The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial.
Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.
Division of Hematology and Hematological Malignancies, Huntsman Cancer Institute/University of Utah School of Medicine, Primary Children's Hospital, Salt Lake City, UT;
Michael A
MA
Pulsipher
Bryan
B
Langholz
Donna A
DA
Wall
Kirk R
KR
Schultz
Nancy
N
Bunin
William L
WL
Carroll
Elizabeth
E
Raetz
Sharon
S
Gardner
Julie M
JM
Gastier-Foster
Denise
D
Howrie
Rakesh K
RK
Goyal
James G
JG
Douglas
Michael
M
Borowitz
Yvonne
Y
Barnes
David T
DT
Teachey
Candace
C
Taylor
Stephan A
SA
Grupp
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D020123:Sirolimus / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage*; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation; D055815:Young Adult
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate