BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia
Year: 2021
Type: article
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 T-cell receptor 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 a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by 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 antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the 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 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.
Source: Blood
Authors: Charles Herbaux, Christoph Kornauth, Stéphanie Poulain, Stephen J. F. Chong, Mary C. Collins, Rebecca Valentin, Liam Hackett, Olivier Tournilhac, François Lemonnier, Jehan Dupuis, Adrien Daniel, Cecile Tomowiak, Kamel Laribi, Loïc Renaud, Damien Roos-Weil, Cedric Rossi, Eric Van Den Neste, Cecile Leyronnas, Fatiha Merabet, Jean Valère Malfuson, Mourad Tiab, Loïc Ysebaert, Samuel Ng, Franck Morschhauser, Philipp B. Staber, Matthew S. Davids
Institutions: Centre National de la Recherche Scientifique, Inserm, Université de Lille, Centre Hospitalier Universitaire de Lille, Dana-Farber Cancer Institute, Centre de Recherches en Cancérologie de Lille, Medical University of Vienna, Université Clermont Auvergne, Clonal Heterogeneity, Leukemic environment, ThErapy Resistance of chronic leukemias, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique – Hôpitaux de Paris, Hôpitaux Universitaires Henri-Mondor, Centre Hospitalier Universitaire de Poitiers, Centre Hospitalier du Mans, Sorbonne Université, Pitié-Salpêtrière Hospital, CHU Dijon Bourgogne, Cliniques Universitaires Saint-Luc, Hôpital André Mignot, Hôpital d'instruction des Armées Percy, Institut universitaire du cancer de Toulouse Oncopole
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3130267604