PF181 PEDIATRIC-INSPIRED REGIMEN PLUS HDACI CHIDAMIDE YIELDED PROMISING RESPONSE IN PH-LIKE AND ETP ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: H. Zhou, Y. Gao, Q. Wang, R. Cao, C. Yin, X. Zhou, Q. Li, X. He, K. Huang, N. Liu, D. Lin, X. Liu, Q. Liu
Journal: HemaSphere (2019)

Background: Ph-like ALL is a B-cell neoplasm which lack BCR-ABL1 translocation but similar expression-pattern of the BCR-ABL1-positive ALL. Early T-cell precursor ALL is a neoplasm with a unique T-cell immunophenotype indicating limited early T differentiation. The optimal therapeutic approaches for ETP-ALL and Ph-like ALL are poorly characterized. Chidamide is a novel and orally active benzamide class of histone deacetylase inhibitor (HDACi) and approved for peripheral T-cell lymphoma (PTCL) in CHINA. Aims: We designed two pediatric-inspired, PEG-L-asparaginase-intensified PDT-ETP-ALL and PDT-Ph-Like trials to evaluate the safety and effect of HDACi chidamide for adult ETP-ALL and Ph-Like-ALL group. Methods: Based on the pediatric-inspired, PEG-L-asparaginase-intensified and MRD-directed PDT-ALL-2016 protocol, we designed two open-label, one-arm trials, PDT-ETP-ALL (NCT03553238) and PDT-Ph-Like (NCT03564470). The protocols were approved by Institutional Review Broad (IRB). Chidamide at a dose of 10 mg/day will be added to ETP-ALL group from induction therapy to consolidation therapy according to PDT-ETP-ALL protocol. Chidamide will be added to HDACi cohort based on cytogenetics and next-generation-sequencing classification, according to PDT-Ph-Like protocol. Primary study endpoint is event-free survival and secondary study endpoints are complete remission and MRD after induction, adverse event and overall survival. Results: Between FEB 2016 to JAN 2018, 29 patients with ETP-ALL were enrolled into PDT-ETP-ALL trial, a median age 22 years old (range, 14–26 years old). A total of 39 patients with Ph-like ALL has been enrolled into PDT-Ph-Like trial, a median age of 26 years old (range, 14–55 years old) and 28 patients in HDACi arm. Ph-like ALL with CRLF2 high-expression, CRLF2/EPOR/JAK2 rearrangement, JAK/STAT/IL-7R/SH2B3 mutation, will be assigned to HDACi arm. Targeted next-generation sequencing revealed ETP-ALL patients harbor high rates of mutations in factors involved in cytokine and JAK/STAT signaling pathway (62%), epigenetic regulation (52%) and hematopoietic development (35%). At the same time, we also performed NGS assessment with the same panel of Ph-like ALL patients. Of note, ETP-ALL and Ph-like ALL share the mutations involved in JAK/STAT signaling pathway (JAK1, JAK2, IL-7R) and epigenetic modification (SETD2, KMT2A, EZH2, KMT2C, EP300). Chidadmide was well-tolerated in ETP-ALL and Ph-like ALL patients. Fatigue, nausea, vomit, neutropenia and thrombocytopenia are common chidamide-associated adverse events with Common Terminology Criteria for Adverse Events (CTCAE) grade I-II. Complete remission and Flow-MRD-negative rate after induction therapy for ETP-ALL and Ph-Like-ALL were 87% and 67%, 77% and 60%, respectively. Six patients with ETP-ALL (21%, 6/29) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), and 11 patients with Ph-like (28%, 11/39) ALL received allo-HSCT. With a median follow-up of 23 months (range, 7–36 months), estimated 2-year event-free-survival (EFS) of ETP-ALL and Ph-like ALL is 82%, 70%, respectively. Summary/Conclusion: Our preliminary data suggest that a novel HDACi chidamide is effective and well-tolerated in adult ETP-ALL and Ph-like ALL, which deserve further extended clinical trial. (DOI: Supported by Science and Technology Planning Project of Guangdong (2016A020215112), NFSC (81770170), SMU Clinical Trial (LC2016ZD009), CHIPSCREEN).