Atorvastatin May Prevent Graft-vs-Host Disease in Allogeneic Stem Cell Transplant Recipients
Because statins exhibit immunomodulatory and anti-inflammatory effects that may ameliorate graft-vs-host disease, they may be a safe strategy following allogeneic hematopoietic cell transplantation. In a phase II study reported in the Journal of Clinical Oncology, Mehdi Hamadani, MD, and colleagues from West Virginia University assessed the effects of prophylactic atorvastatin treatment in adult sibling donors and recipients of hematopoietic cell transplantation. They found the strategy to be safe and potentially effective in preventing acute graft-vs-host disease.
Study Methods
In the study, 30 sibling donors received 40 mg/d of oral atorvastatin starting 14 to 28 days before the first day of stem cell collection. Thirty hematopoietic cell transplantation recipients received graft-vs-host disease prophylaxis consisting of tacrolimus, short-course methotrexate, and 40 mg/d of oral atorvastatin starting 14 days before transplantation.
Median ages were 54.5 years for patients and 52.5 years for donors, and 67% and 57% were male, respectively. Among the patients, median Karnofsky performance score was 90. Thirty percent had acute myeloid leukemia, 27% had non-Hodgkin lymphoma, 10% had Hodgkin lymphoma, 10% had myelodysplastic syndrome, and 7% had primary myelofibrosis.
The American Society for Blood and Marrow transplantation risk category was low in 27% of patients, intermediate in 33%, and high in 33%. Approximately 17% of patients had undergone prior autologous transplantation, 43% had undergone myeloablative conditioning, 37% had chemotherapy-refractory disease, and 17% were using statins at the time of enrollment (which were discontinued prior to starting atorvastatin).
Overall, 33% of allografts were ABO mismatched and 30% were from a multiparous female donor to a male recipient. Donors or recipients were Epstein-Barr virus–positive in 100% of pairs and cytomegalovirus positive in 80%.
Study Findings
Median follow up of survivors was 12 months (range, 4 to 29 months). There were no primary graft failures. Cumulative rates of grade 2 to 4 acute graft-vs-host disease at days 100 and 180 were 3.3% and 11.1%, respectively, with grade 3 to 4 graft-vs-host disease occurring in 0% and 7.8%, respectively. The cumulative incidence of chronic graft-vs-host disease at 1 year was 52.3%, consisting of mild graft-vs-host disease in 8.8% and moderate/severe graft-vs-host disease in 43.5% of patients. Median time to onset of chronic graft-vs-host disease was 209 days (range, 147 to 405 days).
Cytomegalovirus reactivation and BK-viral hemorrhagic cystitis occurred in 10% of patients. There were no Epstein-Barr virus reactivations or cytomegalovirus, adenoviral, or invasive fungal infections.
The cumulative rate of nonrelapse mortality was 0% at day 100 and 9% at 1 year. The cumulative incidence of relapse at 1 year was 25.4%. At 1 year, progression-free survival was 65% and overall survival was 74%.
IL-10 Levels
Atorvastatin treatment in donors was associated with a trend toward increased mean plasma interleukin (IL)-10 concentrations vs baseline (5.6 vs 7.1 pg/mL, P = .06). As noted by the investigators, IL-10 downregulates immune response and may facilitate the induction of tolerance after allogeneic hematopoietic cell transplantation via suppression of the proinflammatory cytokines tumor necrosis factor-α, IL-1α, IL-1β, IL-6, IL-12, and interferon-γ.
Adverse Events
Atorvastatin was not associated with any grade 3 or 4 adverse events. For adverse events considered at least possibly related to atorvastatin, 6 donors had grade 1 adverse events (ankle edema, fatigue, myalgia in 2, liver function test elevation, and palpitations); 1 donor had grade 2 myalgia, and 1 recipient had grade 1 liver function test elevation.
“A novel two-pronged strategy of atorvastatin administration in both donors and recipients of matched sibling allogeneic [hematopoietic cell transplantation] seems to be a feasible, safe, and potentially effective strategy to prevent acute [graft-vs-host disease],” concluded the researchers.
The study was supported by a grant from the American Cancer Society, the Conquer Cancer Foundation of American Society of Clinical Oncology Career Development Award, and the American Society for Blood and Marrow Transplantation New Investigator Award. Correlative studies performed in the West Virginia University biospecimen processing and flow cytometry cores were supported by a National Institutes of Health grant.
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