TOPLINE:

Prophylactic administration of obinutuzumab, a B-cell-depleting antibody, reduces the incidence of corticosteroid-requiring chronic graft-vs-host disease (cGVHD) at 1 year from 35.2% to 13.3% in allogeneic transplant recipients. The greatest benefit occurs in patients without preformed antibodies against Y chromosome-encoded minor histocompatibility antigens (H-Y), where the incidence drops to 8.6%.

METHODOLOGY:

• Previous phase II studies demonstrated that cGVHD could be prevented with B-cell depletion using rituximab, a monoclonal antibody directed at CD20, providing rationale for testing obinutuzumab, a second-generation antibody with greater direct B-cell killing activity. Current prevention methods including T-cell depletion through graft engineering, anti-T-cell antibodies, or posttransplantation cyclophosphamide are associated with lower cGVHD rates but also with impaired engraftment, long-lasting immunity defects, and excess relapse risk.
• Researchers conducted a prospective, multicenter, randomized, blinded, placebo-controlled trial at five sites in the US between November 2016 and January 2023, enrolling 181 participants who underwent 7/8 or 8/8 HLA-matched peripheral blood stem cell transplantation with tacrolimus-based GVHD prophylaxis.
• A total of 178 participants who received the stem cell transplantation were analyzed and randomly assigned to obinutuzumab (1000 mg administered intravenously at 90, 180, 270, and 365 days after transplantation, n = 90) or placebo (n = 88).
• Participants were screened 60 days following hematopoietic stem cell transplantation (HSCT) and required to have more than 80% total donor chimerism, white blood cell count ≥ 2500/μL, absolute neutrophil count ≥ 1000/μL, platelet count ≥ 50,000/μL, and no more than residual stage I cutaneous acute GVHD.
• The primary end point was the 1-year incidence of corticosteroid-requiring cGVHD, with secondary end points including incidence of National Institutes of Health moderate-to-severe cGVHD, nonrelapse mortality, relapse, immunosuppression-free relapse-free survival (IRFS), progression-free survival, and overall survival at 1 and 2 years.
• Immunologic correlations included measurement of B-cell depletion by flow cytometry and detection of antibody responses against Y chromosome-encoded minor H-Y using proteomic microarray in 87 male participants with stored plasma samples.

TAKEAWAY:

• Obinutuzumab administration resulted in profound B-cell depletion and a significant reduction in the incidence of steroid-requiring cGVHD at 1 year (13.3% vs 35.2%; P = .0005), with a 22% absolute difference.
• IRFS improved significantly in the obinutuzumab group compared with placebo at 2 years (48% vs 34%; P = .02), while no differences were observed in progression-free survival (72% vs 73%; P = .70) or overall survival (84% vs 85%; P = .83).
• In multivariable logistic regression analysis controlling for age, donor type, conditioning intensity, and prior GVHD, the odds ratio for corticosteroid-requiring cGVHD in the obinutuzumab group was 0.29 (P = .0015).
• Among participants without preformed H-Y antibodies at study intervention, obinutuzumab reduced steroid-requiring cGVHD incidence to 8.6% at 12 months, compared with 40% in obinutuzumab participants with H-Y antibodies and 41-57% in placebo participants regardless of antibody status (P = .017).

IN PRACTICE:

“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…. In selected patients undergoing HSCT using tacrolimus-based GVHD prophylaxis, a strategy that incorporates earlier prophylactic B-cell depletion should be considered to minimize the risk of corticosteroid-requiring cGVHD,” the authors of the study wrote.

SOURCE:

The study was led by Corey Cutler, MD, MPH, Division of Transplantation and Cellular Therapy, Dana-Farber Cancer Institute in Boston. It was published online on April 30 in Journal of Clinical Oncology.

LIMITATIONS:

The trial was halted before completion due to slow enrollment related to the COVID pandemic, resulting in a smaller sample size than originally planned (178 participants analyzed vs 200 planned). Participants were enrolled 60 days following hematopoietic stem cell transplantation, excluding those with active acute GVHD or severe ongoing complications, which may limit generalizability to all transplant recipients. The study systematically excluded participants with lower risk for cGVHD, such as bone marrow or umbilical cord blood graft recipients, further limiting applicability to broader transplant populations. Although not statistically significant, three COVID-related deaths occurred in the obinutuzumab arm compared with none in the placebo group, raising concerns about B-cell depletion during pandemic conditions. The results are not directly comparable with published posttransplantation cyclophosphamide experiences due to differences in study design as this trial enrolled participants after successful engraftment rather than as primary GVHD prevention.

DISCLOSURES:

This study received support from grant P01 CA142106. Cutler is supported by the Stem Cell Cyclists of the Pan-Mass Challenge. Genentech supplied the research drug compound for this investigation. Cutler disclosed stock ownership in multiple biotechnology companies including Verastem, Northwest Biotherapeutics, Actinium Pharmaceuticals, Alimera Sciences, CUE Biopharma, Omeros, Orca Bio, and Cimeio Therapeutics. Cutler also reported receiving honoraria from Incyte, Sanofi, CSL Behring, CareDX, GSK, Syndax, and Orca Bio, and serving in consulting or advisory roles for Incyte, Jazz Pharmaceuticals, CareDX, Mallinckrodt/Therakos, Sanofi, CTI BioPharma Corp, Equillium, Bristol Myers Squibb, Cimeio, and Editas Medicine. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.