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

Abstract

• Adding sirolimus to tacrolimus/methotrexate GVHD prophylaxis decreased grade 2-4 aGVHD but did not improve survival in pediatric ALL.• The addition of sirolimus to tacrolimus/methotrexate increased rates of VOD and TMA compared with tacrolimus/methotrexate alone.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 5 .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P 5 .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P 5 .05; 1% vs 10% TMA, P 5 .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 5 .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 5 .04). Grades 1-3 aGVHD were associated with improved EFS (P 5 .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

A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation

“…28 More recently, in randomized trials, the addition of sirolimus to tacrolimus or as a substitute for methotrexate has been shown to reduce acute GvHD without affecting overall survival. [29][30][31] To our knowledge, the current study is the first phase II randomized trial to investigate the efficacy of sirolimus as acute GvHD prophylaxis in truly non-myeloablative HCT. However, there has been some experience in the reduced-intensity conditioning setting, and there has been a recent preliminary abstract report from a randomized phase III trial comparing tacrolimus, methotrexate and sirolimus to conventional sirolimus-free regimens.…”

Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy

“…7,8,13,14 In the first prospective study of TMA in pediatric patients, incidence was reported to be as high as 35% and presence of TMA associated with higher non-relapse mortality than in patients without TMA. 1 Jodele et al 15 proposed that TMA is characterized by multi-organ endothelial injury affecting kidneys, gut, serosal surfaces, heart, skin and lungs, all in the setting of hemolytic anemia and thrombocytopenia.…”

Acute myeloid leukemia in children. Prospects for the optimization of treatment (review)

“…Име-ются данные об использовании сиролимуса для лече-ния реакции «трансплантат против хозяина» (РТПХ) у больных, получивших ТГСК. Результаты исследова-ния у детей показали, что сиролимус снизил частоту развития острой РТПХ, но показатели выживаемости не улучшились [33].…”