Post-treatment outcomes of TP53-mutant Mantle Cell Lymphoma patients treated with frontline zanubrutinib, obinutuzumab, and venetoclax (BOVen): Durable responses in patients who achieve complete remissions with undetectable MRD

Abstract

Abstract Background: Mantle cell lymphoma (MCL) patients with TP53 mutations have poor outcomes with standard chemoimmunotherapy (Eskelund, Blood 2017). The phase 2 BOVen (Zanubrutinib, Obinutuzumab and Venetoclax) study conducted in TP53-mutated MCL patients is a minimal residual disease (MRD) driven, time-limited treatment which demonstrated improved 2-year progression-free survival compared to standard chemoimmunotherapy. Time-limited, MRD-guided therapy is a valuable strategy to limit toxicity and potential therapy resistance, but the feasibility of MRD-directed treatment cessation in treating high-risk MCL is not clear. Here we report the extended follow-up of the BOVen study with particular attention to the outcomes of patients who completed 24 cycles of treatment. Methods: The BOVen trial methods were reported previously (Kumar, Blood 2025). BOVen is administered in 28-day cycles: Zanu 160mg PO BID C1D1; Obin 1g IV D1 (or split D1-2), 8, 15 of C1, D1 of C2-8; Ven ramp up C3D1 (target 400mg QD).Treatment duration is 2 years at minimum, with subsequent treatment guided by MRD – patients with undetectable MRD (10-6; uMRD6) in peripheral blood (PB) and bone marrow (BM) and in complete remission (CR) may discontinue treatment; for patients with indeterminate MRD testing at 10-6, a sensitivity of 10-5 was used (uMRD5). Patients could be re-treated in the case of clinical progression or MRD detectability. Results: Twenty-five patients with TP53 mutated MCL were enrolled with median age 65 years (range 29-82), male predominance (19/25, 76%), and various histologic subtypes including 15 conventional, 5 non-nodal leukemic, and 5 blastoid variant. The majority were high-risk by MIPI (17/25, 68%). One third of patients had Ki67>50% and nearly half (48%, 12/25) had 17p deletion. Treatment continued to be well-tolerated with no new safety events. Median follow up was 39 months (95% CI: 37,44) data cut-off 4/30/2025). The median PFS was 45 months (95% CI: 28 – NR) and median OS and disease specific survival were not reached. 3-year estimates of PFS, OS and DSS were 64% (95% CI: 48-86%), 76% (95% CI: 61-95%), and 95% (95% CI: 87-100%), respectively. There were four deaths on treatment (2 COVID-related, 1 post-operative aspiration pneumonia, 1 unknown cause) in patients who were in ongoing response and three early progression events. The remaining 18 patients completed 24 cycles of therapy and all achieved a complete response. Median follow-up for all patients who reached C24 was 17 months (range: 3.2-25). Seventeen of these patients had MRD results available (one lacked baseline pathology for MRD testing) and all achieved uMRD5 in peripheral blood. Of 13 patients with MRD results at a sensitivity of 1x10-6, 11 (85%) achieved uMRD6. Three patients were continued on therapy – one patient who lacked MRD testing continued treatment due to treating physician preference, two others had detectable MRD in either the PB or BM. Of the 18 patients completing 24 cycles of treatment, 77.8% (14/18) remain in CR. Of the patients who achieved a uMRD-6 CR, 91% (10/11) remain in CR off treatment with a median off-treatment monitoring time of 17 months (range 11.5 – 23.2). There were four relapses after C24 (range 3-24 months after end of treatment). Two patients were retreated with Zanu and Ven, remaining on therapy for six and seven months, respectively, before disease progression. One subsequently received CAR-T, but relapsed at day 90 post with a de-differentiated MCL and ultimately died. The other received chemoimmunotherapy (R-DHAX) with rituximab maintenance and remains in CR. For the other two patients who were not retreated, one received CAR-T and one a bispecific antibody in the context of a clinical trial; both remain in CR. Conclusions: BOVen continues to be a well-tolerated regimen with high rates of uMRD6 in TP53-mutated, treatment-naïve MCL patients. The majority of patients who completed 24 cycles of therapy remain in CR with undetectable MRD. Importantly, nearly all patients (91%) who achieved uMRD6 CR have maintained their complete response. Whether retreatment with Zanu and Ven in patients with dMRD or clinical relapse is a viable strategy remains an open question – neither patient who was retreated achieved a CR or uMRD and both required additional therapies within 1 year of relapse. Overall, our results support an MRD-driven approach to therapy discontinuation in patients with deep remissions for this high-risk patient population.