Efficacy and safety of zanubrutinib plus bendamustine-rituximab in newly diagnosed Mantle Cell Lymphoma with TP53 abnormalities or chemotherapy intolerance

Abstract Introduction: Mantle cell lymphoma (MCL) in elderly patients, especially those with TP53 aberrations or who are intolerant to chemoimmunotherapy, has a poor prognosis. This prospective, single-arm, interventional study evaluated the efficacy and safety of zanubrutinib in combination with bendamustine and rituximab (ZBR) as first-line therapy in patients with high-risk disease. Methods: Previously untreated MCL patients aged ≥60 years old, with TP53 mutation/deletion, or with ineligibility for standard chemotherapy, were enrolled. Induction involved six 28-day cycles of zanubrutinib (160 mg BID), bendamustine (90 mg/m² IV, days 1-2), and rituximab (375 mg/m² IV, day 1). Patients with CR or PR moved to up to two years of zanubrutinib maintenance. The primary endpoint was 2-year PFS. Secondary endpoints included ORR, CRR, OS, and safety. Exploratory endpoints covered genomic profiling via tissue and ctDNA, RNA-based molecular subtyping, and MRD monitoring. Results: Of the 23 patients enrolled, 16 (69.6%) were aged 60 or older, 16 (69.6%) had a high MIPI score, 10 (43.5%) had TP53 mutations, and 6 (26.1%) had blastoid histology. Among the 7 individuals under 60, 4 had blastoid histology or TP53 mutations, 2 had poor ECOG performance status, and one refused ASCT. The median PFS has not been reached, based on a median follow-up of 19.6 months. The ORR was 91.30%, and the CRR was 82.6%. In subgroup analysis, patients with blastoid histology had worse outcomes, whereas those with TP53 mutations had a prognosis similar to patients without TP53 mutations. The most common treatment-related AEs were hematological toxicities. Grade 3-4 adverse events included decreased neutrophil counts (26.1%) and lung infections (4.3%). ctDNA profiling indicated a reduction in mutation burden after treatment; however, relapse was associated with the re-emergence of TP53-mutant clones. Additionally, genomic profiling of tumor samples showed a rising trend of KMT2D and TP53 mutations in relapse samples. RNA-seq revealed activation of cell-cycle pathways and reduced CD8⁺ T-cell infiltration in relapse samples. Conclusion: In newly diagnosed elderly patients with MCL and high-risk features, ZBR therapy showed encouraging efficacy and tolerability. Combining molecular profiling with continuous ctDNA monitoring may enhance the accuracy of predicting treatment response and aid in detecting disease relapse early.