Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are two manifestations of the same B-cell non-Hodgkin lymphoma, distinguished by the location of malignant cells—CLL primarily affects the blood and bone marrow, while SLL involves the lymph nodes—and together, they represent approximately 19% of all B-cell lymphomas, making them the third most common subtype according to the Lymphoma Research Foundation.

IMBRUVICA (ibrutinib), a BTK inhibitor and VENCLEXTA (venetoclax), a BCL-2 inhibitor, are both approved for treating adult patients with CLL or SLL. 

The data presented demonstrated that around 202 patients completed fixed-duration ibrutinib + venetoclax (fixed duration cohort, n = 159; MRD cohort placebo arm, n = 43). With a median follow-up of 68.9 months, 5.5-year progression-free survival (PFS) and overall survival (OS) rates (95% CI) were 66% (58–72) and 97% (93–99), respectively. 5.5-year PFS rates (95% CI) in patients without and with del(17p)/mutated TP53 were 70% (62–76) and 36% (17–55), respectively. In patients with unmutated IGHV, 5.5-year PFS was 55% (45–64); 63% (49–74) in patients without, and 44% (28–60) in patients with concomitant del(17p)/mutated TP53/complex karyotype. 

The corresponding rates for patients with mutated IGHV were 79% (68–87), 85% (71–93), and 62% (34–81). Undetectable MRD (uMRD4; <10–4 by flow cytometry) was achieved in peripheral blood (PB) in 54% of patients at cycle 7 and 69% at EOT, and in bone marrow in 69% of patients at EOT. 5.5-year PFS rates (95% CI) were higher in patients with uMRD4 in PB at EOT (75% [67–82]) vs. those with MRD (47% [33–59]). 64 patients had PD after completion of fixed duration ibrutinib + venetoclax. 5.5-year freedom from next-line treatment was 73% (95% CI 66–79). Of 40 patients with available samples, one had an acquired subclonal mutation in BCL2 of unclear significance (A113G, VAF 8.3%); none had acquired resistance-associated mutations in BTK or PLCG2. 36 patients initiated retreatment with ibrutinib (n=25) or ibrutinib + venetoclax (n = 11). With 28.4 months median follow-up on ibrutinib retreatment (range, 3.7–59.1), the overall response rate (ORR) was 76% (best response: 1 CR; 1 nodular PR; 17 PR; 4 SD; 1 PD [Richter transformation]; 1 no assessment); 2-year PFS and OS rates from the start of retreatment were 91% and 96%, respectively. With 15.2 months median follow-up on ibrutinib + venetoclax retreatment (range, 7.4–29.3), ORR was 82% (best response: 1 CR; 8 PR; 2 SD); 1-year PFS and OS rates from the start of retreatment were both 100%. Second malignancies occurred in 24 patients across the entire study period, including 12 initial treatments and 4 retreatment treatment-emergent adverse events.

KOL insights

“After more than five years, the CAPTIVATE study findings confirm the sustained benefit of the fixed duration combination of ibrutinib and venetoclax as a first-line treatment for patients living with CLL, including in those with higher risk genomic features. This all-oral, chemotherapy-free, fixed-duration regimen offers eligible patients the advantage of an extended, treatment-free interval while effectively keeping their disease under control.” – Expert Opinion

Conclusion

The treatment landscape for CLL and SLL is undergoing a significant transformation, driven by the rise of next-generation targeted therapies. Newer BTK inhibitors such as acalabrutinib, zanubrutinib, and the non-covalent agent pirtobrutinib are steadily replacing ibrutinib due to their improved safety, tolerability, and selectivity. At the same time, venetoclax, a BCL-2 inhibitor, is emerging as a central component of therapy—particularly in fixed-duration regimens that offer the advantage of deeper remissions and treatment-free intervals.

Combining BTK inhibitors with venetoclax is showing synergistic potential, effectively addressing limitations seen with BTK monotherapy, such as resistance and toxicity. Although ibrutinib initially led the shift away from chemotherapy, its role is being redefined as clinicians increasingly adopt venetoclax-based combinations capable of achieving undetectable minimal residual disease (uMRD).

Further shaping the competitive landscape are novel modalities such as bispecific antibodies, CAR-T cell therapies, and other next-generation agents, which bring alternative mechanisms and the potential for curative outcomes in select patient groups. In this evolving environment, the combination of IMBRUVICA and VENCLEXTA/VENCLYXTO stands out as a transformative advancement, offering effective oral, chemotherapy-free treatment options that reflect a broader shift in the standard of care for CLL/SLL.