title: Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease.
abstract: 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.
authors.affiliation: Department of Hematology, Hospital Virgen de las Nieves, Granada, Spain. manuel.jurado.sspa@juntadeandalucia.es
authors.forename: Manuel
authors.initials: M
authors.lastname: Jurado
authors.forename: Carlos
authors.initials: C
authors.lastname: Vallejo
authors.forename: José A
authors.initials: JA
authors.lastname: Pérez-Simón
authors.forename: Salut
authors.initials: S
authors.lastname: Brunet
authors.forename: Christelle
authors.initials: C
authors.lastname: Ferra
authors.forename: Pascual
authors.initials: P
authors.lastname: Balsalobre
authors.forename: Jaime
authors.initials: J
authors.lastname: Pérez-Oteyza
authors.forename: Ildefonso
authors.initials: I
authors.lastname: Espigado
authors.forename: Antonio
authors.initials: A
authors.lastname: Romero
authors.forename: Dolores
authors.initials: D
authors.lastname: Caballero
authors.forename: Jorge
authors.initials: J
authors.lastname: Sierra
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ribera
authors.forename: Jose L
authors.initials: JL
authors.lastname: Díez
mesh_terms: D000328:Adult; D065095:Calcineurin Inhibitors; D002908:Chronic Disease; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000401:mortality; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000139:chemically induced; D012189:Retrospective Studies; D016879:Salvage Therapy / Q000379:methods; D020123:Sirolimus / Q000008:administration & dosage* / Q000633:toxicity; D016019:Survival Analysis; D013927:Thrombosis / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D020123:Sirolimus