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, 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

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.

Figures

Figure 1
Figure 1
Consort diagram. Flow of patients enrolled on the trial.
Figure 2
Figure 2
Survival outcomes. (A) EFS by treatment arm. (B) OS by treatment arm. (C) EFS by risk category. (D) EFS by subgroups of very high-risk CR1 patients.
Figure 3
Figure 3
The effect of aGVHD and MRD on relapse and survival. (A) Relapse probability curves for patients with grade 1-3 aGVHD by day 55 and with no aGVHD by day 55. (B) EFS probability by aGVHD status and treatment arm. (C) Relapse probability by pre-HCT MRD status.

Source: PubMed

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