Fiche publication
Date publication
février 2021
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROSSI Cédric
Tous les auteurs :
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 EW, Leyronnas C, Merabet F, Malfuson JV, Tiab M, Ysebaert L, Ng SY, Morschhauser F, Staber PB, Davids MS
Lien Pubmed
Résumé
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.
Référence
Blood. 2021 Feb 17;:
