While hematopoietic cell transplantation (HCT) is a curative therapy for many blood cancers, graft-versus-host-disease (GVHD) is a potentially life-threatening complication. GVHD results from graft immune cells attacking host tissues, like the gut and skin, and is a particular concern in HLA mismatched donor/patient pairs. Fully matched donors can be found for approximately 16-75% of patients depending on ethnicity, so many patients must rely on mismatched donors. Current GVHD prophylaxis consists of a cocktail of two immune suppressive drugs, cyclosporine A (CsA) and mycophenolate mofetil (MMF), taken daily for 150-180 days post-transplant. Even with this prophylaxis, a recent study of HLA mismatched donor/patient pairs showed that 69% and 26% of patients experienced grade 2-4 or grade 3-4 acute GVHD, respectively, leaving much room for improvement. The Sandmaier group, from the Clinical Research Division, wanted to find a way to improve GVHD prophylaxis and sought to study inclusion of the mTOR inhibitor and immune suppressant, sirolimus. The results of their study were recently published in Blood.
The study included patients with hematologic malignancies treatable with allogenic HCT, where donors were HLA-mismatched. The authors desired outcome was an overall incidence of grade 2-4 GVHD of less than 70%. Overall, 76 patients completed the trial where sirolimus was taken once daily through day 180 and tapered through day 365, in addition to the traditional treatment of daily CsA until day 180 and daily MMF until day 150. Cumulative incidence of grade 2-4 acute GVHD at day 100 was 36%. No patient experienced grade 4 GVHD and only 1 patient experienced grade 3 GVHD. This translated to a grade 3-4 GVHD incidence of 1% compared to historical controls of 26%, an outstanding improvement. This also translated to an improvement in nonrelapse mortality, death from causes other than cancer recurrence, from 47% by year 4 in previous studies to 17% in the current study. Importantly, addition of sirolimus did not lead to an increase in relapse. Progression free survival was 64% and 52% for year 1 and year 4, respectively, with overall survival at 72% and 62% for the same time frame. In all, 14 patients died due to causes other than relapse: 6 due to infection, 4 from GVHD, and 3 from GVHD complicated by infection. The last patient died from brain injury due to pre-transplant radiation therapy. In all, this study showed large improvement in nonrelapse mortality largely due to a significant reduction in incidence of life threatening GVHD.
This study was supported by the National Institutes of Health.
UW/Fred Hutch Cancer Consortium members Thomas Chauncey, Effie Petersdorf, Mary Flowers, Rainer Storb, David Maloney, and Brenda Sandmaier contributed to this work.
Kornblit B, Storer B, Andersen N, Maris M, Chauncey T, Petersdorf E, Woolfrey A, Flowers M, Storb R, Maloney D, Sandmaier B. 2020. Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen mismatched donors. Blood. doi: 10.1182/blood.2020005338. Online ahead of print.