Randomized, Placebo-Controlled Trial of B-Cell Depletion for Prevention of Corticosteroid-Requiring Chronic Graft-Versus-Host Disease
Abstract
PURPOSE Chronic graft-versus-host disease (cGVHD) is a multisystem alloimmune disorder associated with abnormal B-cell biology and aberrant antibody responses. As B-cell–directed therapy can effectively treat established cGVHD, we tested whether prophylactic B-cell depletion could prevent the development of corticosteroid-requiring cGVHD following allogeneic transplantation. METHODS We performed a randomized, placebo-controlled, and blinded trial comparing four doses of the B-cell–depleting antibody obinutuzumab (1,000 mg once on days 90, 180, 270, and 365 after transplantation) with placebo in transplant recipients receiving tacrolimus-based GVHD prevention at higher risk of cGVHD. The primary end point was the 1-year incidence of corticosteroid-requiring cGVHD. We measured antibody responses against Y chromosome–encoded minor histocompatibility (H-Y) antigens and correlated their occurrence with corticosteroid-requiring cGVHD incidence. RESULTS One hundred seventy-eight participants were analyzed. The prophylactic administration of obinutuzumab resulted in profound B-cell depletion, a significant reduction in the incidence of steroid-requiring cGVHD at 1 year (13.3% v 35.2%; P = .0005), and an improvement in immunosuppression-free, relapse-free survival (48% v 34% at 2 years; P = .02). Neutropenia was more common in the obinutuzumab arm, but nonrelapse mortality was not different. In participants without preformed H-Y antibodies at the time of study intervention, obinutuzumab resulted in the most significant reduction in steroid-requiring cGVHD at 12 months (8.6%) compared with obinutuzumab participants with H-Y antibodies (40%) or placebo participants regardless of antibody status (41% with antibodies, 57% without antibodies). CONCLUSION In allogeneic transplant recipients at higher risk of cGVHD, early B-cell depletion results in a significant reduction in the incidence of corticosteroid-requiring cGVHD.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (34)
Corey Cutler
1Dana Farber Cancer Institute, Boston, United States
Haesook T. Kim
2Department of Data Science, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA
Hassan El Banna
Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, MA
Elizabeth Halloran
Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, MA
Emily Matozel
Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, MA
Vincent T. Ho
Dana-Farber Cancer Institute, Boston, MA
John Koreth
1Dana Farber Cancer Institute, Boston, United States
Mahasweta Gooptu
1Dana Farber Cancer Institute, Boston, United States
Roman Shapiro
1Dana Farber Cancer Institute, Boston, United States
Amar Kelkar
1Dana Farber Cancer Institute, Boston, United States
Christopher Gibson
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Sarah Nikiforow
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Prashant Nageshwar
1Dana Farber Cancer Institute, Boston, United States
Carol Reynolds
1Dana Farber Cancer Institute, Boston, United States
Michela Ansuinelli
1Sapienza University, Rome, Italy
Rakuyo Tamada
Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, MA
Chloe Au
Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, MA
Kevin Panaro
Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, MA
Casey Gervais
Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, MA
Zachariah Defilipp
7Massachusetts General Hospital, Hematopoietic Cell Transplant and Cellular Therapy Program, Boston, United States
Areej El-Jawahri
1Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
Yi-Bin Chen
1Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
Najla El Jurdi
3CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, United States
Daniel Weisdorf
1University of Minnesota, Division of Hematology, Oncology and Transplantation, Minneapolis, United States
Daniel Couriel
1Huntsman Cancer Institute, SALT LAKE CITY, United States
Catherine Lee
Sally Arai
Bita Sahaf
Juliana Bacigalupi
BMT and Cell Therapy Program, Stanford University, Palo Alto, CA
Kathleen Ji
BMT and Cell Therapy Program, Stanford University, Palo Alto, CA
Robert Soiffer
1Dana Farber Cancer Institute, Boston, United States
David Miklos
Joseph H. Antin
1Dana-Farber Cancer Institute
Jerome Ritz
Dana–Farber Cancer Institute, Boston