Frontline Ibrutinib/Venetoclax Yields Response in Older Patients With MCL

Patients had an ORR of 95% with a 69% rate of CR.

Ibrutinib (Imbruvica) plus venetoclax (Venclexta) displayed a high rate of complete response (CR) as a first-line treatment for older patients with mantle cell lymphoma (MCL) including those harboring TP53 mutations, per phase 3 data from the SYMPATICO study (NCT03112174) presented during the 2025 ASCO Annual Meeting.¹

Patients who were at least 65 years of age with TP53-mutated disease (n = 18) achieved a CR rate of 44% (95% CI, 22%-69%); those who did not have TP53 mutations (n = 42) experienced a CR rate of 76% (95% CI, 61%-88%). The overall response rates (ORRs) were 89% (95% CI, 65%-99%) and 98% (95% CI, 87%-100%), respectively. The respective median durations of response (DORs) were 20.5 months (95% CI, 12.0-not evaluable [NE]) and 37.1 months (95% CI, 34.2-NE). The median duration of CR (DOCR) was not reached (NR; 95% CI, 11.1 months-NE) and NR (95% CI, 34.0 months-NE), respectively.

The median progression-free survival (PFS) among patients who were at least 65 years of age and had TP53-mutated disease was 22.0 months (95% CI, 11.3-NE). The 3-year PFS rate was 35% (95% CI, 14%-57%). Among patients with TP53-unmutated disease, the median PFS and 3-year PFS rate was 40.2 months (95% CI, 37.2-NE) and 71% (95% CI, 53%-83%), respectively.

“There is an unmet clinical need for patients with MCL, especially for those who are older and those who have TP53 mutations,” Michael Wang, MD, said during the presentation. “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.”

Wang is a 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.

Examining the Study Design and Baseline Characteristics

SYMPATICO was an international, double-blinded trial that enrolled patients with pathologically confirmed MCL with at least 1 measurable disease site on cross-sectional imaging.² Patients were also required to have an ECOG performance status of 2 or less; have received 1 to 5 prior treatments for MCL; and have adequate hematologic, hepatic and renal function. The study also included 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 a dose of 400 mg once daily following a 5-week ramp-up period, or placebo for 2 years.³ After 2 years, patients received single-agent ibrutinib at the same dosing schedule until disease progression or unacceptable toxicity.

The primary end point in the treatment-naive arm was CR rate.¹ Secondary end points included ORR, overall survival (OS), DOR, time to next treatment (TTNT), and safety.

At baseline, the median age in the treatment-naive population (n = 78) was 70 years (range, 41-86); most patients were at least 65 years of age (83%). Additionally, most patients were male (68%), had typical MCL histology (68%), and had bone marrow involvement (78%). Extranodal disease (50%), splenomegaly (46%), and TP53-mutated disease (37%) were all reported.

Showcasing Additional Efficacy Results and Safety Data

Additional findings from the presentation showed that among all treatment-naive patients, the ORR was 95% (95% CI, 87%-99%), with a 69% (95% CI, 58%-79%) CR rate. The median DOR was 37.1 month (95% CI, 30.3-NE), and the median DOCR was 37.1 months (95% CI, 34.0-NE). The median TTNT was NR (95% CI, NE-NE), and the 3-year rate of freedom from next line of therapy was 66% (95% CI, 53%-77%). Among evaluable patients with a CR, 59% (n = 13/22) achieved minimal residual disease (MRD)–negative remission in bone marrow, and 76% experienced an MRD-negative remission in peripheral blood.

The median PFS among all treatment-naive patients was 40.2 months (95% CI, 29.4-NE), and the 3-year PFS rate was 59% (95% CI, 46%-69%). The median OS was NR (95% CI, 44.2-NE), and the 3-year OS rate was 79% (95% CI, 68%-86%). The CR rates among patients with TP53-mutated (n = 29) and -unmutated (n = 44) disease were 55% (95% CI, 36%-74%) and 77% (95% CI, 62%-89%), respectively.

In patients who were younger than 65 years of age, the CR rate was 73% (95% CI, 39%-94%) among those with TP53-mutated disease (n = 11) and 100% among those without TP53-mutated disease (n = 2). The median DOCR and DOR were NR (95% CI, 2.8-NE) and NR (95% CI, 8.2-NE), respectively. The median PFS was 15.4 months (95% CI, 8.2-NE) and NR (95% CI, 11.1-NE), respectively, and the 3-month PFS rates were 46 months (95% CI, 17%-71%) and NE (95% CI, NE-NE), respectively.

The median time on study among all patients was 40.5 months (range, 0.6+ to 46.9). The median treatment duration was 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%. Ibrutinib and venetoclax were discontinued due to disease progression (23% vs 22%) and adverse effects (AEs; 19% vs 14%). Thirty-three percent of patients remained on single-agent ibrutinib at the data cutoff.

Treatment-emergent AEs (TEAEs) were reported in 100% of patients in the treatment-naive population. Grade 3 or higher AEs (86%), serious AEs (59%), and AEs leading to death (9%) were also reported.

Any-grade TEAEs occurred in all evaluable patients who were at least 65 years of age (n = 65). Most patients also experienced grade 3 or higher AEs (88%) and serious AEs (62%). Common any-grade AEs included diarrhea (48%), fatigue (40%), and neutropenia (35%). Eleven percent of patients experienced an AE 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 said in his conclusion. “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.”

References

1. Wang M, Hoffmann MS, Wrobel T, et al. Efficacy and safety of first-line ibrutinib plus venetoclax in patients with mantle cell lymphoma (MCL) who were older or had TP53 mutations in the SYMPATICO study. J Clin Oncol. 2025;43(suppl 16):7017. doi:10.1200/JCO.2025.43.16_suppl.7017
2. Study of ibrutinib combined with venetoclax in subjects with mantle cell lymphoma (SYMPATICO). ClinicalTrials.gov. Updated July 1, 2024. Accessed June 13, 2025. https://clinicaltrials.gov/study/NCT03112174
3. Wang M, Jurczak W, Trneny M, et al. Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2025;26(2):200-213. doi:10.1016/S1470-2045(24)00682-X