title: Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy.
abstract: Reduced conditioning intensity has extended the option of allogeneic hematopoietic stem cell transplantation to patients who cannot tolerate fully myeloablative regimens. However, relapse and graft-versus-host disease (GVHD) continue to be major causes of morbidity and mortality. We prospectively tested whether a moderate reduction of the intensity of the preparative regimen would lead to significant reduction in regimen-related toxicity without compromising tumor control in a cohort of 44 patients ineligible for conventional hematopoietic stem cell transplantation. Patients were conditioned with fludarabine, busulfan, mycophenolate, and total lymphoid irradiation. Tacrolimus and methotrexate were given as prophylaxis for GVHD. Donors were 5 of 6 or 6 of 6 matched family members. The median age was 61 years. Eleven patients had comorbid conditions that precluded conventional myeloablative transplantation. Fatal regimen-related organ toxicity occurred in 3 patients. The cumulative incidence of grade 2 to 4 or grade 3 to 4 acute GVHD by day 100 was 38% (95% confidence interval [CI] = 25%, 55%) and 20% (95% CI = 10%, 39%), respectively, with a median time to onset of 66 days. For the entire cohort, 1-year overall survival, disease-free survival, and relapse rates were 54% (95% CI = 41%, 71%), 47% (95% CI = 35%, 65%), and 37% (95% CI = 19%, 51%), respectively. Outcomes differed based on stage of disease at time of transplantation, advanced (n = 19) versus nonadvanced (n = 25). Median survival times were 138 days and 685 days for subjects with advanced and nonadvanced disease, respectively (P =.005). After adjusting for age and comorbidity, disease stage continued to be significantly associated with overall survival (P =.005). In conclusion, a moderate reduction in conditioning dose intensity resulted in delayed onset of acute GVHD (compared with historical controls). A reduction in conditioning intensity is associated with poor survival for patients with advanced-stage disease, highlighting the importance of the conditioning regimen for tumor control.
authors.affiliation: Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109-0914, USA. jelevine@umich.edu
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Uberti
authors.forename: Lois
authors.initials: L
authors.lastname: Ayash
authors.forename: Christopher
authors.initials: C
authors.lastname: Reynolds
authors.forename: James L m
authors.initials: JL
authors.lastname: Ferrara
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Silver
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Gregory
authors.initials: G
authors.lastname: Yanik
authors.forename: Raymond
authors.initials: R
authors.lastname: Hutchinson
authors.forename: Voravit
authors.initials: V
authors.lastname: Ratanatharathorn
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity; D002066:Busulfan / Q000008:administration & dosage; D006086:Graft vs Host Disease / Q000139:chemically induced / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000150:complications / Q000401:mortality / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D006801:Humans; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage; D018714:Radiotherapy, Adjuvant; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D014740:Vidarabine; D002066:Busulfan; D009173:Mycophenolic Acid; C024352:fludarabine