Abstract 1620: In vivo and in vitro efficacy of birinapant in preclinical models of Ph-like pediatric acute lymphoblastic leukemia
Authors: Richmond Jennifer , Evans Kathryn , Robbins Alissa , Kurmasheva Raushan T. , Houghton Peter J. , Smith Malcolm A. , Lock Richard B. 
Published: August 2015

Abstract
Despite the success of current therapies for pediatric acute lymphoblastic leukemia (ALL) more effective treatments are required for the management of high-risk subtypes. Ph-like ALL is a high-risk subtype defined by a gene expression signature similar to that of BCR-ABL1-positive ALL despite the absence of the BCR-ABL1 translocation. Approximately 50% of Ph-like pediatric ALLs harbor mutations in Janus kinases (JAKs). Birinapant is a small molecule SMAC (second mitochondria-derived activator of caspase) mimetic that potently and specifically antagonizes inhibitors of apoptosis proteins (IAPs), resulting in IAP degradation, inactivation of NF-κB survival signaling and tumor necrosis factor (TNF)-dependent apoptosis. The combination of birinapant plus azacitidine is being evaluated in a Phase 2 clinical trial for the treatment of high-risk myeloid dysplastic syndrome. The aim of this study was to evaluate the efficacy of birinapant against patient-derived xenografts (PDXs) of pediatric ALL subtypes. Birinapant (30 mg/kg IP Q3 days × 5) significantly delayed the progression of 17/19 PDXs derived from Ph-like ALL (n = 7), B-cell precursor ALL (BCP-ALL, n = 8), and infant MLL¬-rearranged ALL (MLL-ALL, n = 4) by between 2 and 80 days compared with vehicle-treated controls. Using stringent objective response criteria modeled after the clinical setting, birinapant induced objective responses in 12/19 PDXs, including 7/7 Ph-like ALL (5 complete responses, CRs; 2 maintained CRs, MCRs), which was significantly better than BCP-ALL (4/8; 2 partial responses, PRs; 1 CR; 1 MCR) or infant MLL-ALL (1/4; 1 CR) PDXs (P&lt;0.05). Birinapant induced a CR in a Ph-like PDX at a dose 1/8th (3.8 mg/kg) of its maximum tolerated dose (30 mg/kg). Analysis at 14 days following treatment initiation revealed &gt;98% clearance of human leukemia cells from the bone marrow, spleen and peripheral blood of mice treated with birinapant doses that achieve drug levels attainable in humans. In vitro apoptosis assays confirmed the greater sensitivity of the Ph-like ALL PDX panel. Moreover, the cIAP1 protein was rapidly degraded in PDXs upon birinapant treatment both in vitro and in vivo, regardless of their relative sensitivity. Microarray analysis of gene expression revealed a significant correlation between baseline TNFα expression and in vivo birinapant sensitivity across 19 PDXs (P = 0.002; R2 = 0.46). While exogenously-added TNFα did not potentiate apoptosis induced by birinapant, a TNFα blocking antibody partially reversed apoptosis in 3/4 Ph-like PDXs. These results show that birinapant exerts profound single-agent in vivo efficacy against Ph-like pediatric ALL PDXs, indicate a role for endogenous TNFα in the birinapant mechanism of action against this high-risk pediatric ALL subtype, and support further evaluation of birinapant in the treatment of Ph-like ALL. Supported by NCI NO1CM42216.
Citation Format: Jennifer Richmond, Kathryn Evans, Alissa Robbins, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock. In vivo and in vitro efficacy of birinapant in preclinical models of Ph-like pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1620. doi:10.1158/1538-7445.AM2015-1620