Investigators from Australia have identified a genetic mutation that causes resistance to the targeted drug venetoclax (Venclexta) in patients with chronic lymphocytic leukemia (CLL), according to research presented by Blombery et al at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract LBA7) and simultaneously published in Cancer Discovery.
Venetoclax promotes cancer cell death by blocking a protein known as B-cell leukemia/lymphoma 2 protein, or BCL2. Levels of BCL2 are abnormally high in many patients with CLL. The newly discovered mutation in BCL2 significantly reduces the ability of venetoclax to latch on to and block the protein, explained lead author Piers Blombery, MD, of the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne.
“Although venetoclax is a highly effective drug for CLL, most patients eventually relapse,” Dr. Blombery said in a statement. “The mutation we have found helps to explain why venetoclax stops working in some patients. Furthermore, we have shown that in some cases the mutation can be detected in patients’ bone marrow years before clinical signs of relapse appear.”
Dr. Blombery and his colleagues performed genomic sequencing on tumor samples from 67 patients whose CLL relapsed after treatment with venetoclax. For 15 of these patients, the investigators were able to evaluate tumor samples from before and after venetoclax treatment. The mutation was identified in after-treatment tumor samples from 7 of these 15 patients.
“We also tested almost 400 patients with CLL and other blood cancers who had never been treated with venetoclax, and we did not find this mutation in any of those patients,” said Dr. Blombery. “This is evidence that the mutation only develops during venetoclax treatment, so it is something that patients can be screened for. In patients who develop this mutation at a low level, it would be prudent for the hematologist to begin to look for other therapies to use instead.”
Venetoclax was the first drug targeting BCL2 to be approved by the U.S. Food and Drug Administration (FDA). Initially it was approved only for the treatment of patients with CLL whose tumors had a genetic alteration in which a piece of one chromosome was missing. In June 2018, the FDA expanded the drug’s approval to include all patients with CLL whose disease progressed after at least one previous treatment, regardless of whether their cancer cells have this genetic alteration.
While identification of the BCL2 mutation helps explain why CLL recurs in some patients treated with venetoclax, much remains to be understood about the factors underlying CLL recurrence after venetoclax treatment.
“We don’t know what caused the cancer to relapse in the eight patients in whom we did not find the BCL2 mutation,” Dr. Blombery said. “Moreover, in the seven patients who had the mutation, we found it in only some of their cancer cells—and yet the cells that did not carry the mutation were still contributing to the cancer’s growth. So, clearly, even among patients who have the mutation, other factors are at play in causing resistance to venetoclax therapy.”
In one patient, the investigators found a second genetic abnormality generating resistance to venetoclax treatment in cells that did not carry the BCL2 mutation. “This demonstrates the importance of considering multiple angles of attack with combination therapies—for example, venetoclax and rituximab [Rituxan]—rather than relying on a single targeted agent in a disease that has multiple genomic tricks up its sleeve,” Dr. Blombery said.
The investigators are planning to conduct more extensive genomic analysis of the patients who did not develop the BCL2 mutation to identify other mechanisms of resistance to venetoclax. They also plan to gather more data on the time course of acquisition of the BCL2 mutation.
Disclosure: This study was supported by Peter MacCallum Cancer Centre, the Royal Melbourne Hospital, the University of Melbourne and the Walter and Eliza Hall Institute of Medical Research. External funding also supported this research including from the Snowdome Foundation, the Christine and Bruce Wilson Centre for Lymphoma Genomics based at Peter Mac, the Leukemia and Lymphoma Society (USA), the Leukaemia Foundation, NHMRC, Australian Cancer Research Foundation and Cancer Council Victoria. See the study authors’ full disclosures at ash.confex.com.
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