Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study

Abstract

Background: MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement.

Methods: We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov (NCT01092182).

Findings: 53 patients were enrolled, with median age of 61 years (range 29-80; IQR 50-70); 43 (81%) patients had stage III-IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5-61·1), 48-month event-free survival was 71·0% (95% CI 56·5-81·4) and 48-month overall survival was 76·7% (95% CI 62·6-86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections).

Interpretation: In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases.

Funding: Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.

Conflict of interest statement

DECLARATION OF INTERESTS

Kieron Dunleavy: Reports other from Abbvie, other from Adaptive Technologies, other from Celgene, other from Amgen, other from Seattle Genetics, other from Kite, other from Jannsen, other from Karyopharm, outside the submitted work.

Michelle A. Fanale: Reports grants and personal fees from Seattle Genetics, grants and personal fees from Celgene, grants and personal fees from Takeda, grants from ADC Therapeutics, grants from Molecular Templates, grants and personal fees from Merck, grants and personal fees from BMS, outside the submitted work.

Jeremy S. Abramson: Reports personal fees from Abbvie, personal fees from Celgene, personal fees from Gilead, personal fees from Humaningen, personal fees from Kite Pharma, personal fees from Juno Therapeutics, personal fees from Novartis, personal fees from Verastem, from Merck, outside the submitted work.

Ariela Noy: Reports grants from NIH, grants from NIH, during the conduct of the study; personal fees from Pharmacyclics, grants from Pharmacyclics, grants from Pharmacyclics, personal fees from Janssen Global, personal fees from Medscape, personal fees from targeted Oncology, and Prime Oncology outside the submitted work.

Paolo Fabrizio Caimi: Reports grants from Eastern Cooperative Oncology Group, during the conduct of the study; grants from Genentech, personal fees from Celgene, personal fees from Kite pharmaceutics, personal fees from Genentech, outside the submitted work.

Stefania Pittaluga: None

Samir Parekh: None

Ann Lacasce: None

John W Hayslip: Reports personal fees from AbbVie, outside the submitted work.

Deepa Jagadeesh: Reports other from null, during the conduct of the study; personal fees from Seattle Genetics, personal fees from Celgene, outside the submitted work.

Sunil Nagpal: Reports and Owns Stock in Pfizer, Bristol Myers, Merck, Roche.

Mary Jo Lechowicz: None

Rakesh Gaur: None

Andrea Lucas: None

Christopher Melani: None

Mark Roschewski: None

Seth M. Steinberg: None

Elaine S. Jaffe: None

Brad Kahl: Report grants from National Cancer Institute, during the conduct of the study; personal fees from Genentech, outside the submitted work.

Jonathan W. Friedberg: Reports other from Bayer, other from Astellas, outside the submitted work.

Richard F. Little: None

Nancy L. Bartlett: None

Wyndham H. Wilson: None

Copyright © 2018 Elsevier Ltd. All rights reserved.

Figures

Figure 1.

Flow diagram of patients enrolled on study. The analysis of survival outcome includes all patients enrolled. The analysis of treatment response excludes 3 patients who died prior to restaging.

Figure 2.

Kaplan–Meier Estimates of event-free (EFS) and overall survival (OS) of MYC-R lymphoma. A. EFS of 53 patients with MYC-R lymphoma at 48-months was 71% (95% confidence interval [CI], 56.5–81.4%). B. OS of 53 patients with MYC-R lymphoma at 48-months was 76.7 (95% CI: 62.6–86.1%). C. EFS of single-hit (n=19) versus double-hit (n=24) lymphoma at 48-months was 62.7% (95% CI: 37.2–80.2%) and 73.4% (95% CI: 50.1–87.1%), respectively. D. OS of single-hit (n=19) versus double-hit (n=24) lymphoma at 48-months was 63.2% (95% CI: 38–80.4%) and 82% (95% CI: 58.892.8%), respectively. E. EFS of MYC-R lymphoma by negative (n=17) verus positive (n=31) interim FDG-PET at 48-months was 87.4% (95% CI: 58.1–96.7%) and 64.5% (95% CI: 45.2–78.5%), respectively. F. OS of MYC-R lymphoma by negative (n=17) verus positive (n=31) interim FDG-PET at 48-months was 87.5% (95% CI: 58.6–96.7%) and 74.2% (95% CI: 55–86.2%), respectively.