Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments

Abstract

The field of mantle cell lymphoma (MCL) has witnessed remarkable progress due to relentless advances in molecular pathogenesis, prognostication, and newer treatments. MCL consists of a spectrum of clinical subtypes. Rarely, atypical cyclin D1-negative MCL and in situ MCL neoplasia are identified. Prognostication of MCL is further refined by identifying somatic mutations (such as TP53, NSD2, KMT2D), methylation status, chromatin organization pattern, SOX-11 expression, minimal residual disease (MRD), and genomic clusters. Lymphoid tissue microenvironment studies demonstrated the role of B-cell receptor signaling, nuclear factor kappa B (NF-kB), colony-stimulating factor (CSF)-1, the CD70-SOX-11 axis. Molecular mechanism of resistance, mutation dynamics, and pathogenic pathways (B-cell receptor (BCR), oxidative phosphorylation, and MYC) were identified in mediating resistance to various treatments (bruton tyrosine kinase (BTK) inhibitors [ibrutinib, acalabrutinib]. Treatment options range from conventional chemoimmunotherapy and stem cell transplantation (SCT) to targeted therapies against BTK (covalent and noncovalent), Bcl2, ROR1, cellular therapy such as anti-CD19 chimeric antigen receptor therapy (CAR-T), and most recently bispecific antibodies against CD19 and CD20. MCL patients frequently relapse. Complex pathogenesis and the management of patients with progression after treatment with BTK/Bcl2 inhibitors and CAR-T (triple-resistant MCL) remain a challenge. Next-generation clinical trials incorporating newer agents and concurrent translational and molecular investigations are ongoing. 1 | INTRODUCTION Mantle cell lymphoma (MCL) is an uncommon subtype of aggressive B cell non-Hodgkin's lymphoma (B-NHL). In 1982, Weisenburger et al. 1 first described 12 cases of malignant lymphoma with lymph node biopsies showing widened mantle zones around germinal centers in the secondary lymphoid follicles. The diagnosis of MCL 2 is now well characterized. MCL is no longer considered a single disease but is a mixed bag of various subcategories with a spectrum of molecular and clinical features. MCL patients have varied clinical presentations (generally symptomatic to an asymptomatic indolent clinical course).Advances in MCL research have significantly enhanced our understanding of pathogenesis, tumor microenvironment, 3 risk factor prognostication, 4 and molecular categories. 5 With the available treatment modalities (chemoimmunotherapy, 6 stem cell transplantation [SCT], 7 covalent and noncovalent BTK inhibitors, 8,9 bispecific antibodies, 10 an ROR1 drug conjugate, 11 and Bcl2 antagonists 12 ), the response rates and patient survival have improved. 13 The FDA approval of anti-CD19-chimeric antigen receptor therapy (CAR-T)-brexucabtagene autoleucel 14 -is a landmark

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

“…Mantle cell lymphoma relies on deregulated signaling and the activity of transcription factors, such as MYC and NFκB [ 96 ]. The bromodomain and extra-terminal domain (BET) family proteins are important transcriptional regulators in MCL [ 97 ].…”

BTK-Inhibitoren und CAR-T-Zell-Therapie bei der Behandlung des Mantelzelllymphoms – einen Tanzpartner finden

“…Die Pathogenese des Mantelzelllymphoms (MCL) wird durch verschiedene Mechanismen angetrieben, darunter eine anomale Zellzyklusregulierung, eine Dysregulation der B-Zell-Rezeptor-Signalübertragung (BCR), molekulare und genomische Veränderungen, DNA-Schäden und Mikroumgebungseffekte [1]. Da die Bruton-Tyrosinkinase (BTK) ein wichtiges Bindeglied in der BCR-Signalübertragung ist, sind BTK-Inhibitoren (BTKi) bei der Behandlung von MCL sehr wirksam [2].…”

Protein Kinase CK2 represents a new target to boost Ibrutinib and Venetoclax induced cytotoxicity in mantle cell lymphoma

“…Mantle cell lymphoma (MCL) accounts for about 3–10% of all B-cell non-Hodgkin lymphomas (NHL) and is characterized by the propensity to frequent relapses and poor prognosis ( Jain and Wang, 2022 ).…”

“…Venetoclax is a first-in class selective Bcl-2 inhibitor with demonstrated clinical activity in MCL, in particular in combination with Ibrutinib ( Davids et al, 2017 ; Tam et al, 2018 ). However, primary and acquired resistance to Ibrutinib, mainly due to BTK C481 or PLCγ mutations ( Hershkovitz-Rokah et al, 2018 ), and to Venetoclax, mainly due to upregulation of other pro-survival Bcl-2 family members, may occur ( Huang et al, 2022 ; Jain and Wang, 2022 ). Therefore, even with the introduction of these novel drugs, the development of refractoriness and resistance is still the main unsolved clinical-biological issue.…”