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Original Investigation
June 4, 2020

Association of Reduced-Intensity Conditioning Regimens With Overall Survival Among Patients With Non-Hodgkin Lymphoma Undergoing Allogeneic Transplant

Author Affiliations
  • 1Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina
  • 2Department of Myeloma and Lymphoma, University of Texas, MD Anderson Cancer Center, Houston
  • 3Department of Medicine, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee
  • 4Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee
  • 5Department of Oncology, King Faisal Specialist Hospital Center and Research, Riyadh, Saudi Arabia
  • 6Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Switzerland
  • 7The Ottawa Hospital Blood and Marrow Transplant Program, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • 8Division of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus
  • 9Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville
  • 10Texas Transplant Institute, San Antonio, Texas
  • 11Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City
  • 12Department of Medicine, University of Colorado Hospital, Aurora, Colorado
  • 13Division of Hematology, Mayo Clinic, Rochester, Minnesota
  • 14Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
  • 15Department of Hematology and Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio
  • 16Department of Medicine, University of Miami, Miami, Florida
  • 17Division of Hematology–Oncology, Blood and Marrow Transplantation Program, Mayo Clinic Florida, Jacksonville
  • 18Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida
  • 19Lymphoma, Bone Marrow Transplant and Cellular Therapy Program, UT Southwestern Medical Center, Dallas, Texas
  • 20Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina
  • 21Division of Hematology and Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, Blood and Marrow Transplantation Program, University of Maryland, Baltimore
  • 22Institut Català d'Oncologia–Hospitalet, Hematology Department, University of Barcelona, Barcelona, Spain
JAMA Oncol. 2020;6(7):1011-1018. doi:10.1001/jamaoncol.2020.1278
Key Points

Question  Are reduced-intensity conditioning and nonmyeloablative conditioning (RIC-NMAC) regimens at a higher spectrum of intensity associated with higher nonrelapse mortality and inferior overall survival compared with RIC-NMAC regimens at a lower spectrum of intensity in patients with non-Hodgkin lymphoma undergoing allogeneic transplant?

Findings  In this cohort study of registry data from 1823 adult patients with non-Hodgkin lymphoma, the most commonly used RIC-NMAC regimen, fludarabine-melphalan 140, was associated with the highest nonrelapse mortality risk and inferior overall survival compared with the other regimens.

Meaning  The findings suggest that use of a more intense RIC-NMAC regimen, such as fludarabine-melphalan 140, for allogeneic transplant in patients with non-Hodgkin lymphoma should be considered with caution.

Abstract

Importance  Reduced-intensity conditioning and nonmyeloablative conditioning (RIC-NMAC) regimens are frequently used in allogeneic hematopoietic cell transplant (HCT) for non-Hodgkin lymphoma. However, the optimal RIC-NMAC regimen in allogeneic HCT for non-Hodgkin lymphoma is not known.

Objective  To investigate whether RIC-NMAC regimens at a higher end of the intensity spectrum are associated with increased nonrelapse mortality and lower overall survival compared with RIC-NMAC regimens at the lower end of the intensity spectrum in patients with non-Hodgkin lymphoma undergoing allogeneic HCT.

Design, Setting, and Participants  This cohort study used data from 1823 adult patients with non-Hodgkin lymphoma in the Center for International Blood and Marrow Transplant Research registry. Included patients underwent allogeneic HCT using matched related or unrelated donors between January 2008 and December 2016. Statistical analysis was performed from June 1, 2019, to February 10, 2020.

Interventions  Patients received 1 of 4 RIC-NMAC regimens: fludarabine-intravenous busulfan (Flu-Bu), approximately 6.4 mg/kg (n = 458); fludarabine-melphalan (Flu-Mel140), 140 mg/m2 (n = 885); fludarabine-cyclophosphamide (Flu-Cy) (n = 391); or Flu-Cy with 2 Gy total body irradiation (Flu-Cy-2GyTBI) (n = 89).

Main Outcomes and Measures  The primary outcome was overall survival. Secondary outcomes were nonrelapse mortality, incidence of relapse, progression-free survival, and the incidence of acute and chronic graft-vs-host disease (GVHD).

Results  Of 1823 patients, 1186 (65%) were male, with a mean (SD) age of 54.8 (9.9) years. The 4-year adjusted OS was 58% in the Flu-Bu cohort, 67% in the Flu-Cy-2GyTBI cohort, 49% in the Flu-Mel140 cohort, and 63% in the Flu-Cy cohort (P < .001). After adjustment for age, Karnofsky performance score, HCT comorbidity index, NHL subtype, remission status at HCT, and the use of antithymocyte globulin or alemtuzumab, the regression analysis showed a significantly higher mortality risk associated with Flu-Mel140 compared with Flu-Bu (hazard ratio [HR], 1.34; 95% CI, 1.13-1.59; P < .001). Compared with the Flu-Cy cohort, the Flu-Mel140 cohort had a higher risk of chronic GVHD (HR, 1.38; 95% CI, 1.15-1.65; P < .001). The Flu-Mel140 regimen was associated with a higher nonrelapse mortality risk (HR, 1.78; 95% CI, 1.37-2.31; P < .001) compared with the Flu-Bu regimen.

Conclusions and Relevance  The findings suggest that use of the more intense RIC-NMAC regimen, Flu-Mel140, may have a negative association with overall survival and may be associated with higher nonrelapse mortality. The Flu-Bu and Flu-Cy regimens with or without 2GyTBI regimens appeared to provide comparable overall survival.

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