Mantle cell lymphoma management trends and novel agents: where are we going?

Abstract

The heterogeneity in disease pathology, the unpredictability in disease prognosis, and the variability in response to therapy make mantle cell lymphoma (MCL) a focus of novel therapeutic development. MCL is characterized by dysregulated expression of cyclin D1 through a chromosome t(11;14) translocation. MCL international prognostic index (MIPI), ki-67 proliferation index, and TP53 mutation status are currently utilized for prognostication. With advances in pharmacokinetic analysis and drug discovery, treatment strategy has evolved from chemotherapy to combination of targeted, epigenetic, and immune therapies. In this review, we discuss investigational and newly approved treatment approaches. In a short time, the US Food and Drug Administration (FDA) has approved five agents for the treatment of MCL: lenalidomide, an immunomodulatory agent; bortezomib, a proteasome inhibitor; and ibrutinib, acalabrutinib, and zanubrutinib, all Bruton kinase inhibitors. Epigenetic agents (e.g. cladribine and vorinostat), mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus and everolimus), and monoclonal antibodies and/or antibody-drug conjugates (e.g. obinutuzumab, polatuzumab, and ublituximab) are promising therapeutic agents currently under clinical trial investigation. Most recently, chimeric antigen receptor (CAR)-T cell therapy and bispecific T-cell engager (BiTE) therapy even open a new venue for MCL treatment. However, due to its intricate pathology nature and high relapse incidence, there are still unmet needs in developing optimal therapeutic strategies for both frontline and relapsed/refractory settings. The ultimate goal is to develop innovative personalized combination therapy approaches for the purpose of delivering precision medicine to cure this disease.

Yeast Ribonucleotide Reductase Is a Direct Target of the Proteasome and Provides Hyper Resistance to the Carcinogen 4-NQO

“…Proteasome inhibitors are used to treat several malignancies, such as multiple myeloma [ 62 , 63 ], mantle cell lymphoma [ 64 ], acute lymphoblastic leukemia [ 65 ], and osteosarcoma [ 66 ]. In combinatorial regimens, proteasome inhibitors can be used together with DNA-damaging therapeutic agents [ 67 , 68 ].…”

Tackling Mantle Cell Lymphoma in Europe

“…There are now possibilities to stratify patients as low, intermediate, or high risk [ 20 ]. However, although multiple treatment options are available as novel monotherapies for relapsed/refractory MCL, no clear standard of care is recognized in EU or US treatment guidelines [ 3 , 14 ]. Differences persist in the guidelines for induction therapy issued in the US and in Europe, and in recommended treatment regimens.…”

“…Mantle cell lymphoma (MCL) is a hematological malignant disease composed of 2.5–6% non-Hodgkin’s lymphomas. The treatment has evolved over time, and different treatment options exist for patients with aggressive variants depending on age, performance status, and possibility of bone marrow transplant [ 1 , 2 , 3 ]. There are over 70 subtypes of lymphomas, with different diagnostic evaluation, different treatment protocols, and different outcomes.…”

Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma

“…The landscape of treatment options for MCL is changing [10]. Many recent therapeutic advances have been made using treatment regimens based on aggressive chemotherapy, novel drug combinations, maintenance therapy and hematopoietic bone marrow stem cell transplant (BMT) [10,11].…”

“…The landscape of treatment options for MCL is changing [10]. Many recent therapeutic advances have been made using treatment regimens based on aggressive chemotherapy, novel drug combinations, maintenance therapy and hematopoietic bone marrow stem cell transplant (BMT) [10,11]. Progress is being made against this disease; however, although survival is improving, relapse remains common, especially in those with advanced and aggressive disease.…”