Mantle Cell Lymphoma (C83.1)

Causes

Mantle cell lymphoma is an aggressive B-cell malignancy that usually arises from mature B lymphocytes within the mantle zone of lymphoid follicles. The disease is most commonly driven by a chromosomal translocation, t(11;14), which places the CCND1 gene under the control of immunoglobulin heavy-chain regulatory elements, leading to overproduction of cyclin D1 and uncontrolled cellular proliferation. Additional abnormalities involving DNA damage response, B-cell receptor signaling, NF-κB activation, and apoptosis regulation — including dependence on BCL-2 survival signaling — contribute to disease progression and therapeutic resistance.

Pathophysiology

Mantle cell lymphoma develops when malignant B lymphocytes acquire abnormalities that promote both uncontrolled proliferation and resistance to apoptosis. The hallmark event, overexpression of cyclin D1 from the t(11;14) translocation, drives inappropriate progression through the cell cycle, causing continuous cellular replication. At the same time, survival pathways involving B-cell receptor signaling, NF-κB activation, and anti-apoptotic proteins such as BCL-2 help the lymphoma cells evade programmed cell death. These malignant cells accumulate within lymph nodes, bone marrow, spleen, blood, and gastrointestinal tissue, where they disrupt normal immune architecture and progressively outcompete healthy lymphocytes.

Clinical features

Painless lymphadenopathy (enlarged lymph nodes) Fatigue and generalized weakness Unintentional weight loss Fevers Night sweats (“B symptoms”) Splenomegaly causing abdominal fullness or early satiety Hepatomegaly Bone marrow involvement leading to: anemia, thrombocytopenia, leukopenia Recurrent infections due to immune dysfunction Gastrointestinal involvement, which may cause: abdominal pain, diarrhea, GI bleeding, bowel obstruction, multiple lymphomatous polyposis Elevated white blood cell count in leukemic-phase disease Advanced-stage presentation at diagnosis is common Mantle cell lymphoma is often clinically aggressive and widely disseminated by the time it is detected.

Diagnosis

Mantle cell lymphoma is diagnosed through a combination of tissue biopsy, immunophenotyping, cytogenetics, and molecular testing. 1. Lymph node or tissue biopsy The definitive diagnosis usually begins with an excisional lymph node biopsy or biopsy of involved tissue. Microscopy typically shows: small- to medium-sized atypical lymphocytes diffuse or nodular infiltration irregular nuclear contours 2. Immunophenotyping Flow cytometry and immunohistochemistry identify the characteristic B-cell markers. Typical mantle cell lymphoma phenotype: CD19 positive CD20 positive CD5 positive Cyclin D1 positive Usually: CD23 negative CD10 negative This helps distinguish it from other B-cell lymphomas such as CLL/SLL. 3. Detection of the hallmark translocation The defining genetic abnormality is: t(11;14)(q13;q32)→CCND1/IGH This translocation causes cyclin D1 overexpression. It is commonly detected by: FISH (fluorescence in situ hybridization) PCR-based methods cytogenetics 4. Cyclin D1 overexpression Immunohistochemistry typically demonstrates strong cyclin D1 staining. This is one of the most important diagnostic markers. Rare cyclin D1–negative cases may express SOX11 instead. 5. Staging evaluation Because mantle cell lymphoma is often disseminated at diagnosis, staging usually includes: PET/CT imaging bone marrow biopsy peripheral blood evaluation sometimes endoscopy/colonoscopy if GI involvement is suspected 6. Additional prognostic markers Tests may also evaluate: Ki-67 proliferation index TP53 mutations complex cytogenetics minimal residual disease (MRD) These help estimate aggressiveness and guide treatment decisions. In simplified terms: diagnosis requires identifying a mature B-cell lymphoma with cyclin D1 overexpression driven by the t(11;14) translocation.

Mechanism of action videos

• Sonrotoclax Approved for Refractory Mantle Cell Lymphoma

Biological pathways

• Transport of connexons to the plasma membrane
• Translocation of SLC2A4 (GLUT4) to the plasma membrane
• The role of GTSE1 in G2/M progression after G2 checkpoint
• Selective autophagy
• Sealing of the nuclear envelope (NE) by ESCRT-III
• Resolution of Sister Chromatid Cohesion
• Recycling pathway of L1
• Recruitment of NuMA to mitotic centrosomes
• RHO GTPases activate IQGAPs
• Protein folding
• Prefoldin mediated transfer of substrate to CCT/TriC
• Post-chaperonin tubulin folding pathway
• Post NMDA receptor activation events
• PKR-mediated signaling
• Nuclear Envelope (NE) Reassembly
• Mitotic G2-G2/M phases
• Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane
• Kinesins
• Intraflagellar transport
• Interferon Signaling
• HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
• Gap junction trafficking and regulation
• Gap junction trafficking
• Gap junction assembly
• G2/M Transition
• Formation of tubulin folding intermediates by CCT/TriC
• EML4 and NUDC in mitotic spindle formation
• Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding
• Chaperonin-mediated protein folding
• Cargo trafficking to the periciliary membrane
• Carboxyterminal post-translational modifications of tubulin
• COPI-independent Golgi-to-ER retrograde traffic
• Assembly and cell surface presentation of NMDA receptors
• Aggrephagy
• Activation of AMPK downstream of NMDARs
• MHC class II antigen presentation
• COPI-mediated anterograde transport
• Activation of NMDA receptors and postsynaptic events
• RHO GTPases Activate Formins
• Antimicrobial mechanism of IFN-stimulated genes

Clinical trials

• A Phase I/II Open-Label Multi-Centre Master Protocol to Evaluate the Safety and Efficacy of AZD0486 Monotherapy or in Combination With Other Anticancer Agents in Participants With Mature B-Cell Malignancies
• A Phase II Study of Sonrotoclax Plus Zanubrutinib in Patients With Relapsed/Refractory Mantle Cell Lymphoma Planned for Standard of Care CAR-T Cell Therapy
• Obinutuzumab, Zanubrutinib, and Lenalidomide as First-Line Therapy for Mantle Cell Lymphoma: A Prospective, Single-Arm, Open-Label, Multicenter Study
• A Phase I Study of Ibrutinib (PCI-32765) in Combination With Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma
• A Phase 1b/2 Proof-of-Concept Study of the Combination of ACP-196 (Acalabrutinib) and Pembrolizumab in Subjects With Hematologic Malignancies
• A Phase II Study of Glofitamab for Relapsed/Refractory Mantle Cell Lymphoma in Patients Previously Treated With CD19-Directed CAR T-Cell Therapy
• A Prospective, Open-Label, Single-Arm Study of Obinutuzumab, Zanubrutinib, and Lenalidomide Followed Short-Cycle Cytarabine in First-Line Treatment of Mantle Cell Lymphoma
• Nivolumab for Relapsed or Refractory Disease Post Chimeric Antigen Receptor T-Cell Treatment in Patients With Hematologic Malignancies
• CD70-targeted PET/ CT in the Diagnosis of Malignant Cancers
• A Pilot Study of Loncastuximab Tesirine in Specific Populations of Relapsed/Refractory B-Cell Malignancies
• A Phase 1/2, Open-Label, Dose-Escalation and -Expansion Study of the Bruton Tyrosine Kinase Targeted Protein Degrader BGB-16673 in Patients With B-Cell Malignancies
• A Randomized Phase 3 Trial of Continuous vs. Intermittent Maintenance Therapy With Zanubrutinib as Upfront Treatment in Older Patients With Mantle Cell Lymphoma
• A Phase 3b, Multicenter, Open-label, PCI-32765 (Ibrutinib) Long-term Extension Study
• A Phase 3 Randomized Double-Blind Multicenter Study of Sonrotoclax Plus Zanubrutinib Versus Placebo Plus Zanubrutinib in Patients With Relapsed/Refractory Mantle Cell Lymphoma
• The SOUND-MCL Study: A Single-arm, Open-label, Multicenter, Phase II Study of Acalabrutinib, in Combination With the R-CHOP Standard of Care, for Previously Untreated Mantle Cell Lymphoma in Spain
• IIT2022-04-Sasine-CAR-T: A Phase 1 Single-arm, Open-label Study to Evaluate the Feasibility and Safety of Collecting and Combining Autologous Hematopoietic Stem Cells With Chimeric Antigen Receptor (CAR) T-Cell Therapy in Subjects With Relapsed/Refractory Hematological Malignancies
• Phase 2 Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Previously Untreated Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) and Mantle Cell Lymphoma (MCL)
• Phase 1b/2, Open-Label Study to Evaluate Safety and Tolerability of Epcoritamab in Combination With Anti-Neoplastic Agents in Subjects With Non-Hodgkin Lymphoma
• Phase II Study of Pirtobrutinib With Venetoclax In Relapsed-Refractory MCL (Mantle Cell Lymphoma) Patients
• A Randomized Phase III Trial of Consolidation With Autologous Hematopoietic Cell Transplantation Followed by Maintenance Rituximab vs Maintenance Rituximab Alone for Patients With Mantle Cell Lymphoma in Minimal Residual Disease-Negative First Complete Remission
• Phase I/II Study of Cellular Immunotherapy Using Central Memory-Enriched CD8+ T Cells Lentivirally Transduced to Express A CD19-Specific Chimeric Immunoreceptor Following Peripheral Blood Stem Cell Transplantation for Patients With High-Risk Intermediate Grade B-Lineage Non-Hodgkin Lymphoma
• A Randomized 3-Arm Phase II Study Comparing 1.) Bendamustine, Rituximab and High Dose Cytarabine (BR/CR) 2.) Bendamustine, Rituximab, High Dose Cytarabine and Acalabrutinib (BR/CR-A), and 3.) Bendamustine, Rituximab and Acalabrutinib (BR-A) in Patients </= 70 Years Old With Untreated Mantle Cell Lymphoma
• A Phase III, Open-Label, Multicenter Randomized Study Evaluating Glofitamab as a Single Agent Versus Investigator's Choice in Patients With Relapsed/Refractory Mantle Cell Lymphoma
• High Dose Chemotherapy and Combination Anti-HIV Therapy for HIV-Associated Hodgkin's and Non-Hodgkin's Lymphoma
• Phase I/II Study of Dendritic Cell Therapy Delivered Intratumorally After Cryoablation and Anti-PD-1 Antibody (Pembrolizumab) for Patients With Non-Hodgkin Lymphoma
• A Modular Phase I/II Open-label Dose Escalation and Dose Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of AZD5492, a T Cell-engaging Antibody Targeting CD20 in Subjects With Relapsed or Refractory B-Cell Malignancies (TITANium)
• A Randomized Phase III Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD After Unrelated Donor Hematopoietic Cell Transplantation Using Nonmyeloablative Conditioning for Patients With Hematologic Malignancies: A Multi-center Trial
• A Multiple-center Phase 2 Study of Acalabrutinib-Lenalidomide-Rituximab (ALR) With an Expansion Cohort of Acalabrutinib-Lenalidomide-Obinutuzumab (ALO) in Patients With Previous Untreated Mantle Cell Lymphoma
• A Single-arm, Multi-center, Open-label, Phase 2 Study to Evaluate the Efficacy and Safety of ICP-248 in Subjects With Relapsed or Refractory Mantle Cell Lymphoma
• A Phase I Study of Pevonedistat (MLN4924, TAK924) in Combination With Ibrutinib in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma
• A Randomized Phase II Trial Comparing Rituximab/Bendamustine(RB) Alternating With Rituximab/Bendamustine/Cytarabine(RBAC) With RB as Induction Therapy in Elderly Patients With Newly Diagnosed and Transplant-ineligible Mantle Cell Lymphoma
• Phase II Study of Pirtobrutinib, Rituximab (PR) in Previously Untreated Low and Intermediate Risk MCL (Mantle Cell Lymphoma) Patients
• Phase I/II Multi-site Study Evaluating the MTD, Safety and Efficacy of the Combination Venetoclax, Lenalidomide and Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma
• SONIC: Escalated Inpatient Ramp-Up of Sonrotoclax in Patients With Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), and Mantle Cell Lymphoma (MCL) (SONIC Study)
• A Pilot Study of Acalabrutinib With Bendamustine / Rituximab Followed by Cytarabine / Rituximab for Untreated Mantle Cell Lymphoma
• A Phase 1b, Multicenter, Open-label Study of Acalabrutinib in Combination With Bendamustine and Rituximab (BR) or Venetoclax and Rituximab (VR) in Subjects With Mantle Cell Lymphoma
• A Phase 1/2 Study of Copanlisib and Venetoclax in Patients With Relapsed or Refractory Mantle Cell Lymphoma
• A Phase 1/2 Open Label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of Acalabrutinib in Chinese Adult Subjects With Relapsed or Refractory Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia or Other B-cell Malignancies
• Feasibility of Treating Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma With Zanubrutinib in Combination With the BCL2 Inhibitor, Sonrotoclax, Focusing on Access for Underrepresented Ethnic/Racial Minorities
• A Multicenter Phase 2 Study of Glofitamab With Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma