High-risk mantle cell lymphoma (MCL) poses significant management-related challenges. Fortunately, the emergence of newer US Food and Drug Administration (FDA)–approved targeted therapies and CAR T cells, used alone or in combination, along with continued drug development efforts, are slowly improving the outlook for patients with high-risk MCL.

Patients with high-risk MCL have a reduced median overall survival compared with that of patients with low- or intermediate-risk disease. We typically use the Mantle Cell Lymphoma International Prognostic Index (MIPI) score to determine a patient’s risk. The score is based on their age, disease stage, performance status, lactate dehydrogenase level, and leukocyte count. But there are other significant factors that are associated with a worse prognosis, including TP53 mutations, higher Ki-67 percentages, complex karyotype, and blastoid or pleomorphic variants. Further, patients who do not respond to frontline therapy or who relapse within 24 months also have a significantly higher risk of a worse prognosis, even without having other high-risk features. Of these, mutant TP53 is perhaps the worst prognostic factor and is associated with chemotherapy resistance and the poorest survivals.

In patients with high-risk MCL and wild-type TP53 for whom a clinical trial is unavailable, I often use frontline chemoimmunotherapy. We traditionally consolidate with high-dose chemotherapy followed by autologous stem cell transplant (ASCT) and maintenance rituximab therapy in patients who are young and fit. Older, frailer patients who could not tolerate ASCT also receive maintenance rituximab therapy.

The recently published TRIANGLE trial randomized patients to the following 3 arms: traditional chemoimmunotherapy followed by ASCT and observation, traditional chemotherapy plus ibrutinib followed by ASCT and 2 years of ibrutinib therapy, or traditional chemotherapy plus ibrutinib followed by 2 years of ibrutinib therapy; rituximab maintenance could be added to all 3 arms. The addition of ibrutinib improved outcomes, and it is unclear if ASCT after the upfront regimen added anything. Based on the data from the TRIANGLE trial and the chemorefractoriness of TP53-mutant MCL, my strategy for high-risk patients with mutant TP53 for whom a clinical trial is unavailable would be upfront chemoimmunotherapy with a BTK inhibitor followed by maintenance therapy with rituximab and the same BTK inhibitor. Since ibrutinib is no longer FDA approved for MCL, this would mean using acalabrutinib or zanubrutinib. Patients who had enhanced p53 expression and a high percentage of Ki-67 in the TRIANGLE study seemed to do as well as patients without those high-risk features. So, I think that this would be a reasonable treatment strategy for these patients if a clinical trial is not available.

When patients relapse, I always use a BTK inhibitor second line if one was not given initially and if a clinical trial is not available. If a patient’s response to BTK monotherapy is suboptimal, I often add venetoclax. If their response remains poor or if their disease progresses, I transition to the CD19-directed CAR T-cell therapies brexucabtagene autoleucel or lisocabtagene maraleucel (if after ≥2 lines of therapy). We are seeing that CAR T-cell therapies work just as well in sicker and higher-risk patients with MCL in the real world as they did in clinical trials, with their efficacy and safety being maintained. That is very reassuring, and it allows us to offer CAR T-cell therapies to more individuals with MCL. If patients progress after all these therapies, the noncovalent BTK inhibitor pirtobrutinib may be useful, even in those who developed resistance to zanubrutinib or acalabrutinib. Of course, clinical trials are always appropriate options for these patients.

An outstanding question is when to refer patients with relapsed MCL that responds to second or later lines of therapy for allogeneic stem cell transplant, the only potentially curative option for MCL. My strategy is generally to do this when I do not think that there are any remaining therapies available that could yield a sufficiently good response for a patient to subsequently get to allogeneic transplant.