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

Author:

Wilson Wyndham H.1,sin-Ho Jung2,Pitcher Brandelyn Nicole3,Hsi Eric D4,Friedberg Jonathan5,Cheson Bruce6,Bartlett Nancy L7,Smith Scott8,Johnston Nina Wagner9,Kahl Brad S10,Staudt Louis M.1,Blum Kristie11,Abramson Jeremy12,Press Oliver W13,Fisher Richard I.14,Richards Kristy L.15,Schoder Heiko16,Chang Julie E17,Zelenetz Andrew D.18,Leonard John P.19

Affiliation:

1. Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

2. Duke University, Durham, NC

3. Alliance Statistics and Data Center, Duke University, Durham, NC

4. Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH

5. Wilmot Cancer Institute, University of Rochester, Rochester, NY

6. Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC

7. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO

8. Alliance Protocol Office, Chicago, IL

9. Johns Hopkins Medical Center, Baltimore, MD

10. Washington University, St. Louis, MO

11. The Ohio State University Comprehensive Cancer Center, Columbus, OH

12. Massachusetts General Hospital, Boston, MA

13. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA

14. Fox Chase Cancer Center, Philadelphia, PA

15. Cornell Medical School, New York, NY

16. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY

17. University of Wisconsin, Madison, WI

18. Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY

19. Department of Medicine, Weill Cornell Medicine, New York, NY

Abstract

Abstract 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:Gilead Sciences: Research Funding.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3