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Many patients receiving allogeneic stem cells develop chronic graft-versus-host disease (cGVHD), which remains as the main cause of morbidity and mortality. Although the first line of therapy is generally with steroids, it is not well known how to manage refractory cases. Those patients are usually treated with alternative experimental agents. Sirolimus (Rapamycin), a new immunosuppressive agent, inhibits signal transduction and cell cycle progression after binding to FKBP12. We report a retrospective analysis with sirolimus in transplant recipients with cGVHD refractory to previous immunosuppressive therapy. Forty-seven patients with refractory or relapsed cGVHD were treated with the combination of sirolimus and calcineurin inhibitors (n = 33), mycophenolate (n = 9), or prednisone (n = 5). Thirty-eight of 47 (81%) patients had clinical responses (complete = 18, partial = 20). The main toxicity was mild renal failure, particularly at the start of therapy. Four patients who presented thrombotic microangiopathy were managed with plasmapheresis and the discontinuation of sirolimus and calcineurin inhibitors. Statistical analysis showed the type of cGVHD onset and presirolimus clinical status as the main variables influencing the response to treatment. The Kaplan-Meier estimate of survival was 57.4% at 3 years. The current study shows the efficacy and safety of sirolimus in refractory cGVHD patients. Further investigation is warranted to elucidate the role of sirolimus in cGVHD, and find the best combination (sirolimus + calcineurin inhibitors versus others) for therapeutic use.

We studied the effectiveness of a fludarabine/cyclophosphamide-based conditioning regimen without anti-thymocyte globulin in 23 aplastic anemia patients who had no response to previous conventional pharmacologic treatment. Patients received oral busulphan 4 mg/kg/day/2 days, IV cyclophosphamide 350 mg/m2/day/3 days, and fludarabine 30 mg/m2/day/3 days. For GVHD prophylaxis, patients received MTX 5 mg/m2 days +1, +3, +6, and +11 and oral cyclosporin A (CyA) 5 mg/kg/day, starting on day −1. Peripheral blood stem cell products were used with a median dose of 5.5 × 106 CD34+/kg. The patients were followed for an average of 25 months. By a median of day +11, an ANC > 0.5 × 109/L was reached; and by day +12, the platelet count had reached >20,000 × 109/L. Acute grade I–II GVHD occurred in 4 patients, whereas limited chronic GVHD presented in 6 cases. Twenty-one patients (91.3%) achieved engraftment. Two patients failed to engraft, and 4 developed late rejection; 2 of these individuals died, 2 have survived with high transfusion requirements, whereas 2 received a second peripheral blood stem cell infusion and achieved sustained engraftment. Currently 21 (91%) of the 23 patients are alive, whereas 19 of 21 (90%) remain in complete remission. The average cost was about USD 15,000 for this kind of reduced-intensity allotransplant. Reduced-intensity stem cell transplantation represents an affordable alternative to traditional more cytotoxic conditioning for severe aplastic anemia (SAA) patients. Long-term effects however, remain to be evaluated. Am. J. Hematol. 81:157–161, 2006. © 2006 Wiley-Liss, Inc.