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Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia.

ABSTRACT: Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.

SUBMITTER: Herling CD

PROVIDER: S-EPMC5820258 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia.

Herling Carmen D CD Abedpour Nima N Weiss Jonathan J Schmitt Anna A Jachimowicz Ron Daniel RD Merkel Olaf O Cartolano Maria M Oberbeck Sebastian S Mayer Petra P Berg Valeska V Thomalla Daniel D Kutsch Nadine N Stiefelhagen Marius M Cramer Paula P Wendtner Clemens-Martin CM Persigehl Thorsten T Saleh Andreas A Altmüller Janine J Nürnberg Peter P Pallasch Christian C Achter Viktor V Lang Ulrich U Eichhorst Barbara B Castiglione Roberta R Schäfer Stephan C SC Büttner Reinhard R Kreuzer Karl-Anton KA Reinhardt Hans Christian HC Hallek Michael M Frenzel Lukas P LP Peifer Martin M

Nature communications 20180220 1

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and ...[more]

PMID: 29463802

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Project description:BackgroundNew treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.MethodsWe conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.ResultsThe majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.ConclusionsSelective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

Dataset Information

Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia.

Publications

Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia.

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