Mantle Cell Lymphoma Overview

Mantle Cell Lymphoma

• Mantle cell lymphoma (MCL) is a chronic B-lineage lymphoproliferative disorder.
• Characterized by variable cytological and histological features, with a distinctive cytogenetic and molecular genetic defect.
• Although histologically low-grade, it has an intermediate prognosis, with a median survival of only 3-4 years.
• Generally considered incurable, and shows an increased incidence associated with a family history of MCL or other non-Hodgkin lymphomas.
• Characterized by the t(11;14) translocation leading to cyclin D1 overexpression.
• Shows significant clinical and biological heterogeneity, ranging from indolent non-nodal leukemic variants to highly aggressive blastoid variants.
• Risk stratification at diagnosis is essential for optimal treatment approach.

Clinical Presentation

• Primarily affects middle-aged and older individuals, with a median age of 60 years.
• Marked male predominance.
• Usually presents with advanced stage disease, often exhibiting lymphadenopathy and splenomegaly.
• Extranodal involvement is common, including Waldeyer's ring, lung, pleura, and the gastrointestinal tract.
• Peripheral blood involvement occurs in about two-thirds of patients, associated with a worse prognosis.
• Leukemic non-nodal mantle cell lymphoma, usually involving the spleen, tends to be clinically indolent.
• Central nervous system disease may be more likely in patients with peripheral blood involvement.

Diagnosis

• Peripheral blood cytopenias (due to marrow infiltration) and circulating lymphoma cells may be present.
• Mantle cell lymphoma cells exhibit significant pleomorphism, typically medium-sized with irregular nuclei.
• Some cells may show inconspicuous nucleoli or pronounced nuclear indentations/clefts.
• Cytoplasmic vacuoles and rarely, cytoplasmic granules may be present.
• Chromatin pattern can vary, with some cells exhibiting a diffuse pattern.
• Blastoid variant (comprising 10-20% of cases) shows predominantly diffuse chromatin pattern, resembling acute lymphoblastic leukemia (ALL) cells or showing more mature features.
• Bone marrow infiltration is frequent (up to 80% of patients). Infiltration patterns include interstitial/focal, nodules or irregularly shaped infiltrates, etc.
• Trephine biopsy sections display lymphoma cells with regular round nuclei or irregular, cleaved nuclei, and relatively dense chromatin.

Immunophenotype

• Characteristic immunophenotype includes expression of B-cell-associated antigens (CD19, CD20, CD22, CD24, CD79a), CD5, CD79b, FMC7, and BCL2.
• CD10, CD11c, CD103, and BCL6 are typically not expressed.
• CD20 expression is strong, often stronger than CD19.
• CD5 expression is common, but 10-15% of patients lack CD5 expression.
• CD23 expression is variable (generally weak).
• Immunophenotyping is crucial for differentiating MCL from other B-cell malignancies.

Cytogenetic Abnormalities

• Hallmark cytogenetic abnormality is t(11;14)(q13;q32), leading to dysregulation of the CCND1 gene (encoding cyclin D1), bringing CCNDI into proximity with the IGH locus, leading to cyclin D1 overexpression.
• This rearrangement is not specific to Mantle Cell Lymphoma, but diagnostic in the appropriate clinical and histological context, which includes multiple myeloma.
• Additional cytogenetic abnormalities (deletions 1p, 6q, 9p, 11q, and 13q; gains in chromosomes 3 and 12) are also common.

Molecular Genetic Features

• MCL cells typically exhibit unmutated IGHV genes, indicating a pre-germinal center origin.
• A significant minority exhibit IGHV somatic hypermutation, correlating with predominantly non-nodal disease and can include a subgroup of patients with indolent disease.
• Common secondary genetic abnormalities include gains of MYC, CDK2, CDKN1B, and MDM2, and losses of RB1, CDKN2A, ATM, and TP53.
• Mutations in TP53, CDKN2A, and CDKN2C are specifically associated with the blastoid variant and poorer prognosis.
• ATM function loss may occur through point mutation or deletion, impacting both alleles in most cases with del(11)(q23).

Pitfalls

• MCL is a differential diagnosis for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) due to shared CD5 positivity.
• Most MCL cases have intermediate lymphocytes and centrocytes with irregular nuclear contours, but some MCL cases exhibit small sized cells resembling CLL/SLL making distinction challenging.
• Immunophenotyping and genetic analysis are crucial for accurate diagnosis.
• MCL is typically positive for cyclin D1 and SOX11, markers that are negative in CLL/SLL.
• The t(11;14) translocation characteristic of MCL is absent in CLL/SLL.

CD23-Positive Mantle Cell Lymphoma

• While CD23 positivity is typically associated with CLL/SLL, approximately 13% of MCL cases are weakly positive for CD23.
• CD23-positive cases often have increased leukocyte count, bone marrow involvement, and leukemic presentation, similar to CLL.
• CD23-positive MCL is frequently associated with CD200 positivity and weak SOX11 expression.
• Despite leukemic presentation, CD23-positive MCL shows a better prognosis compared to CD23-negative MCL.

CD200 Expression

• CD200 is a marker for CLL/SLL, but a small subset of MCL cases express CD200.
• Approximately 4% of MCL cases are CD200-positive, most also being positive for CD23.
• CD200-positive MCL has distinct features: only 24% express SOX11, 39% exhibit round nuclear contours similar to CLL, and 44% present as a non-nodal leukemic variant of MCL.
• These cases are frequently associated with IGHV-mutated status, indicative of a potentially more indolent clinical course.

Mantle Cell Lymphoma International Prognostic Index (MIPI)

• MIPI is a key prognostic tool for MCL, incorporating age, ECOG Performance Status, lactate dehydrogenase level, and white blood cell count, stratifying patients into low, intermediate, and high-risk groups.
• Simplified MIPI (s-MIPI) is for routine use. The biological MIPI (MIPI-b) adds the Ki67 proliferation index for improved power.
• Five-year overall survival (OS) rates for low, intermediate, and high-risk groups are 83%, 63%, and 34%, respectively.
• Combined MIPI (MIPI-c) integrates the Ki67 index with standard MIPI score for greater discriminatory power.
• Four risk groups (low, low-intermediate, high-intermediate, and high-risk) show 5-year OS rates of 85%, 72%, 43%, and 17%, respectively.

TP53 Aberration

• TP53 aberrations (deletions [del17p] and/or mutations) are important prognostic factors in MCL.
• High TP53 expression is linked to inferior time-to-treatment failure and overall survival.
• Patients harboring TP53 mutations are frequently enriched for higher Ki67 index (>30%), blastoid morphology, and a high-risk MIPI, with a short median OS (1.8 years).
• Only the MIPI-c high-risk group and TP53 mutation group exhibit independent prognostic significance for overall survival, in multivariable analysis.

Early Disease Progression

• Early disease progression (within 24 months) is a strong negative prognostic marker for OS.
• A recent study observed outcomes based on relapse after intensive induction and autologous stem cell transplantation.
• The impact of relapse was notably greater for patients who relapsed within 6 months.

Prognostic Factors in Relapsed/Refractory MCL

• Several factors correlate with poor outcomes in relapsed/refractory MCL treated with BTK inhibitors, these factors include high-risk s-MIPI score, blastoid morphology, and TP53 mutations.
• Patients with these features show overall response rates (ORR) of about 55%, 50%, and 55%, respectively, and median progression-free survival (PFS) of 6.5 months, 5 months, and 4 months, respectively.
• Patients with a Ki67 index greater than or equal to 50% are associated with inferior outcomes, characterized by lower response rates and shorter survival.

New Treatment Strategies

• Chemoimmunotherapy regimens are standard first-line treatments for naïve MCL.
• A subset of patients with indolent disease may be observed, but most require therapy.
• Current treatments incorporate BTK inhibitors (e.g., ibrutinib) in the absence of chemotherapy.
• The combination of ibrutinib and rituximab for two years followed by ibrutinib continuation demonstrates a high overall response rate (>96%) in patients over 65.
• Beyond BTK inhibitors, new therapies are needed for patients who progress, focusing on CAR T-cell therapy, bispecific antibodies, antibody-drug conjugates, and next-generation small molecule inhibitors.

Novel Therapeutic Approaches

• Various novel targeted therapies are currently under investigation for MCL.
• These therapies show distinct mechanisms of action and potential for overcoming resistance to current treatments. قيم السمنار من ١٠٠