title: Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave., North, D1-100, P.O. Box 19204, Seattle, WA 98109-1204, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Benito
authors.forename: T
authors.initials: T
authors.lastname: Furlong
authors.forename: P J
authors.initials: PJ
authors.lastname: Martin
authors.forename: C
authors.initials: C
authors.lastname: Anasetti
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: K
authors.initials: K
authors.lastname: Doney
authors.forename: R A
authors.initials: RA
authors.lastname: Nash
authors.forename: T
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: R
authors.initials: R
authors.lastname: Storb
authors.forename: K M
authors.initials: KM
authors.lastname: Sullivan
authors.forename: R
authors.initials: R
authors.lastname: Witherspoon
authors.forename: H J
authors.initials: HJ
authors.lastname: Deeg
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use*; D008875:Middle Aged; D010865:Pilot Projects; D019233:Retreatment; D020123:Sirolimus / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D020123:Sirolimus; D008775:Methylprednisolone