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

Michael A. Pulsipher, Bryan Langholz, Donna A. Wall, Kirk R. Schultz, Nancy Bunin, William L. Carroll, Elizabeth Raetz, Sharon Gardner, Julie M. Gastier-Foster, Denise Howrie, Rakesh K. Goyal, James G. Douglas, Michael Borowitz, Yvonne Barnes, David T. Teachey, Candace Taylor, Stephan A. Grupp

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2017-2025
Number of pages9
JournalBlood
Volume123
Issue number13
DOIs
StatePublished - Mar 27 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Pulsipher, M. A., Langholz, B., Wall, D. A., Schultz, K. R., Bunin, N., Carroll, W. L., Raetz, E., Gardner, S., Gastier-Foster, J. M., Howrie, D., Goyal, R. K., Douglas, J. G., Borowitz, M., Barnes, Y., Teachey, D. T., Taylor, C., & Grupp, S. A. (2014). 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. Blood, 123(13), 2017-2025. https://doi.org/10.1182/blood-2013-10-534297