Latest advances in the treatment of mantle cell lymphoma

The treatment landscape for mantle cell lymphoma (MCL) is rapidly advancing. During the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago, US, we were excited to attend the educational session titled New Directions for Mantle Cell Lymphoma in 2022. Topics of discussion were prognostic markers, presented by Toby Eyre,¹ new strategies for treatment-naïve MCL, presented by Anita Kumar,² and treatment options beyond first-generation Bruton’s tyrosine kinase (BTK) inhibition, presented by Chan Cheah.³ Below, we summarize the key educational points.

Prognostic markers in mantle cell lymphoma¹

MIPI and cMIPI score

Prognostic markers are important parameters for predicting the response of patients to different therapies. The Mantle Cell Lymphoma Prognostic Scoring Index (MIPI) involves the use of biochemical parameters including age, Eastern Cooperative Oncology Group performance status, white blood cell count, and lactate dehydrogenase levels. Developed in 2008 by the European Mantle Cell Lymphoma network, it classifies patients into three distinct risk groups, low, intermediate, and high. Each group acts as a predictor for time to treatment failure and overall survival (OS). More recently, Ki-67, which corresponds to the tumor disease proliferation level, was added to the MIPI index producing a combined MIPI score and allows for greater separation of patents into four more distinctive prognostic groups. These are low, low-intermediate, high-intermediate, and high risk.

TP53, POD24, and ctDNA

High expression of TP53 is a strong prognostic factor for treatment relapse and inferior OS; therefore, patients can be divided into groups according to their levels of immunohistochemistry determined TP53 expression: a negative group corresponds to 0% expression, low 1–10% expression, intermediate 10–50% expression, and high >50% expression. Moreover, patients with TP53-mutated MCL have inferior OS, progression free survival (PFS), and cumulative incidence of relapse compared with patients who have unmutated TP53 and, comparatively, a TP53 mutation appears to be an even more powerful marker of poor prognosis than a high TP53 expression.

Progression of disease within 24 months (POD24) after front-line therapy is another indicator of inferior OS when compared with patients who have a longer relapse time, and early clinical data indicates that circulating tumor DNA (ctDNA) also has prognostic potential in MCL.

These prognostic markers remain independent of the MIPI and combined MIPI scores.

Clinical relevance in relapsed disease

Ibrutinib is currently one of the main therapies of choice for relapsed MCL. Recent studies have shown that ibrutinib, if used at first relapse, produced a significantly improved OS and median PFS; highlighting the relevance of relapse as a valuable prognostic marker. Around one third of patients have some form of high-risk feature including blastoid disease, high risk MIPI score, or TP53 mutation and have significantly poorer outcomes after ibrutinib treatment. For these high-risk patients, median PFS is around 6 months whilst overall response rate (ORR) is 55%. Identifying these patients prior to ibrutinib treatment will allow for proactive planning for the next treatment steps, such as CAR T-cell therapy.

New strategies on the horizon for treatment-naïve mantle cell lymphoma²

The current standard of care frontline treatment for MCL is chemoimmunotherapy, with specific therapeutic regimens according to whether patients are transplant eligible or ineligible; however, MCL is both clinically and biologically heterogenous and therefore challenges the universal treatment approach.

MRD assessment

One potential method to refine treatment models is by assessing measurable residual disease (MRD), which is now an established prognostic marker in MCL. Possible applications include early surrogate endpoint prediction, interim or end-of-treatment assessment for risk adapted treatment approaches, guiding treatment duration and early cessation, predicting relapse during surveillance, predicting therapy resistance, and assessment of clonal evolution.

Novel treatment approaches

There are now several novel approaches currently being investigated for frontline treatment of MCL. One example is the addition of novel therapies to a standard chemotherapy backbone; as explored in more detail in this Lymphoma Hub article, which summarizes the SHINE phase 3 trial (NCT01776840) evaluating bendamustine induction therapy followed by rituximab maintenance in conjunction with the BTK inhibitor (BTKi) ibrutinib vs placebo.

Chemotherapy-free combinations are another method currently being evaluated. In particular, lenalidomide plus rituximab induction and maintenance has shown durable remissions with an estimated 5-year PFS at 64% and estimated OS at 77%. Moreover, Ibrutinib plus rituximab has been studied in a single arm, phase 2 trial (NCT01880567) and demonstrated a 3-year PFS of 87%, best ORR of 96%, and complete remission (CR) rate of 71%. However, 34% of patients experienced atrial fibrillation and 60% of these patients discontinued treatment due to Grade 3 fibrillation. More detail on the use of ibrutinib plus rituximab as a frontline therapy for MCL can be found in this Lymphoma Hub article.

Triplet combinations are also being investigated, notably the synergistic combination of ibrutinib, obinutuzumab, and venetoclax in the OASIS trial (NCT02736617). There was a high CR rate by positron emission tomography after Cycle 6 (86.6%), MRD clearance of 100% after Cycle 3, and 1-year PFS of 93%. This combination was shown to be highly active, well tolerated, and active in patients with both TP53 mutations and blastic disease.

Selected patient populations

Lastly, there are several ongoing trials for selected patient populations, notably low-risk and high-risk MCL. The IMCL-15 study (NCT02682641) evaluated ibrutinib and rituximab for indolent clinical forms of MCL and showed an ORR of 84%, CR rate of 80%, and 36-month PFS of 93%; however, this was performed in a very favorable study cohort. Furthermore, the BOVEN study (NCT03824483) evaluated the use of zanubrutinib, obinutuzumab, and venetoclax in patients with high-risk, untreated MCL who had a TP53 mutation. The combination was well tolerated with ORR of 86% and CR rate of 64%.

Beyond first-generation BTK inhibition in mantle cell lymphoma: CAR T-cell therapy, bispecific antibodies, and novel small molecules³

Novel small molecules

Pirtobrutinib is a highly potent, reversible, non-covalent BTKi that has been evaluated in the phase I/II BRUIN study (NCT03740529) of patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma, as previously reported on the Lymphoma Hub. In the analysis presented at ASH 2021, pirtobrutinib had a median duration of response of 18 months and an ORR of 51% for patients with MCL, with very few Grade ≥3 adverse events. The phase III BRUIN-MCL-321 trial of pirtobrutinib vs investigators choice in relapsed/refractory (R/R) MCL (NCT04662255) is ongoing.

Bispecific antibodies

Bispecific antibodies that bind CD20 on B cells and CD3 on T cells are a promising treatment prospect for MCL. Glofitamab, distinct from other CD20 × CD3 bispecific antibodies by its 2:1 configuration for increased potency and binding avidity, demonstrated an ORR and CR rate of 81% and 67%, respectively, in patients with R/R MCL, regardless of prior BTKi treatment exposure (NCT03075696). During the congress, the Lymphoma Hub interviewed Tycel Phillips about the rationale behind step-up dosing of glofitamab, which can be found here.

CAR T-cell therapy

There are several anti-CD19 CAR T-cell products currently undergoing trials that include MCL patient cohorts. Brexucabtagene autoleucel is the only approved CAR T-cell therapy for MCL and has been investigated in the phase II ZUMA-2 trial (NCT02601313). For patients with R/R MCL and <5 prior lines of treatment including BTKi, ORR was 93% and CR rate was 67% after a median follow-up of 12.3 months. The 12-month PFS and OS were 61% and 83%, respectively, as reported by Wang, et al.⁴ in the New England Journal of Medicine in 2020; further details can be found here. Another CAR T-cell product, lisocabtagene maraleucel, is being evaluated in the phase I TRANSCEND NHL 001 trial (NCT02631044) that includes MCL patients who have completed ≥2 lines of treatment including BTKi. For the MCL cohort, ORR was 84% and the CR rate was 66% after a median follow up of 5.9 months; median PFS and OS were not reached. A 2-year follow up of this trial has recently been reported on the Lymphoma Hub.

Antibody drug conjugates

Zilovertamab vedotin is an antibody drug conjugate which targets ROR1, a molecule that is present on many hematologic and solid tumors, but not on normal tissue. It delivers the anti-microtubule toxin monomethyl auristatin E directly to the tumor and is currently being evaluated in a phase I escalation study in patients with hematologic malignancies, including patients with R/R MCL, with starting doses ranging from 0.5–2.5 mg/kg (VLS-101-0001; NCT03833180).

Conclusion

The current and future treatment landscape for MCL looks hopeful, with the development of new treatment regimens and novel therapeutics that offer greater efficacy, precision, and improved OS rates compared to current treatments.