ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

Free Access

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Preetesh Jain

orcid.org/0000-0003-2735-168X

Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas

Search for more papers by this author

Michael Wang,

Corresponding Author

Michael Wang

[email protected]

orcid.org/0000-0001-9748-5486

Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas

Correspondence

Michael Wang, MD, Director of Mantle Cell Lymphoma Program, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.

Email: [email protected]

Search for more papers by this author

Preetesh Jain,

Preetesh Jain

orcid.org/0000-0003-2735-168X

Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas

Search for more papers by this author

Michael Wang,

Corresponding Author

Michael Wang

[email protected]

orcid.org/0000-0001-9748-5486

Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas

Correspondence

Michael Wang, MD, Director of Mantle Cell Lymphoma Program, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.

Email: [email protected]

Search for more papers by this author

First published: 08 April 2019

https://doi.org/10.1002/ajh.25487

Citations: 172

Funding information Fox Family Foundation; The Gary Rogers Foundation; MD Anderson Cancer Center, Grant/Award Number: R21 CA202104

Share a link

Email
Wechat
Bluesky

Abstract

Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL—indolent vs aggressive—is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX-11 expression. Cyclin-D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki-67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long-term follow-up on chemo-immunotherapy studies has demonstrated durable remissions in some patients; however, long-term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy-free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine-microenvironmental milieu, incorporation of positron emission tomography-computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next-generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.

1 INTRODUCTION

Mantle cell lymphoma (MCL) is an interesting and unique subcategory of B-cell non-Hodgkin's lymphoma (NHL) with a generally aggressive, albeit heterogeneous, clinical course. MCL comprises about 3% to 10% of adult-onset NHL in western countries, and its incidence is rising, with an estimated 3320 cases1 diagnosed in 2016.2-4 It appears that the incidence of MCL in Asian countries is lower than the incidence in western countries, and it initially presents at a lower median age in Asian countries compared with the population in western countries.5, 6 Overall, the incidence of MCL is higher in non-Hispanic whites in the United States, and Caucasians have a higher incidence compared to other ethnicities.7 The median age at initial presentation is 68 years.

Although specific risk factors or predispositions for MCL have not been identified, possible associations with Borrelia infection,8 living/working on farm houses,9 polymorphisms in IL-10 −1082A>G,10 and familial MCL11 have been reported. Autoimmune disease has also been observed to be associated with MCL12; it may have a negative impact13 on MCL patients' survival. Similar to findings from studies in small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), antigenic drive is hypothesized to have a role in the development of MCL. This is because of the finding of a biased and highly restricted immunoglobulin (IGHV) gene repertoire14 with stereotyped variable heavy chain (VH) complementary determining region (CDR3s) and recognition of superantigens15 by the B-cell receptor (BCR) of MCL cells. The role of micro-RNA and epigenetic factors in MCL etiology is also being explored. Further, patients with MCL are at higher risk of developing second primary cancers (melanoma, thyroid, nonepithelial skin cancers, SLL/CLL, and other hematologic malignancies).16

This review provides a comprehensive update on recent advances in the diagnostic work up, pathobiology, prognosis, and management of patients with MCL.

2 ADVANCES IN THE PATHOGENESIS OF MCL

Development and maintenance of MCL clones is mediated by a complex interplay of cellular microenvironmental factors.17 We will summarize here the major updates on the pathogenesis of MCL, as details on this aspect are beyond the scope of this article. MCL pathogenesis is largely mediated by aberrant cell cycle regulation, DNA damage response, molecular and genomic alterations, BCR signaling, and interactions with the lymphoid tissue microenvironment. A combination of these factors form the basis of MCL cell growth.

Cyclin D1 overexpression—Cyclin D1 overexpression is a key event in MCL pathogenesis in the naïve pregerminal-center B cells, and it is largely associated with a translocation t [11;14] (q13;q32). Cyclin D1 activates cyclin-dependent kinases 4 and 6 which in turn phosphorylate and inactivate Rb (tumor suppressor gene) and promote G1 to the S phase, leading to rapid cell proliferation. Enhanced cyclin D1 effect in MCL is largely attributed to t(11;14) and the location18 of the CCND1 allele in the cytoplasm, nucleolin transcription factor-rich areas in the perinucleolar area,19 and truncated mRNA of cyclin D1,20 which is associated with poor prognosis. In a subset of patients who are cyclin D1 negative, cyclin D2/cyclin D3 translocations are observed21, 22 and are associated with SOX-11 positivity and a similar genomic profile and clinical course to that of cyclin D1-positive MCL.
SOX-11 overexpression—Overexpression of SOX-11 is observed in a majority of MCL patients.23 This aberrancy impacts MCL cells in various ways—augmentation of BCR signaling,24 suppression of Bcl-625 to avoid germinal center transit of MCL cells which remain having unmutated IGHV, activation of PAX-5,26 blocking the maturation of B cells to plasma cells, promotion of angiogenesis via platelet derived growth factor alpha,27 and migration and adhesion of MCL cells to stromal cells via upregulation of CXCR4 and FAK (focal adhesion kinases)28 —leading to enhanced PI3K/AKT signaling and promoting cell-adhesion-mediated drug resistance.
TP53 mutations—Mutations in TP53 lead to cell cycle upregulation, inhibition of apoptosis, and promotion of cell growth. These mutations are clearly associated with an aggressive disease course and inferior outcomes29 in different subsets of MCL.
Other molecular alterations—Advances in molecular techniques have led to identification of novel genomic alterations in MCL. As the advent of ibrutinib, studies have been conducted to unravel the mystery of ibrutinib resistance and clonal evolution in MCL. Some of these newer molecular alterations include: chromosomal complexity, NSD2, NOTCH2, UBR5, BIRC3, TRAF2, MAP2K14, KMT2D, CARD11, SMARCA4, and BTK.30 Activation of PI3K/AKT and the integrin-β1 signaling pathway31 has been shown as another mechanism of acquired ibrutinib resistance.
Microenvironmental impact—In addition to the pathogenic features described above, the tissue microenvironmental milieu is critical to support MCL cell growth and survival and promote drug resistance. In contrast to peripheral blood, the lymph node microenvironment in MCL patients is unique, having a differential expression of genes involved in BCR signaling and canonical NFkB pathways.32 This feature in MCL provides activation signals to MCL cells and is involved in drug resistance. Targeting various components of BCR signaling33, 34 and interactions with stromal cells has a great potential to overcome treatment resistance and eradicate dormant residual cells in MCL.35 Additional studies on the cytokine-chemokine milieu and its interaction with MCL cells and stromal cells are needed to fully understand the MCL tissue microenvironment.

Recently, MCL has been categorized into two major subgroups, and these subgroups are now included in the WHO 2016 update of lymphoid malignancies.36 The two subgroups of MCL, which are distinct in clinical presentation and molecular features,37, 38 are:

Nodal MCL—This is a common variant with an aggressive disease course. These patients exhibit unmutated IGHV gene rearrangement, SOX-11 overexpression, a higher degree of genomic instability (ATM, CDKN2A, chromatin modifier mutations are common), and other oncogenic mutations and epigenetic modifications. Additionally, naïve B cells here do not undergo germinal center reactions.39
Leukemic non-nodal MCL40—This is seen in 10% to 20% MCL patients and commonly presents with lymphocytosis and splenomegaly. In most cases, it is generally associated with indolent disease course and superior outcome. The cell of origin is thought to be memory B cells with mutated IGHV and germinal center experienced cells with SOX-11 negativity. These patients have a stable genome and few epigenetic modifications. They have a clinical picture similar to CLL, may exhibit aberrant immunophenotype (CD200 expression,41 loss of CD5), and TLR2 and CCND1 mutations are overrepresented. A high number of DNA methylation changes39 or presence of oncogenic mutations in a subset can negatively impact the prognosis.

Most recently, our group has been studying various aspects of MCL to further enhance our knowledge of pathogenic mechanisms in MCL. We found that MALT1 inhibition can induce MCL cell death and suppress NF-kB and mTOR signaling in ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells, and these results were further confirmed in MCL xenograft models where significant inhibition of in vivo lymphoma growth of ibrutinib-venetoclax dual-resistant MCL was observed with a MALT1 inhibitor (Unpublished observation). Moreover, we have also shown that a dysregulated metabolic program exists in MCL cells and contributes to ibrutinib resistance. Inhibition of oxidative phosphorylation in MCL cells can provide an opportunity to inhibit ibrutinib-resistant MCL cell growth in patient derived mouse models (Unpublished observation).

3 CLINICAL PRESENTATION, DIAGNOSTIC APPROACH AND ADVANCES IN THE CLINICAL PATHOLOGY OF MCL

3.1 Clinical course

Patients with MCL have varied clinical presentations. They can present with asymptomatic monoclonal MCL type lymphocytosis or non-bulky nodal/extra nodal disease with minimal symptoms or with a progressive generalized lymphadenopathy, cytopenia, splenomegaly, extra-nodal disease—including involvement of various sections of the gastrointestinal tract (lymphomatous polyposis),42, 43 the kidneys, the central nervous system (CNS, although rarely),44, 45 or any other organ system—with significant symptoms.

The clinical course of MCL (Table 1) can be smoldering nodal/extra-nodal46 or asymptomatic non-blastoid leukemic non-nodal,36, 47 and these clinical variants (about 10%-20% of MCL cases) generally do not need immediate systemic treatment, meaning the watch-and-wait strategy48 is safely pursued. On the other hand, most MCL patients (70%-80% of MCL cases) present with symptomatic lymphadenopathy or symptomatic extra-nodal disease requiring systemic therapy. Distinction between these clinical presentations is further delineated by appropriate information obtained from the diagnostic work up of MCL patients. In a subset of patients, MCL can transform from one histologic presentation to another. This is referred to as transformed MCL, and generally this transformation occurs from classic to blastoid variant MCL.

Table 1. Clinical presentations in MCL patients

Clinical presentation	Clinico-pathologic features
Smoldering MCL46	Lack of B symptoms (drenching night sweats, unintentional weight loss of >10% of normal body weight over a period of 6 mo or less, fever >38°C) Normal serum lactate dehydrogenase (LDH), Beta2 microglobin levels White blood cell count <30 000 K/μL Low MIPI (mantle cell lymphoma international prognostic index) score Ki-67% on lymphoma cells in non-marrow tissue biopsy of <30% Non-blastoid/pleomorphic cytomorphologic pattern in tissue biopsy Maximum lymph node diameter <3 cm, spleen size <20 cm PET scan (positron emission tomography) showing the maximum standardized uptake value (SUV) <6 Absence of TP53 or NOTCH1/2 mutations by DNA sequencing Absence of deletion 17p or MYC translocation by FISH testing, absence of complex karyotype
Asymptomatic purely leukemic non-blastoid MCL	Monoclonal B lymphocytosis (with MCL immunophenotype and non-blastoid morphology) in peripheral blood or in bone marrow with/without splenomegaly
Conventional MCL (most common)	Symptomatic bulky nodal/extra-nodal disease Classic or Blastoid/pleomorphic cytomorphology Evidence of clinical progression

Abbreviation: MCL, mantle cell lymphoma.

3.2 Clinical evaluation, diagnostic work up, and clinical significance

Clinical evaluation of MCL patients includes history and physical exam, assessment of performance status, co-morbidities, and B symptoms. Lab workup must include a complete blood cell count with differential count, comprehensive metabolic panel, lactate dehydrogenase (LDH), beta2 microglobin levels, hepatitis panel, HIV status, and serum immunoglobulin levels. Bone marrow aspiration/biopsy and involved tissue biopsy is routinely performed at the time of the initial diagnosis. Flow cytometry immunophenotype on peripheral blood/bone marrow/involved tissue biopsy showing typical MCL immunophenotype36 (CD5, CD20, CD19, sIgM/sIgD, FMC-7 + B cells with monoclonal kappa/lambda light chains, and dim/negative CD23, dim/negative CD200 and strong cyclin D1 expression) is frequent. Immunohistochemical analysis of involved nodal/extra-nodal tissues show a strong nuclear staining for cyclin D1 (BCL-1 or PRAD-1) expression on MCL cells and SOX-11 (a transcription factor) expression (SRY [sex determining region Y] related HMG-box [high mobility group]). Via cytogenetic assessment of involved tissues with FISH (fluorescent in situ hybridization) testing, a karyotype positive for translocation t(11;14) (q13; q32) is observed in the majority (90%) of MCL cases. Detailed hematopathologic assessment of involved tissue biopsies is critical, and the histology can vary from classic (nodal, mantle zone, interstitial, and diffuse) to aggressive (blastoid/pleomorphic). MCL cells can appear in numerous ways, from small- to medium-size with irregular nuclei to lymphoblast-like cells (medium to large size) that are blastoid or pleomorphic. In addition to morphology, immunophenotype of cerebrospinal fluid and/or ascitic or pleural fluid should be obtained wherever applicable. Imaging studies should be obtained for staging purposes and include assessment with whole-body positron emission tomography–computed tomography (PET-CT) scan or CT (computerized tomography) scan. A pregnancy test, fertility preservation, MRI (magnetic resonance imaging) of the brain, electrocardiogram, echocardiogram, and endoscopic evaluation of the gastrointestinal tract (essential to confirm stage I-II disease) should be conducted depending upon the clinical presentation and/or requirement by the clinical trial protocol (if applicable). It is mandatory to obtain the Ki-67%49 of MCL cells from the involved non-marrow tissue biopsies for prognostic purposes (as described in the prognosis section below). Lumbar puncture is performed in cases with clinically suspected CNS involvement and can be performed in patients with blastoid/pleomorphic cytomorphology MCL.

Of further note, aberrations from the typical immunophenotype of MCL are also reported and should be looked for during the initial evaluation of these patients. These variants include CD10+ MCL,50 CD5 negative MCL,51 Cyclin D1 negative MCL,21, 52 CD200+ MCL,41 SOX-11 negative MCL,37, 53 and CD23 positive MCL,54 and these variants are described in different case series. In some cases, biopsies may reveal presence of cyclin D1+ cells in the inner mantle zone of lymphoid follicles (termed as in situ mantle cell neoplasia)36, 55 which should not lead to a diagnosis of MCL. These patients have a very low risk of progression to overt MCL and should not get systemic therapy. Using these tools, it is critical to distinguish MCL from other masquerading lymphoid malignancies such as SLL/CLL,56 follicular lymphoma, marginal zone lymphoma, and B cell-prolymphocytic leukemia (B-PLL). Translocation t(11;14) (q13;q32) can be observed in a fraction of patients with multiple myeloma (20%-25%), SLL/CLL (2%-5%), and plasma cell leukemia and B-PLL (20% with t(11;14) and cyclin D1+ cells, and these are considered as the leukemic phase of MCL57). Cyclin D1 expression is also observed in a subset of patients with myeloma, hairy cell leukemia, and splenic lymphoma, and SOX-11 expression can be seen in Burkitt's lymphoma, hairy cell leukemia, and lymphoblastic lymphoma.

If available to the clinicians, then somatic mutation of IGHV genes, percent deviation from germline IGHV sequence, type of VH gene usage, and stereotypy assessment should also be obtained. Presence or absence of complex karyotype in involved tissues and targeted sequencing of DNA from involved tissues for TP53, NOTCH1/2, BIRC3, CDKN2A, NSD2, BTK, and ATM is helpful. At specialized MCL centers such as ours, serial plasma samples, and tissue biopsies at relapses are also obtained for the analysis of minimal residual disease (MRD) and copy number changes, as well as for chromosomal aberrations assessment and clonal evolution tracking by ctDNA testing. Single-cell sequencing studies for translational research are also performed.

4 ADVANCES IN MCL PROGNOSTICATION

Information obtained from the initial assessment of patients based on the workup described above is extremely useful to risk-stratify patients. The relevance of these prognostic factors in MCL is unclear in the era of newer therapies such as BCR signaling kinases, Bcl2 inhibitors, and CAR-T cells. So far, the relevance of these conventional prognostic factors is well established in patients with MCL who are treated with chemoimmunotherapies. Currently, practiced prognostic factors include the MIPI risk score and simplified MIPI score (performance status, age, LDH levels > upper limit of normal, and white blood cell count), which divides the patients into low-, intermediate-, and high-risk categories.58 It is used as a continuous variable. The prognostic value of the simplified MIPI risk score is further improved by adding the Ki-67% (obtained from lymphoma-rich areas on non-bone-marrow involved tissue biopsies) which is also called biologic MIPI.59 Generally, a Ki-67% >30% is considered to be the high-risk category. Blastoid and pleomorphic cytomorphology has a significantly inferior outcome compared to classic MCL. SOX-11 expression is also relevant in a subset of patients with leukemic non-nodal presentation, and negative SOX-11 with mutated IGHV identified a subset of MCL patients with a favorable prognosis.37, 60 The relevance of SOX-11 in nodal MCL is not clear.61 TP53-mutated MCL patients generally have a poor prognosis62, 63 and have a poor response to standard frontline chemoimmunotherapy.29 Patients with a complex karyotype, defined as having three or more chromosomal abnormalities in addition to t(11;14) or additional chromosomal abnormalities detected by array CGH (comparative genomic hybridization)64 generally have poorer outcomes.65, 66

Similar to CLL, IGHV mutation status and VH gene usage type is important in MCL,67 and mutated MCL patients have a better outcome compared to unmutated IGHV patients; however, the significance of IGHV mutation status in MCL is underestimated.37 Other factors with inferior outcomes include CDKN2A (locus 9p21) mutations,68, 69 MYC overexpression,70-73 NOTCH174 and/or NOTCH275 mutations, NSD2 mutations (NSD2 [WHSC1] mutations76 are associated with an increase in H3K36 and a decrease in H3K27 methylation across the genome, thus promoting oncogenesis),75 CCND1 mutations,77 and elevated absolute monocyte count.78 Baculoviral IAP repeat containing three mutations (BIRC3) are seen in 10%-15% of patients with MCL. BIRC3 deletions of 11q21-q23 are common alterations in MCL, and in addition to ATM, BIRC3 is also located in this region (11q22.2). BIRC3 aberrations in MCL may result in decreased response to ibrutinib because of failure to suppress the alternate NFkB pathway mediated by MAP3K14, which is proposed as a therapeutic target in BIRC3-mutated lymphomas.79

Additionally, mutations in the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatic remodeling complex (including SMARCA4 mutations)69 have been recently identified and predict poor response to treatment with ibrutinib-venetoclax in MCL. Recently, a NanoString RNA- expression-based molecular assay (MCL3580-82) with a 17-gene proliferation signature was validated to predict prognosis in MCL patients treated with R-CHOP or treated with intensive first line chemoimmunotherapy. In another study, a six-gene signature (AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK) was predictive of poor outcome83 but higher sensitivity to ibrutinib.84 Micro RNAs (miRNA) profile has been shown to have impact on patient prognosis.38, 85 Particularly, patients with overexpression of miR18b86 experienced the prognostic impact of biologic MIPI and were identified as a high-risk subset of patients with MCL in the NORDIC MCL3 prospective clinical trial. For imaging studies, few reports have emerged on the impact of complete metabolic response after treatment completion to correlate with a better clinical outcome87; however, this aspect requires further validation for MCL in prospective studies. Table 2 summarizes prognostic factors with negative impact on MCL patient outcomes.

Table 2. Summary of prognostic markers with negative impact on outcomes, response to treatment in patients with MCL

Currently used	Potential for inclusion in clinical practice
Poor performance status CNS involvement at diagnosis Transformed MCL Blastoid/pleomorphic cytomorphology Simple MIPI high-risk category58 Ki-67% >30%59 Complex karyotype66 TP53 mutations or overexpression of TP53 by immunohistochemistry29 MYC translocation or overexpression70 Unmutated IGHV status37	NOTCH1 and NOTCH2 mutations75 CCND1 NSD2 (WHSC1)75 a SWI/SNF (SMARCA4)a BIRC3 KMT2D/MLL2 BTK88 a CDKN2Aa MAP3K14a CARD11a MCL35 RNA expression assay80 Tumor metabolic volume by PET-CT scans ctDNA-based clonal evolution MRD testing by flow cytometry, PCR for IgH, t(11;14) miRNA18b86

Abbreviations: CNS, central nervous system; IGHV, immunoglobulin heavy chain; MCL, mantle cell lymphoma; miRNA, micro RNAs.
^a Including those with documented79, 89 ibrutinib/venetoclax resistance.

The concept of MRD in MCL is still evolving and being optimized; however, few reports have shown that achieving MRD-negative status significantly improves outcome and obviates the need for maintenance therapy after stem cell transplant (SCT).90 The optimal technique to detect MRD in MCL remains unclear (either flow cytometry from bone marrow [if involved], peripheral blood PCR for IgH or t(11; 14), or ctDNA), and one of the problems is that, unlike in SLL/CLL, not all patients have circulating clonal B cells or marrow involvement.

5 ADVANCES IN THE TREATMENT OF MCL

We are fortunate to witness and to be able to contribute to the paradigm shifts in the treatment landscape in MCL, which is moving toward the use of chemotherapy-free treatments with orally administered nonchemotherapeutic agents in the frontline and in the relapsed-refractory setting. Until about 5 years ago, the treatment options in MCL were restricted to intensive chemo immunotherapies or in some cases with consolidation SCT. However, these options were limited by chemotherapy-associated toxicities and by new-onset second cancers, and they could only be used in young, physically fit patients. Moreover, myelosuppression, infection-associated mortality, therapy-related myelodysplasia, and second cancers remain a serious concern with the use of bendamustine-rituximab (BR) in elderly patients. Development of bortezomib,91 lenalidomide,92 and temsirolimus93 provided a transient respite in inducing responses in the relapsed setting; however, these options provided modest responses with toxicities, and patients eventually progressed.

The relevance of BTK (Bruton's tyrosine kinase) inhibitors in canine lymphoma models by Honigberg and colleagues94 was a breakthrough in the treatment of B-cell NHL.95 This initial report paved the way for landmark clinical trials of ibrutinib in MCL96 and other B-cell NHLs.97 Our group has been involved in various clinical trials with ibrutinib,96, 98 acalabrutinib,99 venetoclax (a Bcl2 inhibitor),100, 101 and their combinations with anti-CD20 monoclonal antibodies (mAb), rituximab, or with obinutuzumab. Furthermore, we are characterizing ibrutinib,88 acalabrutinib,102 and venetoclax-refractory103 MCL and championing the CAR-T cell clinical trials (Zuma-2) in MCL in the United States.

Overall, the treatment in MCL has undergone a major shift in recent years. Long- and short-term toxicities from chemotherapy and SCT-based treatments have a negative impact on survival and quality of life of MCL patients. Facility to perform SCT is not available everywhere and therefore we developed R-HCVAD/methotrexate/ara-C regimen at our center, however, hematologic toxicities, infections, and second cancers remain an issue with this regimen. Therefore, the advent of orally available chemo-free treatments has been a boon for the MCL patients. We and others are developing next-generation chemotherapy free clinical trials incorporating proteomics, genomic sequencing and these efforts would offer an opportunity to select treatment modalities based on an individual patient's gene signature. Despite these advances, we firmly believe that more research and new clinical trials are needed to find a cure for MCL.

Here, we will discuss the current approaches to treatment in MCL, provide an insight into our treatment approach in MCL, and give an overview on future therapies and ongoing clinical trials. We believe that it is appropriate to refer patients with MCL to specialized centers, as management of MCL is dynamic and is challenging. A recent study from the United Kingdom showed that patients who received treatment at specialized centers had greater survival benefit compared to those treated at nonspecialized centers.104

The main factors to consider while choosing an appropriate management strategy for patients with MCL include: assessment of physical fitness, comorbidities, disease status (smoldering nodal MCL vs leukemic non-nodal vs conventional MCL presentation), non-blastoid/blastoid morphology, Ki-67% (low vs high), access to drugs in various countries and their cost, and availability of clinical trials for the patient.

5.1 Wait-and-watch strategy

Similar to low grade lymphoma, a subset of MCL patients (those with good performance status, no B symptoms, normal LDH levels, asymptomatic, non-bulky disease, low Ki-67%, and nonaggressive cytomorphology) do not need immediate systemic therapy. It is critical to identify these patients, and they need to be counseled about the risks and benefits of deferred therapy and observation alone.105 A Canadian group48 reported their experience in 440 patients (75 were managed with observation alone for ≥3 months and 365 received early treatment). The majority (72%) of patients in the observation group had a nodal presentation, and overall 80% of patients underwent observation for >12 months, including 10 patients who were observed for >5 years. The median follow up in the observation group was 48 months, and the median time to first treatment was 35 months (range 5-79 months). The median overall survival was significantly longer in the observation group compared with the early treatment group (72 vs 52.5 months; P = .04). Patients with non-nodal clinical presentation or those with negative TP53 by immunohistochemistry had longer survival in the observation group. Another study using the National Cancer Database reported that among 8029 MCL patients, 492 experienced deferred therapy as their management strategy, and younger age, male gender, and lack of comorbidities were predictive of overall survival.106

At this time, detailed molecular studies to identify the clonal evolution pattern in patients with smoldering MCL are not reported, and we do not know whether early intervention using newer oral targeted agents can improve the time to progression and/or survival.

5.2 Previously untreated newly diagnosed MCL patient

Appropriate management approach in patients requiring systemic treatment for MCL should be again stratified with the following factors in mind: availability of clinical trials for various patient subsets, eligibility for SCT, high risk (blastoid MCL, high Ki-67% >30%, or CNS involvement), physician's choice for treatment, and young and physically fit vs elderly (≥65 years) and/or physically unfit/frail patients. Limited-stage, non-bulky disease may benefit from addition of radiation to chemotherapy; however, this strategy has not been confirmed in large randomized studies.107 Outside clinical trials, the general approach for frontline treatment of MCL is chemoimmunotherapy with/without autologous SCT and with/without maintenance therapy.

Below, we will provide an overview of published major frontline clinical trials and commonly used treatment approaches in young and physically fit and elderly or physically unfit patients with MCL. Pivotal frontline trials in MCL are summarized in Table 3.

Table 3. Summary of pivotal studies in the frontline setting in MCL

Protocol used	Number of Patients	Median Follow up	ORR (CR) %	Median remission duration/PFS	Median OS	Comments
R-HCVAD/Mtx-ara-C108-110 (no auto-SCT)	97	13.4 y	97 (87)	4.8 y	10.7 y	In young (<65 y; n = 65) patients, median FFS 6.5 y and OS 13.4 while in elderly (>65 y; n = 32), median FFS 3 y and OS 4.9 y 6.2% rate of myelodysplasia and acute myeloid leukemia Blastoid/pleomorphic histology (n = 15) not associated with survival FFS plateaued after 10 y
R-maxi-CHOP/R-HiDAC (with auto-SCT), Nordic regimen111-113	160	11.4 y	96 (54/89a)	8.5 y	12.7 y	145 patients got auto-SCT, and median PFS and OS were 11 y and NR 9.4% rate of second cancers (n = 20 with 15 solid tumors and 5 myeloid cancers) Plateau in survival curves not reached, 50% patients relapsed after 12 y
R-CHOP + auto-SCT R-CHOP/R-DHAP + auto-SCT114	234 and 232	6.1 y	97 (61) vs 98 (63)	4.3 vs 9.1 y	NR vs 9.8 y	Time to treatment failure longer in ara-C group (9.1 vs 4.3 y) OS was not significantly different 2.4% secondary leukemia and 4.3% other cancers with ara-C group
R-DHAP (four cycles) + auto-SCT followed by rituximab maintenance vs observation alone90	120 each	50 mo	89 (77) after 4b R-DHAP	4 y % (83% vs 64%)	4 y % (89% vs 80%)	• Maintenance rituximab after R-DHAP induction therapy, followed by R-BEAM consolidation therapy, prevented relapses and was associated with a low risk of major infection
BR vs R-CHOP (StiL)115	46 and 48	45 mo	93b (40) vs 91 (30)	35.1 vs 22.1 mo	NR in both	Response rates were reported from both indolent and MCL patients Trend of longer time to next treatment with BR but OS was similar in BR vs R-CHOP Long-term follow up and detailed subset analysis is not reported
BR vs R-CHOP (BRIGHT)116, 117	37 and 37	65 mo	97b (31) vs 91 (25)	5 y 40% vs 14%	82% vs 85% alive at 5 y	Higher second cancers in BR group Detailed subset analysis is not reported Lesser toxicities with BR
Bortezomib-R-CHOP vs R-CHOP alone118	243c and 244	82 mo	92 (53) vs 89 (42)	25 vs 14.4 mo	91c vs 56 mo	Improved overall survival with bortezomib-R-CHOP in patients with high Ki-67 (>30%) 42% died in bortezomib group vs 57% in R-CHOP alone group Similar incidence of second cancers
Lenalidomide-Rituximab119, 120	38	64	92 (64)	5 y 64%	5 y 77%	Six patients (16%) had second primary cancers (mostly skin cancers) 42% grade ≥3 neutropenia Th2 to Th1 cytokine/chemokine switch after three cycles of induction showing immune modulation and effect on inflammation

Abbreviations: CR, complete response rate; NR, not reached; ORR, overall response rate; y, Years; R-DHAP, (rituximab - dexamethasone, cisplatin, ara-C); R-HCVAD/Mtx-ara-C, (rituximab with hyper fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate and cytosine arabinoside); StiL, (study group indolent lymphoma).
^a CR 89% after auto-SCT.
^b In both indolent and MCL patients.
^c 140 and 128 patients were included at 82 mo follow up.

5.3 Young physically fit patients

In our opinion, in the absence of access to clinical trials, intensive chemo-immunotherapy such as rituximab with HCVAD/methotrexate-ara-C should be administered as the first line treatment for this group of patients. R-HCVAD/ methotrexate-ara-C does not require consolidation with SCT which is a major advantage over other chemotherapy-based treatment modalities. Some physicians also opt for intensive chemoimmunotherapy followed by autologous SCT as consolidation therapy.121 Finally, the choice of chemoimmunotherapy is dependent upon the local physician's experience and patient preference.

Our group has reported results in a phase II trial with 97 patients treated with R-HCVAD/methotrexate-ara-C (without consolidation auto-SCT) with a median follow up of 13.4 years.108 Our overall response rates (ORR) and complete remission (CR) rates were 97% and 87%, respectively. Furthermore, we have also reported that addition of bortezomib to R-HCVAD/methotrexate-ara-C122 did not improve response rates over R-HCVAD alone. Two multicenter phase II studies (with similar patient characteristics to our MDACC study) from Italy123 (n = 60) and from the Southwestern Oncology Group124 (n = 49) evaluated R-HCVAD/methotrexate-ara-C. The studies' ORRs were 83% and 86%, respectively. The median follow up was shorter in these two studies, and 40% to 60% of enrolled patients could not complete therapy because of hematologic toxicities.

Another commonly used treatment approach, adopted in European countries, is intensive chemoimmunotherapy with high dose ara-C followed by consolidation auto-SCT. The Nordic group111, 112 reported their initial results in a phase II trial in 2008 with R-maxi CHOP with R-high dose ara-C with durable responses. A phase II study from France125 used three cycles of R-CHOP and three cycles of R-DHAP followed by auto-SCT in 60 patients with 90% to 94% ORR. With a median follow up of 67 months, its 5-year overall survival was 75%. Taking these studies forward, a phase III trial from the European MCL network114 confirmed the superiority of R-CHOP/R-DHAP followed by auto-SCT against R-CHOP alone followed by auto-SCT. Time to treatment failure was significantly longer with R-CHOP/R-DHAP over R-CHOP.

Another study assessed induction with BR followed by rituximab and high dose ara-C and auto-SCT in 23 patients in a phase II study.126 Its median follow up was 13 months, its progression-free survival rate was 96%, and median overall survival was not reached. The majority of the patients attained MRD-negative disease after chemotherapy alone (93%). Whether BR induction, prior to auto-SCT, is superior to R-CHOP is unclear.

5.4 Elderly or physically unfit patients (any age)

As the median age of MCL patients is 68 years, studies focusing on elderly patients (≥65 years) or those patients who are transplant-ineligible because of poor physical fitness are relevant. In our report on long-term follow up of R-HCVAD/Mtx-ara-C,108 we showed that elderly patients (n = 32) had significantly inferior failure-free and overall survival compared to patients aged <65 years (see figure 1C,D in Reference 108). Furthermore, in a small cohort of patients (n = 38) in a retrospective study,127 progression-free survival with R-CHOP alone was significantly inferior compared to R-HCVAD/Mtx-ara-C alone, albeit with higher toxicity in the R-HCVAD/Mtx-ara-C cohort. Therefore, it became important to determine the efficacy and safety of other agents, such as bendamustine, compared to R-CHOP for improved tolerability without compromising efficacy in elderly or transplant-ineligible patients.

Bendamustine was initially reported to have a cytotoxic effect on CLL and MCL cell lines in p53- deficient tumors via promoting apoptosis and generation of reactive oxygen species.128 A combination of BR was considered the most appropriate alternative to R-CHOP, and therefore, BR was tested in two different phase III randomized trials: one in Germany115 and another in North America.116, 117 In 2013, Rummel and colleagues115 presented the initial pivotal trial showing that BR significantly improved progression-free survival in MCL patients compared with R-CHOP,115 and it showed that BR was a less toxic regimen than R-CHOP. They confirmed these results at the 9-year follow up of the study.129 Similar results demonstrating superiority of BR over R-CHOP for improved PFS but similar OS were reported after a 5-year follow up from the BRIGHT study.117 However, the incidence of second cancers was higher in the BR group (19%) compared to the R-CHOP group (11%) in the BRIGHT study, and the incidence of second cancers was similar between the BR group (8%) and the R-CHOP group (9%) in the German study. Of note, these percentages included all patients (indolent and MCL) from both studies. BR was also studied in combination with low dose ara-C130 (BR-AC-500; n = 57; BR + ara-C 500 mg/m² on days 2-4 q 4 weekly) with 50% of patients developing grade 3 to 4 neutropenia. Two studies tested lenalidomide with BR, one study131 (n = 51) reported that 42% of patients experienced grade 3 to 4 infections and 16% of patients developed second cancers. The combination of lenalidomide with bortezomib and dexamethasone132 was tested, resulting in 2-year PFS of 70%, but 51% of patients experienced grade 3 to 4 neutropenia.

Promising overall survival results were obtained from adding bortezomib to the R-CHOP regimen compared to R-CHOP alone in a randomized study, but an increase in hematologic toxicity was noted.118, 133 Recently, a 5 year follow up study on the lenalidomide with rituximab combination119, 120 was reported. It included induction and maintenance with lenalidomide and rituximab in 38 elderly patients, and the majority (75%) completed >3 years of treatment. In a subset of patients (8/10), MRD was negative at the last follow up assessment.

5.5 Minimal residual disease in MCL

Considering the risk of molecular relapse after SCT and that preemptive treatment with rituximab maintenance can clear MRD, a phase III trial90 randomized patients (n = 240) who had received four cycles of R-DHAP induction followed by auto-SCT into observation vs rituximab maintenance groups. The rituximab maintenance group received 375 mg/m² rituximab once every 2 months for 3 years. This study demonstrated that rituximab maintenance can improve survival after SCT. MRD assessment in MCL has not been systematically implemented in clinical practice; however, a few studies134 have shown the critical clinical significance of MRD-positive disease status and risk of predicting future relapses.135-137 Another issue for MRD assessment in MCL is optimization of the technique according to the tissue type used to test MRD, as not all patients have bone marrow involvement at diagnosis and not all patients have peripheral blood lymphocytosis sufficient enough for testing MRD by either flow cytometry or PCR (allele specific quantitative oligonucleotide polymerase chain reaction). Therefore, efforts are underway to utilize newer methods138 for detecting IgH clones or PCR-based quantification of t(11; 14) in serially collected peripheral blood from patients with MCL. Utilizing rituximab or ibrutinib or lenalidomide as a maintenance strategy to achieve MRD-negative remissions is also being explored.

5.6 Treatment approaches in 2019

Apart from the standard of care treatment options discussed above in various settings, enrollment into clinical trials should be considered wherever feasible. Broadly, current and future set of clinical trials are attempting to address various questions in MCL treatment. Whether BTKi and/or venetoclax with/without anti-CD20 monoclonal antibodies can replace chemoimmunotherapy altogether as a frontline treatment without compromising efficacy and safety, optimal time and the need for SCT in the era of BTKi and venetoclax, chemoimmunotherapy with/without BTKi or with venetoclax as frontline treatment, which BTKi to use preferentially, optimal maintenance strategy, role of anti CD19-CAR-T as consolidation instead of SCT in high risk MCL, how to treat patients who progressed on BTKi or on venetoclax or on CAR-T therapy. Apart from this, next generation clinical trials are also testing for serial MRD, clonal evolution on BTKi/venetoclax and identify the mechanisms of drug resistance using cutting edge molecular techniques. An appropriate example of this approach is the recently reported ibrutinib-venetoclax study from Australia which was well designed and reported important clinical139 and new molecular data69 on drug resistance in MCL. We hope that in the coming years, we hope to answer some of these questions. Readers are referred to http://clinicaltrials.gov to learn about various ongoing clinical trials in the frontline and relapsed setting in MCL. We will briefly list some of the frontline clinical trials of interest.

TRIANGLE study—The TRIANGLE study is a phase III trial in young, transplant-eligible patients in Europe. It is a three-arm randomized trial with six cycles of R-CHOP/R-DHAP + auto-SCT vs six cycles of R-CHOP + ibrutinib/R-DHAP + auto-SCT + 2 years of ibrutinib maintenance vs six cycles of R-CHOP + ibrutinib/R-DHAP +2 years of ibrutinib maintenance. Results of this trial would indicate whether ibrutinib and ara-C based induction is efficacious and can improve upon the previous results with chemoimmunotherapy alone in induction prior to auto-SCT (NCT02858258).
E4151 study—This phase III randomized study by a United States intergroup is looking at relevance of maintenance rituximab in patients who achieve MRD-negative CR after induction therapy who are then randomized to auto-SCT + MR vs MR alone. This study may provide insight into the role of consolidation SCT after achieving MRD-negative CR (NCT03267433).
ECOG-E1411 study—The ECOG-E1411 study is a four-arm randomized phase II trial. Arm 1 is BR induction followed by rituximab maintenance, arm 2 is BR + bortezomib followed by rituximab maintenance, arm 3 is BR followed by lenalidomide + rituximab maintenance, and arm 4 is BR + bortezomib followed by lenalidomide + rituximab maintenance. This study will provide information on ideal maintenance strategy with lenalidomide (NCT 01415752).
MCL-R2 elderly trial—The MCL-R2 elderly study is a phase III randomized trial to assess the efficacy of ara-C induction and lenalidomide maintenance. It randomizes patients into groups receiving induction R-CHOP alternating with R-HAD (rituximab, ara-C, dexamethasone) vs R-CHOP followed by second randomization into rituximab maintenance vs lenalidomide + rituximab as maintenance. This study will provide clarity on ideal maintenance strategy with lenalidomide (NCT01865110).
Various other studies involving venetoclax, BTK inhibitors, and obinutuzumab with/without chemotherapy combinations (BR, R-HVAD/methotrexate/ara-C are ongoing and some are being planned (venetoclax + BR in elderly, venetoclax + lenalidomide and rituximab, venetoclax with bendamustine and obinutuzumab, acalabrutinib + lenalidomide and rituximab).

5.7 Our treatment approach in 2019

At our center, intensive efforts are underway to incorporate nonchemotherapeutic agents in the frontline setting in hope of eventually replacing chemotherapy. Some of these efforts include:

Window-1 trial—ibrutinib with rituximab (IR) induction followed by short-course R-HCVAD-Methotrexate/ara-C in young patients. This study intends to minimize chemotherapy and relies on chemo-free induction to induce deep response and prevent undue toxicities with intensive chemoimmunotherapy (NCT02427620)
Window-2 trial—IR induction followed by venetoclax and short-course R-HCVAD-Methotrexate/ara-C (NCT03710772)
SHINE study—BR followed by rituximab maintenance vs ibrutinib with BR followed by ibrutinib + rituximab maintenance in the elderly (NCT01776840)
Acalabrutinib with bendamustine rituximab (BR) vs BR ± placebo (NCT 02972840)
IR combination for elderly patients. Chemo-free treatment strategy for elderly patients. (NCT01880567)
IR ± lenalidomide for elderly patients (NCT03232307)

5.8 Previously treated, relapsed MCL

Development of BTK inhibitors (ibrutinib,96, 140 acalabrutinib,99 and zanubritinib141) and Bcl-2 antagonist (venetoclax)100, 139 has revolutionized our treatment options for relapsed MCL. Remarkable efficacy, durable responses, tolerability, and safety from ibrutinib or acalabrutinib or a combination of ibrutinib with venetoclax in various age groups and disease subsets of MCL has completely overshadowed results from older agents, such as chemotherapy regimens BR (ORR 82%, 40% CR),129 R-CHOP or other salvage regimen such as R-HCVA/methotrexate-ara-C (ORR 93%, 45% CR),142 R-ICE or R-DHAP. Other agents such as bortezomib (ORR 25-50% with a CR of 4%-8%),91, 143, 144 temsirolimus (ORR 22%), 145 lenalidomide (ORR 28% with single agent and 57% with rituximab), 146, 147 or their combinations with rituximab92 produce modest response rates and single agent obinutuzumab (ORR 30%)148 and idelalisib (ORR 40% with 5% CR).149

However, we recognize that even after the emergence of ibrutinib or acalabrutinib or venetoclax resistance, intolerance of these agents, management after their discontinuation,88, 150 disease transformation, and MRD-positive disease remain a constant challenge in MCL.

5.9 Chemotherapy-free treatment options in relapsed MCL

Lenalidomide with rituximab (LR)—In a phase 1/2 clinical trial,92 the combination of chemo-free regimen of LR was tested in 52 patients. Forty four patients were enrolled in phase 2 cohort with an ORR of 57% and CR of 36%. The median PFS was 11.1 months and the median OS was 24.3 months.

Ibrutinib—Ibrutinib (previously known as PCI-32765) is an irreversible inhibitor of BTK, which binds to cysteine 481 within the ATP binding site of the BTK kinase domain. Ibrutinib cross-reacts with other TEC kinases (BMX, ITK, and BLK) distributed in various tissues, thereby leading to various off-target effects such as atrial fibrillation,151, 152 ventricular arrhythmias,153 and bleeding.154 Inhibition of BTK leads to abrogation of MCL cell survival, proliferation, and growth.155 These agents interfere with the chemokine-receptor interactions and homing of MCL cells, leading to redistribution lymphocytosis149 after starting treatment, and this observation should not be confused as disease progression.

Efficacy and safety data of single agent-ibrutinib in relapsed MCL patients (n = 111) was initially reported in 2013.96 With a median age of 68 years and a median of three prior lines of therapies, an ORR of 68% and CR of 21% after a median follow up of 15.4 months was obtained. Grade 3 or 4 adverse events were infrequent and included 16% neutropenia and 11% thrombocytopenia. After the 26.7 month follow up analysis,98 the CR rate slightly improved to 23%, and 22% of patients continued treatment for >2 years. Two-year PFS and OS were 31% and 47%, respectively. Six percent of patients had grade 3 or 4 bleeding events (none fatal), 11% had atrial fibrillation (grade 3 in 6%), and 5% developed second cancers. In the long-term follow up of the randomized RAY study,93 ibrutinib was clearly superior to temsirolimus after a 3-year follow up, with an improved PFS and a clear trend for longer overall survival and better toxicity profile.

Recently, a pooled analysis of 370 single-agent-ibrutinib-treated relapsed MCL patients with a median of 41.5 months of follow up was reported.140 Seventeen percent of patients continued to receive treatment for more than 4 years. The median PFS and OS were 12.5 and 26.7 months, respectively. A higher number of prior lines of therapy was associated with shorter PFS in the multivariate analysis. Of note, 14% of patients were TP53-mutated and demonstrated inferior response rates (55%), shorter PFS (4 months), and shorter OS (10.3 months) compared to the corresponding values (70.2%, 12 months, and 33.6 months, respectively) in patients with wild-type TP53 status. Although atrial fibrillation occurred in 11% of patients (any grade), none discontinued treatment caused by atrial fibrillation, and 70% of patients who had a prior history of arrhythmia did not experience recurrence of arrhythmia on ibrutinib. Major bleeding leading to fatal hemorrhage was not observed. Patients who received ibrutinib as first salvage therapy had a superior response rate 77% (37% CR) and longer duration of response (36 months) compared to those who received ibrutinib in subsequent lines of therapy. Furthermore, non-blastoid cytomorphology, low Ki-67% (<30%), and TP53 wild-type subsets exhibited better outcomes with ibrutinib compared to blastoid, high Ki-67%, and TP53-mutated subsets.156

In addition, the combination of ibrutinib with rituximab was studied and demonstrated remarkable efficacy in relapsed MCL (with a median of three prior therapies). After a median follow up of 47 months, the CR improved from 44%157 to 58%,158 the median PFS was 43 months, and the median OS was not reached. Patients with high Ki-67% (>50%) and blastoid cytomorphology had inferior outcomes compared to patients with low Ki-67% and non-blastoid cytomorphology. The combination of IR with lenalidomide was also reported from a European phase II multicenter trial159 with 50 previously treated MCL patients, which demonstrated an ORR of 76% with 56% CR after a median follow up of 17.8 months. In that trial, 38% of patients had grade 3-4 neutropenia.

To further improve upon the success of ibrutinib, and based on preclinical data showing synergy between ibrutinib and venetoclax,160 a combination of ibrutinib (560 mg daily) with venetoclax (weekly dose escalation up to 400 mg daily dose) (I + V) was studied in the AIM trial. Twenty-three patients with relapsed MCL (75% had high-risk MIPI score and 50% had TP53 mutations) were treated with a median follow up duration of 15.9 months. The I + V combination139 resulted in an ORR of 71% with 62% CR (with PET-based assessment) at week 16. In all patients, MRD-negative response was 67% by flow cytometry and 38% by PCR blood testing. The median PFS was not reached, with 12-month PFS of 75%. Interestingly, among the patients with TP53 mutation (n = 12), 50% achieved a CR. Grade 3-4 diarrhea was noted in 71%, and neutropenia was noted in 33% of patients. Of great importance, a landmark paper on resistance mechanisms for the venetoclax and ibrutinib combination was published by the same group, demonstrating that mutations in the SWI/SNF chromatin remodeling complex were associated with drug resistance.69 Other promising combinations of ibrutinib include ibrutinib with palbociclib, as suggested from a phase I trial providing an ORR of 67%, 37% CR, and 2-year PFS of 59%.161

Of further interest, ibrutinib has been reported to cross the blood-brain barrier and has recently shown efficacy in CNS lymphomas162-164 and in MCL involving the CNS.165 These results have potential to impact future therapies for high-risk MCL patients who have CNS involvement or at high risk of CNS involvement.

Overall, the advent of ibrutinib is a “great leap forward” in the treatment of MCL; however, problems with ibrutinib discontinuation,88, 150 management of ibrutinib-refractory disease, and mechanisms of ibrutinib resistance30 pose new challenges. In contrast with SLL/CLL, where the C481S mutation is commonly associated with ibrutinib resistance,166 this mutation is infrequent in ibrutinib-resistant MCL,88 and other mechanisms of ibrutinib resistance71 and ways to overcome ibrutinib resistance167, 168 must be explored. A detailed discussion about the molecular aspects of ibrutinib resistance is beyond the scope of the current article.

Acalabrutinib—This is a newer highly selective orally administered BTK inhibitor. Acalabrutinib is a covalent inhibitor of C481S in the ATP binding pocket of BTK with a short half-life. Acalabrutinib and its major metabolite ACP-5862 have limited off-target kinase activity,169 inhibiting only two kinases [ErbB4] and the BMX gene in chromosome X. Acalabrutinib preserves Src family kinase (collagen to platelet adhesion) activity and thus avoids the unstable platelet thrombus formation seen with ibrutinib therapy.170 These mechanisms potentially explain why the risk of bleeding and atrial fibrillation is significantly more minimal with acalabrutinib compared to ibrutinib.

Acalabrutinib was studied in a multicenter phase II trial including 124 patients with relapsed MCL who had a median of two lines of prior therapy.99 After a median follow up of 15.2 months, the ORR was 81% with 40% CR, and at the 26-month follow up analysis,171 the median PFS was 19.5 months, and the median OS was not reached with 40% of patients remaining on acalabrutinib. Three patients experienced grade 3 bleeding events, and no patients had atrial fibrillation.

Considering the efficacy and safety of single-agent acalabrutinib, this agent is now being actively pursued in relapsed MCL in combination with venetoclax. In the frontline setting, the combination of acalabrutinib with rituximab and lenalidomide or combination of acalabrutinib with venetoclax and rituximab is being tested. Longer follow up on these acalabrutinib trials and analysis of outcomes after acalabrutinib progression102 will enhance our knowledge of this agent.

Venetoclax—Venetoclax is an orally available, selective inhibitor of the Bcl-2 protein, which has an anti-apoptotic function, preventing MCL cells from undergoing apoptosis. Overexpression of Bcl-2 is generally observed in B-cell NHL, including MCL, and this overexpression can promote cell survival. In a phase I trial,100 28 relapsed-refractory MCL patients (median age 72 years and median of three prior lines of treatments) were enrolled, and patients attained an ORR of 75%, CR of 21%, and a median PFS of 14 months. Results from the ibrutinib with venetoclax combination trial139 were described above in the ibrutinib section. Venetoclax has great potential in MCL treatment, even among patients who have progressed on BTK inhibitors (53% ORR).101 Of late, a few studies have reported venetoclax-resistant mutations in CLL,172, 173 and the mechanism of venetoclax resistance is being studied in MCL. Venetoclax is now being tested in the relapsed setting in combination with ibrutinib in a phase III multicenter trial (NCT03112174).

Allogenic SCT—This modality can be useful in high-risk, transplant-eligible TP53-mutated relapsed MCL. Allo-SCT can provide long term disease control in 30% of MCL patients.174, 175

5.10 Other promising newer modalities

Although there are several agents exhibiting preclinical activity against MCL, we will discuss those with potential for clinical use or that have been clinically tested.

Chimeric antigen receptor T cell (CAR-T) therapy—ZUMA-2 is a currently ongoing trial with axicabtagene ciloleucel, which is an anti-CD19 CAR T-cell product, for patients with relapsed/refractory MCL (NCT02601313). Another anti-CD19 CAR-T cell therapy is JCAR-017 or lisocabtagene-maraleucel, which is a CD19-directed 4-1BB CAR T-cell product. Presently, these agents provide the greatest hope for treating refractory patients with MCL, especially those who have progressed on BTK inhibitors. Results in MCL patients are awaited. Other potential antigenic targets are being pursued in MCL and these include CD79b, CD22, Sox-11, and CCND1.
LOXO-305—This is a reversible inhibitor with non-covalent binding to BTK that preserves activity in the presence of the C481S mutations and avoids off-target kinases inhibition.
Zanubrutinib—This is a selective BTK inhibitor with a 90% ORR and 20% CR in a phase I trial176 in MCL. Another study from China141 reported an ORR of 81% with a PET-negative CR of 58%. This molecule is being studied further in MCL, and more data is awaited.
Vecabrutinib (SNS-062)—this is another reversible and non-covalent BTK inhibitor. This molecule does not interact with cysteine 481 residue within the kinase domain unlike other inhibitors and may be relevant in C481S mutants.
ARQ-531—This is another reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. It is tested for ibrutinib resistant cases.177

6 SUMMARY

We firmly believe that 2019 is a very exciting time in the field of MCL. We are progressing toward increased understanding of disease mechanisms, identification of novel therapeutic targets, and advances in bioinformatics, adoptive immunotherapy, and molecular techniques. We anticipate that in the coming years, next-generation clinical trials will incorporate nonchemotherapeutic agents or chimeric antigen receptor T-cell therapy and minimize the use of chemotherapy in the treatment of MCL. In addition, efforts for personalized therapy in MCL are also underway, and with collaborative efforts, we aim to reach our goal of curing patients with MCL in the coming years.

ACKNOWLEDGMENTS

Funding for various MCL studies at MD Anderson Cancer Center was provided in part by the generous philanthropy donated to the MD Anderson Cancer Center B-Cell Lymphoma Moon Shot Program; R21 CA202104 (Michael Wang, PI); and philanthropy funds from The Gary Rogers Foundation and the Fox Family Foundation. Kelley Murfin at MD Anderson Cancer Center is a scientific writer and helped in editing the manuscript.

CONFLICT OF INTEREST

M.W. has received research funding from Acerta Pharma, Asana Biosciences, BeiGene, Celgene, Janssen, Juno Therapeutics, Kite Pharma, Amgen, Pharmacyclics, AstraZeneca, BioInvent International, Karus, Oncternal, and Novartis; has received honoraria from Janssen, Dava Oncology, OMI, PeerView Institute for Medical Education (PVI); has been a consultant for Acerta Pharma, AstraZeneca, BioInvent International, IO Biotech, Celgene, Juno Therapeutics, Pharmacyclics, MoreHealth, Pulse Biosciences, AxImmune, and Janssen; is on the Board of Directors and advisory committees for Janssen; and received stock or other ownership from MoreHealth. P.J. - none.

REFERENCES

1Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016; 66(6): 443-459.
10.3322/caac.21357
PubMed Web of Science® Google Scholar
2Sant M, Allemani C, Tereanu C, et al, and the HAEMACARE Working Group. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010; 116(19): 3724-3734.
10.1182/blood-2010-05-282632
CAS PubMed Web of Science® Google Scholar
3Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological malignancy by sub-type: a report from the haematological malignancy research network. Br J Cancer. 2011; 105(11): 1684-1692.
10.1038/bjc.2011.450
CAS PubMed Web of Science® Google Scholar
4Fu S, Wang M, Lairson DR, Li R, Zhao B, Du XL. Trends and variations in mantle cell lymphoma incidence from 1995 to 2013: a comparative study between Texas and National SEER areas. Oncotarget. 2017; 8(68): 112516-112529.
10.18632/oncotarget.22367
PubMed Web of Science® Google Scholar
5Sun J, Yang Q, Lu Z, et al. Distribution of lymphoid neoplasms in China: analysis of 4638 cases according to the World Health Organization classification. Am J Clin Pathol. 2012; 138(3): 429-434.
10.1309/AJCP7YLTQPUSDQ5C
PubMed Web of Science® Google Scholar
6Nair R, Arora N, Mallath MK. Epidemiology of non-Hodgkin's lymphoma in India. Oncology. 2016; 91(Suppl 1): 18-25.
10.1159/000447577
PubMed Web of Science® Google Scholar
7Wang Y, Ma S. Racial differences in mantle cell lymphoma in the United States. BMC Cancer. 2014; 14: 764.
10.1186/1471-2407-14-764
PubMed Web of Science® Google Scholar
8Schollkopf C, Melbye M, Munksgaard L, et al. Borrelia infection and risk of non-Hodgkin lymphoma. Blood. 2008; 111(12): 5524-5529.
10.1182/blood-2007-08-109611
CAS PubMed Web of Science® Google Scholar
9Smedby KE, Sampson JN, Turner JJ, et al. Medical history, lifestyle, family history, and occupational risk factors for mantle cell lymphoma: the interlymph non-Hodgkin lymphoma subtypes project. J Natl Cancer Inst Monogr. 2014; 2014(48): 76-86.
10.1093/jncimonographs/lgu007
PubMed Google Scholar
10Skibola CF, Bracci PM, Nieters A, et al. Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) polymorphisms and risk of non-Hodgkin lymphoma in the InterLymph consortium. Am J Epidemiol. 2010; 171(3): 267-276.
10.1093/aje/kwp383
PubMed Web of Science® Google Scholar
11Wang SS, Slager SL, Brennan P, et al. Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the international lymphoma epidemiology consortium (InterLymph). Blood. 2007; 109(8): 3479-3488.
10.1182/blood-2006-06-031948
CAS PubMed Web of Science® Google Scholar
12Smedby KE, Hjalgrim H, Askling J, et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J Natl Cancer Inst. 2006; 98(1): 51-60.
10.1093/jnci/djj004
PubMed Web of Science® Google Scholar
13Kleinstern G, Maurer MJ, Liebow M, et al. History of autoimmune conditions and lymphoma prognosis. Blood Cancer J. 2018; 8(8): 73.
10.1038/s41408-018-0105-4
PubMed Web of Science® Google Scholar
14Hadzidimitriou A, Agathangelidis A, Darzentas N, et al. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood. 2011; 118(11): 3088-3095.
10.1182/blood-2011-03-343434
CAS PubMed Web of Science® Google Scholar
15Fichtner M, Spies E, Seismann H, et al. Complementarity determining region-independent recognition of a superantigen by B-cell antigen receptors of mantle cell lymphoma. Haematologica. 2016; 101(9): e378-e381.
10.3324/haematol.2016.141929
PubMed Web of Science® Google Scholar
16Shah BK, Khanal A. Second primary malignancies in mantle cell lymphoma: a US population-based study. Anticancer Res. 2015; 35(6): 3437-3440.
PubMed Web of Science® Google Scholar
17Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest. 2012; 122(10): 3416-3423.
10.1172/JCI61272
CAS PubMed Web of Science® Google Scholar
18Body S, Esteve-Arenys A, Miloudi H, et al. Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells. Sci Rep. 2017; 7(1): 13946.
10.1038/s41598-017-14222-1
PubMed Web of Science® Google Scholar
19Allinne J, Pichugin A, Iarovaia O, et al. Perinucleolar relocalization and nucleolin as crucial events in the transcriptional activation of key genes in mantle cell lymphoma. Blood. 2014; 123(13): 2044-2053.
10.1182/blood-2013-06-510511
CAS PubMed Web of Science® Google Scholar
20Wiestner A, Tehrani M, Chiorazzi M, et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood. 2007; 109(11): 4599-4606.
10.1182/blood-2006-08-039859
CAS PubMed Web of Science® Google Scholar
21Salaverria I, Royo C, Carvajal-Cuenca A, et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1(−) mantle cell lymphoma. Blood. 2013; 121(8): 1394-1402.
10.1182/blood-2012-08-452284
CAS PubMed Web of Science® Google Scholar
22Martin-Garcia D, Navarro A, Valdes-Mas R, et al. CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1(−) mantle cell lymphoma. Blood. 2019; 133(9): 940-951.
10.1182/blood-2018-07-862151
CAS PubMed Web of Science® Google Scholar
23Ek S, Dictor M, Jerkeman M, Jirstrom K, Borrebaeck CA. Nuclear expression of the non B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood. 2008; 111(2): 800-805.
10.1182/blood-2007-06-093401
CAS PubMed Web of Science® Google Scholar
24Kuo PY, Jatiani SS, Rahman AH, et al. SOX11 augments BCR signaling to drive MCL-like tumor development. Blood. 2018; 131(20): 2247-2255.
10.1182/blood-2018-02-832535
CAS PubMed Web of Science® Google Scholar
25Palomero J, Vegliante MC, Eguileor A, et al. SOX11 defines two different subtypes of mantle cell lymphoma through transcriptional regulation of BCL6. Leukemia. 2016; 30(7): 1596-1599.
10.1038/leu.2015.355
CAS PubMed Web of Science® Google Scholar
26Vegliante MC, Palomero J, Perez-Galan P, et al. SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma. Blood. 2013; 121(12): 2175-2185.
10.1182/blood-2012-06-438937
CAS PubMed Web of Science® Google Scholar
27Palomero J, Vegliante MC, Rodriguez ML, et al. SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma. Blood. 2014; 124(14): 2235-2247.
10.1182/blood-2014-04-569566
CAS PubMed Web of Science® Google Scholar
28Balsas P, Palomero J, Eguileor A, et al. SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma. Blood. 2017; 130(4): 501-513.
10.1182/blood-2017-04-776740
CAS PubMed Web of Science® Google Scholar
29Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017; 130(17): 1903-1910.
10.1182/blood-2017-04-779736
CAS PubMed Web of Science® Google Scholar
30Hershkovitz-Rokah O, Pulver D, Lenz G, Shpilberg O. Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects. Br J Haematol. 2018; 181(3): 306-319.
10.1111/bjh.15108
CAS PubMed Web of Science® Google Scholar
31Zhao X, Lwin T, Silva A, et al. Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat Commun. 2017; 8: 14920.
10.1038/ncomms14920
CAS PubMed Web of Science® Google Scholar
32Saba NS, Liu D, Herman SE, et al. Pathogenic role of B-cell receptor signaling and canonical NF-kappaB activation in mantle cell lymphoma. Blood. 2016; 128(1): 82-92.
10.1182/blood-2015-11-681460
CAS PubMed Web of Science® Google Scholar
33Rudelius M, Rosenfeldt MT, Leich E, et al. Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment. Haematologica. 2018; 103(1): 116-125.
10.3324/haematol.2017.177162
CAS PubMed Web of Science® Google Scholar
34Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009; 113(19): 4604-4613.
10.1182/blood-2008-10-185827
CAS PubMed Web of Science® Google Scholar
35Bernard S, Danglade D, Gardano L, et al. Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma. Int J Cancer. 2015; 136(12): 2761-2774.
10.1002/ijc.29326
CAS PubMed Web of Science® Google Scholar
36Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20): 2375-2390.
10.1182/blood-2016-01-643569
CAS PubMed Web of Science® Google Scholar
37Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res. 2012; 72(20): 5307-5316.
10.1158/0008-5472.CAN-12-1615
CAS PubMed Web of Science® Google Scholar
38Navarro A, Clot G, Prieto M, et al. microRNA expression profiles identify subtypes of mantle cell lymphoma with different clinicobiological characteristics. Clin Cancer Res. 2013; 19(12): 3121-3129.
10.1158/1078-0432.CCR-12-3077
CAS PubMed Web of Science® Google Scholar
39Queiros AC, Beekman R, Vilarrasa-Blasi R, et al. Decoding the DNA Methylome of mantle cell lymphoma in the light of the entire B cell lineage. Cancer Cell. 2016; 30(5): 806-821.
10.1016/j.ccell.2016.09.014
CAS PubMed Web of Science® Google Scholar
40Royo C, Navarro A, Clot G, et al. Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease. Leukemia. 2012; 26(8): 1895-1898.
10.1038/leu.2012.72
CAS PubMed Web of Science® Google Scholar
41Hu Z, Sun Y, Schlette EJ, et al. CD200 expression in mantle cell lymphoma identifies a unique subgroup of patients with frequent IGHV mutations, absence of SOX11 expression, and an indolent clinical course. Mod Pathol. 2018; 31(2): 327-336.
10.1038/modpathol.2017.135
CAS PubMed Web of Science® Google Scholar
42Ruskone-Fourmestraux A, Delmer A, Lavergne A, et al. Multiple lymphomatous polyposis of the gastrointestinal tract: prospective clinicopathologic study of 31 cases. Gastroenterology. 1997; 112(1): 7-16.
10.1016/S0016-5085(97)70212-9
PubMed Web of Science® Google Scholar
43Romaguera JE, Medeiros LJ, Hagemeister FB, et al. Frequency of gastrointestinal involvement and its clinical significance in mantle cell lymphoma. Cancer. 2003; 97(3): 586-591.
10.1002/cncr.11096
PubMed Web of Science® Google Scholar
44Gill S, Herbert KE, Prince HM, et al. Mantle cell lymphoma with central nervous system involvement: frequency and clinical features. Br J Haematol. 2009; 147(1): 83-88.
10.1111/j.1365-2141.2009.07835.x
CAS PubMed Web of Science® Google Scholar
45Cheah CY, George A, Gine E, et al. Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European mantle cell lymphoma network. Ann Oncol. 2013; 24(8): 2119-2123.
10.1093/annonc/mdt139
CAS PubMed Web of Science® Google Scholar
46Ye H, Desai A, Zeng D, et al. Smoldering mantle cell lymphoma. J Exp Clin Cancer Res. 2017; 36(1): 185.
10.1186/s13046-017-0652-8
PubMed Web of Science® Google Scholar
47Ondrejka SL, Lai R, Smith SD, Hsi ED. Indolent mantle cell leukemia: a clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica. 2011; 96(8): 1121-1127.
10.3324/haematol.2010.036277
PubMed Web of Science® Google Scholar
48Abrisqueta P, Scott DW, Slack GW, et al. Observation as the initial management strategy in patients with mantle cell lymphoma. Ann Oncol. 2017; 28(10): 2489-2495.
10.1093/annonc/mdx333
CAS PubMed Web of Science® Google Scholar
49Klapper W, Hoster E, Determann O, et al. Ki-67 as a prognostic marker in mantle cell lymphoma-consensus guidelines of the pathology panel of the European MCL network. J Hematop. 2009; 2(2): 103-111.
10.1007/s12308-009-0036-x
PubMed Google Scholar
50Akhter A, Mahe E, Street L, et al. CD10-positive mantle cell lymphoma: biologically distinct entity or an aberrant immunophenotype? Insight, through gene expression profile in a unique case series. J Clin Pathol. 2015; 68(10): 844-848.
10.1136/jclinpath-2015-202955
CAS PubMed Web of Science® Google Scholar
51Liu Z, Dong HY, Gorczyca W, et al. CD5- mantle cell lymphoma. Am J Clin Pathol. 2002; 118(2): 216-224.
10.1309/TE56-A43X-29TT-5H8G
PubMed Web of Science® Google Scholar
52Fu K, Weisenburger DD, Greiner TC, et al. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood. 2005; 106(13): 4315-4321.
10.1182/blood-2005-04-1753
CAS PubMed Web of Science® Google Scholar
53Xu J, Wang L, Li J, et al. SOX11-negative mantle cell lymphoma: Clinicopathologic and prognostic features of 75 patients. Am J Surg Pathol. 2019; 43(5): 710-716.
10.1097/PAS.0000000000001233
PubMed Web of Science® Google Scholar
54Schlette E, Fu K, Medeiros LJ. CD23 expression in mantle cell lymphoma: clinicopathologic features of 18 cases. Am J Clin Pathol. 2003; 120(5): 760-766.
10.1309/XV4AG7EMWQU7ER67
CAS PubMed Web of Science® Google Scholar
55Carvajal-Cuenca A, Sua LF, Silva NM, et al. In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior. Haematologica. 2012; 97(2): 270-278.
10.3324/haematol.2011.052621
PubMed Web of Science® Google Scholar
56Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. Blood. 2018; 131(21): 2283-2296.
10.1182/blood-2017-10-764373
CAS PubMed Web of Science® Google Scholar
57van der Velden VH, Hoogeveen PG, de Ridder D, et al. B-cell prolymphocytic leukemia: a specific subgroup of mantle cell lymphoma. Blood. 2014; 124(3): 412-419.
10.1182/blood-2013-10-533869
CAS PubMed Web of Science® Google Scholar
58Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008; 111(2): 558-565.
10.1182/blood-2007-06-095331
CAS PubMed Web of Science® Google Scholar
59Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European mantle cell lymphoma network. J Clin Oncol. 2016; 34(12): 1386-1394.
10.1200/JCO.2015.63.8387
CAS PubMed Web of Science® Google Scholar
60Nygren L, Baumgartner Wennerholm S, Klimkowska M, Christensson B, Kimby E, Sander B. Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood. 2012; 119(18): 4215-4223.
10.1182/blood-2011-12-400580
CAS PubMed Web of Science® Google Scholar
61Nordstrom L, Sernbo S, Eden P, et al. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma--a Nordic lymphoma group study. Br J Haematol. 2014; 166(1): 98-108.
10.1111/bjh.12854
CAS PubMed Web of Science® Google Scholar
62Aukema SM, Hoster E, Rosenwald A, et al. Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL network. Blood. 2018; 131(4): 417-420.
10.1182/blood-2017-07-797019
CAS PubMed Web of Science® Google Scholar
63Clot G, Jares P, Gine E, et al. A gene signature that distinguishes conventional and leukemic nonnodal mantle cell lymphoma helps predict outcome. Blood. 2018; 132(4): 413-422.
10.1182/blood-2018-03-838136
CAS PubMed Web of Science® Google Scholar
64Schraders M, Pfundt R, Straatman HM, et al. Novel chromosomal imbalances in mantle cell lymphoma detected by genome-wide array-based comparative genomic hybridization. Blood. 2005; 105(4): 1686-1693.
10.1182/blood-2004-07-2730
CAS PubMed Web of Science® Google Scholar
65Sarkozy C, Terre C, Jardin F, et al. Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival, independent of the MCL international prognostic index. Genes Chromosomes Cancer. 2014; 53(1): 106-116.
10.1002/gcc.22123
CAS PubMed Web of Science® Google Scholar
66Greenwell IB, Staton AD, Lee MJ, et al. Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy. Cancer. 2018; 124(11): 2306-2315.
10.1002/cncr.31328
PubMed Web of Science® Google Scholar
67Thorselius M, Walsh S, Eriksson I, et al. Somatic hypermutation and V(H) gene usage in mantle cell lymphoma. Eur J Haematol. 2002; 68(4): 217-224.
10.1034/j.1600-0609.2002.01662.x
CAS PubMed Web of Science® Google Scholar
68Pinyol M, Hernandez L, Cazorla M, et al. Deletions and loss of expression of p16INK4a and p21Waf1 genes are associated with aggressive variants of mantle cell lymphomas. Blood. 1997; 89(1): 272-280.
10.1182/blood.V89.1.272
CAS PubMed Web of Science® Google Scholar
69Agarwal R, Chan YC, Tam CS, et al. Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat Med. 2018; 25(1): 119-129.
10.1038/s41591-018-0243-z
PubMed Web of Science® Google Scholar
70Choe JY, Yun JY, Na HY, et al. MYC overexpression correlates with MYC amplification or translocation, and is associated with poor prognosis in mantle cell lymphoma. Histopathology. 2016; 68(3): 442-449.
10.1111/his.12760
PubMed Web of Science® Google Scholar
71Lee J, Zhang LL, Wu W, et al. Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma. Blood Adv. 2018; 2(16): 2039-2051.
10.1182/bloodadvances.2018016048
CAS PubMed Web of Science® Google Scholar
72Hu Z, Medeiros LJ, Chen Z, et al. Mantle cell lymphoma with MYC rearrangement: a report of 17 patients. Am J Surg Pathol. 2017; 41(2): 216-224.
10.1097/PAS.0000000000000758
PubMed Web of Science® Google Scholar
73Nagy B, Lundan T, Larramendy ML, et al. Abnormal expression of apoptosis-related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma. Br J Haematol. 2003; 120(3): 434-441.
10.1046/j.1365-2141.2003.04121.x
CAS PubMed Web of Science® Google Scholar
74Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood. 2012; 119(9): 1963-1971.
10.1182/blood-2011-11-391474
CAS PubMed Web of Science® Google Scholar
75Bea S, Valdes-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA. 2013; 110(45): 18250-18 255.
10.1073/pnas.1314608110
CAS PubMed Web of Science® Google Scholar
76Yang P, Zhang W, Wang J, Liu Y, An R, Jing H. Genomic landscape and prognostic analysis of mantle cell lymphoma. Cancer Gene Ther. 2018; 25(5-6): 129-140.
10.1038/s41417-018-0022-5
CAS PubMed Web of Science® Google Scholar
77Mohanty A, Sandoval N, Das M, et al. CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma. Oncotarget. 2016; 7(45): 73558-73 572.
10.18632/oncotarget.12434
PubMed Google Scholar
78von Hohenstaufen KA, Conconi A, de Campos CP, et al. Prognostic impact of monocyte count at presentation in mantle cell lymphoma. Br J Haematol. 2013; 162(4): 465-473.
10.1111/bjh.12409
CAS PubMed Web of Science® Google Scholar
79Rahal R, Frick M, Romero R, et al. Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat Med. 2014; 20(1): 87-92.
10.1038/nm.3435
CAS PubMed Web of Science® Google Scholar
80Scott DW, Abrisqueta P, Wright GW, et al. New molecular assay for the proliferation signature in mantle cell lymphoma applicable to formalin-fixed paraffin-embedded biopsies. J Clin Oncol. 2017; 35(15): 1668-1677.
10.1200/JCO.2016.70.7901
CAS PubMed Web of Science® Google Scholar
81Rauert-Wunderlich H, Mottok A, Scott DW, et al. Validation of the MCL35 gene expression proliferation assay in randomized trials of the European mantle cell lymphoma network. Br J Haematol. 2019; 184(4): 616-624.
10.1111/bjh.15519
CAS PubMed Web of Science® Google Scholar
82Holte H, Beiske K, Boyle M, et al. The MCL35 gene expression proliferation assay predicts high-risk MCL patients in a Norwegian cohort of younger patients given intensive first line therapy. Br J Haematol. 2018; 183(2): 225-234.
10.1111/bjh.15518
CAS PubMed Web of Science® Google Scholar
83Bomben R, Ferrero S, D'Agaro T, et al. A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: results from the Fondazione Italiana Linfomi MCL-0208 trial. Haematologica. 2018; 103(5): 849-856.
10.3324/haematol.2017.184325
CAS PubMed Web of Science® Google Scholar
84D'Agaro T, Zucchetto A, Vit F, et al. A B-cell receptor-related gene signature predicts response to ibrutinib treatment in mantle cell lymphoma cell lines. Haematologica. 2019; haematol.2018.212811.
PubMed Google Scholar
85Goswami RS, Atenafu EG, Xuan Y, et al. MicroRNA signature obtained from the comparison of aggressive with indolent non-Hodgkin lymphomas: potential prognostic value in mantle-cell lymphoma. J Clin Oncol. 2013; 31(23): 2903-2911.
10.1200/JCO.2012.45.3050
PubMed Web of Science® Google Scholar
86Husby S, Ralfkiaer U, Garde C, et al. miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood. 2015; 125(17): 2669-2677.
10.1182/blood-2014-06-584193
CAS PubMed Web of Science® Google Scholar
87Lamonica D, Graf DA, Munteanu MC, Czuczman MS. 18F-FDG PET for measurement of response and prediction of outcome to relapsed or refractory mantle cell lymphoma therapy with Bendamustine-rituximab. J Nucl Med. 2017; 58(1): 62-68.
10.2967/jnumed.116.173542
CAS PubMed Web of Science® Google Scholar
88Jain P, Kanagal-Shamanna R, Zhang S, et al. Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib. Br J Haematol. 2018; 183(4): 578-587.
10.1111/bjh.15567
CAS PubMed Web of Science® Google Scholar
89Agarwal R, Dawson MA, Dreyling M, Tam CS. Understanding resistance mechanisms to BTK and BCL2 inhibitors in mantle cell lymphoma: implications for design of clinical trials. Leuk Lymphoma. 2018; 59(12): 2769-2781.
10.1080/10428194.2018.1457148
CAS PubMed Web of Science® Google Scholar
90Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017; 377(13): 1250-1260.
10.1056/NEJMoa1701769
CAS PubMed Web of Science® Google Scholar
91Goy A, Bernstein SH, Kahl BS, et al. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol. 2009; 20(3): 520-525.
10.1093/annonc/mdn656
CAS PubMed Web of Science® Google Scholar
92Wang M, Fayad L, Wagner-Bartak N, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012; 13(7): 716-723.
10.1016/S1470-2045(12)70200-0
PubMed Web of Science® Google Scholar
93Rule S, Jurczak W, Jerkeman M, et al. Ibrutinib vs temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia. 2018; 32: 1799-1803.
10.1038/s41375-018-0023-2
CAS PubMed Web of Science® Google Scholar
94Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010; 107(29): 13075-13 080.
10.1073/pnas.1004594107
CAS PubMed Web of Science® Google Scholar
95Harrington BK, Gardner HL, Izumi R, et al. Preclinical evaluation of the novel BTK inhibitor Acalabrutinib in canine models of B-cell non-Hodgkin lymphoma. PLoS One. 2016; 11(7): e0159607.
10.1371/journal.pone.0159607
PubMed Web of Science® Google Scholar
96Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013; 369(6): 507-516.
10.1056/NEJMoa1306220
CAS PubMed Web of Science® Google Scholar
97Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369(1): 32-42.
10.1056/NEJMoa1215637
CAS PubMed Web of Science® Google Scholar
98Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015; 126(6): 739-745.
10.1182/blood-2015-03-635326
CAS PubMed Web of Science® Google Scholar
99Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018; 391(10121): 659-667.
10.1016/S0140-6736(17)33108-2
CAS PubMed Web of Science® Google Scholar
100Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of Venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017; 35(8): 826-833.
10.1200/JCO.2016.70.4320
CAS PubMed Web of Science® Google Scholar
101Eyre TA, Walter HS, Iyengar S, et al. Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy. Haematologica. 2019; 104(2): e68-e71.
10.3324/haematol.2018.198812
CAS PubMed Web of Science® Google Scholar
102Jain P, Kanagal-Shamanna R, Zhang S, et al. Outcomes, causes of discontinuation and mutation profile of patients with mantle cell lymphoma who progressed on Acalabrutinib. Blood. 2018; 132(Suppl 1): 4151-4151.
10.1182/blood-2018-99-115179
Web of Science® Google Scholar
103Pham LV, Huang S, Zhang H, et al. Strategic therapeutic targeting to overcome Venetoclax resistance in aggressive B-cell lymphomas. Clin Cancer Res. 2018; 24(16): 3967-3980.
10.1158/1078-0432.CCR-17-3004
CAS PubMed Web of Science® Google Scholar
104McCulloch R, Smith A, Crosbie N, Patmore R, Rule S. Receiving treatment at a specialist Centre confers an overall survival benefit for patients with mantle cell lymphoma. Br J Haematol. 2018.
10.1111/bjh.15696
PubMed Web of Science® Google Scholar
105Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009; 27(8): 1209-1213.
10.1200/JCO.2008.19.6121
PubMed Web of Science® Google Scholar
106Cohen JB, Han X, Jemal A, Ward EM, Flowers CR. Deferred therapy is associated with improved overall survival in patients with newly diagnosed mantle cell lymphoma. Cancer. 2016; 122(15): 2356-2363.
10.1002/cncr.30068
CAS PubMed Web of Science® Google Scholar
107Leitch HA, Gascoyne RD, Chhanabhai M, Voss NJ, Klasa R, Connors JM. Limited-stage mantle-cell lymphoma. Ann Oncol. 2003; 14(10): 1555-1561.
10.1093/annonc/mdg414
CAS PubMed Web of Science® Google Scholar
108Chihara D, Cheah CY, Westin JR, et al. Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center. Br J Haematol. 2016; 172(1): 80-88.
10.1111/bjh.13796
CAS PubMed Web of Science® Google Scholar
109Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005; 23(28): 7013-7023.
10.1200/JCO.2005.01.1825
CAS PubMed Web of Science® Google Scholar
110Romaguera JE, Fayad LE, Feng L, et al. Ten-year follow-up after intense chemoimmunotherapy with rituximab-HyperCVAD alternating with rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol. 2010; 150(2): 200-208.
10.1111/j.1365-2141.2010.08228.x
CAS PubMed Web of Science® Google Scholar
111Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic lymphoma group. Blood. 2008; 112(7): 2687-2693.
10.1182/blood-2008-03-147025
CAS PubMed Web of Science® Google Scholar
112Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the second Nordic mantle cell lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016; 175(3): 410-418.
10.1111/bjh.14241
CAS PubMed Web of Science® Google Scholar
113Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012; 158(3): 355-362.
10.1111/j.1365-2141.2012.09174.x
CAS PubMed Web of Science® Google Scholar
114Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL younger): a randomised, open-label, phase 3 trial of the European mantle cell lymphoma network. Lancet. 2016; 388(10044): 565-575.
10.1016/S0140-6736(16)00739-X
CAS PubMed Web of Science® Google Scholar
115Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab vs CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013; 381(9873): 1203-1210.
10.1016/S0140-6736(12)61763-2
CAS PubMed Web of Science® Google Scholar
116Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014; 123(19): 2944-2952.
10.1182/blood-2013-11-531327
CAS PubMed Web of Science® Google Scholar
117Flinn IW, van der Jagt R, Kahl B, et al. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with Bendamustine plus rituximab vs R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019; JCO1800605.
Web of Science® Google Scholar
118Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018; 19(11): 1449-1458.
10.1016/S1470-2045(18)30685-5
CAS PubMed Web of Science® Google Scholar
119Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015; 373(19): 1835-1844.
10.1056/NEJMoa1505237
CAS PubMed Web of Science® Google Scholar
120Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018; 132(19): 2016-2025.
10.1182/blood-2018-07-859769
CAS PubMed Web of Science® Google Scholar
121Gerson JN, Handorf E, Villa D, et al. Survival outcomes of younger patients with mantle cell lymphoma treated in the rituximab era. J Clin Oncol. 2019; 37(6): 471-480.
10.1200/JCO.18.00690
CAS PubMed Web of Science® Google Scholar
122Romaguera JE, Wang M, Feng L, et al. Phase 2 trial of bortezomib in combination with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with bortezomib, rituximab, methotrexate, and cytarabine for untreated mantle cell lymphoma. Cancer. 2018; 124(12): 2561-2569.
10.1002/cncr.31361
CAS PubMed Web of Science® Google Scholar
123Merli F, Luminari S, Ilariucci F, et al. Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano studio Linfomi. Br J Haematol. 2012; 156(3): 346-353.
10.1111/j.1365-2141.2011.08958.x
CAS PubMed Web of Science® Google Scholar
124Bernstein SH, Epner E, Unger JM, et al. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Ann Oncol. 2013; 24(6): 1587-1593.
10.1093/annonc/mdt070
CAS PubMed Web of Science® Google Scholar
125Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013; 121(1): 48-53.
10.1182/blood-2011-09-370320
CAS PubMed Web of Science® Google Scholar
126Armand P, Redd R, Bsat J, et al. A phase 2 study of rituximab-Bendamustine and rituximab-Cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 2016; 173(1): 89-95.
10.1111/bjh.13929
CAS PubMed Web of Science® Google Scholar
127Frosch Z, Luskin MR, Landsburg DJ, et al. R-CHOP or R-HyperCVAD with or without autologous stem cell transplantation for older patients with mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2015; 15(2): 92-97.
10.1016/j.clml.2014.07.017
PubMed Web of Science® Google Scholar
128Roue G, Lopez-Guerra M, Milpied P, et al. Bendamustine is effective in p53-deficient B-cell neoplasms and requires oxidative stress and caspase-independent signaling. Clin Cancer Res. 2008; 14(21): 6907-6915.
10.1158/1078-0432.CCR-08-0388
CAS PubMed Web of Science® Google Scholar
129Rummel MJ, Maschmeyer G, Ganser A, et al. Bendamustine plus rituximab (B-R) vs CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: nine-year updated results from the StiL NHL1 study. J Clin Oncol. 2017; 35(15_suppl): 7501-7501.
10.1200/JCO.2017.35.15_suppl.7501
Web of Science® Google Scholar
130Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017; 4(1): e15-e23.
10.1016/S2352-3026(16)30185-5
PubMed Web of Science® Google Scholar
131Albertsson-Lindblad A, Kolstad A, Laurell A, et al. Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma. Blood. 2016; 128(14): 1814-1820.
10.1182/blood-2016-03-704023
CAS PubMed Web of Science® Google Scholar
132Gressin R, Daguindau N, Tempescul A, et al. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma. Haematologica. 2019; 104(1): 138-146.
10.3324/haematol.2018.191429
CAS PubMed Web of Science® Google Scholar
133Robak T, Huang H, Jin J, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015; 372(10): 944-953.
10.1056/NEJMoa1412096
CAS PubMed Web of Science® Google Scholar
134Hoster E, Pott C. Minimal residual disease in mantle cell lymphoma: insights into biology and impact on treatment. Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 437-445.
10.1182/asheducation-2016.1.437
PubMed Web of Science® Google Scholar
135Ferrero S, Dreyling M. European mantle cell lymphoma N. minimal residual disease in mantle cell lymphoma: are we ready for a personalized treatment approach? Haematologica. 2017; 102(7): 1133-1136.
10.3324/haematol.2017.167627
CAS PubMed Web of Science® Google Scholar
136Kolstad A, Pedersen LB, Eskelund CW, et al. Molecular monitoring after autologous stem cell transplantation and preemptive rituximab treatment of molecular relapse; results from the Nordic mantle cell lymphoma studies (MCL2 and MCL3) with median follow-up of 8.5 years. Biol Blood Marrow Transplant. 2017; 23(3): 428-435.
10.1016/j.bbmt.2016.12.634
CAS PubMed Web of Science® Google Scholar
137Liu H, Johnson JL, Koval G, et al. Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909. Haematologica. 2012; 97(4): 579-585.
10.3324/haematol.2011.050203
CAS PubMed Web of Science® Google Scholar
138Pott C, Bruggemann M, Ritgen M, van der Velden VHJ, van Dongen JJM, Kneba M. MRD detection in B-cell non-Hodgkin lymphomas using Ig gene rearrangements and chromosomal translocations as targets for real-time quantitative PCR. Methods Mol Biol. 1956; 2019: 199-228.
Google Scholar
139Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus Venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018; 378(13): 1211-1223.
10.1056/NEJMoa1715519
CAS PubMed Web of Science® Google Scholar
140Rule S, Dreyling M, Goy A, et al. Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow-up from a pooled analysis. Haematologica. 2018; haematol.2018.205229.
PubMed Google Scholar
141Song Y, Zhou K, Zou D, et al. Safety and activity of the investigational Bruton tyrosine kinase inhibitor Zanubrutinib (BGB-3111) in patients with mantle cell lymphoma from a phase 2 trial. Blood. 2018; 132(Suppl 1): 148-148.
10.1182/blood-2018-99-117956
PubMed Web of Science® Google Scholar
142Wang M, Fayad L, Cabanillas F, et al. Phase 2 trial of rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine for relapsed or refractory aggressive mantle cell lymphoma. Cancer. 2008; 113(10): 2734-2741.
10.1002/cncr.23880
CAS PubMed Web of Science® Google Scholar
143Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006; 24(30): 4867-4874.
10.1200/JCO.2006.07.9665
PubMed Web of Science® Google Scholar
144O'Connor OA, Moskowitz C, Portlock C, et al. Patients with chemotherapy-refractory mantle cell lymphoma experience high response rates and identical progression-free survivals compared with patients with relapsed disease following treatment with single agent bortezomib: results of a multicentre phase 2 clinical trial. Br J Haematol. 2009; 145(1): 34-39.
10.1111/j.1365-2141.2008.07466.x
CAS PubMed Web of Science® Google Scholar
145Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009; 27(23): 3822-3829.
10.1200/JCO.2008.20.7977
CAS PubMed Web of Science® Google Scholar
146Trneny M, Lamy T, Walewski J, et al. Lenalidomide vs investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016; 17(3): 319-331.
10.1016/S1470-2045(15)00559-8
CAS PubMed Web of Science® Google Scholar
147Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol. 2013; 31(29): 3688-3695.
10.1200/JCO.2013.49.2835
CAS PubMed Web of Science® Google Scholar
148Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013; 31(23): 2912-2919.
10.1200/JCO.2012.46.9585
CAS PubMed Web of Science® Google Scholar
149Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014; 123(22): 3398-3405.
10.1182/blood-2013-11-537555
CAS PubMed Web of Science® Google Scholar
150Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016; 127(12): 1559-1563.
10.1182/blood-2015-10-673145
CAS PubMed Web of Science® Google Scholar
151McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014; 124(25): 3829-3830.
10.1182/blood-2014-10-604272
CAS PubMed Web of Science® Google Scholar
152Tuomi JM, Xenocostas A, Jones DL. Increased susceptibility for atrial and ventricular cardiac arrhythmias in mice treated with a single high dose of Ibrutinib. Can J Cardiol. 2018; 34(3): 337-341.
10.1016/j.cjca.2017.12.001
PubMed Web of Science® Google Scholar
153Cheng C, Woronow D, Nayernama A, Wroblewski T, Jones SC. Ibrutinib-associated ventricular arrhythmia in the FDA adverse event reporting system. Leuk Lymphoma. 2018; 59(12): 3016-3017.
10.1080/10428194.2018.1457149
PubMed Web of Science® Google Scholar
154Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014; 124(26): 3991-3995.
10.1182/blood-2014-06-583294
CAS PubMed Web of Science® Google Scholar
155Chang BY, Francesco M, De Rooij MF, et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013; 122(14): 2412-2424.
10.1182/blood-2013-02-482125
CAS PubMed Web of Science® Google Scholar
156Rule S, Dreyling M, Goy A, et al. Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies. Br J Haematol. 2017; 179(3): 430-438.
10.1111/bjh.14870
CAS PubMed Web of Science® Google Scholar
157Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-Centre, open-label, phase 2 trial. Lancet Oncol. 2016; 17(1): 48-56.
10.1016/S1470-2045(15)00438-6
CAS PubMed Web of Science® Google Scholar
158Jain P, Romaguera J, Srour SA, et al. Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL). Br J Haematol. 2018; 182(3): 404-411.
10.1111/bjh.15411
CAS PubMed Web of Science® Google Scholar
159Jerkeman M, Eskelund CW, Hutchings M, et al. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Lancet Haematol. 2018; 5(3): e109-e116.
10.1016/S2352-3026(18)30018-8
PubMed Web of Science® Google Scholar
160Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests Venetoclax (ABT-199) as optimal partner with Ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015; 21(16): 3705-3715.
10.1158/1078-0432.CCR-14-2809
CAS PubMed Web of Science® Google Scholar
161Martin P, Bartlett NL, Blum KA, et al. A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma. Blood. 2019; 133(11): 1201-1204.
10.1182/blood-2018-11-886457
CAS PubMed Web of Science® Google Scholar
162Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell receptor signaling by Ibrutinib in primary CNS lymphoma. Cancer Cell. 2017; 31(6): 833-843. e835.
10.1016/j.ccell.2017.04.012
CAS PubMed Web of Science® Google Scholar
163Grommes C, Pastore A, Palaskas N, et al. Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov. 2017; 7(9): 1018-1029.
10.1158/2159-8290.CD-17-0613
CAS PubMed Web of Science® Google Scholar
164Grommes C, Tang SS, Wolfe J, et al. Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood. 2019; 133(5): 436-445.
10.1182/blood-2018-09-875732
CAS PubMed Web of Science® Google Scholar
165Bernard S, Goldwirt L, Amorim S, et al. Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Blood. 2015; 126(14): 1695-1698.
10.1182/blood-2015-05-647834
CAS PubMed Web of Science® Google Scholar
166Kanagal-Shamanna R, Jain P, Patel KP, et al. Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor-resistant chronic lymphocytic leukemia with disease progression and Richter transformation. Cancer. 2019; 125(4): 559-574.
10.1002/cncr.31831
CAS PubMed Web of Science® Google Scholar
167Dobrovolsky D, Wang ES, Morrow S, et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood. 2019; 133(9): 952-961.
10.1182/blood-2018-07-862953
CAS PubMed Web of Science® Google Scholar
168Ming M, Wu W, Xie B, et al. XPO1 inhibitor Selinexor overcomes intrinsic Ibrutinib resistance in mantle cell lymphoma via nuclear retention of IkappaB. Mol Cancer Ther. 2018; 17(12): 2564-2574.
CAS PubMed Web of Science® Google Scholar
169Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017; 363(2): 240-252.
10.1124/jpet.117.242909
CAS PubMed Web of Science® Google Scholar
170Bye AP, Unsworth AJ, Desborough MJ, et al. Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib. Blood Adv. 2017; 1(26): 2610-2623.
10.1182/bloodadvances.2017011999
CAS PubMed Web of Science® Google Scholar
171Wang M, Rule S, Zinzani PL, et al. Long-term follow-up of Acalabrutinib Monotherapy in patients with relapsed/refractory mantle cell lymphoma. Blood. 2018; 132(Suppl 1): 2876-2876.
10.1182/blood-2018-99-110327
Web of Science® Google Scholar
172Blombery P, Anderson MA, Gong JN, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to Venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019; 9(3): 342-353.
10.1158/2159-8290.CD-18-1119
CAS PubMed Web of Science® Google Scholar
173Herling CD, Abedpour N, Weiss J, et al. Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun. 2018; 9(1): 727.
10.1038/s41467-018-03170-7
PubMed Web of Science® Google Scholar
174Robinson SP, Boumendil A, Finel H, et al. Long-term outcome analysis of reduced-intensity allogeneic stem cell transplantation in patients with mantle cell lymphoma: a retrospective study from the EBMT lymphoma working party. Bone Marrow Transplant. 2018; 53(5): 617-624.
10.1038/s41409-017-0067-3
CAS PubMed Web of Science® Google Scholar
175Lin RJ, Ho C, Hilden PD, et al. Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with TP53 alterations. Br J Haematol. 2019; 184(6): 1006-1010.
10.1111/bjh.15721
CAS PubMed Web of Science® Google Scholar
176Tam CS, Wang M, Simpson D, et al. Updated safety and activity of the investigational Bruton tyrosine kinase inhibitor Zanubrutinib (BGB-3111) in patients with mantle cell lymphoma. Blood. 2018; 132(Suppl 1): 1592-1592.
Google Scholar
177Reiff SD, Mantel R, Smith LL, et al. The BTK inhibitor ARQ 531 targets Ibrutinib-resistant CLL and Richter transformation. Cancer Discov. 2018; 8(10): 1300-1315.
10.1158/2159-8290.CD-17-1409
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume94, Issue6

June 2019

Pages 710-725

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Abstract

1 INTRODUCTION

2 ADVANCES IN THE PATHOGENESIS OF MCL

3 CLINICAL PRESENTATION, DIAGNOSTIC APPROACH AND ADVANCES IN THE CLINICAL PATHOLOGY OF MCL

3.1 Clinical course

3.2 Clinical evaluation, diagnostic work up, and clinical significance

4 ADVANCES IN MCL PROGNOSTICATION

5 ADVANCES IN THE TREATMENT OF MCL

5.1 Wait-and-watch strategy

5.2 Previously untreated newly diagnosed MCL patient

5.3 Young physically fit patients

5.4 Elderly or physically unfit patients (any age)

5.5 Minimal residual disease in MCL

5.6 Treatment approaches in 2019

5.7 Our treatment approach in 2019

5.8 Previously treated, relapsed MCL

5.9 Chemotherapy-free treatment options in relapsed MCL

5.10 Other promising newer modalities

6 SUMMARY

ACKNOWLEDGMENTS

CONFLICT OF INTEREST

REFERENCES

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Abstract

1 INTRODUCTION

2 ADVANCES IN THE PATHOGENESIS OF MCL

3 CLINICAL PRESENTATION, DIAGNOSTIC APPROACH AND ADVANCES IN THE CLINICAL PATHOLOGY OF MCL

3.1 Clinical course

3.2 Clinical evaluation, diagnostic work up, and clinical significance

4 ADVANCES IN MCL PROGNOSTICATION

5 ADVANCES IN THE TREATMENT OF MCL

5.1 Wait-and-watch strategy

5.2 Previously untreated newly diagnosed MCL patient

5.3 Young physically fit patients

5.4 Elderly or physically unfit patients (any age)

5.5 Minimal residual disease in MCL

5.6 Treatment approaches in 2019

5.7 Our treatment approach in 2019

5.8 Previously treated, relapsed MCL

5.9 Chemotherapy-free treatment options in relapsed MCL

5.10 Other promising newer modalities

6 SUMMARY

ACKNOWLEDGMENTS

CONFLICT OF INTEREST

REFERENCES

Citing Literature

References

Related

Information