Venetoclax/Ibrutinib Safe, Induces Durable Response in Marginal Zone Lymphoma

In patients with marginal zone lymphoma (MZL), venetoclax (Venclexta) plus ibrutinib (Imbruvica) demonstrated safety and rates of deep and durable clinical responses higher than historical controls, according to findings from the phase 2 AIM study (NCT02471391).¹

Of 15 total patients with MZL who were treated with the combination regimen, 14 were evaluable for efficacy. At 16 weeks, the overall response rate (ORR) was 79% (95% CI, 49%-95%); 29% (95% CI, 8%-58%) of this group achieved complete response (CR) as assessed by computed tomography at 16 weeks. Furthermore, while the median progression-free survival (PFS) had not been reached, the estimated PFS at 5 years was 56% (95% CI, 27%-78%).

Notably, responses held durably among those exhibiting minimal residual disease (MRD) negativity in bone marrow and peripheral blood. Approximately 40% of the cohort had cleared their MRD status at week 56, with 4 MRD-negative patients remaining disease-free for a median of 4 years after elective treatment interruption.

While authors cited the small sample size as a key limitation, the findings support further investigation in larger, prospective studies and suggest meaningful clinical activity of the combination in this population.

“The CR rate and PFS are highly encouraging when considered against historical ibrutinib monotherapy, confirming combinatorial benefit,” study authors Handunnetti et al wrote in the Blood Advances publication. “Moreover, there is evidence that time-limited treatment is feasible and can afford excellent ongoing disease control. A larger study, including a time-limited approach in its design, is warranted.”

Safety and Tolerability

The safety profile of the venetoclax and ibrutinib combination was generally tolerable and consistent with the known adverse event (AE) profiles of each individual agent. The most common treatment-emergent AEs were gastrointestinal in nature, including diarrhea (80%), nausea (47%), and gastroesophageal reflux (47%), all of which were grade 1 or 2.

However, hematologic toxicities were noteworthy. Neutropenia occurred in 80% of patients, with grade 3 or higher events reported in 40% of the cohort. No cases of clinical tumor lysis syndrome (TLS) were observed, a critical finding given the potential for TLS with venetoclax in other B-cell malignancies. Infections were reported as the cause of most serious adverse events, which occurred in 53% of the group.

About the AIM Study

The AIM study was a single-center, open-label phase 2 trial conducted in Australia that enrolled patients with MZL who were either treatment naive or relapsed or refractory to prior therapies and considered to be unfit for cytotoxic chemotherapy.² The patient population was inclusive of multiple MZL subtypes, including extranodal, splenic, and nodal MZL.

The objective of the study was to evaluate the efficacy and safety of the venetoclax and ibrutinib combination in this patient population, similar to the investigators’ original protocol for patients with mantle cell lymphoma. As such, the study’s primary end point was CR at week 16; secondary end points included ORR at 16 weeks, MRD clearance, PFS, time to progression, duration of response, overall survival, and safety and tolerability.

Patients received daily ibrutinib at 560 mg as a lead-in for 4 weeks, followed by the addition of venetoclax with a weekly ramp-up to a target dose of 400 mg daily. Treatment continued until disease progression or unacceptable toxicity.

REFERENCES

1. Handunnetti SM, Khot A, Blombery P, et al. Venetoclax and ibrutinib induces durable clinical responses in marginal zone lymphoma. Blood Advances. 2026;10(5):1733-1742. doi:10.1182/bloodadvances.2025016646

2. ABT-199 & Ibrutinib in Mantle Cell Lymphoma (AIM) (AIM). ClinicalTrials.gov. Updated August 21, 2023. Accessed March 23, 2026. https://clinicaltrials.gov/study/NCT02471391