What can we base the decision on for the choice of initial treatment modality for CLL?
We now have a range of highly effective treatment options for patients with chronic lymphocytic leukemia (CLL). New drugs have significantly contributed to improved overall survival (OS). However, there are still questions about the most appropriate treatment regimen or criteria for choosing the initial therapeutic modality. Some of these questions are posed—and answers sought—by Professor John F. Seymour from the University of Melbourne in his recent communication.
What circumstances should be considered?
For chemotherapy-naive patients, targeted therapy is the main choice, including both Bruton’s tyrosine kinase inhibitors (BTKi; particularly ibrutinib), which are administered long-term, and Bcl2 inhibitors (venetoclax) combined with an anti-CD20 antibody (rituximab or obinutuzumab), which are administered for a limited time. The response rates to both treatments in clinical trials were high, but conventional complete remissions were rare with ibrutinib as compared to venetoclax.
However, there is a lack of direct comparative data from phase III studies, making it impossible to definitively determine which approach shows better efficacy based on progression-free survival (PFS). Exceptions might be CLL with unmutated IGHV status or TP53 aberration at diagnosis, where BTKi seem to have the potential for longer initial disease control. Nonetheless, clinical data on using venetoclax as monotherapy in relapsed patients have shown efficacy and sustained disease control despite del(17p). Retrospective analysis thus confirmed that targeted drugs are definitely more suitable for treating CLL with TP53±del(17p) aberration than chemoimmunotherapy.
Other factors certainly play a role in decision-making, including tolerability, comorbidities, long-term toxicity, the need for intravenous antibody administration, cost, and other treatment options. It's also crucial to consider the risk of resistance development associated with treatment administration. Time-limited therapy helps prevent resistance development. Therefore, maintaining a response to venetoclax allows for regaining disease control upon recurrence even with repeated therapy.
Guidelines for individualizing treatment
With available data and no clear evidence of one regimen's superiority, it is imperative to make treatment decisions based on the specific patient, their organ dysfunctions, or comorbidities. For example, BTKi is preferred for patients with severe renal failure, while venetoclax is favored for those with arrhythmias.
The COVID-19 pandemic has shown that initiating treatment with BTKi was logistically simpler and less burdensome for patients. However, for those expected to stay on therapy for more than 2-3 years, the time-limited administration of venetoclax might be preferred due to continuous BTKi administration's toxicity and cost.
Conclusion
Repeated treatment with venetoclax or switching to BTKi results in remission for the majority of patients, assuring both doctors and patients that their disease will be under long-term control.
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Source: Seymour J. F. Is BTKi or BCL2i preferable as the first novel therapy in patients with CLL? The case for BCL2i. Blood Adv 2022 Feb 22; 6 (4): 1365−1370, doi: 10.1182/bloodadvances.2019001205.
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