Several novel treatment regimens are showing promise in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), offering the potential for durable remissions and improved outcomes for patients. Recent data presented at the American Society of Hematology (ASH) Annual Meeting & Exposition and published in journals such as the Journal of Clinical Oncology and The Lancet Oncology highlight the efficacy and safety of these approaches.
Fixed-Duration Ibrutinib and Venetoclax in CLL/SLL
Updated findings from the phase 2 CAPTIVATE study (NCT02910583) demonstrate that fixed-duration ibrutinib (Imbruvica) with venetoclax (Venclexta) leads to durable outcomes in patients with CLL/SLL, even those with bulky disease at baseline. With up to 5.5 years of follow-up, the fixed-duration regimen showed durable progression-free survival and overall survival rates, including in high-risk patients with genomic features like del(17p) or mutated TP53. The safety profile was manageable, with grade 3 or greater adverse events observed in approximately 60% of patients.
Paolo Ghia, MD, PhD, deputy director of the Division of Experimental Oncology in San Raffaele Scientific Institute in Milan, Italy, noted that the findings are highly positive for general hematologists because they demonstrate the availability of an easy-to-administer treatment combination. Both ibrutinib and venetoclax are oral therapies, which simplifies administration after the initial debulking phase with ibrutinib. The regimen involves 3 months of debulking with ibrutinib followed by 12 months of the combination.
Zanubrutinib and Venetoclax in Relapsed/Refractory CLL
Data from an interim analysis of a phase 2 study (NCT05168930) presented at the 2024 ASH Annual Meeting & Exposition showed that the fixed-duration combination of zanubrutinib (Brukinsa) and venetoclax (Venclexta) demonstrated activity with acceptable tolerability in patients with relapsed/refractory CLL. At a median follow-up of 8 months, the doublet elicited an overall response rate of 95% in evaluable patients (n = 22), comprising a complete response rate of 17% and a partial response rate of 78%. Notably, a partial response was observed in a patient with prior exposure to both a BTK inhibitor and a BCL2 inhibitor, as well as another patient with prior exposure to acalabrutinib (Calquence).
Inhye E. Ahn, MD, of the Department of Medical Oncology, Dana-Farber Cancer Institute, stated that fixed-duration combination therapy with zanubrutinib/venetoclax is effective and well tolerated in relapsed/refractory CLL, including patients who had prior treatment with targeted agents. All patients received up to 15 cycles of zanubrutinib plus venetoclax, after which treatment was stopped irrespective of clinical response or MRD status.
Zanubrutinib Monotherapy vs Bendamustine/Rituximab in Treatment-Naive CLL/SLL
A 5-year follow-up study of the randomized, open-label phase 3 SEQUOIA trial (NCT03336333) found that zanubrutinib remained a favorable treatment option for previously untreated patients with CLL and SLL without a del(17p). At a median follow-up of 61.2 months, median PFS was not reached in patients who received zanubrutinib vs 44.1 months in patients who received bendamustine plus rituximab (HR, 0.29; 95% CI, 0.21-0.40; P <.0001). Estimated OS rates at 60 months were 85.8% for patients who received zanubrutinib and 85.0% for patients who received bendamustine plus rituximab (HR, 0.89; 95% CI, 0.55-1.43; P = .309).
Mazyar Shadman, MD, MPH, associate professor in the Clinical Research Division and medical director of Cellular Immunotherapy at the Fred Hutch Cancer Center, concluded that zanubrutinib provided greater PFS in treatment-naïve patients without del(17p) and was well tolerated over a median follow-up of 61.2 months, supporting its use as a preferred first-line treatment for patients with CLL/SLL.
Time-Limited Zanubrutinib/Rituximab in Treatment-Naive CLL
Findings from an early analysis from an ongoing phase 2 trial (NCT04458610) presented at the 2024 ASH Annual Meeting showed that time-limited therapy with zanubrutinib plus rituximab was safe and generated durable remissions in patients with treatment-naive CLL. At a median follow-up of 24 months, 21 of 23 enrolled patients remained on the study. At a median follow-up of 13 months after discontinuation of zanubrutinib/rituximab, 10 patients remained off therapy and in remission.
Jan A. Burger, MD, PhD, a professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, noted that this early analysis indicates that time-limited therapy with zanubrutinib and rituximab is well tolerated and induces durable remissions, suggesting a potential alternative to long-term BTK inhibitor monotherapy. Eligible patients are treated with zanubrutinib at 160 mg orally twice daily and rituximab at 375 mg/m2 intravenously for a defined number of cycles, followed by observation.
Venetoclax/Ibrutinib Significantly Improves PFS in Mantle Cell Lymphoma
Ibrutinib (Imbruvica) plus venetoclax (Venclexta) elicited a statistically significant improvement in progression-free survival (PFS) vs ibrutinib/placebo in adult patients with pathologically confirmed relapsed or refractory mantle cell lymphoma (MCL), according to results from the phase 3 SYMPATICO trial (NCT03112174) published in Lancet Oncology. Data from the trial revealed that the median PFS with ibrutinib/venetoclax was 31.9 months (95% CI, 22.8-47.0) vs 22.1 months (95% CI, 16.5-29.5) with ibrutinib/placebo per investigator assessment (HR, 0.65; 95% CI, 0.47-0.88; P = .0052).
