Sequential BTK and BCL2 Therapy Yields High Initial Real-World Response in CLL

While covalent Bruton tyrosine kinase inhibitors (BTKi) have revolutionized the management of chronic lymphocytic leukemia (CLL), the real-world challenge begins when therapy ends, as most patients eventually discontinue therapy. New data from a retrospective analysis at Dana-Farber Cancer Institute, published in Advances in Hematology, reveal significant challenges in managing these patients after discontinuation and highlight an unmet need for more effective therapies.¹

Investigators reviewed the medical records of 104 adults with CLL who initiated a covalent BTKi between 2011 and 2019 and were documented as relapsed, refractory, resistant, or intolerant to BTKi therapy. The cohort reflects modern treatment practice, with nearly 60% of patients receiving their first BTKi as first- or second-line therapy. The median age of patients at BTKi initiation was 66.7 years, and patients had lived with CLL for a median of 6.7 years before initiating BTK-targeted therapy.

Real-World Patterns of BTK Inhibition Use and Interruption in CLL

Ibrutinib was the most commonly used BTKi, administered to 92.3% of patients, predominantly as monotherapy (59.4%). The remaining 7.7% received acalabrutinib as monotherapy. Nearly all patients (98.1%) eventually discontinued their index BTKi, with a median time to discontinuation of 1.8 years. Adverse events were the primary reason for BTKi discontinuation, affecting 52.9% of patients, with atrial fibrillation and bleeding being the most frequently reported toxicities. Disease progression accounted for 40.2% of discontinuations, whereas histologic transformation accounted for 2.9%.

These findings are consistent with prior real-world studies that have identified adverse events as the leading cause of BTKi discontinuation.^2,3 The authors note, "This pattern was observed even though the majority of patients received their index BTKi treatment in the first or second line of therapy,” suggesting that “toxicities associated with BTKi can lead to treatment discontinuation in any line of therapy, thereby preventing some patients from achieving disease control even in earlier lines of therapy."

The study followed patients for a median of 5.7 years after initiating BTKi therapy. Among those with documented first response assessments, more than 80% achieved an objective response, including complete responses in 16.7% and partial responses in 66.7%. Median progression-free survival (PFS) from BTKi initiation was 3.2 years, while median overall survival (OS) reached 8.9 years. The researchers found a strong association between PFS and OS, supporting the clinical relevance of PFS as a meaningful end point in CLL trials and treatment evaluation.³

Outcomes of Sequential BCL2 Inhibitor Therapy

After discontinuing BTKi therapy, approximately 60% of patients received subsequent treatment. The majority of these patients (80.6%) were treated with venetoclax-containing regimens, reflecting current practice patterns following BTKi failure. Other therapies included combinations of targeted agents, chemotherapy, and monoclonal antibody–based regimens, though these were used less frequently. Among patients treated sequentially with a BTKi followed by BCL2 inhibitors (BCL2i), the overall response rate to venetoclax-based therapy at first assessment was 77.8%, with complete responses observed in more than one-third of patients and partial responses in approximately 42%.

Despite these initial responses, treatment durability declined with sequential targeted therapy. Nearly three-quarters (73.8%) of patients exposed to both BTKi and BCL2i ultimately discontinued BCL2i treatment, with a median treatment duration of 0.8 years. Among double-exposed patients, more than one-third (36.1%) died during a median follow-up of 2.6 years after BCL2i initiation. Outcomes were poorest among patients classified as post-BTKi and post-BCL2i, defined as those who were relapsed, refractory, resistant, or intolerant to both classes. Among post-BTKi and post-BCL2i patients with documented response assessments, 85% initially responded to BCL2i therapy, 15% already had progressive disease at their first check-up, and 44% died during the follow-up period.

"The poor prognosis of patients in our study following the discontinuation of the index BTKi is suggested by the observed changes in the mutation profile," the authors note. Among patients assessed for BTK mutations after BTKi discontinuation, the C481S substitution, associated with resistance to covalent BTKi, was detected in more than 70% of mutation-positive cases. The most common other mutations were TP53, SF3B1, NOTCH1, and ATM. Their prevalence was numerically lowest in samples assessed prior to BTKi initiation and trended higher in samples assessed during treatment and after discontinuation.

While BTKi have substantially improved outcomes for patients with CLL, the authors emphasize that many patients ultimately discontinue therapy due to intolerance or disease progression. Sequential treatment with BCL2i can induce meaningful responses, but these responses are often not durable, particularly among patients who progress after exposure to agents targeting both pathways.

Overall, the study highlights that patients who have received both BTKi and BCL2i therapy represent a growing population with limited treatment options and poor outcomes.⁴

Recently approved noncovalent BTKi and chimeric antigen receptor T-cell therapies are beginning to address this gap; however, the authors conclude, “Even with the recent approvals of pirtobrutinib and liso-cel [lisocabtagene maraleucel], the evolving therapeutic need of this emerging patient population necessitates continued investigation and improved treatment options.”

References

1. Lin KH, Huynh L, Yang X, et al. Clinical outcomes in patients with CLL treated with BTKi at a large US cancer center. Adv Hematol. 2025;2025:7492594. doi:10.1155/ah/7492594

2. Hampel PJ, Ding W, Call TG, et al. Rapid disease progression following discontinuation of ibrutinib in patients with chronic lymphocytic leukemia treated in routine clinical practice. Leuk Lymphoma. 2019;60(11):2712-2719. doi:10.1080/10428194.2019.1602268

3. Beauchemin C, Johnston JB, Lapierre MÈ, Aissa F, Lachaine J. Relationship between progression-free survival and overall survival in chronic lymphocytic leukemia: a literature-based analysis. Curr Oncol. 2015;22(3):e148-56. doi:10.3747/co.22.2119

4. Eyre TA, Hess LM, Sugihara T, et al. Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study. Leuk Lymphoma. 2023;64(5):1005-1016. doi:10.1080/10428194.2023.2190436