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

• Published in: Blood Vol. 130; no. 23; pp. 2499 - 2503
• Main Authors: Boidol, Bernd, Kornauth, Christoph, van der Kouwe, Emiel, Prutsch, Nicole, Kazianka, Lukas, Gültekin, Sinan, Hoermann, Gregor, Mayerhoefer, Marius E., Hopfinger, Georg, Hauswirth, Alexander, Panny, Michael, Aretin, Marie-Bernadette, Hilgarth, Bernadette, Sperr, Wolfgang R., Valent, Peter, Simonitsch-Klupp, Ingrid, Moriggl, Richard, Merkel, Olaf, Kenner, Lukas, Jäger, Ulrich, Kubicek, Stefan, Staber, Philipp B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.12.2017
• Subjects: Adult; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Drug Resistance, Neoplasm; Female; High-Throughput Screening Assays; Humans; Leukemia, Prolymphocytic, T-Cell - diagnosis; Leukemia, Prolymphocytic, T-Cell - drug therapy; Leukemia, Prolymphocytic, T-Cell - metabolism; Male; Middle Aged; Molecular Targeted Therapy; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Recurrence; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Treatment Outcome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-05-785683

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. •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.