Chronic Lymphocytic Leukemia: Evolving Management With New Data From EHA 2025 - Episode 5
Are Oral Fixed-Duration Doublets Right for High-Risk CLL?
Panelists discuss how oral fixed-duration Bruton tyrosine kinase (BTK) inhibitor–venetoclax doublets may be considered for patients with high-risk TP53-disrupted chronic lymphocytic leukemia (CLL) based on promising phase 2 data showing high undetectable minimal residual disease (MRD) rates, but express concerns about infection risks with triplet regimens and emphasize the need for longer follow-up data to determine durability of remissions, with some preferring MRD-guided longer duration approaches over standard 14-cycle regimens for these highest-risk patients.
Are Oral Fixed-Duration Doublets Right for High-Risk CLL?
The treatment of high-risk patients with CLL with TP53 disruption using fixed-duration oral doublets remains a contentious area, with expert opinions varying on optimal approaches. Although continuous BTK inhibitor therapy is often preferred for these patients, emerging data suggest that fixed-duration combinations may have a role in carefully selected cases. The key consideration centers on whether high-risk patients should receive their best opportunity for fixed-duration therapy in the frontline setting, as this strategy may be less effective in the relapsed/refractory setting. However, clinicians must honestly discuss realistic expectations about treatment-free intervals, as current data suggest potentially shorter remission durations in this population.
Triplet combination approaches have shown promise but come with significant safety concerns that must be balanced against potential efficacy benefits. Published phase 2 studies initially enrolling all-comers subsequently focused on TP53-disrupted patients after observing encouraging signals, demonstrating high rates of undetectable MRD in peripheral blood and bone marrow. However, infection risks represent a major challenge with triplet regimens, exemplified by studies like the Alliance HIV trial, which experienced high COVID-19 mortality rates that ultimately rendered the study negative. Similar safety signals have emerged from other triplet studies, requiring careful patient selection and monitoring protocols.
The current evidence base for fixed-duration approaches in high-risk patients remains limited, with insufficient long-term follow-up data to definitively guide treatment decisions. Notably, many pivotal studies specifically excluded TP53-disrupted patients, limiting the applicability of their results to this population. For clinicians considering oral doublet therapy in high-risk patients, longer treatment durations with MRD-guided stopping criteria may be preferable to standard fixed time frames. The absence of extended follow-up data from triplet studies means that treatment decisions must be individualized based on patient preferences, comorbidities, and risk tolerance, while acknowledging the uncertainty regarding duration of treatment-free intervals in this challenging patient population.
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