BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia

Blood. 2021 Jun 24;137(25):3495-3506. doi: 10.1182/blood.2020007303.


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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Bridged Bicyclo Compounds, Heterocyclic
  • Neoplasm Proteins
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • Sulfonamides
  • ruxolitinib
  • venetoclax