title: A phase I/II study of the safety and efficacy of the addition of sirolimus to tacrolimus/methotrexate graft versus host disease prophylaxis after allogeneic haematopoietic cell transplantation in paediatric acute lymphoblastic leukaemia (ALL).
abstract: Sirolimus has been shown to have activity against human acute lymphoblastic leukaemia at serum levels used for immunosuppression. We hypothesized that the addition of sirolimus to a tacrolimus/methotrexate graft-versus-host disease (GVHD) prophylaxis regimen would decrease relapse after haematopoietic stem cell transplantation and initiated a phase I/II study to demonstrate safety, feasibility, and efficacy. The study cohort included 18 patients in high-risk (HR) first complete remission (CR1), 16 in HR CR2, 17 in intermediate risk (IR) CR2, and 12 in CR3+. The 2-year event-free survival (EFS) of the cohort was 66% (standard error 6.4). EFS of risk groups was 74%, 81%, 44% and 46% for CR1, IR CR2, HR CR2 and CR3+ patients respectively, and did not differ by stem cell source. Cumulative incidence of acute GVHD grade II-IV and III-IV was 38% and 21% respectively, while the cumulative incidence of chronic GVHD was 32%. Cumulative incidence of transplant-related mortality and relapse was 10% and 25% respectively. Significant toxicities included veno-occlusive disease [seven patients (11%)], transplant-associated microangiopathy (three patients), and idiopathic pneumonitis (one patient). In summary, sirolimus-based GVHD prophylaxis can be given safely in this population and early survival results are promising. A phase III trial to test whether sirolimus decreases relapse and improves outcome after transplantation for ALL is ongoing.
authors.affiliation: Division of Hematology/Blood and Marrow Transplant, Primary Children's Medical Center, University of Utah School of Medicine, Salt Lake City, UT 84132-2408, USA. michael.pulsipher@hsc.utah.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pulsipher
authors.forename: Donna A
authors.initials: DA
authors.lastname: Wall
authors.forename: Michael
authors.initials: M
authors.lastname: Grimley
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Goyal
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boucher
authors.forename: Patricia
authors.initials: P
authors.lastname: Hankins
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: Nancy
authors.initials: N
authors.lastname: Bunin
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004812:Epidemiologic Methods; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D012008:Recurrence; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate