Venetoclax Resistance in Patients With MCL Tied to Non-BCL2 Mutations

Study findings show that resistance to venetoclax therapy in patients with mantle cell lymphoma (MCL) is primarily associated with non-BCL2 gene mutations (Am J Hematol. 2020 Jun;95[6]:623-629).

Although venetoclax has demonstrated efficacy in the treatment of patients with relapsed MCL, mechanisms of resistance to the drug in this patient population are poorly understood.

Thus, Shuangtao Zhao, MD, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, and colleagues sought to establish the clinical outcomes and genomic characteristics of 24 patients with relapsed MCL who had received a median of 5 prior therapy lines. These patients were given venetoclax-based therapies, and 67% had disease progression with BTK inhibitors and 54% had blastoid or pleomorphic histology.

Following treatment with venetoclax, patients were followed-up with for a median of 17 months. These patients had an overall response rate of 50% and complete response (CR) rate of 21%. Disease progression was reported in 16 patients, and 15 died.

The median progression-free survival was 8 months, while overall and post-venetoclax survival durations were 13.5 and 7.3 months, respectively.

Dr Zhao et al performed whole-exome sequencing on samples collected from 7 patients before they initiated venetoclax therapy and after progression with venetoclax occurred.

Although TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2, and ATM were altered more frequently following disease progression, SMARCA4 and BCL2 alterations were only observed after progression.

Specifically, the investigators observed clonal evolution of novel SMARCA4 and KMT2C/D mutations at the point of progression in 2 patients with serial samples.

“Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations,” Dr Zhao and colleagues wrote.

“Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL,” they concluded.—Hina M. Porcelli