Rare case of mantle cell lymphoma of the lacrimal sac

ABSTRACT Mantle cell lymphoma of the ocular and periorbital regions is extremely rare but should be considered in the differential diagnosis of lesions affecting the periorbital tissues. In this study, we present a rare case of mantle cell lymphoma of the lacrimal sac in a 65-year-old male presenting with a mass in the lacrimal sac region and epiphora. After clinical examinations and imaging studies, the mucocele was misdiagnosed. Considering the unexpected findings during external dacryocystorhinostomy, a frozen biopsy was performed, which confirmed the diagnosis of lymphoma.

[Update on treatment strategies for mantle cell lymphoma].

Mantle cell lymphoma (MCL) is a type of lymphoid malignancy that is rare in Japan. MCL is refractory to conventional chemotherapy and has dismal outcomes. Nonetheless, the prognosis of MCL has gradually improved with the advent of autologous stem cell transplantation and BTK inhibitors. First-line therapies incorporating BTK inhibitors are currently under development, and are expected to further improve the prognosis. Nevertheless, subsets with poor prognosis have been identified, including p53 abnormalities (TP53 mutations or deletions), blastoid variant, high MIPI-c, and POD24, and these show resistance to conventional treatments including BTK inhibitors. To overcome these challenges, novel therapies such as CAR-T therapy and combination therapy with BTK and BCL2 inhibitors are being developed, and should soon become clinically available in Japan. The therapeutic landscape for MCL is evolving dynamically, and this article will discuss the future of MCL treatment strategies in Japan.

Mantle Cell Lymphoma in the Oral Cavity: Exploring the Differential Microscopic Diagnosis of a Rare Case.

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin's lymphoma (NHL), which generally has an aggressive course. Its pathophysiology seems to be related with the malignant transformation of B-cell mantle zone lymphocytes due to the CCND1 rearrangement. The occurrence of MCL in the oral cavity is especially rare. In this report, we present an exceptional case of oral MCL diagnosed in the palate in a 56-year-old male patient, highlighting its distinct morphological and immunohistochemical features that may assist in the accurate diagnosis.

[A multicenter retrospective study discussion on maintenance treatment strategies for mantle cell lymphoma].

Objective: This study aims to explore the survival advantages of different maintenance strategies for MCL. Methods: Clinical data of 693 newly diagnosed MCL patients in multi-centers admitted from April 1999 to December 2019 were collected. 309 cases received maintenance treatment. The characteristics of patients in different maintenance treatment groups were summarized and Kaplan-Meier survival and prognosis analysis were conducted. Results: The overall 3-year and 5-year progression-free survival (PFS) rates were (73.5±2.9) % and (53.6±4.3) %, respectively. The 3-year and 5-year overall survival (OS) rates were (94.2±1.5) % and (82.7±3.2) %, respectively. The clinical features of different maintenance treatment groups were generally consistent. The 3-year PFS rates of rituximab maintenance, lenalidomide maintenance, BTK inhibitor maintenance and dual-drug maintenance were (70.4±4.1) %, (69.1±7.6) %, (86.9±5.0) %, and (80.4±5.1) %, respectively. Corresponding 3-year OS rates were (92.9±2.4) %, (97.3±2.7) %, (97.9±2.1) %, and (95.3±2.7) %, respectively. There were no significant difference in different groups (P=0.632, 0.313). Survival analysis identified the MCL International Prognostic Index (MIPI) high-risk group and achieving complete remission before maintenance treatment as independent risk factors for PFS. The MIPI high-risk group, high-dose cytarabine application, treatment lines, and early disease progression (POD24) emerged as independent risk factors for OS. Conclusion: Comparing the different maintenance strategies of MCL, the result showed that BTK inhibitors (BTKi) maintenance demonstrated preliminary advantages in survival. Meanwhile, high-risk group according to MIPI and incomplete remission before maintenance treatment were significant factors related to disease progression.

Regulation of Biomineralization and Autophagy by the Stress-Sensing Transcription Factor CgRunx1 in Crassostrea gigas Under Daylight Ultraviolet B Radiation.

As human activities increase and environmental changes persist, increased ultraviolet B (UVB) radiation in aquatic ecosystems poses significant threats to aquatic life. This study, through transcriptomic analysis of the mantle tissue of Crassostrea gigas following UVB radiation exposure, identified and validated two key transcription factors, CgRunx1 and CgCBFß. The highest expression levels of CgRunx1 and CgCBFß in the mantle suggest their pivotal roles in this tissue. Co-immunoprecipitation experiments revealed that CgRunx1 and CgCBFß could form heterodimers and interact with each other. Furthermore, this study assessed the impact of UVB radiation on the levels of reactive oxygen species of the C. gigas, speculating that CgRunx1, as a potential redox-sensitive transcription factor, might be regulated by intracellular ROS. Through screening and binding site prediction analysis of target genes, coupled with dual-luciferase reporter assays, we verified that CgRunx1 might participate in regulating the biomineralization and autophagy processes in C. gigas by activating the transcriptional expression of target genes Transport and Golgi organization 1 and V-type proton ATPase catalytic subunit A. These findings provide new insights into the molecular response mechanisms of the C. gigas to UVB radiation and lay an important foundation for studying the adaptive evolution of bivalves to environmental stress.

Mantle cell lymphoma in the sphenoid sinus showing acute bilateral blindness.

A 57-year-old man was referred to our department with a mass in the sphenoid sinus. Surgical removal of the tumor was performed. However, a testicular mass was found that showed rapid growth. He had undergone inguinal orchiectomy. Five days after the urological surgery, he noticed visual disturbances and bilateral visual loss. Ophthalmological examination revealed total blindness, and magnetic resonance imaging revealed sphenoid mass growth. The patient underwent emergent removal of the tumor, and a diagnosis of malignant lymphoma was made. A final diagnosis of mantle cell lymphoma (MCL) in the testis and sphenoid sinus was made. After receiving treatment with intravenous corticosteroids and chemotherapy for lymphoma, his left vision completely recovered. Although his right vision was lost, he returned to normal social activities. This is the first report in the literature on MCL developing in the sphenoid sinus presenting with bilateral blindness and ipsilateral recovery.

Comparative analysis of the quality of the cement mantle in hip hemiarthroplasty after femoral neck fracture between three different surgical approaches: a single-center retrospective observational study.

PURPOSE: Achieving the initial stability of implants is necessary for hip hemiarthroplasty (HHA), especially in elderly patients, and this can be achieved with a cement mantle of quality. The direct anterior approach (DAA) for HHA lately has shown positive results. However, evidence is lacking of HHA in elderly patients with osteoporosis after femoral neck fracture (FNF). This study compares differences in cement mantle quality after HHA, its complications, radiological outcomes and functional status in elderly patients with FNF intervened through different approaches. METHODS: A non-interventional, retrospective case-control study was conducted. 150 cases were selected based on the surgical approach (DAA, DLA and PLA) in a 1:1:1 proportion between 2018 and 2019. Under 75 years old suspicion or confirmation of a pathological fracture were excluded. Antibiotic-loaded cement was utilized. Cement preparation involved vacuum centrifugation and standard instructions for preparation canal and filling, and prosthesis placement were followed. RESULTS: No statistically significant differences in cement mantle quality, radiological outcomes, and the majority of the postoperative complications and functional status considering the surgical approach (p > 0.05). However, the DAA was associated significantly with shorter hospital stays (8.3 days vs 11.3 and 13 days for DLA and PLA) a decrease in postoperative blood transfusion (22% vs 34% and 53%), and lower rate of loss of walking (8% vs 20% and 28.6%). CONCLUSION: The DAA for HHA in patients with FNF provides a high-quality cement mantle, similar to other approaches. Also, the DAA shows advantages like shorter hospital stays and lower transfusion rates in elderly patients.

Characterization of two carbonic anhydrase isoforms in the pulmonate snail (Lymnaea Stagnalis) and their involvement in Molluskan calcification.

Calcifying organisms are suffering from negative impacts induced by climate change, such as CO2-induced acidification, which may impair external calcified structures. Freshwater mollusks have the potential to suffer more from CO2-induced acidification than marine calcifiers due to the lower buffering capacity of many freshwater systems. One of the most important enzymes contributing to the biomineralization reaction is carbonic anhydrase (CA), which catalyzes the reversible conversion of CO2 to bicarbonate, the major carbon source of the calcareous structure in calcifiers. In this study we characterized two α-CA isoforms (LsCA1 and LsCA4) from the freshwater snail Lymnaea stagnalis using a combination of gene sequencing, gene expression, phylogenetic analysis and biochemical assays. Both CA isoforms demonstrated high expression levels in the mantle tissue, the major site for biomineralization. Furthermore, expression of LsCA4 during development parallels shell formation. The primary protein structure analysis, active site configuration and the catalytic activity of LsCA4 together suggest that the LsCA4 is embedded in the apical and basolateral membranes of mantle cells; while LsCA1 is proposed to be cytosolic and might play an important role in acid-base regulation. These findings of LsCA isoforms form a strong basis for a more detailed physiological understanding of the effects of elevated CO2 on calcification in freshwater mollusks.

Relapsed mantle cell lymphoma manifesting with soft tissue tumors of the extremities: University of Miami experience and review of the literature.

Mantle cell lymphoma (MCL) is frequently diagnosed at advanced stages and is characterized by multiple extranodal sites of disease, most notably the bone marrow, peripheral blood, and gastrointestinal tract. Historically the prognosis of mantle cell lymphoma has been poor with median survival of four to five years. With new treatment regimens, however, patients have been able to achieve prolonged remissions and require special attention while being evaluated for relapse. This report describes four patients treated for stage IV mantle cell lymphoma at the University of Miami who developed soft tissue relapse presenting as non-tender large masses of the extremities, including one patient who presented without associated nodal involvement. Average time to soft tissue relapse was 99 months (range: 28-240) following initial diagnosis. Providers who care for patients with mantle cell lymphoma should be aware of soft tissue lesions as a presentation of mantle cell lymphoma that merits evaluation for disease relapse.

Chimeric antigen receptor T-cell therapy in relapsed or refractory mantle cell lymphoma: a systematic review and meta-analysis.

Background: Chimeric antigen receptor (CAR) T-cell therapy (CAR-T therapy) has demonstrated significant efficacy in the ZUMA-2 study. After regulatory approvals, several clinical trials and real-world studies on CAR-T therapy for relapsed or refractory mantle cell lymphoma (R/R MCL) were conducted. However, data on clinical safety and efficacy are inconsistent. In this study, we aimed to conduct a systematic analysis of the effectiveness and safety of CAR-T therapy across a wider and more representative cohort of patients with R/R MCL. Methods: We performed a systematic review and meta-analysis of studies on patients with R/R MCL who received CAR-T cell therapy. Data were extracted and consolidated, with primary focus on the evaluation of safety and efficacy outcome measures. This study has not been registered with PROSPERO. Results: This meta-analysis identified and included 16 studies with 984 patients. The pooled estimate for overall response rate (ORR) was 89%; complete remission (CR) rate was 74%. The 6-month and 12-month progression-free survival (PFS) rates were 69% and 53%, respectively, while the overall survival (OS) rates were 80% and 69%, respectively. Cytokine release syndrome (CRS) of grade 3 or higher was observed in 8% of patients, whereas neurotoxicity of grade 3 or higher was observed in 22% of patients. The risk of bias was assessed as low in 9 studies and moderate in 7 studies. Conclusion: CAR-T therapy exhibited promising efficacy and manageable adverse reactions in patients with R/R MCL.

Emerging Role of Functional Magnetic Resonance Spectroscopy (MRS) to Monitor Response to Kinase Inhibitors in Cancer.

Inhibitors of kinases involved in signaling and other intracellular pathways, have revolutionized cancer treatment by providing highly targeted and effective therapies. However, timely monitoring treatment response remains a considerable challenge since conventional methods such as assessing changes in tumor volume do not adequately capture early responses or resistance development, due to the predominantly cytostatic rather than cytotoxic effect of kinase inhibitors. Magnetic resonance spectroscopy (MRS) is a non-invasive imaging technique that can provide insights into cellular metabolism by detecting changes in metabolite concentrations. By measuring metabolite levels, MRS offers a means to assess treatment response in real-time, providing earlier indications of efficacy or resistance compared to conventional imaging modalities. Bruton's Tyrosine Kinase (BTK) is a critical enzyme involved in B-cell receptor signaling. BTK inhibitors have been approved for the treatment of Mantle Cell Lymphoma (MCL) and other B-cell malignancies. Recent studies involving genome-scale gene expression, metabolomic, and fluxomic analyses have demonstrated that ibrutinib, an index BTK inhibitor, profoundly affects the key metabolic pathways in MCL cells., including glycolysis, glutaminolysis, pentose shunt, TCA cycle and phospholipid metabolism. Importantly, the effects of ibrutinib on MCL cells directly and proportionately correlates with their sensitivity to the drug. Consequently, changes in specific metabolite concentrations detectable non-invasively by MRS such as lactate and alanine reflecting mostly the status of cellular glycolysis and glutaminolysis, respectively, have emerged as potential biomarkers for predicting response and resistance of MCL cells to BTK inhibition, both in vitro and in vivo. Preparations to validate the utility of these biomarkers in clinical setting are under way. These studies may pave the way to monitor therapeutic response to kinase inhibitors also in other types of cancer.

Mantle plume trail beneath the ca. 1.1 Ga North American Midcontinent Rift revealed by magnetotelluric data.

Whilst the 1.1 Ga North American Midcontinent Rift (MCR) system is formed in association with the Keweenaw mantle plume, the absence of a northern third rift arm or aulacogen (a general characteristic of mantle plumes) has previously not been well understood. To help clarify this unusual plume-rift relationship and to better establish the region affected by the Keweenaw mantle plume, we present the first electrical resistivity model of the MCR derived from 3D inversion of EarthScope USArray and Lithoprobe magnetotelluric (MT) data, extending northwards into the Archean Superior Province. Our model shows a prominent highly conductive anomaly trending NW-SE at the base of Western Superior's cratonic lithospheric mantle, cross-cutting and extending for over 300 km on both sides of the western rift branch. We propose that this anomaly reflects the ancient signature of a plume trail, resulting from metasomatism and/or partial melting of the sulfide-rich basal lithospheric mantle during impingement of the Keweenaw mantle plume.

Clinical and pathological characteristics of blastoid mantle cell lymphoma: a single institution experience.

Background: Blastoid mantle cell lymphoma (B-MCL) is a rare aggressive lymphoma. It is characterized by blastoid morphology with high proliferation and inconsistent immunohistochemistry (IHC), making it a diagnostic challenge for the pathologist. Methods: This is a retrospective analytical cohort study. We reviewed biopsy confirmed cases of B-MCL diagnosed over a period of 10 years (January 2012 to December 2022). The clinical presentation, histopathological and IHC findings, treatment received, and survival outcomes were studied. Randomly selected cases of classic MCL (n=12), diagnosed during the same period served as controls. Results: A total of 12 cases were studied. Four cases were transformed from previously diagnosed MCL; 8 cases arose de novo. Mean age was 61.17 years and the male: female ratio was 5:1. Half of the cases showed extra nodal extension and 81.8% had bone marrow involvement. Gastrointestinal tract was the most common site of extra nodal involvement. Histopathological examination showed diffuse involvement of the lymph node with medium sized cells. On immunohistochemistry, one of the cases showed loss of CD5 expression while the other had aberrant CD10 expression. Mean Ki-67 index was 58.09% in the cases and 16.33% in controls and was statistically significant ( p=0.005). The median overall survival (OS) for cases was 2 years vs 8 years in controls. The p53 over expression (>30% nuclear positivity) was seen in 66.6% cases (4/6). Conclusion: There are several factors that contribute to the aggressiveness of B-MCL, and new treatment approaches might be required to improve patient outcomes.

MegaAppendix: a rare case of mantle cell lymphoma in an appendix presented as volvulus.

Mantle cell lymphoma (MCL), representing 5% of cases, is an aggressive B-cell non-Hodgkin lymphoma. Rarely, it can spread to other areas. This case illustrates a unique occurrence of MCL involving the appendix, leading to obstructive symptoms. Additionally, its presentation as volvulus added complexity to diagnosis and treatment. A 72-year-old man with a history of MCL came to the ER with right lower quadrant abdominal pain and nausea for 7 days. A computed tomography scan showed a swirling sign, concerning for volvulus. The patient required emergent surgery for exploratory laparotomy. Intraoperatively, the patient was found to have an enlarged appendix measuring 16.5 cm in length and 5 cm in diameter. An appendectomy was performed, and the pathology was confirmed to be MCL. This is a rare case of MCL presenting in the appendix as a volvulus, resulting in obstructive symptoms. This distinctive manifestation posed significant challenges in diagnosis and management. Appreciating such cases is pivotal for accurate diagnosis and effective medical and surgical interventions for this aggressive lymphoma subtype.

Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance.

INTRODUCTION: Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature. OBJECTIVES: To elucidate the role of LAMs in mediating ibrutinib resistance in MCL. METHODS: We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 inhibitor, could reverse ibrutinib resistance through CCK-8 and caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line. RESULTS: In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone. CONCLUSION: Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.

From the archives of MD Anderson Cancer Center: Composite mantle cell lymphoma and lymphoplasmacytic lymphoma involving bone marrow at presentation.

Composite lymphoma, defined as two or more distinct well-defined entities involving the same anatomic site, is rare. Here we report a 79-year-old woman with composite mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma (LPL) involving bone marrow at the time of initial diagnosis. The patient presented with splenomegaly and lymphadenopathy and laboratory studies showed an elevated serum IgM level and IgM kappa paraprotein. Bone marrow evaluation showed concurrent involvement by MCL and LPL, supported by immunophenotypic studies that revealed two distinct aberrant B-cell populations. Next-generation sequencing analysis identified concurrent MYD88 and CXCR4 mutations and fluorescence in-situ hybridization showed CCND1 translocation, supporting the diagnosis of concomitant MCL and LPL. In conclusion, composite lymphoma can present in the bone marrow. The use of ancillary studies was essential in reaching the diagnosis in this case, as the results excluded the possibility of MCL lymphoma with plasmacytic differentiation, as well as other CD5- and CD10-negative small B-cell lymphomas.

Lymphocyte recovery after bendamustine therapy in patients with mantle cell lymphoma. Results of a retrospective analysis and prognostic impact in the CAR-T era.

Bendamustine in combination with rituximab (BR) or with rituximab and cytarabine (R-BAC) is the standard first-line immunochemotherapy in mantle cell lymphoma (MCL) for elderly patients and patients ineligible for intensive regimens or autologous transplantation. As bendamustine causes prolonged lymphopenia and the literature lacks evidence of its persistence in patients with MCL, this retrospective analysis aims to estimate the lymphocyte recovery time, also in view of potential immunotherapy with CAR-T cells. Data were collected from 44 consecutive MCL patients who received bendamustine (BR or R-BAC) as first-line therapy at the Hematology Unit of Sapienza University Hospital between May 2011 and April 2022. Twenty patients (45%) were treated with R-BAC and 24 (55%) with BR. At baseline, the median lymphocyte count was 1795/µl (range: 370-11730/µL). One month after the end of therapy, it was 450/µl (range: 50-3300/µl) and 3 months after 768/µl (range: 260-1650/µl). After 6 and 9 months, we observed a gradual increase in median lymphocyte count of 900/µl (range: 370-2560/µl and 130-2770/µl, respectively). After 12 months median lymphocyte count was 1256/µl (range: 240-4140/µl). Median lymphocyte count at 1, 3, 6, and 9 months post-treatment was significantly lower than baseline but showed recovery by the 12 months. This finding is crucial for MCL patients considering CAR-T cell therapy, suggesting a minimum 9-month interval between bendamustine administration and leukapheresis.

Combined targeting of Hedgehog/GLI1 and Wnt/ß-catenin pathways in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Challenges in its treatment include relapse, drug resistance, and a short survival period. The Hedgehog/GLI1 (Hh/GLI1) and Wnt/ß-catenin pathways are crucial in cancer cell proliferation, survival, and drug resistance, making them significant targets for anticancer research. This study aimed to assess the effectiveness of combining inhibitors for both pathways against MCL and investigate the underlying molecular mechanisms. The co-expression of key proteins from the Hh/GLI1 and Wnt/ß-catenin pathways was observed in MCL. Targeting the Hh/GLI1 pathway with the GLI1 inhibitor GANT61 and the Wnt/ß-catenin pathway with the CBP/ß-catenin transcription inhibitor ICG-001, dual-target therapy was demonstrated to synergistically suppressed the activity of MCL cells. This approach promoted MCL cell apoptosis, induced G0/G1 phase blockade, decreased the percentage of S-phase cells, and enhanced the sensitivity of MCL cells to the drugs adriamycin and ibrutinib. Both GANT61 and ICG-001 downregulated GLI1 and ß-catenin while upregulating GSK-3ß expression. The interaction between Hh/GLI1 and Wnt/ß-catenin pathways was mediated by GANT61-dependent Hh/GLI1 inhibition. Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. GANT61 attenuated the overexpression of ß-catenin and decreased the inhibition of GSK-3ß in MCL cells. Overall, the combined targeting of both the Hh/GLI1 and Wnt/ß-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

Evaluating pirtobrutinib for the treatment of relapsed or refractory mantle cell lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) is an uncommon non-Hodgkin lymphoma that is generally considered incurable. Covalent BTK inhibitors (cBTKi) are the cornerstone of treatment for relapsed or refractory (R/R) MCL, but treatment options are limited and prognosis is poor after cBTKi failure. Pirtobrutinib is a non-covalent BTK inhibitor that has demonstrated excellent efficacy and safety and represents an important new treatment in the evolving treatment landscape of R/R MCL. AREAS COVERED: This review will provide an overview of the therapeutic landscape of R/R MCL, characteristics of pirtobrutinib, and efficacy and safety data of pirtobrutinib in R/R MCL from pivotal clinical trials. PubMed and major hematology conference proceedings were searched to identify relevant studies involving pirtobrutinib. EXPERT OPINION: For patients with R/R MCL that has progressed after treatment with cBTKi, pirtobrutinib is an important and efficacious treatment that confers favorable outcomes. In the post-cBTKi setting, when chimeric antigen receptor (CAR) T-cell therapy is not available or feasible, pirtobrutinib is the preferred treatment for R/R MCL. How to sequence or combine pirtobrutinib with CAR T-cell therapy and other available or emerging therapies requires further investigation. Future studies should also explore the role of pirtobrutinib in earlier lines of therapy for MCL.