{'fraction_non_alphanumeric': 0.030084125822970008, 'fraction_numerical': 0.017008046817849305, 'mean_word_length': 5.282021826536473, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Mantle cell lymphoma: A clinical review of the changing treatment paradigms with the advent of novel therapies, and an insight into Indian data

Abstract Background Mantle cell lymphoma (MCL) is a rare type of mature B‐cell lymphoid malignancy with the pathologic hallmark of translocation t(11;14) (q13, q32), which leads to an overexpression of Cyclin D1 (CCND1). The disease is also characterized by the presence of a high number of recurrent genetic alterations, which include aberrations in several cellular pathways. MCL is a heterogeneous disease with a wide range of clinical presentations and a majority presenting with aggressive disease in advanced stages. Recent findings Management of MCL is bereft with challenges due to its resistant and relapsing pattern. Despite improvements in remission durations, the disease is currently incurable with standard therapy and has a median survival of about 3–5 years. The use of small molecules like the bruton tyrosine kinase (BTK) and BCL2 inhibitors, for treating relapsed MCL has been established leading to a diminishing role for conventional chemotherapy. Combinations of small molecule inhibitors with or without chemoimmunotherapy, are showing promising results. Cellular therapy in the form of CAR‐T cell therapy, has been approved recently. Conclusions Personalized cancer treatment and chemo‐free regimens are showing promise and results from well‐planned long‐term studies are evolving. In India, there is a paucity of epidemiological, clinical, and research data in this field.

also influenced by other factors like the age of the patient, functional status, comorbidities, morphology, disease stage, cost and access to drugs, tolerance to treatment and availability of clinical trials for patients among others. 4 This article attempts to review the presentation and management of MCL, with a glimpse into its pathophysiology, and emphasis on treatment options with the current role and impact of novel therapies.
We also reflect on the data available from Indian centres.

| PATHOPHYSIOLOGY
MCL is a lymphoproliferative disorder characterized by proliferation of mature B-lymphocytes, with most cases derived from naïve pregerminal center and some, developing from post-germinal Centre B-cell populations. The pathologic hallmark of MCL is the presence of t (11;14) (q13, q32) translocation leading to an overexpression of Cyclin D1 (CCND1) which deregulates the cell cycle progression at G1-S checkpoint by overcoming the suppressor effect of retinoblastoma 1 (RB1) and the cell cycle inhibitor p27. 5 In less than 5% cases, a variant CCND1 translocation with immunoglobulin (IG) light chains kappa and lambda, leading to over expression of Cyclin D1 has been noted. 6 The 2016 revision of the WHO classification of lymphoid neoplasms identifies two different pathways for development of MCL. 7 CCND1 overexpression by itself is incapable of driving the malignant process in MCL. A myriad of secondary genetic and epigenetic changes leads to alterations in the key signaling pathways, which contribute to malignant transformation. Figure 1 shows a schematic diagram of the pathogenesis of MCL with an outline of the management options based on disease state.
In situ Mantle-cell Neoplasia: This is a rare lesion of uncertain clinical significance and most often 'incidentally' diagnosed. It is characterized by CD5 and Cyclin D1 positive cells in the mantle zone of the lymphoid follicle in a morphologically reactive lymph node. It has an indolent course and rarely progresses to overt mantle cell lymphoma. 7 toms due to extra-nodal involvement of GI tract, lungs, and/or CNS and orbit. An uncommon, but distinctive, presentation is the occurrence of multiple lymphomatous polyposis. 9,10 4 | DIAGNOSIS A complete history and physical examination undertaken to assess B symptoms, co-morbidities and performance status of MCL patients is essential. Laboratory investigations should include a complete blood count with differential counts to assess for cytopenias secondary to Immunophenotyping of tumor cells by multi-parameter flow cytometry or immunohistochemistry tumor tissue biopsy, bone marrow sample or peripheral blood helps differentiate MCL from other B cell tumors and confirms diagnosis. Lymph node biopsy is preferred over aspiration. A typical immunophenotyping report by flow cytometry and immunohistochemistry report on tissue biopsy of MCL will be positive for CD5 (a T-cell-associated antigen), CD20, CD19, FMC7, sIgM/sIgD, CD22, CD79b and strongly Cyclin D1, and negative for CD23 (a key cell surface molecule for B-cell activation and growth) and CD10 (a germinal centre-associated antigen). MCL phenotype can be confused with a CLL immunophenotype. Table 1 shows the differences between MCL and different Lymphomas. 12,13 Expression of cyclin D1 is seen in more than 95% of cases. Cytogenetic analysis by Fluorescence in situ hybridization (FISH) will show the classic chromosome translocation, t(11;14) (q13;q32) in most cases.
Cyclin D1 negative MCL: This is a rare type of MCL identifiable by its lack of Cyclin D1 immunophenotypic expression or gene rearrangement. They are identical in morphology, immunophenotype (except Cyclin D1 expression) and clinical features to the classical MCL. Comprehensive gene expression profiling can confirm them as MCL, while molecularly, most demonstrate CCND2 (accounting to around 50% cases) or CCND3 gene rearrangements. 14 They are positive for SOX11. 15 Staging by good quality contrast enhanced imaging of chest, abdomen and pelvis, is recommended. Whole body PET-CT, though not mandatory, is a common staging modality and has replaced conventional CT based staging in many centres. Staging is important not only to determine the extent of disease, but also to decide an appropriate treatment strategy. A lumbar puncture and CSF cytology is recommended in patients with blastoid morphology or neurological signs and symptoms. Patients with significant gastrointestinal symptoms must be evaluated with endoscopic examination (and biopsies) where appropriate to rule out involvement. MCL is commonly staged now using the Lugano classification for Non-Hodgkin Lymphoma ( Note: Summary of important Trials supporting use of different regimens in management of treatment naïve MCL. Abbreviations: BR, bendamustine + rituximab; Hyper CVAD, cyclophosphamide vincristine doxorubicin dexamethasone alternating with high dose methotrexate and cytarabine; L + R, lenalidomide + rituximab; mo, months; NORDIC Regimen, dose intensifying induction immunochemotherapy with rituximab + cyclophosphamide vincristine doxorubicin prednisone (maxi CHOP) alternating with rituximab + high dose cytarabine; R, rituximab; RBCA500, rituximab bendamustine cytarabine; RCHOP, rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone; RDHAP, rituximab + dexamethasone + cytarabine + cisplatin; VR-CAP, bortezomib + rituximab + cyclophosphamide + doxorubicin + prednisone.  52 The HDT regimens routinely used are BEAM or TBI based.
Patients, who do not achieve CR despite multiple chemotherapy regimens, are not ideal candidates for ASCT. As the treatment landscape of MCL is quickly evolving, it would be appropriate to re-visit the role of ASCT in real-world practice soon. 53 There is an active interest in radio immunotherapy in some groups. 54 Whether ASCT can be safely  Table 6.
The ability of bortezomib to induce tumor cell apoptosis in lymphomas primarily through NFKB inhibition and caspase independent mechanisms led to its exploration in R/R MCL. 76 The phase II PINNA-CLE trial used bortezomib in combination with rituximab showing an overall response rate of 32% with 8% CR/uCR (unconfirmed CR) with median time to progression (TTP) of 6.7 months and a median OS of 23.5 months in an updated analysis. 65 Further combinations, with chemotherapeutic agents, improved PFS although at the expense of some increased toxicity. 64 Prior treatments with neurotoxic chemotherapeutic agents increased the incidence of neuropathy. 77 Lenalidomide as an immunomodulatory agent demonstrated notable activity in mantle cell lymphoma through it antineoplastic and antiproliferative effects. The NHL 003 study, which also included R/R  [73] chronic lymphatic leukemia when used in combination with ibrutinib.
As a single agent in MCL the ORR was 75% (CR 21%) and a PFS of 14 months. 87 Two other venetoclax monotherapy studies report ORR in the range of 50%-60%, with nearly 21% achieving CR at follow-up periods of up to 17 months. The mPFS and OS were in the range of 2.6-8 months and 4.3-13.5 months, respectively. 88,89 Given its synergy with ibrutinib, the AIM study explored this combination with a lead-on period for ibrutinib followed by addition of venetoclax. The Given the invariable resistance encountered for Ibrutinib in MCL, palbociclib, an oral CDK4/6 inhibitor capable of overcoming primary ibrutinib resistance was explored in combination with ibrutinib. 91 The phase I study demonstrated an ORR of 67% with 37% and a 2-year PFS of 59%. 92 The study gave credence for this rationale behind the combination, and further studies are underway.
The future of treatment for mantle cell lymphoma particularly in the R/R setting is evolving. The use of small molecules for treating relapsed MCL is now established, with diminishing role for conventional chemotherapy. The emerging role for CAR-T cell and other immunotherapy-based approaches (discussed separately) will redefine MCL treatments. The key lies in defining subsets for optimized outcomes in subgroup of patients.

| GUIDELINE RECOMMENDATIONS FOR MANTLE CELL LYMPHOMA
Current recommendations from the European Society for Medical Oncology (ESMO), 28 British Society for Hematology (BSH) 24 and National Comprehensive cancer Network NCCN 29 are summarized in Table 5.

| Newer Bruton's tyrosine kinase inhibitors
Ibrutinib use is associated with certain toxicities in the long term like higher rates of cardiac arrhythmias, hypertension, and risk of bleeding.
These and emergent resistance lead to discontinuation of the therapy in many patients. 93 To overcome these, BTK inhibitors with higher specificity, the second-generation BTK inhibitors like acalabrutinib, zanubrutinib, orelabrutinib, tirabrutinib and pirtobrutinib (formerly LOXO-305) have emerged. [94][95][96][97] As discussed above, the secondgeneration BTK inhibitors have much better selectivity, reducing the off-target effects of the drugs. 98

ACKNOWLEDGMENTS
We would like to acknowledge the contribution of Dr. Ashish Babu Gorantla, for his contribution in revising the sections on pathology and molecular studies.

CONFLICT OF INTEREST
Vivek S. Radhakrishnan reports advisory fees (institutional) and non-

ETHICAL STATEMENT
Not applicable.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.