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Jeremy S. Abramson, MD, MMSc
Jeremy S. Abramson, MD, MMSc
Posted: Monday, May 5, 2025
While BTK Inhibitors have become standard of care for double-refractory chronic lymphocytic leukemia (CLL), a recent review in Cancers highlights the still-unmet needs of patients who progress after treatment with both Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma-2 (Bcl-2) inhibitors. William Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and Ryan Jacobs, MD, of the Atrium Health Levine Cancer Institute of Charlotte, North Carolina, looked at the hypothetical case presentation of a 72-year-old female patient with relapsed/refractory CLL as the basis of a review of current approaches to treatment of patients with double-refractory CLL.
The patient was originally diagnosed in 2007 and had received multiple treatments for her CLL, including bendamustine/rituximab in 2012 and ibrutinib from 2014 through 2016. Ibrutinib was discontinued due to tolerance concerns, but since there was no clinical evidence of active disease, she was followed off treatment for 2 years. After progression, she was treated with venetoclax plus obinutuzumab in 2018, completing a 2-year course of venetoclax in 2020. She was rechallenged with single-agent venetoclax in 2022. She responded for approximately 10 months before progressing while on treatment. Because her first exposure to a BTK inhibitor was discontinued due to intolerance and not progression, the patient received acalabrutinib in late 2022 and responded for approximately 1 year, but she eventually developed symptomatic CLL progression. However, the patient did not have any new FISH abnormalities at this time, nor any clonal evolution. She also had a mutated IGHV gene, no TP53 mutation, and a T474I mutation in Bruton tyrosine kinase.
“As more and more patients are treated with these small-molecule inhibitors, there will be a growing number of patients who become double refractory,” the authors said, “There is a growing body of research revealing the mechanisms that underlie resistance to [BTK inhibitors] and BCL2i treatment with venetoclax.” These include pirtobrutinib, a non-covalent BTK inhibitor approved by the FDA for patients with CLL/SLL, and the CAR T-cell therapy agent lisocabtagene maraleucel. While responses to pirtobrutinib are relatively short, combinations with immunotherapy are being extensively investigated.
Disclosures: For full disclosures of the authors, visit mdpi.com.
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