title: Prophylaxis of graft-versus-host disease in unrelated donor transplantation with pentostatin, tacrolimus, and mini-methotrexate: a phase I/II controlled, adaptively randomized study.
abstract: OBJECTIVE
  Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after matched unrelated, related, or mismatched related donor hematopoietic stem-cell transplantation (HSCT). Improved GVHD prevention methods are needed. Pentostatin, an adenosine deaminase inhibitor, leads to lymphocyte depletion with low risk of myelosuppression. We hypothesized that addition of pentostatin to GVHD prophylaxis with tacrolimus and mini-methotrexate may improve outcomes, and we conducted a Bayesian adaptively randomized, controlled, dose-finding study, taking into account toxicity and efficacy.
  
  
  METHODS
  Success was defined as the patient being alive, engrafted, in remission, without GVHD 100 days post-HSCT and no grade ≥ 3 GVHD at any time. Patients were randomly assigned to pentostatin doses of 0, 0.5, 1.0, 1.5, and 2.0 mg/m(2) with drug administered on HSCT days 8, 15, 22, and 30. Eligible patients were recipients of mismatched related (n = 10) or unrelated (n = 137) donor HSCT.
  
  
  RESULTS
  Median age was 47 years. Thirty-seven, 10, 29, 61, and 10 patients were assigned to the control and four treatment groups, respectively, with comparable baseline characteristics. Pentostatin doses of 1.0 and 1.5 mg/m(2) had the highest success rates (69.0% and 70.5%) versus control (54.1%). The posterior probabilities that the success rates were greater with 1.5 mg/m(2) or 1.0 mg/m(2) versus control are 0.944 and 0.821, respectively. Hepatic aGVHD rates were 0%, 17.2%, and 11.1%, respectively, for 1.5 mg/m(2), 1.0 mg/m(2), and control groups. No grades 3 to 4 aGVHD occurred in 11 HLA-mismatched recipients in the 1.5 mg/m(2) group.
  
  
  CONCLUSIONS
  Pentostatin increased the likelihood of success as defined here, and should be further investigated in larger randomized, confirmatory studies.
authors.affiliation: Department of Stem Cell Transplantation and Cell Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 423, Houston, TX 77030, USA.
authors.forename: Simrit
authors.initials: S
authors.lastname: Parmar
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
authors.forename: Daniel
authors.initials: D
authors.lastname: Couriel
authors.forename: Mark F
authors.initials: MF
authors.lastname: Munsell
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernandez-Vina
authors.forename: Roy B
authors.initials: RB
authors.lastname: Jones
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Uday
authors.initials: U
authors.lastname: Popat
authors.forename: Paolo
authors.initials: P
authors.lastname: Anderlini
authors.forename: Sergio
authors.initials: S
authors.lastname: Giralt
authors.forename: Amin
authors.initials: A
authors.lastname: Alousi
authors.forename: Pedro
authors.initials: P
authors.lastname: Cano
authors.forename: Doyle
authors.initials: D
authors.lastname: Bosque
authors.forename: Chitra
authors.initials: C
authors.lastname: Hosing
authors.forename: Leandro de Padua
authors.initials: Lde P
authors.lastname: Silva
authors.forename: Michael
authors.initials: M
authors.lastname: Westmoreland
authors.forename: J Kyle
authors.initials: JK
authors.lastname: Wathen
authors.forename: Donald
authors.initials: D
authors.lastname: Berry
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: de Lima
mesh_terms: D058892:Adenosine Deaminase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D057194:Intention to Treat Analysis; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D008875:Middle Aged; D015649:Pentostatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D058892:Adenosine Deaminase Inhibitors; D007166:Immunosuppressive Agents; D015649:Pentostatin; D016559:Tacrolimus; D008727:Methotrexate