A Randomized Trial of Sirolimus-Based Graft Versus Host Disease (GVHD) Prophylaxis After Hematopoietic Stem Cell Transplantation (HSCT) in Selected Patients with CR1 and CR2 ALL: Results From Children's Oncology Group Study ASCT0431
Authors: Pulsipher Michael A. , Langholz Bryan , Wall Donna A. , Schultz Kirk R. , Bunin Nancy , Carroll William L. , Raetz Elizabeth A. , Gardner Sharon , Gastier-Foster Julie M. , Howrie Denise , Goyal Rakesh , James Douglas , Borowitz Michael J. , Barnes Yvonne Jean , Patil Shivanand R. , Teachey David T , Taylor Candace , Grupp Stephan A 
Published: October 2019

Abstract
Abstract 837
Based upon demonstrated activity of mTOR inhibitors in preclinical models of ALL and a promising pilot study, we hypothesized that the use of sirolimus added to a standard GVHD prophylaxis regimen would decrease relapse and improve survival after HSCT for children with high-risk CR1 and CR2 ALL. The COG performed a randomized phase III trial comparing tacrolimus/methotrexate (tac/mtx) with tac/mtx plus sirolimus. Sirolimus was initiated on day 0 of transplant and continued at therapeutic levels for 6 months. All patients received a preparative regimen consisting of fractionated TBI (1200–1320 cGy), and cyclophosphamide (60mg/kg × 2) +/− thiotepa (5mg/kg × 2) or VP-16 (1500mg/m2). Patients with primary induction failure who attained CR, hypodipoid ALL (<44 chromosomes), and Ph+ ALL were eligible for HCT in CR1 (intermediate risk); eligible CR2 patients included B-lineage with early bone marrow (BM) relapse (<36m from diagnosis) or T-lineage with BM relapse at any time (high risk, HR) and B-lineage with late BM relapse or isolated extramedullary relapse occurring <18m from diagnosis (intermediate risk, IR). HLA-matched sibling donors, 7–8/8 HLA matched related or unrelated donors, and 4–6/6 HLA matched cord blood stem cell sources were allowed. Randomization was stratified by donor type and relapse risk group. Events included relapse and treatment related mortality (TRM); the study was designed to enroll 259 patients to detect a two-year event free survival difference of 16% with 80% power. Results: A total of 146 patients enrolled, with 142 providing data to the analysis. As of July 1, 2011, there were 27 events in the 69 control arm patients and 31 events in the 73 experimental arm patients. The study was closed on May 10, 2011 when a stopping rule for futility of the primary endpoint (improved EFS) was met. The rates of grade III–IV acute GVHD, relapse, and TRM were 22%, 28% and 12% in control and 15%, 29%, and 14% in experimental arm patients (p=NS). Rates of CMV reactivation, venoocclusive Disease (VOD), and transplant associated microangiopathy (TAM) were 19%, 9%, and 1% in control arm patients and 12%, 17%, and 8% in experimental arm patients (p=0.26, 0.13, 0.10, respectively). Multistate modeling results indicate that the treatment group experienced less grade 2 to 4 aGVHD, but relapse rates in aGVHD patients were a quarter of those in non-aGVHD patients (p=<.001) while TRM rates were 1.5 times that of patients with no or grade I aGVHD (p=NS, see table). Survival after sibling donor transplantation was identical to URD transplantation. There was a trend toward increased risk of relapse in recipients of cord blood (p=0.14); further analysis of HLA type, pre-HSCT minimal residual disease (MRD), and patient risk is underway to clarify this finding.NaGVHD (III–IV)RelapseTRM1 year EFSaGVHD (II–IV) not present9333 (31%)10 (11%).45a (.32–.61)aGVHD (II–IV) present497 (15%)8 (16%).79a (.60–.89)P value<0.0010.38Matched Sib7513 (17%)20 (27%)5 (7%).58 (.42–.71)URD/Other RD387 (18%)7 (18%)7 (18%).54 (.32–.71)Cord296 (21%)13 (45%)6 (21%).33 (.16–.51)P value0.720.140.30

Conclusions:
The addition of sirolimus to tac/mtx resulted in a trend toward higher rates of non-fatal TAM and VOD, but identical rates of severe VOD and TRM. There was a lower rate of grade II–IV aGVHD in the experimental arm, but no decrease in relapse. For the combined cohort, grade II–IV acute GVHD was associated with significantly less relapse and improved survival, suggesting that GVL is important in decreasing relapse after HSCT for pediatric ALL. The cytotoxic effect of sirolimus against ALL was insufficient to decrease relapse when given to very high risk ALL patients after HSCT as part of GVHD prophylaxis, possibly because of the offsetting effect of decreasing GVL.

Disclosures:
Off Label Use: The trial used sirolimus for graft vs. host disease prophylaxis in children. Sirolimus is approved for kidney transplantation in children. Borowitz:BD Biosciences: Research Funding. Grupp:Children's Hospital of Philadelphia: Patents & Royalties.