The first-line combination of ibrutinib (Imbruvica) plus venetoclax (Venclexta) demonstrated significant clinical activity in older patients with mantle cell lymphoma (MCL), including those harboring challenging TP53 mutations, according to phase 3 data from the SYMPATICO study (NCT03112174) presented at the 2025 ASCO Annual Meeting.
Patients who were at least 65 years of age with TP53-mutated disease (n = 18) achieved a complete response (CR) rate of 44% (95% CI, 22%-69%), while those without TP53 mutations (n = 42) experienced a CR rate of 76% (95% CI, 61%-88%). The overall response rates were 89% (95% CI, 65%-99%) and 98% (95% CI, 87%-100%), respectively.
"There is an unmet clinical need for patients with MCL, especially for those who are older and those who have TP53 mutations," said Michael Wang, MD, professor in the Department of Lymphoma/Myeloma and the Department of Stem Cell Transplantation in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. "The first-line combination of ibrutinib plus venetoclax showed promising efficacy with high CR rates and durable remissions in younger and older patients with treatment-naive MCL."
Durable Response and Survival Outcomes
The combination demonstrated impressive durability of response across patient subgroups. The respective median durations of response were 20.5 months (95% CI, 12.0-not evaluable) for TP53-mutated patients and 37.1 months (95% CI, 34.2-NE) for TP53-unmutated patients. The median duration of CR was not reached in both groups.
Progression-free survival outcomes showed clear differences based on TP53 mutation status. Among patients who were at least 65 years of age with TP53-mutated disease, the median progression-free survival was 22.0 months (95% CI, 11.3-NE) with a 3-year PFS rate of 35% (95% CI, 14%-57%). Patients with TP53-unmutated disease achieved a median PFS of 40.2 months (95% CI, 37.2-NE) and a 3-year PFS rate of 71% (95% CI, 53%-83%).
Study Design and Patient Population
SYMPATICO was an international, double-blinded trial that enrolled patients with pathologically confirmed MCL with at least one measurable disease site on cross-sectional imaging. Patients were required to have an ECOG performance status of 2 or less and adequate hematologic, hepatic and renal function. The study included both previously treated patients and a treatment-naive arm.
Patients were randomly assigned 1:1 to receive oral ibrutinib at 560 mg once daily in combination with oral venetoclax at 400 mg once daily following a 5-week ramp-up period, or placebo for 2 years. After 2 years, patients received single-agent ibrutinib at the same dosing schedule until disease progression or unacceptable toxicity.
The treatment-naive population (n = 78) had a median age of 70 years (range, 41-86), with 83% of patients being at least 65 years of age. Most patients were male (68%), had typical MCL histology (68%), and had bone marrow involvement (78%). Extranodal disease was present in 50% of patients, splenomegaly in 46%, and TP53-mutated disease in 37%.
Comprehensive Efficacy Results
Among all treatment-naive patients, the overall response rate was 95% (95% CI, 87%-99%), with a 69% (95% CI, 58%-79%) complete response rate. The median duration of response was 37.1 months (95% CI, 30.3-NE), and the median duration of CR was 37.1 months (95% CI, 34.0-NE).
The median time to next treatment was not reached, and the 3-year rate of freedom from next line of therapy was 66% (95% CI, 53%-77%). Among evaluable patients with a complete response, 59% (n = 13/22) achieved minimal residual disease-negative remission in bone marrow, and 76% experienced MRD-negative remission in peripheral blood.
Overall survival outcomes were encouraging, with a median overall survival not reached (95% CI, 44.2-NE) and a 3-year OS rate of 79% (95% CI, 68%-86%). The median progression-free survival among all treatment-naive patients was 40.2 months (95% CI, 29.4-NE), with a 3-year PFS rate of 59% (95% CI, 46%-69%).
Safety Profile and Treatment Duration
The median time on study among all patients was 40.5 months (range, 0.6+ to 46.9), with a median treatment duration of 24.0 months (range, 0.3-46.9). Patients discontinued treatment with ibrutinib at a rate of 67% and venetoclax at a rate of 50%. The primary reasons for discontinuation were disease progression (23% vs 22%) and adverse effects (19% vs 14%). Thirty-three percent of patients remained on single-agent ibrutinib at the data cutoff.
Treatment-emergent adverse events were reported in 100% of patients in the treatment-naive population. Grade 3 or higher adverse events occurred in 86% of patients, serious adverse events in 59%, and adverse events leading to death in 9%.
Among patients who were at least 65 years of age (n = 65), all experienced any-grade treatment-emergent adverse events. Most patients also experienced grade 3 or higher adverse events (88%) and serious adverse events (62%). Common any-grade adverse events included diarrhea (48%), fatigue (40%), and neutropenia (35%). Eleven percent of patients experienced an adverse event leading to death.
"The safety profile of the combination in patients with treatment-naive MCL was consistent with the known safety profiles of the individual agents with no new safety signals," Wang concluded. "Ibrutinib plus venetoclax may be an option for patients with treatment-naive MCL who are 65 years of age or older, or in patients of any age with a TP53 mutation."
