Methotrexate in combination with a
calcineurin inhibitor is a standard
graft-versus-host disease (GVHD) prophylactic regimen in allogeneic
stem cell transplantation. However,
methotrexate is associated with delayed engraftment,
mucositis, idiopathic
pneumonia syndrome, and other transplant-related complications.
Sirolimus, a novel
immunosuppressant without
methotrexate's toxicities, has been used successfully in solid
organ transplantation. We hypothesized that replacing
methotrexate with
sirolimus would preserve effective prophylaxis of GVHD while minimizing transplant-related toxicity after allogeneic
peripheral blood stem cell transplantation. We enrolled 30 patients in a phase II study to test the efficacy of
tacrolimus in combination with
sirolimus in lieu of
methotrexate in preventing GVHD after allogeneic
peripheral blood stem cell transplantation from HLA-matched related donors. Grade II GVHD occurred in 3 patients (10%), and no patient developed grade III or IV GVHD. Neutrophil and platelet engraftment were prompt, occurring on days 14 and 13, respectively. All patients survived to hospital discharge (median, 18 days), and peritransplantation toxicity was mild. Four patients developed
thrombotic microangiopathy, and 3 patients developed
hepatic veno-occlusive disease. Chronic GVHD occurred in 11 patients. Relapse-free and overall survival at 100 days were 93% and 97%, respectively, and were 71% and 67% at 1 year. Causes of death included relapse (n = 6), veno-occlusive disease (n = 1), and late pulmonary toxicity (n = 1).
Sirolimus in combination with
tacrolimus is a promising alternative to
methotrexate-based regimens for GVHD prophylaxis after matched related donor
peripheral blood stem cell transplantation.
Mucositis was modest, engraftment was prompt, and transplant-related toxicity was modest.
Methotrexate-free,
sirolimus-based GVHD prophylactic regimens should be tested in randomized trials against the current standard of care.