RRC ID 63734
Author Herbaux C, Kornauth C, Poulain S, Chong SJF, Collins MC, Valentin R, Hackett L, Tournilhac O, Lemonnier F, Dupuis J, Daniel A, Tomowiak C, Laribi K, Renaud L, Roos-Weil D, Rossi C, Van Den Neste E, Leyronnas C, Merabet F, Malfuson JV, Tiab M, Ysebaert L, Ng S, Morschhauser F, Staber PB, Davids MS.
Title BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia.
Journal Blood
Abstract Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL) such as cytotoxic chemotherapy and alemtuzumab have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and TCR pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify novel combination therapy in this disease. Twenty-four primary T-PLL patient samples were studied using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis ('priming') and the relative dependence of a cell on different anti-apoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis, and predominantly depended on BCL-2 and MCL-1 for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated two patients with refractory T-PLL with the combination of venetoclax and ruxolitinib. We observed a deep response in the JAK3-mutated T-PLL and a stabilization of the unmutated disease. Our functional, precision medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting further exploration of such combinations clinically in T-PLL.
Volume 137(25)
Pages 3495-3506
Published 2021-6-24
DOI 10.1182/blood.2020007303
PII S0006-4971(21)00356-6
PMID 33598678
MeSH Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols / pharmacology* Bridged Bicyclo Compounds, Heterocyclic / pharmacology Female Humans Leukemia, Prolymphocytic, T-Cell / drug therapy* Leukemia, Prolymphocytic, T-Cell / metabolism Leukemia, Prolymphocytic, T-Cell / pathology MAP Kinase Signaling System / drug effects* Male Middle Aged Neoplasm Proteins* / antagonists & inhibitors Neoplasm Proteins* / metabolism Nitriles / pharmacology Pyrazoles / pharmacology Pyrimidines / pharmacology Sulfonamides / pharmacology
IF 17.794
Human and Animal Cells StromaNKtert(RCB2350)