 30% and 53% respectively. Patients who were in CR prior to auto-HCT had a significantly lower relapse risk and overall mortality risk. 10. With this background information, auto-HCT may be a reasonable consolidation option for eligible patients with PBL in CR1 or in salvage setting. However it would be important to study this in large cohort of patients and a retrospective study using CIBMTR database will potentially give us more insight to choose the best treatment approach for PBL patients. Patient eligibility population: All patients age 18 years or more with Plasmablastic lymphoma who underwent auto-HCT from 1996 to 2016 regardless of HIV status, conditioning regimen or remission of the patients. Data requirements:

• Patients Pre-HCT Data • Year 1,3,5 Post-HCT Data • Post-Transplant Essential Data

Study design: This is a retrospective study with review of CIBMTR database. Plan will be to analyze all patients with PBL that got an auto-HCT, in HAART era from year 1996-2016. Variables to be evaluated include the demographics (age, gender, race, etc), disease status at transplant, transplant characteristics like preparative regimen, outcome data including engraftment and post-transplant outcomes. We will use descriptive statistics, discuss relevant characteristics and discuss the outcomes of patients as related to the donor type. Outcome analysis: Overall survival (OS) is defined as time from HCT to last follow-up. Similarly, non-relapse mortality (NRM) will be computed from time of HCT to last known vital sign. Time-to-progression is defined time of HCT and date of disease progression. Patients who are alive and did not experience progression of disease at the last follow-up date will be censored. The Kaplan-Meier method will be used to estimate OS and DFS and the log-rank test was used to assess differences between specific groups11. NRM and time-to-progression will be determined by the cumulative incidence function using the competing risks method. References: 1. Malki MM, Castillo J, Solan JM, Re A. Hematopoietic cell transplantation for Plasmablastic

lymphoma: A review. Biol Blood Marrow Transplant 2014; 20: 1877-1884. 2. Castillo JJ, Winer ES, Stachurski D, et al. HIV negative plasmablastic lymphoma: not in the mouth.

Clin Lymphoma Myeloma Leuk. 2011; 11: 185-189.

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3. Castillo JJ, Furman M, Beltran BE, et al. Human immunodeficiency virus associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy. Cancer. 2012 ; 118:5270-5277.

4. Castillo JJ, Winer ES, Stachurski D, et al. Prognostic factors in chemotherapy treated patients with HIV associated plasmablastic lymphoma. Oncologist. 2010; 15:293-299.

5. Krishnan A, Molina A, Zaia J, et al. Durable remissions with autologous stem cell transplantation for high risk HIV associated lymphomas. Blood. 2005; 105:874-878.

6. Krishnan A, Palmer J, Zaia J, et al. HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for Non Hodgkin Lymphoma (NHL). Biol Blood Marrow Transplant. 2010;16: 1302-1308.

7. Re A, Cattaneo C, Mariagrazia M, et al. High dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving highly active anti-retroviral therapy. J Clin Oncol. 2003; 23:4423-4427.

8. Diez Martin J, Balsabore P, Carrion R, et al. Long term survival after autologous stem cell transplantation in AIDS related lymphoma patients. Blood. 2003 ; 102:247a.

9. Liu JJ, Zhang L, Ayala E, et al. Human immunodeficiency virus (HIV) negative plasmablastic lymphoma: a single institutional experience and literature review. Leuk Res. 2011; 35: 1571-1577.

10. Cattaneo C, Finel H, Mcquaker G et al. Autologous Hematopoietic stem cell transplantation for Plasmablastic lymphoma: The European Society for Blood and Marrow Transplantation Experience. Biol Blood Marrow Transplant. 21 (2015) 1145-1147.

11. Kaplan EL, M. P. " Nonparametric estimation for incomplete observations." J Am Stat Assoc 1958( 53): 457-481.

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Characteristics of first autoHCT for plasmablastic lymphoma patients reported to the CIBMTR from 2001-2016

N (%)


Median (range) 50 (25-76) 18-29 2 (2) 30-39 16 (19) 40-49 23 (28) 50-59 24 (29) ≥ 60 18 (22) Patient sex Male 74 (89) Female 9 (11) Karnofsky performance score ≥ 90 48 (58) < 90 29 (35) Missing 6 (7) Patient race Caucasian 56 (67) African-American 9 (11) Asian 2 (2) Native American 1 (1) Missing 15 (18) Disease status Sensitive 77 (93) Resistant 4 (5) Missing 2 (2) Graft type Peripheral blood 83 Year of transplant 2001 1 (1) 2002 1 (1) 2005 1 (1) 2007 3 (4) 2008 1 (1)

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N (%)

Number of patients 83 2009 4 (5) 2010 6 (7) 2011 9 (11) 2012 7 (8) 2013 9 (11) 2014 10 (12) 2015 17 (20) 2016 14 (17) Median follow-up of survivors (range), months 25 (2-75)

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Proposal: 1711-156

Title: Role of Autologous Hematopoietic Cell Transplantation in NK/T-Cell Lymphomas

Talha Badar, MD, [email protected], Medical College of Wisconsin

Hypothesis: Autologous hematopoietic cell transplantation (auto-HCT) provides durable disease control in extra-nodal NK/T-cell lymphoma, nasal type (ENKCL-nasal) and aggressive NK-cell leukemia.

Specific aims: • Primary aim

1. To describe the post-transplantation outcomes in patients with ENKCL-nasal and aggressiveNK-cell leukemia undergoing auto-HCT. The following outcomes will be evaluated:

• Secondary aims1. Neutrophil and platelet recovery;2. Cumulative incidence of non-relapse mortality (NRM);3. Cumulative incidence of disease relapse or progression;4. Progression-free survival (PFS);5. Overall Survival (OS).

Scientific justification: Natural Killer (NK)/T cell neoplasms including ENKCL-nasal type and aggressive NK-cell leukemia are rare but aggressive malignancies with a predilection for Asian and South American population.1 Approximately two-thirds of the ENKCL at presentation have localized disease whereas aggressive NK-cell leukemia presents systemically with bone marrow involvement and hepatosplenomegaly.2 Anthracycline-based (eg: CHOP) chemotherapy is often associated with poor outcomes and is considered ineffective.3 While no randomized trials exist, recent prospective studies incorporating concurrent chemo-radiation and the use L-asparaginase have shown improved survival outcomes, specifically in ENKCL-nasal.4, 5 However, even with aggressive initial therapy about 40-50% patients have relapsed/progressive disease. The outcomes of advanced stage ENKCL-nasal and aggressive NK-cell leukemia is poor with a median survival of <6 months.2, 6 Extra-nasal presentation, advanced stage disease including bone marrow involvement, presence of B-symptoms, high lactate dehydrogenase (LDH), low absolute lymphocyte count (ALC <1x109/L) and high circulating Epstein-Barr virus (EBV) DNA (≥ 6.1x107 copies) at the time of diagnosis are all considered poor risk factors.7-9 The NK/T-cell lymphoma prognostic index (applicable to nasal subtype) stratifies patients into 4 risk groups based on high LDH, presence of B-symptoms, regional lymph node involvement and stage IV disease.10

The role of auto-HCT has been mainly explored in retrospective studies, limited by sample size, non-uniform inclusion criteria and transplant protocols making interpretation difficult.1, 11 High dose therapy and auto-HCT as a consolidative strategy was noted to improve survival compared to historical controls.11-13 However, this benefit seems to be restricted to those achieving a CR prior to transplant. The role of auto-HCT in relapsed/refractory lymphoma as well as in the era of aggressive initial chemotherapy (L-asparaginase containing regimen) +/- radiation remains undefined.

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Autologous hemopoietic stem cell transplant has a potentially to improve response duration and outcome in various hematological malignancies including, lymphoma. The role of auto-HCT in NK/T-cell malignancies has been reported in a few retrospective and some small prospective studies.12-14 Table 1 shows post auto-HCT outcomes in ENKCL from selected studies predominantly in an Asian cohort. In one multicenter, retrospective study of 47 patients with NK/T cell lymphoma, survival benefit of auto-HCT was compared with historical control group.12 In patients who were in complete remission (CR) at the time of auto-HCT disease-specific survival rates were significantly higher in the transplant group compared with the control group; 5 yrs disease-specific survival rates were 87.3% vs 67.8% ( P = 0.027). In another small prospective study conducted in stage IV ENKTL patients, who received L-asparginase containing induction regimen underwent upfront auto-HCT. Out of 27 patients, 11 were able to received auto-HCT. Survival outcome was better in patients who received auto-HCT compare to those who did not.14 Although the data is sparse and no randomized study done to evaluate the benefit of auto-HCT in patients with ENKTL, experts in the field recommend upfront auto-HCT in advanced ENKTL.15 Aggressive NK-cell leukemia is a biologically distinct and extremely aggressive disease, associated with disseminated disease and coagulopathy at presentation. Usually affecting younger patients (median age 40 years), this rare entity is associated with a median survival of ~ 2 months. Ishida et al, described the outcomes of 34 patients with aggressive NK-cell leukemia. The median survival for all patients was 51 days. Among the 8 patients who received HCT (2 autografts and 6 allografts), the median survival was 266 days. Pre-transplant use of L-asparaginase was also noted to improve outcomes.16 The role of allo-HCT in aggressive NK-cell leukemia is otherwise limited to case reports with varying outcomes thus making it difficult to draw conclusions.17, 18 As noted the data regarding the role of auto-HCT in ENKCL-nasal type and aggressive NK-cell leukemia is limited to retrospective studies and case reports respectively. Moreover, the available data is overwhelmingly Asian, hence the applicability of auto-HCT in a North American/European cohort remains unknown. Identifying the appropriate patient who may benefit from a potentially curative strategy, is of clinical importance. We hypothesize that autologous transplantation would be a viable treatment option in ENKTL to improve survival outcome. Due to the relative rarity of the disease, it is unlikely that a randomized prospective study will put this to the test. In the current analysis we will utilize the data reported to CIBMTR registry to analyze outcomes of ENKTL and aggressive NK-cell leukemia following auto-HCT. The outcomes of these two histologic subtypes will be analyzed separately. Study population: Inclusion criteria:

1. Adult (age ≥18years) patients with a histologically confirmed diagnosis of ENKCL-nasal type or aggressive NK-cell Leukemia, undergoing first auto-HCT between 2000-2015, reported to the CIBMTR.

2. All types of conditioning including TBI based regimen as per standard CIBMTR criteria will be included.

Outcomes: Outcomes of ENKCL-nasal type and aggressive NK-cell leukemia will be analyzed separately. No comparison between the two histological types is planned.

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Primary Outcome: 1. Overall survival (OS): time to death. Death from any cause will be considered an event. Surviving

patients will be censored at time of last follow-up.

Secondary Outcomes: 2. Hematopoietic recovery: The primary measures for hematopoietic recovery will be:

• Time to neutrophils (ANC) > 0.5 x109/L sustained for three consecutive days within 28 and 100 days post-transplant. This endpoint does not specify whether recovery is engraftment of donor cells or autologous reconstitution.

• Time to achieve a platelet count of (a) >20 x 109/L independent of platelet transfusions for 3 consecutive days.

• Non-relapse mortality (NRM): Cumulative incidence of NRM. NRM is defined as death without preceding disease relapse/progression. Relapse and progression are competing events.

• Relapse/Progression: Cumulative incidence of disease relapse/progression with NRM as competing event.

• Progression-free survival (PFS): survival without disease progression or relapse . Progression, relapse, and death are considered events. Patients who are alive and in remission are censored at time of last follow-up.

• Primary cause of death: descriptive only. Variables: Patient related

• Age at HCT: [in decades] • Gender: male vs. female • Karnofsky performance score: 80-100% vs. <80 vs. missing • HCT Co-morbidity index: 0 vs. 1-2 vs. ≥3 vs. missing vs. N/A (pre2007) • Race: Caucasian vs. Asian vs. African American vs. Others vs. missing

Disease related

• Disease stage at diagnosis: I/II vs III/IV • Elevated LDH at diagnosis: yes vs no vs. missing • B-symptoms at diagnosis: yes vs no vs. missing • Regional lymph node involvement at diagnosis: yes vs no vs. missing • NK/T-cell Lymphoma Prognostic index: Low (0) vs. low-intermediate (1) vs. high intermediate (2)

vs. high (3 or 4) vs. missing • Bone marrow involvement at any time before HCT: yes vs no vs missing • History of CNS involvement: at diagnosis vs. at relapse/progression vs. no vs. unknown vs.

missing • Type of first-line therapy: Chemotherapy alone vs. radiation alone vs. chemoradiation vs.

unknown vs. missing • Intrathecal chemotherapy given with first line therapy: For prophylaxis vs. For treatment of CNS

involvement • Response to first-line therapy: CR vs. <CR vs. missing • Number of prior therapy regimens received before HCT: continuous • History of radiotherapy before HCT: yes vs no

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• L-asparaginase or Peg-asparaginase use before HCT: yes vs no vs. missing • Gemcitabine use before HCT: yes vs no vs. missing • Response to last therapy line before HCT: CR vs. PR vs. chemoresistant vs. untreated/unknown • PET negative at the time of HCT: yes vs. no vs. not done • Prior autologous HCT: yes vs no

o Time from diagnosis to HCT: <1year vs. ≥1 year Transplant related • Conditioning regimen: • TBI conditioning regimen: yes vs no • Year of auto-HCT: Continuous Study design: A retrospective multicenter study will be conducted utilizing CIBMTR dataset. Patients will be eligible if they satisfied the criteria detailed in the “Study population” section. The objective of this analysis is to compare these two approaches and their effects on auto-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, 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, 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.

Univariate analysis with Gray test and log-rank test will be used for cumulative incidence and survival respectively. The proportional hazards Cox model will be conducted. Backward elimination will be used to select significant covariates. The treatment group will be included in all steps of model building regardless of level of significance. Results will be expressed as hazard ratio (HR) with 95% confidence intervals (CI). Possible interactions within the treatment groups and significant variables will be tested. All models will be tested regarding proportional hazard of assumptions. If the assumption will be violated, time dependent covariates will be constructed. References: 1. Tse E, Kwong YL. How I treat NK/T-cell lymphomas. Blood 2013; 121(25): 4997-5005. e-pub ahead of

print 2013/05/09; doi: 10.1182/blood-2013-01-453233 2. Suzuki R. Treatment of advanced extranodal NK/T cell lymphoma, nasal-type and aggressive NK-cell

leukemia. International journal of hematology 2010; 92(5): 697-701. e-pub ahead of print 2010/12/01; doi: 10.1007/s12185-010-0726-2

3. Corradini P, Marchetti M, Barosi G, Billio A, Gallamini A, Pileri S et al. SIE-SIES-GITMO guidelines for the management of adult peripheral T- and NK-cell lymphomas, excluding mature T-cell leukaemias. Annals of oncology : official journal of the European Society for Medical Oncology 2014; 25(12): 2339-2350. e-pub ahead of print 2014/04/12; doi: 10.1093/annonc/mdu152

4. Yamaguchi M, Tobinai K, Oguchi M, Ishizuka N, Kobayashi Y, Isobe Y 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 2009; 27(33): 5594-5600. e-pub ahead of print 2009/10/07; doi: 10.1200/jco.2009.23.8295

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5. Yamaguchi M, Kwong YL, Kim WS, Maeda Y, Hashimoto C, Suh C et al. Phase II study of SMILE

chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J Clin Oncol 2011; 29(33): 4410-4416. e-pub ahead of print 2011/10/13; doi: 10.1200/jco.2011.35.6287

6. Au WY, Weisenburger DD, Intragumtornchai T, Nakamura S, Kim WS, Sng I 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. Blood 2009; 113(17): 3931-3937. e-pub ahead of print 2008/11/26; doi: 10.1182/blood-2008-10-185256

7. Kohrt H, Lee M, Advani R. Risk stratification in extranodal natural killer/T-cell lymphoma. Expert review of anticancer therapy 2010; 10(9): 1395-1405. e-pub ahead of print 2010/09/15; doi: 10.1586/era.10.130

8. Huang JJ, Jiang WQ, Lin TY, Huang Y, Xu RH, Huang HQ et al. Absolute lymphocyte count is a novel prognostic indicator in extranodal natural killer/T-cell lymphoma, nasal type. Annals of oncology : official journal of the European Society for Medical Oncology 2011; 22(1): 149-155. e-pub ahead of print 2010/07/03; doi: 10.1093/annonc/mdq314

9. Tse E, Kwong YL. Management of advanced NK/T-cell lymphoma. Current hematologic malignancy reports 2014; 9(3): 233-242. e-pub ahead of print 2014/06/14; doi: 10.1007/s11899-014-0216-3

10. Lee J, Suh C, Park YH, Ko YH, Bang SM, Lee JH et al. Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study. J Clin Oncol 2006; 24(4): 612-618. e-pub ahead of print 2005/12/29; doi: 10.1200/jco.2005.04.1384

11. Kwong YL. High-dose chemotherapy and hematopoietic SCT in the management of natural killer-cell malignancies. Bone Marrow Transplant 2009; 44(11): 709-714. e-pub ahead of print 2009/09/22; doi: 10.1038/bmt.2009.239

12. Lee J, Au WY, Park MJ, Suzumiya J, Nakamura S, Kameoka J et al. Autologous hematopoietic stem cell transplantation in extranodal natural killer/T cell lymphoma: a multinational, multicenter, matched controlled study. Biol Blood Marrow Transplant 2008; 14(12): 1356-1364. e-pub ahead of print 2008/12/02; doi: 10.1016/j.bbmt.2008.09.014

13. Yhim HY, Kim JS, Mun YC, Moon JH, Chae YS, Park Y et al. Clinical Outcomes and Prognostic Factors of Up-Front Autologous Stem Cell Transplantation in Patients with Extranodal Natural Killer/T Cell Lymphoma. Biol Blood Marrow Transplant 2015; 21(9): 1597-1604. e-pub ahead of print 2015/05/13; doi: 10.1016/j.bbmt.2015.05.003

14. Kim SJ, Park S, Kang ES, Choi JY, Lim DH, Ko YH et al. Induction treatment with SMILE and consolidation with autologous stem cell transplantation for newly diagnosed stage IV extranodal natural killer/T-cell lymphoma patients. Ann Hematol 2015; 94(1): 71-78. e-pub ahead of print 2014/08/02; doi: 10.1007/s00277-014-2171-4

15. Kharfan-Dabaja MA, Kumar A, Ayala E, Hamadani M, Reimer P, Gisselbrecht C et al. Clinical Practice Recommendations on Indication and Timing of Hematopoietic Cell Transplantation in Mature T Cell and NK/T Cell Lymphomas: An International Collaborative Effort on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2017; 23(11): 1826-1838. e-pub ahead of print 2017/08/12; doi: 10.1016/j.bbmt.2017.07.027

16. Ishida F, Ko YH, Kim WS, Suzumiya J, Isobe Y, Oshimi K et al. Aggressive natural killer cell leukemia: therapeutic potential of L-asparaginase and allogeneic hematopoietic stem cell transplantation. Cancer science 2012; 103(6): 1079-1083. e-pub ahead of print 2012/03/01; doi: 10.1111/j.1349-7006.2012.02251.x

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17. Ino K, Masuya M, Nakamori Y, Suzuki K, Mizutani M, Sekine T et al. [Aggressive NK-cell leukemia with sustained relapse-free survival after allogeneic peripheral blood stem cell transplantation]. [Rinsho ketsueki] The Japanese journal of clinical hematology 2010; 51(4): 258-263. e-pub ahead of print 2010/05/15;

18. Park JA, Jun KR, Nam SH, Ghim TT. Favorable outcome in a child with EBV-negative aggressive NK cell leukemia. International journal of hematology 2013; 97(5): 673-676. e-pub ahead of print 2013/04/04; doi: 10.1007/s12185-013-1319-7

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Table.1 Selected studies evaluating role of autologous stem cell transplant in extra-nodal NK/T-cell lymphoma, nasal subtype.

Author and Year

N Conditioning intensity

OS PFS TRM Comments

Lee J et al 200812

48 CBV =14 BEAM = 12 MCEC = 8 BEAC =2

Cy/TBI= 4 Others = 7

NR at 116 months f/u

23.3 months

0 Patient who were in CR at auto-HCT, disease free survival significantly higher than non transplant patient.

Yhim, HY et al13

62 TBI-based VCT = 8

Non-TBI based BEAM = 54

3 yrs OS: LS 67.4%, AS 60%

3 yrs PFS: LS 64.5%, AS 52.4%

1 (1.6%)

Autologous stem cell transplant did not show significant benefit in limited stage disease.

Kim, SJ et al14

11 TBI-based VCT= 8

Busulphan based = 3

10. 6 months

5.1 months

0 All patients had stage IV disease, received L-asparginase induction with RR of 59%

Abbreviation: OS – overall survival; PFS – progression free survival; TRM – therapy related mortality; PR – partial remission; CR – complete remission. CBV; cyclophosphamide, BCNU (carmustine), and VP-16 (etoposide); BEAM; BCNU (carmustine), etoposide, Ara-C and melphalan. TBI; total brain irradiation, MCEC; MCNU, carboplatin, cyclophosphamide, etoposide; VCT; etoposide, cyclophosphamide and TBI.

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Characteristics of first autoHCT for extranodal NK/T CL and aggressive NK-cell leukemia from 2000-2015

Aggressive NK leukemia N(%)

Extranodal NK/T N(%)


Median (range) 40 (26-61) 47 (6-74) 0-18 0 2 (1) 18-29 1 (25) 19 (13) 30-39 1 (25) 28 (19) 40-49 1 (25) 37 (25) 50-59 0 34 (23) ≥ 60 1 (25) 28 (19) Patient sex Male 4 90 (61) Female 0 58 (39) Karnofsky performance score ≥ 90 3 (75) 72 (49) <90 0 60 (41) Missing 1 (25) 16 (11) Patient race Caucasian 2 (50) 85 (57) African-American 1 (25) 7 (5) Asian 1 (25) 39 (26) Native American 0 1 (<1) Other 0 3 (2) Missing 0 13 (9) Disease status Sensitive 4 142 (96) Resistant 0 4 (3) Missing 0 2 (1) Graft type Bone marrow 0 2 (1) Peripheral blood 4 142 (96) Missing 0 4 (3)

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Aggressive NK leukemia N(%)

Extranodal NK/T N(%)

Number of patients 4 148 Year of HCT 2000 0 2 (1) 2001 0 5 (3) 2002 0 9 (6) 2003 0 11 (7) 2004 0 8 (5) 2006 0 3 (2) 2007 1 (25) 6 (4) 2008 0 13 (9) 2009 1 (25) 6 (4) 2010 1 (25) 20 (14) 2011 0 8 (5) 2012 1 (25) 20 (14) 2013 0 13 (9) 2014 0 13 (9) 2015 0 11 (7) Median follow-up of survivors (range), months Not applicable 47 (3-169)

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A G E N D A CIBMTR WORKING COMMITTEE FOR … · M, Klein A, Lazarus H, Mei M, Mussetti A, Nishihori...

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