A Novel Oral Histone Deacetylase Inhibitor Chidamide Is Highly Effective and Well-Tolerated in Adult Early T-Cell Precursor and Ph-like Acute Lymphoblastic Leukemia
Authors: Zhou Hongsheng , Gao Ya , Wang Qiang , Cao Rui , Zhen Zhongxin , Li Qiuli , Lin Dainan , Zhou Linlin , Yin Changxin , He Han , Liu Xiaoli , Carter Bing Z , Liu Qifa 
Published: October 2019

Background Early T-cell precursor (ETP) lymphoblastic leukemia (ETP-ALL) is a neoplasm with an unique T-cell immunophenotype indicating limited early T differentiation. Ph-like ALL is a B-cell neoplasm which lack BCR-ABL1 translocation but similar expression-pattern of the BCR-ABL1-positive ALL. 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).

Methods Based on the pediatric-inspired, PEG-L-asparaginase-intensified and MRD-directed PDT-ALL-2016 protocol, we designed two open-label, one-arm, multi-site trials, PDT-ETP-ALL (NCT03553238) and PDT-Ph-Like (NCT03564470), to evaluate the safety and effect of HDACi chidamide for adult ETP-ALL and Ph-Like-ALL group, respectively. The protocols were approved by Institutional Review Broad (IRB). Chidamide at a dose of 10mg/day will be added to ETP-ALL group from induction therapy to consolidation therapy according to PDT-ETP-ALL protocol. Chidamide and dasatinib will be added to HDACi cohort and TKI cohort, respectively, 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 (CR) and MRD after induction, adverse event and overall survival.

Result Between FEB 2016 to DEC 2017, 24 patients with ETP-ALL were enrolled into PDT-ETP-ALL trial, 4 female patients and 20 male patients, a median age 22 years old (range, 14-22 years old). A total of 33 patients with Ph-like ALL has been enrolled into PDT-Ph-Like trial, 16 female patients and 17 male patients, a median age of 23 years old (range, 14-55 years old) 11 patients in TKI arm and 22 patients in HDACi arm. Ph-like ALL with CRLF2 high-expression, CRLF2/EPO/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 histone modification (SETD2, KMT2A, EZH2, KMT2C), which might indicate the underlying mechanism of sensitivity of ETP-ALL and Ph-like ALL to HDACi chidamide. Chidadmide was well-tolerated in ETP-ALL and Ph-like ALL patients. Fatigue, nausea, vomit, neutropenia and thrombocytopenia are common chidamide-associated adverse events (AE) 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 (25%, 6/24) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), and 11 patients with Ph-like ALL received allo-HSCT. With a median follow-up of 20 months (range, 7-31 months), estimated 2-year event-free-survival (EFS) of ETP-ALL and Ph-like ALL is 83%, 70%, respectively.

Conclusion: Our preliminary data of PDT-ETP-ALL and PDT-Ph-like ALL trials 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.

Disclosures

Zhou: CHIPSCREEN: Consultancy. Carter:novartis: Research Funding; AstraZeneca: Research Funding.