Background:

Mantle cell lymphoma (MCL) is a biologically and clinically heterogeneous disease with variable prognosis. While the MCL International Prognostic Index (MIPI) score is commonly used for prognosis, it alone does not adequately represent high-risk MCL and excludes critical high-risk biologic and genetic features, such as a TP53 mutation and blastoid/pleomorphic morphology, which are known to predict inferior outcomes. In real-world practice, high-risk MCL remains poorly characterized and inconsistently defined. Therefore, this study aimed to describe the clinical characteristics, treatment patterns, and outcomes of patients with high-risk MCL relative to a broader MCL cohort.

Methods:

This retrospective cohort study used the US-based Flatiron Health Research Database (data cutoff: May 31, 2024) to analyze patients with MCL who initiated first-line (1L) treatment on or after January 1, 2014. Patients were categorized into the high risk cohort if their disease had ≥1 of the following: documented TP53 mutation, blastoid or pleomorphic morphology, or Ki67 proliferation index ≥30%. Baseline demographics, clinical characteristics, treatment patterns, and outcomes, including real-world overall survival (rwOS), real-world time to treatment discontinuation (rwTTD), and real-world time to next treatment or death (rwTTNTD), were summarized descriptively using unadjusted Kaplan-Meier analyses.

Results:

The overall cohort included 1657 patients, of whom 204 (12.3%) were tested for a TP53 mutation, 622 (37.5%) tested for Ki67, and 168 (10.1%) had blastoid or pleomorphic morphology. A total of 465 patients (28.1%) met criteria for the high-risk cohort, of whom 53 (11.4%) had a TP53 mutation, 344 (74.0%) had a Ki-67 proliferation index ≥30%, 113 (24.3%) had blastoid morphology, and 55 (11.8%) had pleomorphic morphology. Median age was 68.0 years in the high-risk cohort, with 293 aged ≥65 years, and 69.0 years in the overall cohort, with 1,065 aged ≥65 years. Most patients in the high-risk cohort were male (73.8%) and White (76.3%) with stage IV disease (54.2%). Patients in the high-risk and overall cohorts had the same median MIPI score of 6.1. Patients in the high-risk cohort were more frequently managed at academic centers than at community centers vs the overall cohort (24.5% vs 19.6%). Median follow-up was 21.4 months (mos) for the high-risk cohort and 28.5 mos for the overall cohort.

Bendamustine-rituximab was the most common 1L regimen in the high-risk (47.7%; n=222) and overall (53.5%; n=886) cohorts. Bruton tyrosine kinase inhibitor (BTKi)-based chemoimmunotherapy was used more often in the high-risk cohort (7.1%; n=33) vs overall cohort (4.8%; n=79). Median 1L treatment duration was similar between the high-risk and overall cohorts (4.6 vs 4.9 mos). 1L maintenance therapy (rituximab monotherapy only) was received by 26.5% of patients in the high-risk cohort and 28.5% in the overall cohort, and had shorter duration in the high-risk vs overall cohort (14.3 vs 19.6 mos). In the high-risk cohort, 51.2% of patients initiated 2L therapy and 28.0% initiated 3L therapy, with median durations of 3.8 mos in 2L and 2.5 mos in 3L. In the overall cohort, 46.8% of patients received 2L therapy and 24.1% received 3L therapy, with median durations of 4.6 mos in 2L and 2.8 mos in 3L. In 2L, BTKi-containing regimens were the most commonly used 2L regimen, received by 58.8% of patients in the high-risk cohort and 49.3% in the overall cohort.

Median rwTTNTD was 12.1 mos (95% CI, 10.3-15.9) in the high-risk cohort and 23.0 mos (95% CI, 19.8-27.1) in the overall cohort. Median rwTTD was 4.9 mos (95% CI, 4.7-6.1) in the high-risk cohort and 6.7 mos (95% CI, 5.9-7.8) in the overall cohort. Median rwOS was 49.7 mos (95% CI, 36.7-65.7) in the high-risk cohort and 73.2 mos (95% CI, 64.3-79.6) in the overall cohort.

Conclusion:

In this real-world study, testing rates for TP53 and Ki67 were low in the overall MCL cohort. This study described a high-risk MCL subgroup showing poor clinical outcomes across multiple therapy lines. Despite the established poor prognosis in high-risk MCL, baseline characteristics, MIPI, and 1L treatment patterns were similar to those of the overall MCL cohort. These findings highlight the need for broader adoption of biomarker testing in routine care to better identify and manage high-risk MCL. Further research is needed to better integrate biomarker-informed strategies to improve patient outcomes.

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2025
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