1 INTRODUCTION

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm and accounts for 5% of all non-Hodgkin's lymphomas (NHL).1 It is morphologically, phenotypically, and genetically well defined. The annual incidence of MCL is around 1 in 200 000 with a male predominance (3:1). The median age of diagnosis is around 71 years.2 In India, 6% of all newly diagnosed NHL are MCL with a median age of diagnosis around 57 years.3 The two subtypes of MCL as defined by the 2016 revision of the WHO Classification of lymphoid neoplasms, the Indolent and Classic variants, have variable clinical course and require varied approaches for their management. The decision on management is 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.

2 PATHOPHYSIOLOGY

MCL is a lymphoproliferative disorder characterized by proliferation of mature B-lymphocytes, with most cases derived from naïve pre-germinal 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.

Schematic diagram of pathophysiology of MCL and outline of management options. ASCR, autologous stem cell rescue; CIT, chemoimmunotherapy; HDT, high dose therapy; IG, immunoglobulin; ISMCN, in-situ mantle cell neoplasia; MC, mantle cell; MCL, mantle cell lymphoma

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, 8

3 CLINICAL PRESENTATION

MCL has a wide range of clinical presentations. Nearly 70%–80% of MCL patients present with an aggressive disease manifesting as symptomatic lymphadenopathy or extra-nodal disease, in an advanced stage (Stage III–IV). However, patients may also present with an indolent disease consisting of asymptomatic lymphocytosis or non-bulky nodal/extra nodal disease, with minimal symptoms. B symptoms (unintentional weight loss, drenching night sweats, and fever) are seen in about 40% of the patients. Patients can present with abdominal distension due to hepatosplenomegaly. Lymph nodes and spleen are common sites of involvement followed by Waldeyer's ring, bone marrow and peripheral blood. Patients can also present with symptoms 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 bone marrow involvement, lactate dehydrogenase levels (correlates with tumor burden), complete metabolic panel, and viral serology (hepatitis and HIV panels).

Morphologically, MCL presents as a spectrum of findings, with classical tumors showing proliferation of small–medium sized lymphocytes with irregular nuclei and inconspicuous nucleoli on one end, and blastoid MCL showing cells with blastoid morphology having rounded nuclei, finely dispersed chromatin, and inconspicuous nucleoli, at the other end. Some tumors have larger cells with irregular and pleomorphic nuclei and distinct small nuclei. The Blastoid and Pleomorphic variants of MCL have an aggressive histology with high proliferation rates and the transformed variants have a high degree of aneuploidy and exhibit KMT2B, KMT2D and other mutations. These variants have an aggressive clinical behavior.11 Rare variants include small cell and marginal zone like MCL.

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

TABLE 1. Immunophenotypic markers in different B-cell malignancies Histologic subtype CD5 CD23 CD43 CD10 BCL6 Cyclin D1 sIg (type) CD 20 CD200 MCL + − + − − + + (M ± D) + − FL − −/+ − +/− + − + (G ± M) + +/− SLL/CLL + + + − − − + (M ± D) + + LPL − − −/+ − − − +/− (M) + SMZL − − − − − − + (M ± D) + +/− EMZL (MALT type) − −/+ −/+ − − − + (M) + +/− HCL − −/+ −/+ − − + + +/− Note: Immunophenotypic markers in different B-cell malignancies. Abbreviations: EMZL, extranodal subtype of marginal zone lymphoma; FL, follicular lymphoma; HCL, hairy cell leukemia; LPL, lymphoplasmacytic lymphoma; MALT, mucosa-associated lymphoid tissue; MCL, mantle cell lymphoma; SLL/CLL, small lymphocytic leukemia/small lymphocytic leukemia; SMZL, splenic marginal zone lymphoma. +, >90% positive; +/−,>50% positive; −/+,<50% positive; and −,<10% positive.

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 (Table 2).16

TABLE 2. Revised staging system for primary nodal lymphomas Stage Involvementa Extranodal statusb I One node or a group of adjacent nodes Single extranodal lesions without nodal involvement II Two or more nodal groups on the same side of the diaphragm Stage I or II by nodal extent with limited contiguous extranodal involvement II (bulky)c as above with “bulky” disease Not applicable III Nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement Not applicable IV Additional noncontiguous extralymphatic involvement Not applicable Note: Lugano classification for non-Hodgkin lymphoma used for staging of MCL. a PET-CT is used for avid lymphomas and CT for nonavid histologies to determine the extent of disease. b Tonsils, Waldeyer's ring, and spleen are considered nodal tissue. c Stage II bulky disease is treated as limited or advanced disease based on histology and number of prognostic factors. 5 PROGNOSIS

Several markers have been evaluated to predict the survival outcomes in MCL. Some of the currently recognized prognostic markers include performance status, CNS involvement at diagnosis, transformed MCL status, blastoid/pleomorphic morphology, Mantle cell International Prognostic index (MIPI) High risk group, Ki 67% >30%, Complex karyotype, Tp53 mutations or overexpression, MYC translocation or overexpression and unmutated IGHV status. Many novel markers like the CCND1, NOTCH 1 and 2 mutations, bruton tyrosine kinase (BTK), MAP3K14, CARD11, PCR for t(11;14), and so forth are being actively explored.4, 17 Among all known prognostic markers, blastoid morphology, TP53 mutation, complex karyotype and high Ki-67 score are clearly associated with poor prognosis.18-20 The simplified MIPI, which is commonly used in practice, is shown in Table 3.21, 22

TABLE 3. Simplified mantle cell International Prognostic Index (MIPI) Points Age (years) ECOG PS LDH (UNL) WBC (×109/L) 0 <50 0–1 <0.67 <6.700 1 50–59 – 0.67–0.99 6.700–9.999 2 60–69 2–4 1.00–1.49 10.000–15.000 3 70 – 1.500 >15.000 Risk stratification based on MIPI score and their overall survival rates SCORE Risk stratification OS in months (5 year OS %) 0–3 Low risk NR (60%) 4–5 Intermediate risk 51 months 6–11 High risk 29 months Note: Simplified mantle cell International Prognostic Index (MIPI). Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; OS, overall survival; UNL, upper normal limit; WBC, white blood cells. 6 MANAGEMENT OF MANTLE CELL LYMPHOMA

MCL is an aggressive disease and is known to exhibit short durations of response, early relapse, shorter progression free survival (PFS) and overall survival (OS) compared to other NHLs.23 The goals of therapy in MCL are symptom reduction, disease control, improvement in quality of life, and cure when feasible. While choosing appropriate management strategy for patients with MCL, one needs to consider the following factors: assessment of physical fitness (performance status, or frailty in the elderly), comorbidities, disease stage, blastoid /non-blastoid morphology, Ki-67/MIPI score, access to therapy in various countries, cost-coverage and availability of ongoing clinical trials.24

6.1 Initial management of mantle cell lymphoma

MCL patients can present with Indolent or aggressive disease based on clinical presentation and prognostic markers. (Figure 1) The management approach differs accordingly.

Indolent MCL patients having a good performance status, asymptomatic disease (no or minimal symptoms, low volume lymphadenopathy, lymphocytosis and splenomegaly), no high-risk prognostic markers and/or low risk MIPI can be managed with “Watchful waiting” without a need for immediate systemic therapy. Such patients can be put under observation and carefully monitored for appearance of signs and symptoms of progressive disease. The MCL Biobank Observational Study by McCulloch et al, evaluated 315 MCL patients and showed that 67.3% of patients received upfront systemic therapy at baseline, 4.1% received localized radiation therapy and 27.6% of the patients were put on wait and watch strategy, 90 days beyond diagnosis. Of the 87 patients put on wait and watch strategy, 73.5% of them were under observation at 1 year, and 50.6% at end of 2 years. The study demonstrated the high prevalence of wait and watch strategy in clinical practice and reassured clinicians that half of them remained on observation beyond 2 years. However, the study also demonstrated the need for better predictive markers for indolent MCL.25

In the aggressive MCL, treatments depend on the extent of disease. In early-stage disease (Stage1A and 2A), the evidence for management is scarce due to the small numbers of patients. Involved field radiotherapy (IFRT) can achieve up to 80% complete remission (CR) rates and long-term remission, with potential cure in some patients.26, 27 In advanced stage disease, most patients need systemic chemoimmunotherapy. Indications for treatment include symptomatic disease (B symptoms, symptomatic organomegaly, organ dysfunction, GI symptoms including bleeding, and so forth), bulky disease, and bone marrow failure (significant cytopenia), among others.

6.2 First Line therapy for mantle cell lymphoma

Once a decision to treat the patient is made, patients who are treatment naïve are initially given induction therapy followed by maintenance therapy. There are two approaches in induction therapy, depending on the fitness of patients, based on current guidelines.28, 29 In the fit patients, an intensive therapy approach consists of high dose cytarabine containing induction regimens like Hyper-CVAD + R/Mtx-HA, R-DHAP, etc.30, 31 This results in PFS and OS rates in the range of 73% and 61% at 46 months respectively.32 Once a response is achieved with induction therapy, the fit patients must be considered for consolidation therapy with high-dose chemotherapy (HDT) like BEAM and autologous stem cell transplantation (ASCT). They receive maintenance therapy with Rituximab monotherapy for 3 years thereafter. In the patients who are not fit, a less aggressive approach with RCHOP or BR is preferred. Maintenance rituximab is administered without a post-induction HDT-ASCT consolidation in these patients. Outcomes in this setting are conservative and yield a PFS and OS rate in the range of 54.7 and 69.6 months, respectively.33 Maintenance therapies are not without controversy.34 Specifically, it is difficult to recommend an optimum duration or regimen for maintenance therapy. In the European MCL Network Study, MCL Elderly Study,35 treatment was continued until disease progression; however, many institutions limit the frequency to rituximab once in 3 months and the duration to 2 years.

Currently there are many studies that aim to improve upfront therapy in the young and fit patients by incorporation of targeted agents already known to have activity in relapsed setting. These agents include ibrutinib, lenalidomide, bortezomib and others. They are incorporated into the induction phase, maintenance phase, or both phases of treatment. A similar approach in the elderly has been tested in the Nordic MCL4 (LENA-BERIT) study. Treatment naïve elderly patients (>65) or younger patients unfit for intensive therapy were treated with BR plus lenalidomide for six cycles followed by maintenance lenalidomide for a total of seven cycles. Despite a high response rate, this study noted significantly higher toxicity.36 A recent update from the European MCL Elderly trial, which evaluated R-CHOP versus R-FC in 560 newly diagnosed MCL patients, showed that, at a median follow-up of 7.6 years, R-CHOP showed superior benefits in terms of OS and median PFS. Rituximab maintenance following R-CHOP had lesser toxicity than after R-FC regimen.37 In the Phase2 WINDOW-1 study, 131 patients were given ibrutinib-rituximab (IR) induction (part-A) until they achieved CR, for a maximum of 12 cycles. This was followed by a maximum of 4 cycles of Hyper-CVAD + R/Mtx-HA as consolidation therapy (part-B). The study showed that frontline treatment with IR followed by a short course Hyper-CVAD + R/Mtx-HA is extremely potent and safe in patients aged ≤65 years with MCL38 Table 4 summarizes the important trials supporting use of therapies in aggressive and less aggressive settings. The commonly used aggressive and less aggressive therapy are listed in Table 5.

TABLE 4. Suggested treatment regimens for first line and supporting references Treatment Comparator Sample size (n) Median follow-up ORR CR PFS OS Safety/AE Reference Aggressive therapy Hyper CVAD + R 97 40 mo 97% 87% 64% 82% Hematologic myelodysplasia/AML 32 63 46 mo 83% 72% 73% 61% 39 Nordic regimen with Maxi-CHOP 160 6 years 96% 54% 66% 70%

Neutropenic fever

Infections

Heart failure

40 RCHOP/RDHAP 60 67 mo 95% 57% 83mos 75%

Renal toxicity

Neurologic toxicity

41 RDHAP 299 50.2 mo 89% 77% 83% 89% 42 Less aggressive therapy BR R-CHOP 274 45 mo – – 69.5 mo – Erythematous skin reactions 43 R-CHOP/R-CVP 447 – 97% 31% – –

Vomiting

Drug hypersensitivity

44 BR+ R(maintenance) BR 120 54.2 mo – – 54.7 mo 69.6 mo 33 VR-CAP R-CHOP 487 82 mo – – – 90.7 mo

Infections

Cardiogenic shock

Acute renal failure

Pulmonary carcinoma

45 R-CHOP FCR 560 37mo – 34% – 62%

Constipation

Neuropathy

Febrile neutropenia

37 Modified Hyper CVAD + R(maintenance) – 22 37 mo 77% 64% 37 mo NR 46 L + R – 38 64 mo – – 80% 90% Cytopenias infections 47 RBAC500 – 57 – – 91% – –

Neutropenia, thrombocytopenia

Fatigue nausea vomiting

48 Maintenance therapy Rituximab R-CHOP vs FCR 560 7.6 years – – 5.4 years 9.8 years

High incidence of death in remission

Leukopenia

infection

37 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. TABLE 5. Guidelines for management of mantle cell lymphoma ESMO guidelines (2017) BSH guidelines (2018) NCCN guidelines (2021) MCL patients First Line Young fit

Dose intensified chemoimmunotherapy

RCHOP

HD-AraC

Followed by

ASCT

Rituximab Maintenance

Suitable for ASCT

High dose cytarabine + rituximab

Followed by

ASCT

Rituximab maintenance

Candidate for HDT/ASCR

- Aggressive therapy

Preferred regimens

RDHA

Alternating R-CHOP/RDHAP

NORDIC regimen

Hyper CVAD + R a

R + bendamustine > R + cytarabine

Other recommended regimens

BR

Consolidation after aggressive therapy

HDT followed by ASCT

Maintenance After HDT/ASCR

Rituximab every 8 weeks × 3 years

aPre-treatment with ibrutinib-rituximab to reduce number of Hyper CVAD cycles (Window-1 study)

Elderly frail

Conventional chemoimmunotherapy

R-CHOP

VR-CAP

BR

R-BAC

Followed by

Rituximab maintenance

Not Suitable for ASCT Fit for conventional immunotherapy