First in human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia

Bernd Boidol, Christoph Kornauth, Emiel van der Kouwe, Nicole Prutsch, Lukas Kazianka, Sinan Gültekin, Gregor Hoermann, Marius E. Mayerhoefer, Georg Hopfinger, Alexander Hauswirth, Michael Panny, Marie-Bernadette Aretin, Bernadette Hilgarth, Wolfgang R. Sperr, Peter Valent, Ingrid Simonitsch-Klupp, Richard Moriggl, Olaf Merkel, Lukas Kenner, Ulrich Jäger, Stefan Kubicek and Philipp B. Staber

Key points

  • Strong responses to venetoclax separates T-PLL from other hematologic malignancies in high- throughput drug screening of clinical samples

  • Two relapsed and refractory T-PLL patients demonstrated clinical response on venetoclax treatment


T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with a short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 FDA-approved anti-cancer drugs or compounds currently in clinical development we pursued to identify novel effective treatments for T-PLL patients. We found that the BCL-2 inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members MCL-1 and BCL-XL in lymphoma-cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses venetoclax treatment was commenced in two late stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single agent activity of venetoclax both, ex vivo and in human offering a novel agent in T-PLL.

  • Submitted May 18, 2017.
  • Accepted September 13, 2017.