A 3-pronged attack on TP53-mutated MCL

In this issue of Blood, Kumar and colleagues report results from, to our knowledge, the first study conducted in mantle cell lymphoma (MCL) specifically for patients with TP53-mutated disease.¹ The highly promising results lay the foundation for a new treatment approach.

Effective treatment of TP53-mutated MCL has been a long-standing challenge in the field. Analysis of outcomes in the Nordic MCL2 and MCL3 trials, which investigated cytarabine-containing chemoimmunotherapy induction followed by consolidative autologous stem cell transplantation, first highlighted the dismal outcomes for such patients. The median overall survival (OS) was 1.8 years vs 12.7 years for patients with and without TP53-mutated disease, respectively.² At present there is no clear effective standard-of-care (SOC) treatment for patients with TP53-mutated MCL, and new frontline approaches are needed.³ 

Bruton’s tyrosine kinase (BTK) inhibitors, which have transformed the field of MCL, are active as monotherapy and in combination with chemoimmunotherapy in TP53-mutated disease (see table).^3-8 The zanubrutinib + obinutuzumab + venetoclax (BOVen) study investigated the triplet combination of the BTK inhibitor zanubrutinib, the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody obinutuzumab with minimal residual disease (MRD)-guided treatment discontinuation after 24 cycles of therapy. This combinatorial approach carries strong preclinical and clinical data support. The recently presented results of the randomized phase 3 SYMPATICO study in relapsed/refractory (R/R) MCL firmly establish the benefit of adding BCL2 inhibition to BTK inhibition in MCL. Superior progression-free survival (PFS) was observed in all patients treated with ibrutinib + venetoclax compared with ibrutinib + placebo including those with TP53-mutated disease (see table).⁸ 

In brief, BOVen was highly efficacious and well tolerated. Nearly all patients responded (24 of 25), and notably most did so within the first 3 months of treatment initiation, which is important in this disease because it can accelerate rapidly. Furthermore, nearly all responders achieved a complete response (22 of 24). Of the 17 patients who completed 24 cycles of therapy and had available MRD results, 100% had peripheral blood MRD negativity at the sensitivity level of 10⁻⁵. The 2-year PFS was 72%, which compares favorably to historical results. The most common treatment-related adverse event was diarrhea (64% all-grade; 56% grade 1), and although 20% of patients did require growth factor support for neutropenia, there were no cases of febrile neutropenia.

The BOVen study also lays the foundation for several important areas of further investigation. First, this study highlights that TP53-mutated MCL is a heterogeneous disease. Overall, 32% of patients had Ki-67 fraction of less than 30%, and only 28% of patients were higher than 50%. Forty percent of patients were SOX-11^–. Twenty percent of patients had blastoid or pleomorphic histology, and these patients experienced inferior PFS and OS. Larger studies are needed to evaluate outcomes across risk groups and to assess whether those with aggressive histologic features might benefit from the inclusion of chemotherapy, such as cytarabine, particularly early in the course of disease given early progression events in this study. The impact of the specific TP53 mutation as well as the presence of additional mutations may also be important. Furthermore, none of these agents target the TP53 mutation itself, which remains an elusive goal across the field of oncology.

Second, whether MRD-directed discontinuation of therapy is an effective strategy in TP53-mutated disease remains to be proven. Only 15 patients achieved MRD undetectable status at the sensitivity level of 10⁻⁶, and the follow-up is short. Although the 2 patients who reinitiated zanubrutinib and venetoclax with the reemergence of detectable disease did not have MRD negativity at the level of 10^–6, their rapid clinical progression is worrisome. Studies comparing discontinuation and reinitiation at first detection of MRD vs continuous therapy are needed to assess OS in this high-risk population.

Third, given that effective options for R/R TP53-mutated MCL are limited, maximizing the duration of initial response is key to achieving improved outcomes. In this study, 3 of the 6 patients with disease progression have already died due to their disease. There are varying results of the efficacy of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in R/R TP53-mutated MCL,^9-11 and the comparative efficacy of bispecific antibodies in this specific subgroup of patients with MCL is unknown. Given that BOVen is a highly active regimen with the majority of patients experiencing a complete remission with high rates of undetectable MRD, future directions should explore how to extend the durability of remission. Consolidation with CAR T-cell therapy, or bispecific antibodies, either alone or in combination with other novel agents including antibody drug conjugates, could be an effective strategy. Such an approach of early escalation to anti-CD19 CAR T-cell therapy is under investigation in generally high-risk patients in the ongoing WINDOW-3 study (NCT05495464).

In conclusion, the authors deserve congratulations for conducting the first dedicated clinical trial in this high-risk MCL population. We look forward to the future data with longer follow-up and additional patients treated. Results from the ongoing trial of acalabrutinib, venetoclax, and obinutuzumab in a cohort enriched for TP53-mutated disease (NCT04855695) could provide additional support for this triplet approach to become a new SOC.

Conflict-of-interest disclosure: C.E.R. has received honoraria from Research to Practice, Curio Science, and AstraZeneca, and has received institutional research funding from Genentech. A.S.L. has received honoraria from Research to Practice, Curio Science, Ideology, MJH Life Sciences, and Genmab.