[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 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.

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.

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.

Late-onset relapsing neurotoxicity after Brexucabtagene autoleucel associated with high chimeric antigen receptor T cells in cerebrospinal fluid.

BACKGROUND AIMS: Mounting evidence suggests that persistent cell expansion is the main driver for both efficacy and toxicity of chimeric antigen receptor (CAR) T-cell therapy. Hereby, we describe a case of delayed recurrent neurotoxicity associated with late CAR T-cells re-expansion. CASE DESCRIPTION: A 44-year-old man suffering from mantle cell lymphoma received brexu-cel. After infusion, he developed grade 2 cytokine release syndrome. On day +11, grade 3 neurotoxicity was reported and high-dose methylprednisolone was started with a complete resolution of neurological manifestations. On day +30, he experienced a late-onset CAR T-cell toxicity associated with CAR T-cell re-expansion. The patient was treated with tocilizumab and dexamethasone, with resolution of symptoms. On day +58, he was readmitted for new onset of neurotoxicity. Notably, a new CAR T-cell expansion was observed, with an unexpectedly elevated cerebrospinal fluid/blood ratio. The patient was promptly treated with dexamethasone and then escalated to high-dose methylprednisolone and anakinra, with resolution of his neurologic condition noted. CONCLUSIONS: CAR T-cell-related neurotoxicity usually has an early monophasic course. To our knowledge, this is the first case of late-onset, recurrent neurotoxicity. Moreover, an elevated level of cerebrospinal fluid CAR T cells was observed, which may suggest that the delayed neurotoxicity was primarily caused by the brain infiltration of CAR T cells rather than driven by cytokine-mediated neuroinflammation.

Knowledge, skills, and confidence gaps impacting treatment decision making in relapsed/refractory chronic lymphocytic leukemia and mantle cell lymphoma: a quantitative survey study in France, Germany, and the United States.

BACKGROUND: With recent advancements in the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), healthcare specialists may face challenges making treatment and management decisions based on latest evidence for the optimal care of patients with these conditions. This study aimed to identify specific knowledge, skills, and confidence gaps impacting the treatment of CLL and MCL, to inform future educational activities. METHODS: Hematologists and hemato-oncologists (HCPs, n = 224) from France (academic settings), Germany, and the United States (academic and community settings) responded to a 15-minute quantitative needs assessment survey that measured perceived knowledge, skills, and confidence levels regarding different aspects of treatment and management of CLL and MCL patients, as well as clinical case questions. Descriptive statistics (cross tabulations) and Chi-square tests were conducted. RESULTS: Four areas of educational need were identified: (1) sub-optimal knowledge of treatment guidelines; (2) sub-optimal knowledge of molecular testing to inform CLL/MCL treatment decisions; (3) sub-optimal skills when making treatment decisions according to patient profile (co-morbidities, molecular testing results); and (4) challenges balancing the risk of toxicities with benefits of treatment. Over one-third of the respondents reported skill gaps when selecting suitable treatment options and prescribing therapies and reported a lack in confidence to initiate and manage treatment. Larger gaps in knowledge of guidelines and skills in patient assessment were identified in MCL, compared to CLL. CONCLUSIONS: This study suggests the need for continuing medical education specifically to improve knowledge of treatment guidelines, and to assist clinicians in developing skills and confidence when faced with clinical decision-making scenarios of patients with specific comorbidities and/or molecular test results, for example, through case-based learning activities.

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.

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.

Warthin tumor concomitant with mantle cell lymphoma: a case report and review of literature.

RATIONALE: Warthin tumor (WT) is the second most common benign tumor in salivary gland. It has a slow growth rate and most frequently occurs in the parotid gland. Most patients present with an incidental finding of a painless mass inferior/anterior to the ear. Besides the epithelial component of the tumor, WT is characteristically associated with lymphoid stroma that is considered benign. While there have been a few reports of malignant transformation of the lymphoid components in WT, cases of WT concomitant with mantle cell lymphoma (MCL) are extremely rare. To the best of our knowledge, two cases have been described in the English literature. Herein, we report a case of WT concomitant with MCL in a 70-year-old female patient, and emphasize the importance of careful examination of lymphoid stroma in WT so that concurrent lymphoma is not missed. PATIENT CONCERNS: A 70-year-old Chinese woman with a 40-year history of cigarette smoking presented with a one year history of a right submaxillary mass with recent enlargement. DIAGNOSIS: Cervical ultrasound (US) and computed tomography (CT) scans of the neck revealed a well-circumscribed mass in the right parotid with a maximum diameter of 3.1 cm. Surgical resection of the mass was performed. Histopathological examination revealed a characteristic double-layer of neoplastic epithelium with prominent lymphoid stroma, suggesting WT. In addition, morphology and immunohistochemistry studies confirmed the coexistence of MCL. Thereafter, the final diagnosis of this case was WT concomitant with MCL. INTERVENTIONS: The patient was staged as stage I after clinical assessment. Due to the slow growth of parotid lesions, close observation was decided with periodic clinical and radiological monitoring. OUTCOMES: Currently, the patient demonstrates a stable disease by clinical evaluation. LESSONS: To the best of our knowledge, reported cases of WT concomitant with MCL are very rare. This case highlights the importance of a comprehensive assessment of the lymphoid stroma of WT to avoid missed diagnosis of a lymphoma component in a collision tumor.

Venous Thromboembolism Risk in Hematological Malignancies Post-Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: A Meta-Analysis of Phase 2 and Phase 3 Clinical Trials.

Chimeric Antigen Receptor T-cell (CAR-T) therapy uses genetically engineered T-cells with specific binding sites. This therapy allows for tumor specificity and durable treatment responses for patients with hematological malignancies. In this review, we study the risk of venous thromboembolism (VTE) associated with CAR-T therapy. We searched the National Institutes of Health library, Cochrane Library Databases, ClinicalTrials.gov database, and medical literature search engines PubMed and Google Scholar for Phase 2 and Phase 3 drug-efficacy and safety trials to determine the aggregate incidence and risk of VTE treated with CAR-T. Of 1127 search results, nine studies were identified and included in our meta-analysis. Of the 1017 patients who received therapy, 805 patients (79.15%) experienced some degree of CRS, and 122 patients (11.9%) experienced severe CRS (higher than grade 3). Only three out of one thousand and seventeen patients were reported to have experienced venous thromboembolism. Our study did not find a statistically significant association between increased VTE incidence (OR = 0.0005, 95% CI [0.0001, 0.0017]) and CRS/ICANS (p < 0.0001). There was a 0.0050 (95% confidence interval [0.0019, 0.0132]) relative risk for VTE. In our study, we did not find a statistically significantly increased risk of developing VTE despite CRS and underlying malignancy, which have been associated with increased risk of VTE.

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.

Intrasinusoidal bone marrow involvement in mantle cell lymphoma: a case series with review of the main differential diagnoses.

Intrasinusoidal bone marrow involvement is an infrequent histological pattern observed in a limited number of B and T cell lymphomas. Mantle cell lymphoma is a biologically and prognostically heterogeneous B cell lymphoma that frequently involves the bone marrow, with interstitial, nodular-paratrabecular, or diffuse patterns. Intrasinusoidal bone marrow involvement has been described only anecdotally in this lymphoma. Here, we describe the clinical, histopathological, and molecular features of four patients diagnosed with advanced-stage mantle cell lymphoma, showing intrasinusoidal bone marrow involvement, and other peculiar immunophenotypical features. As similar cases may represent a relevant issue in bone marrow diagnostic histopathology, we also reviewed the literature to discuss differential diagnoses of B and T cell lymphomas with intrasinusoidal bone marrow involvement.

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.

Mantle Cell Lymphoma With Cardiac Involvement Presenting as Complete Heart Block.

A 50-year-old woman presented with complete heart block on electrocardiogram. Echocardiogram revealed an intracardiac mass with extensive cardiac involvement. The patient was diagnosed with mantle cell lymphoma, confirmed via lymph node biopsy. Pacemaker implantation and chemotherapy were initiated, with subsequent improvement noted. This showcases an unusual manifestation of intracardiac metastasis with conduction system infiltration.

Aplastic anemia triggered by the Bruton tyrosine kinase inhibitor acalabrutinib in two patients with mantle cell lymphoma - A case report.

The use of Bruton's tyrosine kinase inhibitors (BTKi) is rapidly increasing for patients with mantle cell lymphoma (MCL). Side effects reported so far are usually manageable. However, here we present two cases of life-threatening aplastic anemia (AA) upon treatment with the BTKi acalabrutinib for MCL. The first patient died of neutropenic infection secondary to AA. The second patient was successfully treated with immunosuppressive treatment but the MCL relapsed shortly thereafter. AA is a potentially fatal complication that should be considered when patients present with pancytopenia during treatment with BTKi.

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.

[Correlation of CD4+/CD8+Ratio in Peripheral Blood with Prognosis of Mantle Cell Lymphoma].

OBJECTIVE: To investigate the correlation of peripheral blood T lymphocyte subsets with overall survival (OS) and clinical baseline characteristics in mantle cell lymphoma (MCL). METHODS: The clinical data of 55 MCL patients who were newly diagnosed in the Department of Hematology, Second Hospital of Shanxi Medical University from January 2012 to July 2022 were analyzed retrospectively. The percentages of T lymphocyte subsets and CD4+/CD8+ ratio in peripheral blood were detected by flow cytometry, and their correlation with clinical characteristics of patients were analyzed. Kaplan-Meier method was used for survival analysis and survival curves were drawn. Log-rank test was used for univariate analysis, while Cox proportional hazards model was used for multivariate analysis. RESULTS: The median follow-up was 40(1-68) months, and the median overall survival (OS) was 47 months. Among the 55 patients, 30(54.5%) patients had a decrease in peripheral blood CD4+T lymphocyte, while 17(30.9%) patients had a increase in peripheral blood CD8+T lymphocyte, and 20(36.4%) patients had a decrease in CD4+/CD8+ ratio. There were no significant correlations between CD4+/CD8+ ratio and sex, age, Ki-67, B symptoms, leukocytes, hemoglobin, lymphocytes, platelets, albumin, lactate dehydrogenase (LDH), ß2-microglobulin, splenomegaly, bone marrow invasion, primary site and MIPI score. Survival analysis showed that patients with CD4+T cell >23.3%, CD8+T cell ≤33.4% and CD4+/CD8+ ratio >0.6 had longer OS (P =0.020, P <0.001, P <0.001). Univariate analysis showed that Ki-67>30%, LDH>250 U/L, splenomegaly, bone marrow involvement, CD4+T cells ≤23.3%, CD8+ T cells >33.4%, CD4+/CD8+ ratio ≤0.6 were adverse prognostic factors affecting OS of MCL patients. Multivariate analysis showed that CD4+/CD8+ ratio ≤0.6 (HR =4.382, P =0.005) was an independent adverse prognostic factor for OS of MCL patients. CONCLUSIONS: Low CD4+/CD8+ ratio is associated with poor prognosis in MCL, and the CD4+/CD8+ ratio can be used as an important indicator to evaluate the prognosis risk in MCL patients.

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.