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Jeremy S. Abramson, MD, MMSc
Jeremy S. Abramson, MD, MMSc
Posted: Tuesday, June 28, 2022
Inhibition of the antiapoptotic protein BCL2 in combination with Bruton’s tyrosine kinase (BTK) inhibitory therapy may improve clinical outcomes for patients with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma, according to Yi Miao, MD, of Jiangsu Province Hospital, Nanjing, China, and colleagues. In fact, the BCL2 inhibitor venetoclax combined with BTK inhibitory therapy appears to reduce BTK-induced adverse reactions and improve therapeutic effects. The findings of this article were published in the journal Biomarker Research.
“Resistance to BTK inhibitors and severe side effects unavoidably occur during BTK inhibitor monotherapy, frequently resulting in treatment failure. The addition of the BCL2 inhibitor venetoclax to BTK inhibitor may improve the therapeutic effects and result in deeper responses, providing a potential fixed-duration treatment, especially for patients with CLL,” stated the study authors.
The BTK inhibitor ibrutinib blocks the retention, migration, and proliferation of CLL cells. However, some patients exhibit resistance to ibrutinib through compensatory mechanisms that activate a prosurvival pathway, thus increasing B-cell survival and BCL2 levels. BCL2 is partially responsible for the pathogenesis of B-cell lymphoma. Thus, inhibition of BCL2 via venetoclax may reduce drug resistance to ibrutinib. Preclinical studies indicate that ibrutinib and venetoclax target different populations of CLL cells, suggesting the combination of these drugs can reduce proliferation and increase apoptosis of CLL cells.
Clinical trials have supported preclinical studies. For instance, the phase III indicated that a fixed duration of ibrutinib plus venetoclax improved response rates and progression-free survival for elderly patients with CLL when compared with chemoimmunotherapy. In a phase II trial, complete response rates were increased when ibrutinib plus venetoclax was administered to untreated fit patients with CLL (76%) compared with chemoimmunotherapy (54%).
Disclosure: The study authors reported no conflicts of interest.
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