| 著者 |
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.
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| 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.
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