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 separate 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.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (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 myeloid cell leukemia 1 (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 2 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 humans, offering a novel agent in T-PLL.

  • Submitted May 17, 2017.
  • Accepted September 13, 2017.
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