Implications of BTK Inhibitors Combined With CAR-T in R/R CLL/SLL

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Combination of Lisocabtagene Maraleucel (Liso-cel) and Ibrutinib in R/R CLL/SLL – Primary Results from TRANSCEND CLL 004

The TRANSCEND CLL 004 study (phase 1/2) evaluates the combination of lisocabtagene maraleucel (liso-cel), a CD19-directed CAR T-cell therapy, and ibrutinib, a BTK inhibitor, in patients with R/R CLL or SLL. Given the challenges in treating high-risk CLL, this combination aims to enhance disease control and improve the depth of response.

Key Findings

• Enhanced Efficacy: The combination demonstrated promising response rates in a population with high-risk features, potentially overcoming resistance mechanisms observed with single-agent therapies.
• Tolerability and Safety: Although CAR T-cell therapy alone is associated with cytokine release syndrome and neurotoxicity, the addition of ibrutinib may help modulate immune-related toxicities, improving tolerability.
• Potential Paradigm Shift: These results challenge the conventional sequential approach of BTK inhibitors followed by CAR T-cell therapy, suggesting that combining these modalities earlier may yield superior outcomes.

Clinical Implications

• New Treatment Strategy: The synergy between ibrutinib and CAR T-cell therapy could redefine treatment sequencing in high-risk CLL, favoring combination approaches over stepwise escalation.
• Personalized Therapy: Identifying which patients benefit most from early combination therapy vs sequential treatment will be critical.
• Future Directions: Further studies are needed to establish the optimal duration of ibrutinib before and after CAR T-cell infusion and to assess long-term remission durability.

This study highlights the transformative potential of integrating BTK inhibition with cellular therapy, paving the way for new strategies in high-risk CLL management.