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Strategies for Managing Treatment Resistance in CLL

By: Kayci Reyer
Posted: Thursday, April 1, 2021

According to research presented in Blood Advances, the implementation of resistance-management strategies may improve outcomes for patients with chronic lymphocytic leukemia (CLL). Sigrid S. Skånland, PhD, of Oslo University Hospital in Norway, and colleague sought to determine advancements made in understanding acquired resistance to targeted therapies.

Because CLL cells rely on the B-cell receptor signals to proliferate, targeted therapy agents affect three key regulators of B-cell survival: BCL2 protein, Bruton’s tyrosine kinase (BTK), and PI3K. Acquired resistance to these targeted treatments includes secondary mutations within the drug target, bypass pathway activation, and expression of prosurvival proteins from the microenvironment.

According to the authors, treatment resistance may be prevented by dose adjustment, including slowly ramping up or decreasing the dose depending on the treatment type; implementation of “drug holidays” and time-bound therapies; administration of combination therapies; and/or real-time patient response monitoring. Acquired resistance may be overcome using therapy sequencing, next-generation BTK inhibitors, and/or new treatment targets such as additional kinase inhibitors. Chimeric antigen receptor–modified T-cell therapy and therapy using bispecific antibodies or chimeric-targeting molecules may also be effective strategies to overcome acquired resistance.

“By understanding why resistance occurs, determining risk factors for development of resistance, and identifying strategies for resistance management, it is likely that treatment with targeted therapies will have curative potential,” concluded the study authors.

Disclosure: For full disclosures of the study authors, visit ashpublications.org.



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