Patients with chronic lymphocytic leukemia (CLL) whose disease develops resistance to both tyrosine kinase (BTK) and B cell lymphoma 2 (BCL2) inhibition have a poor prognosis, and represent a group with a significant, unmet clinical need, according to research published in Blood Advances.

Inhibitors of BTK, including ibrutinib, and of BCL2, including venetoclax, have improved outcomes among patients with CLL, including those with high-risk characteristics. Resistance to these therapies, however, evolves in a subset of patients, and those within this subset have few treatment options.

Given, furthermore, that venetoclax and BTK inhibitors are being used with increasing frequency in this patient population, the likelihood of evolved treatment resistance is likely to become more widespread. For this study, researchers aimed to evaluate outcomes among patients with CLL who develop resistance to BTK and BCL2 inhibition.

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Overall, data from 17 patients were included in this study. There were 12 patients who first developed resistance to venetoclax followed by a BTI inhibitor; the converse was true in 5 patients. In the overall cohort, the median age was 76 years, the median number of prior therapy lines was 4, 88% of patients had 17p deletion and/or a TP53 mutation, and 100% of patients had a complex karyotype.

Analysis showed that the median time to progression with venetoclax was 24 months (range 6-94 months) compared with 25 months (range, 1-55) with BTK inhibition. A total of 6 patients in the cohort had Richter transmission on second-line targeted therapy; 11 had progressive CLL.

The median overall survival after any progression on a second-line targeted therapy was 3.6 months (95% CI, 2-11).

The authors wrote that “these data establish double class-resistant CLL as a high-risk clinical entity for which novel therapeutic approaches are urgently needed.”

Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054-4058. doi:10.1182/bloodadvances.2021005083