SIROLIMUS (RAPAMYCIN) FOR THE TREATMENT OF STEROID-REFRACTORY ACUTE GRAFT-VERSUS-HOST DISEASE1

Abstract

In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1–46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT). All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19–78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m2) of oral sirolimus on day 1 followed by 5 mg/m2/day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m2/day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9–13 days, two for 6 days, and three for 1–3 days. Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400–907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40–263 days after transplant. These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.