A Look at Current Trends and the Potential Future of Mantle Cell Lymphoma Therapy

Mantle cell lymphoma (MCL) is a difficult type of cancer to treat due to heterogeneity in disease pathology, uncertain prognosis, and varied responses to therapy from patient to patient. Therefore, it has become a focus of novel therapy development to improve outcomes. A recent review covered current trends in MCL management and potential future developments in the treatment of MCL.

MCL is a subtype of B-cell lymphoma characterized by the chromosomal translocation t(11;14), leading to dysregulated cyclin D1 (CCND1) expression. Prognostication can be difficult, but current tools include the MCL international prognostic index, ki-67 proliferation index, and TP53 mutation status.

Like many other cancer types, treatment has evolved from traditional chemotherapy in recent years to include novel targeted drugs, epigenetic therapies, and immunotherapies. As personalized therapies continue to emerge, identifying prognostic values and novel, effective therapy targets have become crucial endeavors for successful treatment.

The treatment landscape is often evolving, with approaches varying from repurposed drugs to new agents and even entirely new approaches such as chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engager (BiTE) therapy. In a relatively short period of time, 5 drugs were approved by the FDA for MCL: the immunomodulatory agent lenalidomide, the proteasome inhibitor bortezomib, and the Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib, acalabrutinib, and zanubrutinib.

The review details current therapy strategies and possible future areas for development.

Proteasome Inhibition

Bortezomib is a first-generation proteasome inhibitor that has been shown to be safe and effective in combination settings, despite limited efficacy as a monotherapy. It has yielded favorable response rates in intensive regimens such as rituximab in combination with hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone alternating with rituximab-methotrexate and cytarabine (R-HyperCVAD). Clinical trials are currently investigating bortezomib in combination with the second-generation oral proteasome inhibitor ixazomib and with immunotherapy and targeted therapy regimens for MCL.

BTK Inhibitors

The original FDA-approved first-in-class BTK inhibitor, ibrutinib, is standard of care for relapsed or refractory MCL. Initial response and complete response rates were 77% and 33%, respectively. Ibrutinib produced a 26.5% complete response rate with a median progression-free survival (PFS) of 13 months, but median PFS increased to 33.6 months and median overall survival (OS) was 26.7 months among patients who had received a prior line of therapy. Ibrutinib plus rituximab and other combinations have also been explored in relapsed MCL and produced favorable results with durable remission.

Acalabrutinib, another recently approved BTK inhibitor, is an option that has limited off-target activity and has shown high response rates in the relapsed and refractory setting. It has a better side-effect profile and better tolerance than ibrutinib and was approved for second-line treatment of MCL in 2019.

Zanubrutinib, another BTK inhibitor, is a second-generation BTK inhibitor that is selective and irreversible and is approved in patients who have had at least one prior line of treatment. Clinical trials are exploring novel BTK inhibition agents including nemtabrutinib, pirtobrutinib, and orelabrtinib.

Immunomodulatory Drugs

The antineoplastic agent lenalidomide has immunomodulatory capabilities and has had mixed results in combination regimens. Toxicity was a limiting factor in at least one study when combined with bortezomib, but rituximab plus lenalidomide showed PFS and OS improvements in the relapsed setting and is still under investigation in the first-line setting. However, lenalidomide can cause treatment-related cancers such as non-invasive skin cancers and others. Molecules related to lenalidomide are also being investigated.

The BCL-2 inhibitor venetoclax is FDA-approved for acute myeloid leukemia and chronic lymphocytic leukemia and is being investigated in relapsed MCL as a single agent. In a phase 1 study, venetoclax had single-agent activity of 75% and a median response duration of 15.7 months. It is also being studied in combination with other therapies for MCL.

Clinical Trials and Future Approaches

There are several types of drugs being studied in trials. Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) inhibitors are being investigated in oncology and other disease settings. Epigenetic agents have also been investigated in MCL treatment with promising results. Monoclonal antibodies and antibody-drug conjugates are promising options also in clinical trials.

CAR T-cell therapy is one of the most recent developments in immunotherapy, and multiple options are currently FDA-approved for hematologic cancers. BiTE therapy is a novel strategy also utilizing T-cells with trials underway. In these therapy types, mitigating potential for cytokine release syndrome is an important factor.

Allogeneic stem cell transplant is a known curative therapy for younger patients and has become more accessible with matched unrelated, cord blood, and haploidentical transplant approaches and post-transplant cyclophosphamide to reduce graft versus host disease.

“Aside from the aforementioned novel agents, many potentially promising new molecules and treatment approaches continuously emerge through the clinical trial pipeline,” study authors wrote, concluding that the rapid advances in recent years point to a promising future for MCL treatment.

Reference

Pu JJ, Savani M, Huang N, Epner EM. Mantle cell lymphoma management trends and novel agents: where are we going? Ther Adv Hematol. Published online February 26, 2022. doi:10.1177/20406207221080743