New Directions in First-Line Treatment for TP53-Mutated Mantle Cell Lymphoma

Patients with mantle cell lymphoma (MCL) harboring TP53 mutations have an aggressive disease course, reduced benefit from chemoimmunotherapy, and a poor prognosis.¹ Analyses of the Nordic MCL2 and MCL3 trials revealed a median overall survival (OS) of 1.8 years for patients with TP53-mutated disease, in stark contrast to 12.7 years for those without the mutation.² This profound difference highlights the unmet need for effective treatments for this high-risk subgroup, comprising up to 20% of previously untreated patients.

Although the optimal risk-adapted strategy remains unclear, this past year has seen a flurry of important updates on the first-line treatment of TP53-mutated MCL. Across studies, the use of targeted therapies—Bruton tyrosine kinase inhibitors (BTKi) and/or B-cell lymphoma 2 inhibitors (BCL2i) alone or in combination with other agents—have shown promising efficacy.

Targeted Therapies in the First-Line Setting for TP53-Mutated MCL

The phase 3 TRIANGLE trial,³ initially presented at ASH 2022 with updated results at ASH 2024, demonstrated that the addition of ibrutinib to intensive chemoimmunotherapy and rituximab maintenance eliminates the need for autologous stem cell transplantation (ASCT) in younger patients with MCL. Patients with high-risk features—including high p53 expression (>50%), a surrogate for TP53 mutation—derived substantial benefit from the addition of ibrutinib to i ntensive chemoimmunotherapy and rituximab maintenance. In the subgroup of patients with high p53 expression, the hazard ratio (HR) for failure-free survival was 0.14 (one-sided 98.3% CI 0-0.57) when comparing ibrutinib + chemoimmunotherapy + ASCT (Group A+I) versus chemoimmunotherapy + ASCT alone (Group A). These results suggested that integrating ibrutinib into both induction and maintenance therapy may improve outcomes among younger patients with MCL in this high-risk subgroup.

In the phase 3 ECHO trial⁴ first presented at EHA 2024, adding acalabrutinib to bendamustine and rituximab (BR) significantly improved progression-free survival (PFS) in older patients with MCL. Data focusing on high-risk subgroups were presented at ASH 2024. Although numbers were relatively small (22 patients in the acalabrutinib arm and 29 in the placebo arm had TP53 mutations), adding acalabrutinib to BR did not appear to improve PFS compared to BR alone in patients with TP53-mutated MCL (HR, 0.88; 95% CI, 0.42-1.78). The lack of significant PFS benefit likely reflects intrinsic chemoresistance, suggesting that the impact of adding a BTKi might vary depending on the specific backbone used and the population treated.

The phase 3 SYMPATICO trail₅, presented at ASCO 2024 and EHA 2024, established the benefit of adding venetoclax to ibrutinib in TP53-mutated MCL. The ASCO 2024 abstract reported pooled efficacy and safety data for 74 patients with TP53 mutations across all cohorts (29 first-line and 45 relapsed or refractory). In the first-line setting, the overall response rate (ORR) was 90%, the complete response (CR) rate was 55%, the median PFS was 22 months, and the median OS was not reached. Measurable residual disease (MRD)–negative remission rates by 8-color flow cytometry were 70% and 67% in the peripheral blood and bone marrow, respectively. These results demonstrated the potential of combined BCL2i and BTKi in previously untreated TP53-mutated MCL.

The phase 2 BOVen trial⁶ evaluated zanubrutinib plus obinutuzumab and venetoclax in previously untreated patients with TP53-mutated MCL. The best ORR was 96% (n=24/25), with an impressive CR rate of 88% (n=22/25). Responses were rapid, with most occurring within the first 3 months of treatment. At cycle 13, undetectable MRD by immunosequencing at a sensitivity level (10^-5) was achieved in 95% of evaluable patients (n=18/19), and at 10^-6 in 84% (n=16/19). With a median follow-up of 28.2 months, the 2-year PFS was 72%, disease-specific survival was 91%, and OS was 76%. Two patients experienced disease progression after stopping treatment. Both were re-treated with zanubrutinib and venetoclax and initially responded, but subsequently progressed again after restarting therapy. The impressive efficacy of the BOVen regimen represents a new standard of care for this high-risk population.

Reconsidering MRD-Guided Therapy Discontinuation

The experience from the BOVen study also highlights a complex clinical decision point: whether MRD-directed discontinuation of therapy is truly an effective long-term strategy in TP53-mutated MCL. Concerns were raised regarding the rapid clinical progression in two patients who reinitiated therapy after disease re-emergence. This suggests that while achieving MRD negativity is a highly desirable end point, the aggressive nature of TP53-mutated MCL may necessitate longer treatment durations or alternative consolidation strategies even after deep responses. The prognostic value of MRD for treatment cessation might differ in this high-risk subgroup compared to other patients, requiring more cautious interpretation and potentially longer follow-up to ensure sustained remission.

While targeted therapies have significantly improved outcomes and are the new standard, these patients remain at high risk for disease progression. Furthermore, the optimal duration of targeted therapy to maximize therapeutic efficacy and minimize toxicity is unclear. Until more robust long-term data are available, particularly from studies with extended follow-up after MRD-driven cessation, continuous therapy or alternative consolidation strategies may be necessary to maximize the duration of response in this subgroup with aggressive disease.

Immune effector cell therapies in the first-line setting could further change the treatment paradigm. The phase 1 WINDOW-3 trial will evaluate the safety and preliminary clinical efficacy of acalabrutinib and rituximab for a maximum of 12 cycles followed by brexucabtagene autoleucel in previously untreated patients with high-risk features. Similar strategies with glofitamab in combination with targeted therapies are also being investigated. These approaches may result in deeper, more durable responses in a population otherwise at high-risk for disease progression following targeted therapy alone.

Personalizing Treatment in the Future

While identifying TP53 mutations remains an essential first step, further molecular characterization (eg, specific TP53 variant, and other co-mutations conferring risk or treatment resistance) is likely needed for precise risk stratification. This implies a future move towards a more granular, risk-adapted approach for this challenging population, where treatment intensity and duration are fine-tuned based on a deeper understanding of the tumor’s biological profile beyond just TP53 status. Thus, in the current landscape, clinical trial options with key correlatives should be explored in all patients when feasible.