Exploring the Synergy Between Idelalisib and Bendamustine in Treating CLL
Posted: Thursday, December 12, 2019
Clinically, some patients with chronic lymphocytic leukemia (CLL) who have been previously treated with chemoimmunotherapy have shown sensitivity to the PI3K inhibitor idelalisib. A team led by senior author Sachin Kaytal, PhD, of the University of Manitoba, Winnipeg, set out to find out why and how this is so, evaluating the activities and cytotoxicity of idelalisib in comparison to the alkylating agent bendamustine in primary CLL cells. Their work, which appeared in Cancers, confirmed that “idelalisib, in contrast to bendamustine, was cytotoxic to cells from extensively treated patients.”
The researchers observed “marked synergy” between bendamustine and idelalisib, “both when quiescent and under conditions to simulate the microenvironment,” they wrote. This held true even in cases resistant to bendamustine and idelalisib individually as well as in those with deletion 17p. The team noted no cross-resistance between the agents, “confirming their different modes of cytotoxicity.” Idelalisib inhibits the δ form of PI3K, a key enzyme in the B-cell receptor pathway. “PI3Kδ-deficient murine splenic B cells were more resistant to idelalisib and showed reduced synergy with bendamustine, thus confirming the importance of functional PI3Kδ protein,” they explained.
When Dr. Kaytal and colleagues simulated the CLL microenvironment with CD40L/interleukin-4 co-treatment, the activity of idelalisib decreased, but the agents’ synergy was retained, they noted. Their synergy appeared to be unrelated to enhanced DNA damage and rather perhaps related to transcriptional modulation.
The synergy that has been seen clinically between idelalisib and chemotherapy has been “associated with increased immunosuppression and associated infections at the commonly used drug doses. Based on our results,” concluded the investigators, “we would suggest that future clinical studies with idelalisib and chemotherapy should use an initial step-up in drug dosages to determine the optimum regimen for therapeutic efficacy.”
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