-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

469 Phase III Randomized Study of R-CHOP Versus DA-EPOCH-R and Molecular Analysis of Untreated Diffuse Large B-Cell Lymphoma: CALGB/Alliance 50303Clinically Relevant Abstract

Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials
Program: Oral and Poster Abstracts
Type: Oral
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Novel Approaches in Aggressive Lymphoma
Sunday, December 4, 2016: 4:30 PM
Room 6B (San Diego Convention Center)

Wyndham H. Wilson, MD, PhD1, Jung sin-Ho2*, Brandelyn Nicole Pitcher, MS3*, Eric D Hsi, MD4, Jonathan Friedberg, MD5, Bruce Cheson, MD6, Nancy L Bartlett, MD7, Scott Smith8*, Nina Wagner Johnston, MD9*, Brad S Kahl10*, Louis M. Staudt, MD, PhD1, Kristie Blum, MD11, Jeremy Abramson12*, Oliver W Press, MD, PhD13, Richard I. Fisher, MD14, Kristy L. Richards, PhD, MD15, Heiko Schoder, MD16*, Julie E Chang17, Andrew D Zelenetz, MD, PhD18 and John P. Leonard, MD19

1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
2Duke University, Durham, NC
3Alliance Statistics and Data Center, Duke University, Durham, NC
4Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH
5Wilmot Cancer Institute, University of Rochester, Rochester, NY
6Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC
7Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO
8Alliance Protocol Office, Chicago, IL
9Johns Hopkins Medical Center, Baltimore, MD
10Washington University, St. Louis, MO
11The Ohio State University Comprehensive Cancer Center, Columbus, OH
12Massachusetts General Hospital, Boston, MA
13Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
14Fox Chase Cancer Center, Philadelphia, PA
15Cornell Medical School, New York, NY
16Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
17University of Wisconsin, Madison, WI
18Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
19Department of Medicine, Weill Cornell Medicine, New York, NY

Background: Diffuse large B-cell lymphoma (DLBCL) is comprised of multiple diseases with different outcomes, cell of origin and molecular pathogenesis. DLBCL derived from germinal center B-cells (GCB) and activated B-cells (ABC) constitutes over 80% of DLBCL. A small number of DLBCL tumors harbor MYC translocations, which are associated with a poorer prognosis. Primary mediastinal B-cell lymphoma (PMBL) occurs in younger patients and is typically treated with intensive or combined modality therapy. R-CHOP is the standard of care for DLBCL but has not been prospectively studied within DLBCL molecular subtypes. DA-EPOCH-R is an alternative and more dose-intensive regimen that showed a PFS of 81% at 4-years in a phase II multicenter CALGB study (Haematologica 2012; 97:758). CALGB/Alliance undertook a phase III randomized study to compare R-CHOP and DA-EPOCH-R in DLBCL and specifically within the GCB and ABC subtypes.

Methods: Patients had stage II or higher newly diagnosed DLBCL, age ≥ 18 years and were HIV negative. Subjects were randomized 1:1 to receive R-CHOP or DA-EPOCH-R as previously published. Central nervous system prophylaxis in at-risk patients was 12 mg intrathecal methotrexate in cycles 3-6 (4 doses total). All subjects with accessible tumor were required to have a biopsy or waiver. Subjects received a total of 6 treatment cycles. The primary study endpoints were EFS of R-CHOP (Arm A) versus DA-EPOCH-R (Arm B) and to develop a molecular predictor of outcome based on GCB and ABC DLBCL. Additional analyses include toxicity, pharmacogenomics and analysis of tumor genetics by next generation sequencing, and.

Results: 524 patients registered (262 on each arm) between May 2005 and May 2013. Efficacy analysis includes R-CHOP (n=233) and R-EPOCH (n=231) assigned patients with confirmed eligibility who received any treatment. Characteristics of patients registered to Arm A and B did not differ with median age (58; 56), male sex (53.2%; 53.7%), high-intermediate/high IPI (33.6%; 38.2%) and primary mediastinal B-cell lymphoma histology (6.9%; 5.2%). Therapy was completed per protocol in 89% and 83%, respectively, for Arm A and B, and disease progression on therapy was 2.6% and 1.7%. Adverse side effects leading to treatment discontinuation were 1.7% and 5.6%, respectively, for Arm A and B. Arm B compared to Arm A was associated with more grade 4 neutropenia (90%; 56%), grade 4 thrombocytopenia (35%; 6%), grade 3/4 febrile neutropenia (37%; 19%) and grade 3 neuropathy (motor: 8%;1% and sensory: 15%; 3%). Grade 5 events on study were the same in both arms. Preliminary analysis of EFS in confirmed eligible subjects shows no difference between Arm A and B with hazard ratio of 1.02 and p=0.89 at a median follow-up of 4.9 years. Overall survival is also similar with hazard ratio of 1.19 and p=0.40 at median 5.0 years. Additional analyses of EFS and OS by age (<60 and >=60) and by GCB versus ABC DLBCL are in process. Conclusions: There was no difference in EFS or OS between R-CHOP and DA-EPOCH-R when considering all patients. DA-EPOCH-R showed increased toxicity consistent with higher dose-intensity but not increased grade 5 toxicity. Compared to R-CHOP, more patients on DA-EPOCH-R did not complete treatment, which may reflect patterns of care or toxicity. Due to the clinical and genetic diversity of DLBCL, subset analyses are necessary to determine the effect of CNS relapse, GCB and ABC subtypes, age and IPI on outcomes of the two arms. These data do not address the efficacy of these regimens in PMBL or MYC+ DLBCL due to their low frequency, and where more dose-intense regimens appear to be important. Full molecular analyses are ongoing. Support: U10CA180821, U10CA180882, U10CA180888, CA180799, CA180820, CA180833, CA21076, CA21115.ClinicalTrials.gov Identifier: NCT00118209.

Disclosures: Hsi: Cellerant Therapeutics: Honoraria, Research Funding; Eli Lilly: Research Funding; Abbvie: Honoraria, Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; HTG Molecular Diagnostics: Consultancy, Honoraria. Friedberg: Bayer: Honoraria, Other: Data Safety Monitoring Board. Cheson: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Bartlett: Gilead: Consultancy. Kahl: This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Zelenetz: Amgen: Consultancy; Hospira: Consultancy; GSK: Consultancy, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Takeda Pharma: Consultancy, Honoraria; Novartis: Consultancy; Nanostring Tech: Membership on an entity's Board of Directors or advisory committees; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Research Funding; Boehringer Ingelheim: Other: DMC Membership; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Cancer Genetics: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Parmacyclics: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Consultancy. Leonard: Nanostring: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Regeneron: Consultancy; BMS: Consultancy; Biotest: Consultancy; Sutro: Consultancy; Gilead: Consultancy; Juno: Consultancy; Sunesis: Consultancy; Genmab: Consultancy; Teva: Consultancy.

Previous Abstract | Next Abstract >>
*signifies non-member of ASH