New Directions in Mantle Cell Lymphoma PDF

New directions in Mantle cell lymphoma. Supervised by DR. ALA`A ALKHAZZAR PRESENTED BY NOOR SABAH KADHIM 2nd year hematopathology student Objectives * overview of mantle cell lymphoma * Clinical manifestations * Diagnostic approach of MCL *Deference between MCL and CL...

New directions in Mantle cell lymphoma. Supervised by DR. ALA`A ALKHAZZAR PRESENTED BY NOOR SABAH KADHIM 2nd year hematopathology student Objectives * overview of mantle cell lymphoma * Clinical manifestations * Diagnostic approach of MCL *Deference between MCL and CLL * Mantle cell lymphoma International prognostic index (MIPI) * New strategies for treatment - NAÏVE mantle cell lymphoma  Overview of mantle cell lymphoma _ Mantle cell lymphoma (MCL): is a chronic B-lineage lymphoproliferative disorder characterized by variable cytological and histological features, but with a distinctive cytogenetic and molecular genetic defect. _ Although histologically low-grade, It has an intermediate prognosis between other low- grade B-cell lymphomas and high-grade lymphomas, with a median survival of only 3-4 years. _ The disease is generally considered incurable and shows an increased incidence associated with family history of mantle cell lymphoma or other non-Hodgkin lymphomas. - Mantle cell lymphoma is characterized by the t(11;14) translocation, leading to cyclin D1 overexpression. - Despite this common genetic feature, MCL exhibits significant clinical and biological heterogeneity. - It can range from indolent non-nodal leukemic variants to highly aggressive blastoid variants. Risk stratification at diagnosis is critical for determining optimal treatment approaches.  CLINICAL PRESENTATION - Mantle cell lymphoma primarily affects middle-aged and older individuals, with a median age of 60 years and a marked male predominance , presentation is usually with advanced stage disease, most often exhibiting lymphadenopathy and splenomegaly. - Extranodal involvement is commen, including Waldeyer's ring, lung, pleura, and the gastrointestinal tract. - Peripheral blood involvement occurs in about two-thirds of patients and has been associated with a worse prognosis, However, 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 : * There can be cytopenias due to marrow infiltration and there may be circulating lymphoma cells visible.However, the presentation can be with a frank leukaemic phase. * Mantle cell lymphoma cells exhibit significant pleomorphism, typically medium-sized with irreguler nuclei. * some calls show inconspicuous nucleoli or pronounced nuclear indentations or clefts. Cytoplasmic vacuoles may be present, and rarely, cytoplasmic granules. The chromatin pattern can vary,with some cells showing e diffuse pattern. * in the blastoid variant , which comprises 10-20% of cases, cells predominantly have a diffuse chromatin pattern and may resemble acute lymphoblastic leukemia (ALL)cells or show some more mature features.  _PB film in mantle cell lymphoma. The cells are markedly pleomorphic. _PB film in blastoid variant of mantle cell lymphoma showing medium-sized cells with a high nucleocytoplasmic ratio; some have a diffuse chromatin pattern and others show some degree of chromatin condensation. Some cells have distinct small or medium-sized nucleoli. _PB film from a patient with blastoid variant of mantle cell lymphoma showing pleomorphic cells ranging from mature lymphocytes to blast-like cells. Some cells have cleft nuclei and some have cytoplasmic vacuoles.  Bone marrow & histological findings : * Bone marrow infiltration is common in mantle cell lymphoma, observed in up to 80% of patients. The infiltration pattern is usually interstitial or focal, with either nodules or irregularly shaped infiltrates. Paratrabecular infiltration is uncommon. * in trephine biopsy sections, lymphoma cells may have regular round nuclei or irregular and cleaved nuclei with relatively dense chromatin and inconspicuous nucleoli. * The blastoid variant may show a 'starry sky' appearance. * Lymph node histology can display mantle zone, nodular,or diffuse pattern of infiltration,with the mantle zone pattern potentially representing the earliest stage of involvement.  Immunophenotype: _ The characteristic immunophenotype of mantle cell lymphoma includes expression of B-cell-associated antigens (CD19, CD20, CD22, CD24, CD79a), CD5, CD79b, FMC7, and BCL2. _ Notably, CD10, CD11C, CD103, and BCL6 are typically not expressed. CD20 expression is strong, often stronger than CD19. _ While CD5 is usually expressed, 10-15% of patients may lack CD5 expression. CD23 expression is variable and generally weak when present. The immunophenotype is crucial for distinguishing mantle cell lymphoma from other B-cell malignancies. Positive markers Negative markers CD19, CD20, CD22, CD24, CD79a, CD5, CD79b, FMC7, CD10, CD11c, CD103, BCL6 BCL2. Variable markers Diagnostic markers CD23(weak when present), CD38, CD43 Cyclin D1, SOX11(useful for cyclin D1 _negative cases)  Cytogenetic Abnormalities : _ The hallmark cytogenetic abnormality in mantle cell lymphoma is t(11;14) (q13.3;932), which leads to dysregulation of the CCNDI gene encoding cyclin D1. This translocation brings CCNDI into proximity with the IGH locus, resulting in cyclin D1 overexpression. _ This rearrangement is not specific to mantle cell lymphoma,being reported also in multiple myeloma; however, this translocation is considered diagnostic in the appropriate clinical and histological context. _ Fluorescence in situ hybridization (FISH) techniques are highly sensitive in detecting this rearrangement. Additional cytogenetic abnormalities are common, including deletions in chromosomes 1p, 6q, 9p. 11q, and 13q, as well as gains in chromosomes 3 and 12. Primary abnormality t(11;14) (q13.3;q32) Gene involved CCND1 (cyclin D1) Detection method FISH, PCR Common secondary abnormalities del(1p),del(6q),del(9p),del(11q),del(13q),+3,+1 2  * Molecular genetic features: _ Mantle cell lymphoma cells typically show unmutated IGHV genes, indicating a pre- germinal center origin. _ However, a significant minority exhibit IGHV somatic hypermutation, which correlates with predominantly non-nodal disease and can include a subgroup of patients with indolent disease. _ Secondary genetic abnormalities are common, including gains of MYC, CDK2, CDKNIB, and MDM2, as well as losses of RB1, CDKN2A, ATM, and TP53. _ Mutations in TP53, CDKN2A, and CDKN2C are particularly associated with the blastoid variant and worse prognosis. _ ATM function may be lost through point mutation or deletion, often affecting both alleles in cases with del(11)(q23)  Pitfalls :- * Mantle cell lymphoma (MCL) is an important differential diagnosis for CLL/SLL due to shared CD5 positivity. Most MCL cases are composed of intermediate lymphocytes and centrocytes with irregular nuclear contours, which is a key distinguishing feature. * However, some MCL cases can be composed of small-sized cells that resemble CLL/SLL, making the distinction challenging. _PB film from a patient with mantle cell lymphoma showing a range of cells from small lymphocytes resembling those of CLL to larger cells with irregular nuclei and ill-defined nucleoli; there are some smear cells. * Immunophenotyping and genetic analysis are crucial for accurate diagnosis. * MCL is typically positive for cyclin D1 and SOX11, which 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, a subset of mantle cell lymphoma (MCL) cases can express CD23, complicating the differential diagnosis. * Studies have shown that approximately 13% of MCL cases are weakly positive for CD23. These CD23-positive MCL cases often present with increased leukocyte count, bone marrow involvement, and leukemic presentation, similar to CLL. * Importantly, CD23-positive MCL is more frequently associated with CD200 positivity and weak SOX11 expression. * Despite the leukemic presentation, patients with CD23-positive MCL tend to have a better prognosis than those with CD23-negative MCL.  *CD200 Expression in mantle cell lymphoma _ CD200 is typically considered a marker for CLL/SLL, but recent studies have shown that a small subset of mantle cell lymphoma (MCL) cases can express CD200, further complicating the differential diagnosis. _ Approximately 4% of MCL cases are CD200-positive, and most of these (76%) are also positive for CD23. _ CD200-positive MCL cases have distinct characteristics: 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 often associated with IGHV- mutated status, which is typically seen in a small subset of MCL with a more indolent clinical course.  Mantle Cell Lymphoma International Prognostic Index (MIPI) - The MIPI is a key prognostic tool for MCL. It incorporates age, ECOG Performance Status, lactate dehydrogenase level, and white cell count to stratify patients into low, intermediate, and high-risk groups. - The simplified MIPI (s-MIPI) was created for routine clinical use. The biological MIPI (MIPI-b) adds the Ki67 proliferation index for enhanced prognostic power. - Five-year overall survival (OS) rates patients of low, intermediate, and high-risk MIPI groups were 83%, 63%, and 34%, respectively, - The European Mantle Cell Lymphoma Network developed the combined MIPI (MIPI-c) , which integrates the Ki67 index with the standard MIPI score. - This modification provides greater discriminatory power, separating patients into four risk groups: low, low-intermediate, high-intermediate, and high risk. - The 5-year overall survival rates for these groups are 85%, 72%, 43%, and 17%, respectively, demonstrating improved stratification compared to the MIPI alone. *TP53 Aberration in MCL : including deletions (del17p) and/or mutation in TP53 gene, are important prognostic factors in MCL. _ High TP53 expression by immunohistochemistry is associated with inferior time-to-treatment failure and overall survival. _ Patients harboring a TP53 mutation were enriched for Ki67 index greater than 30%, blastoid morphology, and a high-risk MIPI, having short median OS of only 1.8 years. _ However, on multivariable analysis, only the MIPI-c high-risk group and TP53 mutation group retained independent prognostic significance for OS.  Early disease progression in MCL - progression of disease within 24 months has been shown to be a strong negative prognostic factor for OS in both younger patients treated with high dose cytarabine-based induction and in older patients who are unable to receive standard immunochemotherapy. - A recent study analyzing patient outcomes according to time-to- relapse after intensive induction and autologous stem cell transplantation. - The impact of relapse was greatest for patients whose disease relapsed within 6 months.  Prognostic factors in Relapsed /Refractory MCL - Several factors are associated with poor outcomes in relapsed/refractory MCL treated with BTK inhibitors. - These include : high-risk s-MIPI score, blastoid morphology, and TP53 mutations. - patients with these features had overall response rates (ORR) of about 55% , 50%, 55% respectively, and median progression-free survival (PFS) rates were 6.5 months, 5 months, and 4 months, respectively. - Patients with Ki67 index greater than or equal to 50% associated with inferior outcomes, including lower response rates and shorter survival.  NEW STRATEGIES FOR TREATMENT-NAÏVE MANTLE CELL LYMPHOMA - Chemoimmunotherapy regimens comprise the standard first-line treatment options for patients with mantle cell lymphoma. - Although a subset of patients with indolent disease may undergo observation, most patients ultimately require therapy. - Multiple studies are incorporating BTK inhibitors into frontline MCL treatment without chemotherapy. The combination of ibrutinib and rituximab for 2 years, followed by ibrutinib continuation, showed a 96% overall response rate in patients >65 years old. -Beyond BTK Inhibition: new therapies are needed for patients who progress on these agents,include: 1_CAR T-cell therapy 2_ bispecific antibodies. 3_antibody-drug conjugates 4_next-generation small molecule inhibitors. -These therapies offer distinct mechanisms of action and overcoming resistance to current treatments. Novel Therapeutic Approaches for Relapsed/Refractory Mantle Cell Lymphoma  References * Barbara J. Bain, Leukemic Diagnosis, Fifth Edition. * HEMATOLOGIC MALIGNANCIES.New Directions for Mantle Cell Lymphoma in 2022 Anita Kumar, MD; Toby A. Eyre, MD²; Katharine L. Lewis; Meghan C. Thompson, MD³; and Chan Y. Cheah, MD34. * Journal of clinical and experimental hematopathology.Vol. 60 No.4, 124-129,2020 Review Article Differential diagnosis of chronic lymphocytic leukemia/ small lymphocytic lymphoma and other indolent lymphomas, including mantle cell lymphoma Tadashi Yoshino, Takehiro Tanaka, Yasuharu Sato.