Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation

Key Points

• •BOVen was safe and effective for the frontline treatment of TP53-mutant MCL.
• •The 2-year progression-free survival of 72% compares favorably with previously reported outcomes with chemoimmunotherapy in TP53-mutant MCL.

Visual Abstract

Abstract

TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. We conducted a multicenter, phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated patients with MCL with a TP53 mutation. Patients initially received 160 mg zanubrutinib twice daily and obinutuzumab. Obinutuzumab at a dose of 1000 mg was given on cycle 1 day 1, 8, and 15, and on day 1 of cycles 2 to 8. After 2 cycles, venetoclax was added with weekly dose ramp-up to 400 mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease (uMRD) using an immunosequencing assay, treatment was discontinued. The primary end point was met if ≥11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with a TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD at a sensitivity level of 1 × 10^–5 and uMRD at a sensitivity level of 1 × 10^–6 at cycle 13 was 95% (18/19) and 84% (16/19), respectively. With a median follow-up of 28.2 months, the 2-year progression-free, disease-specific, and overall survival were 72%, 91%, and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy end point in TP53-mutant MCL. These data support its use and ongoing evaluation. This trial was registered at www.ClinicalTrials.gov as #NCT03824483.

The TP53 mutation is the most significant negative prognostic feature in mantle cell lymphoma (MCL), and more effective treatment for these high-risk patients is needed. Kumar and colleagues report on a multicenter phase 2 study of zanubrutinib, obinutuzumab, and venetoclax in untreated patients with TP53-mutated MCL and show a high response rate in 25 patients, with 22 attaining a complete response and a 2-year progression-free survival of 72%. These promising results support future evaluation of this regimen and possible use of consolidation regimens to further extend the observed benefits.

Introduction

Mantle cell lymphoma (MCL) is an uncommon, incurable subtype of B-cell non-Hodgkin lymphoma that is clinically and biologically heterogeneous.^1,2 In addition to the hallmark translocation t(11;14)(q13;q32) that leads to cyclin D1 overexpression, other genetic alterations have been elucidated in MCL, including aberrations in TP53, CDKN2A, ATM, MYC, and NOTCH.^{3, 4, 5} Among these, the TP53 mutation, which occurs in ∼10% to 20% of newly diagnosed MCL, is the most significant negative prognostic factor in MCL associated with chemoimmunotherapy resistance and markedly inferior survival outcomes.^{6, 7, 8}

The standard of care for untreated MCL is chemoimmunotherapy of varying types and intensities. Despite optimal cytarabine-containing induction chemotherapy, followed by a consolidative autologous stem cell transplantation, patients with TP53-mutant MCL have dismal outcomes with a median progression-free survival (PFS) of <1 year.⁷ There is no standard treatment approach for this high-risk group of patients, and clinical trial enrollment is generally recommended.⁹

Bruton tyrosine kinase inhibitors (BTKis) have dramatically improved the care of patients with relapsed or refractory MCL and are increasingly being studied as part of frontline treatment regimens.^{10, 11, 12} Dual inhibition of BTK and BCL2 with ibrutinib and venetoclax has been shown to be synergistic and demonstrated promising activity in patients with TP53 aberrancy.¹³ The addition of obinutuzumab, a type II glycoengineered humanized anti-CD20 monoclonal antibody, to ibrutinib and venetoclax has also demonstrated promising efficacy in both relapsed and untreated MCL, including in patients with a TP53 mutation.¹⁴

When compared with the first-in-class BTKi, ibrutinib, the second generation BTKi, zanubrutinib, has greater BTK specificity, minimal inhibition of interleukin-2–inducible T-cell kinase (essential for antibody-dependent cytotoxicity), and fewer off-target–related adverse events (AEs).^{15, 16, 17, 18} In randomized phase 3 clinical trials, zanubrutinib demonstrated a more favorable safety profile when compared with ibrutinib with fewer cardiac AEs and lower rates of treatment discontinuation.^19,20 Zanubrutinib is highly active in relapsed or refractory MCL with overall and complete response (CR) rates of 84% and 25% to 78%, respectively, and a median PFS of 21.1 to 33.0 months.^12,21 Therefore, zanubrutinib is an attractive BTKi to combine with venetoclax-obinutuzumab in MCL.

Minimal residual disease (MRD) is a powerful prognostic marker in MCL and can be incorporated to limit treatment duration with targeted therapies that are otherwise administered indefinitely.^22,23

We hypothesized that initial treatment of TP53-mutant MCL with the combination of zanubrutinib, obinutuzumab, and venetoclax (BOVen) using an MRD-driven approach to limit treatment duration would offer superior disease control when compared with standard chemoimmunotherapy. Therefore, we conducted a multicenter, phase 2 study to evaluate the efficacy and safety of this regimen in patients with TP53 mutant, previously untreated MCL.

Methods

Patient population

This was an investigator-initiated, open-label, multicenter, phase 2 study. Adult patients were eligible if they had histologically confirmed and previously untreated MCL. All patients met 1 of the following criteria for initiation of therapy: significant constitutional symptoms, cytopenias, symptomatic splenomegaly, progressive or symptomatic nodal enlargement, or evidence of clinically significant organ compression or involvement. The presence of a TP53 mutation of any variant allele frequency was confirmed in all patients using a Clinical Laboratory Improvement Amendments (CLIA)-approved next-generation sequencing (NGS) or polymerase chain reaction (PCR) assay. To facilitate rapid enrollment, expedited targeted NGS assays that captured the entire coding region of the TP53 gene were performed with a median turnaround time of 7 days. Patients could receive short-course systemic corticosteroids for disease control (≤100 mg/d prednisone for <7 days). Additional key eligibility criteria are listed in the clinical trial protocol in the supplemental Materials, available on the Blood website.

The study was conducted at the Memorial Sloan Kettering Cancer Center and Massachusetts General Hospital. (ClinicalTrials.gov identifier: NCT03824483). The institutional review board of each institution approved the study, and written informed consent was obtained for all patients.

Treatment

BOVen was administered in 28-day cycles. Zanubrutinib was administered at 160 mg by mouth twice daily starting on cycle 1 day 1 (C1D1). Obinutuzumab was administered at a dose of 1000 mg IV on C1D1 (or as a split dose over days 1 [100 mg] and 2 [900 mg] if the absolute lymphocyte count was >25 10⁹/L/μL or if the lymph node diameter was ≥5 cm), day 8, and day 15 and on day 1 of C2 to C8. Venetoclax was initiated on C3D1 using the 5-week ramp-up (20 mg-400 mg) then administered at 400 mg by mouth daily (Figure 1). Tumor lysis syndrome (TLS) monitoring and prevention measures were based on TLS risk assessed within 3 days of venetoclax initiation at C3D1 (supplemental Appendix).¹³

Figure 1.

Study schema. Patients received obinutuzumab on C1 day 1, 8, and 15 and monthly on day 1 of C2 to C8. Patients received zanubrutinib (ZANU) at a dose of 160 mg by mouth twice daily for 2 28-day cycles before the weekly dose escalation of venetoclax (VEN) to a target dose of 400 mg/d began. ZANU and VEN were continued until disease progression or intolerance. After 24 cycles, if patients were in complete response (CR) and had uMRD status, ZANU and VEN were discontinued. dMRD, detectable MRD; uMRD, undetectable MRD; IV, intravenous.

Treatment consisted of at least 24 cycles. For patients who achieved CR with undetectable MRD at a sensitivity level of 1 × 10^–6 (uMRD6) in the peripheral blood and bone marrow after 24 cycles, treatment was discontinued. Of note, the sensitivity of the assay did not always achieve a sensitivity level of 1 × 10^–6 (related to the total number of cells analyzed). For patients with MRD results that were indeterminate at a sensitivity level of 1 × 10^–6, the uMRD at a sensitivity level of 1 × 10^–5 (uMRD5) status in peripheral blood and bone marrow was used to determine if treatment could be discontinued. After end of treatment (EOT), patients were followed with MRD assessment every 3 months and computed tomography surveillance imaging every 6 months. If there was subsequent conversion to detectable MRD at 2 time points or clinical relapse among patients who discontinued therapy, zanubrutinib and venetoclax were restarted.

Assessments

¹⁸F-fluorodeoxyglucose positron emission tomography was performed at baseline, before C3, optionally at C7 and C13 for patients with less than a metabolic CR before C3, and 2 weeks before EOT, defined as 28 days after C24D1. Computed tomography scans of the neck, chest, abdomen, and pelvis were acquired at baseline, before C3, C7, C13, and C19, at EOT, and then every 6 months. A bone marrow biopsy and aspirate were acquired at baseline and EOT. Responses were determined using the Lugano Classification system.²⁴

MRD assessment in peripheral blood occurred at baseline, C3D1, C13D1, and EOT. MRD assessment in bone marrow occurred at baseline and EOT. After EOT, MRD was assessed in peripheral blood every 3 months. MRD was evaluated using an immunosequencing approach (clonoSEQ; Adaptive Biotechnologies, Seattle, WA) for all MRD assessments (limit of detection, 10^–6 if sufficient input).²⁵

AEs were assessed according to the Common Terminology Criteria for Adverse Events v5.0.

Statistical analysis

The primary end point was 2-year PFS rate to allow for comparison with the reported outcomes of patients with TP53-mutant MCL from the Nordic MCL2 and MCL3 trials.⁷ A required sample size of 25 was determined using a single-stage design with 90% power and 10% significance level with a 2-year PFS rate of 30% being the unacceptable null and a rate of being 55% the desirable alternative. Therefore, if ≥11 patients were progression free at 2 years, this treatment regimen would be declared deserving of further exploration. Patient and disease characteristics, peripheral blood uMRD, and response rates were summarized using descriptive statistics. Toxicities were summarized using maximum grade per patient. The survival analysis was performed using the Kaplan-Meier method. Disease-specific survival (DSS) was defined as the time from the start of treatment to death from MCL. Statistical analyses were performed using R (R Core Team, 2023; Vienna, Austria).²⁶ Data were updated on 1 June 2024.

Results

Patients

From September 2020 through April 2022, 25 patients with previously untreated MCL and a confirmed baseline TP53 mutation were enrolled. The variant allele frequency ranged from 4.9% to 96.2% (median, 49.8%), and most mutations were within the region that encodes the p53 protein DNA-binding domain (supplemental Figure 1). Patient characteristics at baseline are shown in Table 1. The median age was 68 years (range, 29-82) with male predominance (76%). In addition to a TP53 mutation, high-risk features were common, and 20% of patients had blastoid or pleomorphic morphology, 52% had Ki-67 ≥30%, 48% had 17p deletion, and 68% had a high-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) score. Three patients (12%) had non-nodal leukemic MCL, defined as meeting the following 3 features: (1) leukemic phase disease at the time of diagnosis (absolute lymphocyte count >5000/μL), (2) mutated immunoglobulin heavy chain variable region gene (IGHV), and (3) absence of lymphadenopathy (lymph nodes measuring <1.5 cm; additional details provided in supplemental Figure 2). There were 8 patients who were initially observed for a median observation time of 8 months (range, 3-27) before they met the criteria for treatment initiation.

Table 1.

Characteristics of all 25 patients at study entry

Characteristic	N = 25
Enrollment site
Memorial Sloan Kettering Cancer Center	13 (52%)
Massachusetts General Hospital	12 (48%)
Age, y	68 (29-82)
Sex
Female	6 (24%)
Male	19 (76%)
MCL histology
Blastoid	5 (20%)
Classic	17 (68%)
Non-nodal leukemic∗	3 (12%)
Disease stage, IV	25 (100%)
Ki-67 proliferation rate
<30%	8 (32%)
30%-49%	6 (24%)
At least 50%	7 (28%)
Unknown	4 (16%)
MIPI classification
Low	1 (4.0%)
Intermediate	7 (28%)
High	17 (68%)
Months from diagnosis to treatment start	1.60 (0.45-26.73)
Days from consent to treatment start	12 (2-37)
Disease bulk at diagnosis
<5 cm	17 (68%)
Between 5 and 9 cm	6 (24%)
At least 10 cm	2 (8%)
Bone marrow involvement
Yes	22 (88%)
No	3 (12%)
Peripheral blood involvement†
Yes	20 (80%)
No	5 (20%)
GI involvement‡
Yes	8 (32%)
No	17 (68%)
t(11;14) translocation by FISH
Yes	18 (72%)
No	2 (8%)
Unknown	5 (20%)
Cyclin-D1 overexpression by IHC
Positive, strong	22 (88%)
Positive, dim	1 (4%)
Negative	2 (8%)
SOX-11 expression by IHC
Positive	12 (48%)
Negative	10 (40%)
Unknown	3 (12%)
TP53 expression by IHC§
Positive	18 (72%)
Negative	3 (12%)
Unknown	4 (16%)
IGHV mutation
Mutated	5 (20%)
Unmutated	13 (52%)
Unknown	7 (28%)
17p deletion by FISH
Yes	12 (48%)
No	13 (52%)

FISH, fluorescence in situ hybridization; GI, gastrointestinal; IGHV, immunoglobulin heavy chain variable region gene.

^∗Definition of non-nodal leukemic MCL: patients with leukemic phase disease at the time of diagnosis (absolute lymphocyte count >5000/μL), mutated IGHV, and absence of lymphadenopathy (lymph nodes measuring <1.5 cm; refer to the supplemental Appendix for details).

^†Abnormal B-cell population detected by flow cytometry in peripheral blood.

^‡Endoscopic evidence of MCL. Of note, baseline upper and lower endoscopy was not required per protocol.

^§More than or equal to 30% tumor nuclei staining and strong intensity.

Efficacy

At a median follow-up period of 28.2 months (7.2-44.6), in an intent-to-treat analysis, the best overall response rate was 96% (24/25) and the CR rate was 88% (22/25). At C3D1, after 2 cycles of obinutuzumab and zanubrutinib, the overall and CR rates were 88% (22/25) and 68% (17/25), respectively. Four patients who had a partial metabolic response and 1 patient who had stable disease at C3D1 converted to a metabolic CR after initiation of venetoclax by C7D1 (n = 3) or C13D1 (n = 2).

The primary end point of the study was met with 18 of 25 evaluable patients being free of progression at 2-years after treatment initiation. Six patients experienced disease progression (3 patients during the first 12 cycles and 3 after completing 24 cycles of therapy). Four deaths occurred among patients who were in ongoing response at the time of death (2 COVID-19–related deaths, 1 postoperative aspiration pneumonia, and 1 unknown cause; additional details provided in supplemental Figure 6). Of the 6 patients who progressed, 3 subsequently died of disease.

The 2-year PFS rate was 72% (95% confidence interval [CI], 56-92), and the 2-year overall survival (OS) rate was 76% (95% CI, 61-95; Figure 2). The 2-year DSS rate was 91% (95% CI, 79-100; Figure 2). The superior DSS rate over OS rate can be explained by deaths related to COVID-19. The median PFS, DSS, and OS have not been reached yet.

Figure 2.

Survival outcomes. (A) PFS. (B) DSS. (C) OS. PD, progressive disease.

MRD assessment in the peripheral blood was possible in 24 of 25 patients; 1 patient lacked a baseline specimen for identification of a baseline clonotypic sequence. For complete MRD results, including the uMRD5 and uMRD6 rates across all timepoints in peripheral blood and bone marrow compartments, refer to supplemental Figure 5. Figure 3A-B depict the MRD results in peripheral blood over time. At C3, C13, and EOT, the uMRD5 rates in the peripheral blood were 77% (17/22), 95% (18/19), and 100% (17/17), respectively. In the intent-to-treat analysis, the uMRD5 rates in the peripheral blood at C3, C13, and EOT were 68% (17/25), 72% (18/25), and 68% (17/25), respectively. At C3, C13, and EOT, the uMRD6 rates in peripheral blood were 32% (7/22), 84% (16/19), and 71% (12/15), respectively. In the intent-to-treat analysis, the uMRD6 rates in the peripheral blood at C3, C13, and EOT were 28% (7/25), 64% (16/25), and 48% (12/25), respectively.

Figure 3.

Swimmer plot depicting responses, the MRD results, and duration of response. All patients (N = 25) are included and had a median follow-up period of 28.2 months. (A) MRD results at a sensitivity level of 1 × 10^–5. (B) MRD results at a sensitivity level of 1 × 10^–6. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

In total, 18 patients completed 24 cycles of therapy and all achieved CR (Figure 4, CONSORT diagram). One patient did not have MRD immunosequencing results available and was continued on zanubrutinib and venetoclax per patient and treating physician preference. Among patients who were MRD evaluable at EOT (n = 17), 2 patients with detectable MRD were continued on zanubrutinib and venetoclax and 1 had clinical progression after 30 months of total therapy. All other patients who achieved CR/uMRD in the peripheral blood and bone marrow (n = 15) discontinued zanubrutinib and venetoclax after C24. Eleven patients achieved uMRD6 in the peripheral blood and bone marrow and remained in remission at a median posttreatment surveillance of 5.8 months (range, 2.8-28.2). Four patients were uMRD5 but had indeterminant MRD results at the 1 × 10^–6 sensitivity level in the peripheral blood and, of these, 2 patients had subsequent progression off treatment at 3 months (clinical relapse) and 6 months (molecular relapse). Both were restarted on zanubrutinib and venetoclax with initial response and then clinically relapsed 6 and 7 months after re-treatment, respectively.

Figure 4.

CONSORT diagram. dMRD, detectable MRD; NED, no evidence of disease; ORR, overall response rate; POD, progression of disease.

Neither the Ki-67, MIPI risk score, biallelic TP53 inactivation, nor MRD status at C3 and C13 were significantly associated with DSS, PFS, or OS. Blastoid or pleomorphic variant morphology was associated with inferior PFS and OS (supplemental Figure 3). Patients who were 65 years or older had inferior OS outcomes (supplemental Figure 3). Of the 3 early progressors, 2 patients had a Ki-67 ≥50%, 1 had blastoid morphology, and none had a concomitant 17p deletion. One patient who progressed shortly after completion of the planned 8 cycles of obinutuzumab had a CARD11 (associated with BTKi resistance) and SMARCA4 (associated with ibrutinib and venetoclax resistance) mutation.^27,28 Another patient had a co-occurring NOTCH2 mutation.

AEs

The treatment-related adverse effects are summarized in Table 2, and the dose modifications are summarized in supplemental Figure 4. The most common treatment-related AEs were diarrhea (64%), COVID-19 infection (56%), neutropenia (32%), and infusion-related reactions (24%). Diarrhea was predominantly grade 1 (56%), largely transient, and manageable with antimotility agents, evening dosing, or dose reduction. Grade 3 neutropenia (16%) was reversible with growth factor support, and there were no instances of febrile neutropenia. Five patients (20%) received growth factor support during treatment. Grade 3 or higher thrombocytopenia occurred in 1 patient (4%) and was addressed with dose reduction. Serious AEs occurred in 48% of patients and included COVID-19 infection (n = 6), atrial fibrillation (n = 1), fever without neutropenia (n = 1), pneumonia (n = 3), rash (n = 1), and TLS (n = 1). Cardiac toxicity was infrequent and zanubrutinib was discontinued in only 1 patient with grade 3 atrial fibrillation. One patient discontinued zanubrutinib and venetoclax because of organizing pneumonia, however, the patient developed recurrent organizing pneumonia off treatment, so it was ultimately considered unrelated to treatment. Additional information regarding drug discontinuations and dose modifications are detailed in supplemental Figure 4. One instance of grade 4 TLS occurred during the initial split dose of obinutuzumab and after the initial zanubrutinib dose in a patient with evidence of spontaneous pretreatment TLS, renal dysfunction, and high tumor burden. No laboratory or clinical TLS (Howard criteria) occurred during the venetoclax ramp-up.²⁹

Table 2.

Recurrent (5% or more) treatment-related events among all 25 treated patients

Events	Any grade	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Diarrhea	16 (64)	14 (56)	2 (8)	—	—	—
COVID-19 infection	14 (56)	1 (4)	10 (40)	1 (4)	—	2 (8)
Neutrophil count decreased	8 (32)	1 (4)	3 (12)	4 (16)	—	—
Infusion-related reaction	6 (24)	2 (8)	2 (8)	2 (8)	—	—
Alanine aminotransferase increased	5 (20)	5 (20)	—	—	—	—
Bruising	5 (20)	5 (20)	—	—	—	—
Fatigue	5 (20)	4 (16)	1 (4)	—	—	—
Nausea	5 (20)	5 (20)	—	—	—	—
Platelet count decreased	5 (20)	4 (16)	—	1 (4)	—	—
Urinary tract infection	5 (20)	1 (4)	4 (16)	—	—	—
Aspartate aminotransferase increased	4 (16)	3 (12)	—	1 (4)	—	—
Constipation	4 (16)	3 (12)	1 (4)	—	—	—
Myalgia	4 (16)	3 (12)	1 (4)	—	—	—
Rash maculo-papular	4 (16)	2 (8)	1 (4)	1 (4)	—	—
Arthralgia	3 (12)	2 (8)	1 (4)	—	—	—
Abdominal pain	2 (8)	2 (8)	—	—	—	—
Anemia	2 (8)	—	2 (8)	—	—	—
Epistaxis	2 (8)	2 (8)	—	—	—	—
Fever	2 (8)	1 (4)	1 (4)	—	—	—
Flatulence	2 (8)	2 (8)	—	—	—	—
Gastroesophageal reflux disease	2 (8)	—	2 (8)	—	—	—
Headache	2 (8)	2 (8)	—	—	—	—
Hypertension	2 (8)	—	1 (4)	1 (4)	—	—
Lung infection	2 (8)	—	1 (4)	1 (4)	—	—
Upper respiratory infection	2 (8)	—	2 (8)	—	—	—

Serious AEs	Any grade	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
COVID-19 infection	6 (24)	—	3 (12)	1 (4)	—	2 (8)
Lung infection	2 (8)	—	—	1 (4)	—	1 (4)
Appendicitis	1 (4)	—	—	1 (4)	—	—
Aspiration	1 (4)	—	—	—	—	1 (4)
Atrial fibrillation	1 (4)	—	—	1 (4)	—	—
Dyspnea	1 (4)	—	—	1 (4)	—	—
Fever	1 (4)	1 (4)	—	—	—	—
Multiorgan failure	1 (4)	—	—	—	1 (4)	—
Nocardia	1 (4)	—	1 (4)	—	—	—
Organizing pneumonia	1 (4)	—	1 (4)	—	—	—
Pneumothorax	1 (4)	—	—	1 (4)	—	—
Rash maculo-papular	1 (4)	—	—	1 (4)	—	—
Retinal detachment	1 (4)	—	—	—	1 (4)	—
Syncope	1 (4)	—	—	1 (4)	—	—
TLS	1 (4)	—	—	—	1 (4)	—
Death of unknown cause	1 (4)	—	—	—	—	1 (4)

Data are presented as n (%).

Discussion

The triple combination of BOVen was well tolerated and highly active as frontline treatment for TP53-mutant MCL. The BOVen study met its primary end point with a 2-year PFS of 72%, which compares favorably with outcomes associated with chemoimmunotherapy. In the Nordic MCL-2 and MCL-3 analysis, patients with TP53-mutant MCL who were treated with intensive chemotherapy and first-line autologous stem cell transplantation had a 2-year PFS of 20% (n = 20).⁷ In the investigational arm of the SHINE study, patients with TP53-mutant MCL who were treated with ibrutinib, in addition to bendamustine plus rituximab and rituximab maintenance therapy, had a 2-year PFS of ∼55% (n = 26).³⁰ In a subgroup analysis of the recently published TRIANGLE study, younger patients with MCL with p53 overexpression (>50% by immunohistochemistry [IHC]) who were treated with intensive induction chemotherapy, followed by an autologous stem cell transplantation with or without ibrutinib, had improved failure-free survival with an ibrutinib-containing regimen when compared with chemoimmunotherapy alone.³¹ Despite the inherent limitations associated with cross-trial historical comparisons, these data suggest that a combination of biologically targeted agents are likely superior to chemoimmunotherapy alone for the treatment of TP53-mutant MCL. These findings are consistent with established data in an alternate but biologically related disease, chronic lymphocytic leukemia (CLL), for which TP53 aberrancy is a well-established marker for chemotherapy resistance, and patients strongly benefit from targeted therapy with B-cell receptor pathway and/or BCL2 inhibitors.^32,33

Several 2- and 3-drug “chemo-free” regimens are currently under investigation as frontline treatment for MCL.^{14,34, 35, 36, 37} In these studies, either very few patients with a TP53 mutation were included or data on the TP53 mutation status at baseline were not collected. For high-risk, TP53 mutant MCL, we hypothesized that triplet therapy, leveraging the known synergy of dual BTK and BCL2 inhibition, would lead to the deepest and most durable uMRD remissions. From the CLL experience, the BOVen triplet has achieved higher uMRD rates than existing doublet therapies.³⁸ We favored obinutuzumab as the optimal anti-CD20 monoclonal antibody based on the preclinical data that demonstrated that obinutuzumab decreases microenvironment–driven BCL-xL upregulation and may sensitize MCL cells to venetoclax-associated cytotoxicity.³⁹ In addition, there is emerging clinical data that obinutuzumab has superior efficacy when compared with rituximab for MCL.⁴⁰

Although treatment of TP53-mutant MCL is recognized as an area of unmet need, executing clinical trials for this rare biologic subset of a rare disease and rapid identification of the TP53 mutation before initiation of treatment is often not practicable. TP53 aberrancy can be defined in different ways, including the presence of a TP53 mutation (assessed by PCR or NGS), 17p deletion (assessed by cytogenetic assays such as fluorescence in situ hybridization or single-nucleotide polymorphism array), or p53 protein overexpression (assessed by IHC). Deletion of 17p is less prognostically significant than TP53 mutation in MCL.^7,41 Although p53 protein overexpression correlates with the presence of a TP53 mutation, routine IHC for p53 will fail to identify frameshift and truncating mutations and miss approximately 20% of missense mutations.^7,42,43 Thus, identification of a TP53 mutation by PCR or NGS is the strongest prognostic marker in MCL. We demonstrated that it is feasible to conduct a frontline study in TP53-mutant MCL. Allowance for a short course of pretreatment steroids and the availability of rapid turnaround testing for TP53 mutations facilitated the inclusion of high-risk patients, including those with a high tumor burden and/or rapidly proliferative disease.

TP53 mutations are associated with high-risk features in MCL.^3,44 The presence of a TP53 mutation, in combination with other high-risk features, such as the presence of hyperproliferation, blastoid morphology, C-MYC aberrancy, and markers of genomic complexity, is likely associated with the worst survival outcomes in MCL.^3,5,43 In our study, there was inferior PFS and OS in patients with blastoid or pleomorphic morphology, although the subset analyses were limited by small numbers. TP53 mutations can also occur in patients with non-nodal leukemic MCL.^5,45 Among these patients, TP53 mutation also seems to be associated with inferior survival outcomes.^5,23 In the future, we hope to more comprehensively characterize the clinical and biologic heterogeneity within TP53-mutant MCL and identify biologic predictors of response with the BOVen combination.

MRD assessment is a robust prognostic marker in MCL that has been applied in prospective clinical trials to inform treatment escalation or de-escalation.^23,46,47 In BOVen, if CR/uMRD was achieved after C24, therapy was discontinued. Patients with uMRD6 seemed to have more sustained remissions with fewer molecular or clinical relapses than those with uMRD5. These data suggest that, for MCL, the limit of detection of the assay is important, particularly for treatment de-escalation in high-risk patients. Additional follow-up time is needed to assess the posttreatment durability of clinical and molecular remissions in patients who achieve CR/uMRD6. Time-limited, MRD-guided treatment is an attractive concept to limit long-term toxicities, financial toxicity, and therapy resistance, but it remains to be seen whether this approach is best for TP53-mutant MCL.

The treatment-related side effects with BOVen were expected and largely similar to previous experiences with similar triplet regimens.^14,38 Severe neutropenia was not a treatment-limiting toxicity (grade ≥3 neutropenia [16%]), consistent with the BOVen CLL study, and febrile neutropenia was not observed.³⁸ The most common nonhematologic AE was COVID-19 infection, including 2 fatal events, which likely occurred because these patients received treatment during the peak of the COVID-19 pandemic before vaccines and effective antiviral therapies were available. After cytoreduction with 2 cycles of obinutuzumab and zanubrutnib, there was no laboratory or clinical TLS observed during the venetoclax ramp-up.

Although the ongoing randomized phase 3 clinical trials MANGROVE (NCT04002297) and ENRICH (CRUK/14/026) will more definitively compare BTKi and rituximab with chemoimmunotherapy in transplant-ineligible MCL, based on our data, the BOVen combination is 1 of the most highly active and well-tolerated novel agent combinations in MCL to our knowledge. Future studies may consider the addition of consolidative CD20-CD3 bispecific antibody therapy in patients with incomplete clinical or molecular response. In conclusion, these data provide compelling evidence to support the use of BOVen for the frontline treatment of TP53-mutant MCL.

Conflict-of-interest disclosure: A.K. reports receiving research support from AbbVie, Adaptive Biotechnologies, Celgene, Pharmacyclics, Loxo/Eli Lilly Pharmaceuticals, Seattle Genetics, Genentech, and Incyte; serving as a consultant for Adaptive Biotechnologies, AstraZeneca, Kite Pharmaceuticals, Janssen, Genentech, and Loxo/Eli Lilly Pharmaceuticals; and serving in a consultation role for Genentech. A.D.Z. reports receiving research support from MEI Pharmaceuticals, Genentech/Roche, and BeiGene; serving as a consultant for Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis, Adaptive Biotechnologies, MorphoSys, AbbVie, AstraZeneca, and MEI Pharmaceuticals; and serving as the data monitoring committee chair for BeiGene and as a data monitoring committee member for Bristol Myers Squibb (BMS), Celgene, and Juno. J.S. reports receiving research support from Adaptive Biotechnologies, BeiGene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics and serving as a consultant for AstraZeneca, BMS, Genentech/Roche, and Loxo/Eli Lilly. L.F. reports receiving research support from Roche, Genentech, Genmab, AbbVie, Innate Pharma, and BeiGene; serving as a consultant for Roche, Genentech, Genmab, AbbVie, Sanofi, and EvolveImmune; serving on the advisory board for AbbVie, Genentech, ADC Therapeutics, Seagen, and Ipsen; and receiving travel support from Genmab and AbbVie. A.D. reports receiving research support from Roche and AstraZeneca. J.K.L. reports receiving research support from Kymera Therapeutics; and serving as a consultant for ADC Therapeutics, Merck, Genmab, and AbbVie. J.S.A. reports serving as a consultant for AbbVie, AstraZeneca, BeiGene, Genentech, Janssen, Lilly, and Roche. P.C.J. reports receiving research support from Medically Home, AstraZeneca, and Incyte; and serving as a consultant for AstraZeneca, ADC Therapeutics, AbbVie, Seagen, Incyte, and BMS. J.E.H. reports serving as a consultant for and receiving research funding from Genmab. The remaining authors declare no competing financial interests.