Medically reviewed by Dr. Brian Koffman
The Bottom Line:
A newly published paper in Clinical Cancer Research found that when patients successfully treated with fixed-duration ibrutinib-venetoclax developed progressive disease, they had no acquired resistance mutations in BTK, BCL2, or PLCG2. This suggests that fixed-duration treatments may prevent the development of resistance mutations, potentially allowing for effective retreatment strategies.
Who Performed the Research and Where Was it Presented:
Dr. Nitin Jain from the University of Texas MD Anderson Cancer Center and colleagues published their findings in Clinical Cancer Research in 2023. An accompanying editorial was written by Dr. Othman Al-Sawaf and Dr. Matthew Davids, explaining the significance of these findings.
Background:
Continuous Bruton tyrosine kinase (BTK) inhibition, with BTK inhibitors such as ibrutinib, is a highly effective strategy to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), both as a first treatment or in relapsed/refractory disease. However, over time, patients can stop responding to these drugs due to the development of resistance mutations. About 80% of patients with CLL who progress on covalent BTK inhibitors have detectable mutations in BTK and/or PLCG2 at the time of progression. Similarly, continuous BCL2 inhibition with venetoclax can lead to resistance mutations. Fixed-duration treatments have been hypothesized to reduce the risk of developing resistance mutations.
Methods and Participants:
This study was a subgroup analysis of a phase 2 clinical trial, which included 191 patients with treatment-naïve CLL who completed treatment with fixed-duration ibrutinib-venetoclax for 15 cycles.
Results:
- With a median follow-up of 39 months, 29 out of the 191 patients (15%) developed progressive disease.
- No resistance-associated mutations in BTK, PLCG2, or BCL2 were detected at the time of progressive disease.
- Nineteen patients required retreatment, and most were retreated with ibrutinib (n=16) or ibrutinib-venetoclax (n=3).
- Of the 19 patients who were retreated, 17 achieved at least a partial response, 1 achieved stable disease, and 1 was pending a response assessment when the data were analyzed.
- While 89% of patients responded to retreatment, longer-term follow-up will be important for understanding the durability of these responses.
- This study was limited in its analyses because only a few patients developed progressive disease and subsequently needed retreatment.
Conclusions:
This study provides the first evidence that fixed-duration treatment strategies may limit the development of genetic resistance mechanisms in CLL. The absence of resistance-associated mutations allows for retreatment with previously used classes of drugs, such as BTK inhibitors or BCL2 inhibitors.
Links and Resources:
The full article by Dr. Jain and colleagues can be found here: Absence of BTK, BCL2, and PLCG2 Mutations in Chronic Lymphocytic Leukemia Relapsing after First-Line Treatment with Fixed-Duration Ibrutinib plus Venetoclax.
The accompanying editorial by Dr. Al-Sawaf and Dr. Davids is currently paywalled and can be found here: Overcoming Resistance in Chronic Lymphocytic Leukemia – Maybe Less is More?
Take care of yourself first.
Ann Liu, PhD
