Treatment Of Mantle Cell Lymphoma Research Articles

A genetically engineered mouse/human chimeric antibody targeting CD99 enhances antibody-dependent cellular phagocytosis against human mantle cell lymphoma Z138 cells

Background: Mantle cell lymphoma (MCL) is an aggressive form of B-cell nonHodgkin lymphoma. The elimination of MCL cells via phagocytosis is essential for cancer eradication. Therefore, discovering novel targeted antibodies that can induce phagocytosis is needed. We have demonstrated that our in-houseproduced mouse anti-CD99 mAb clone MT99/3 could induce potent anticancer activities against MCL cell lines in both in vitro and in vivo mouse xenograft models. Nevertheless, for use in humans, the mouse mAb needs to be transformed into a mouse/human chimeric mAb that contains a human Fc region to activate human immune effector functions, especially macrophage-mediated phagocytosis. Antibody-dependent cellular phagocytosis (ADCP) mediated by mouse/human chimeric mAb MT99/3 against MCL has not been previously reported. Objective: This study aimed to genetically engineer a mouse/human chimeric antibody against human CD99 derived from mouse mAb MT99/3 and to evaluate its effect in mediating the ADCP mechanism for eradicating MCL cells in vitro using monocyte-derived macrophages. Materials and methods: The expression plasmid to produce chimeric anti-CD99 antibody, ChAbMT99/3, was constructed by fusing the variable domains of mouse mAb MT99/3 with the constant domains of human IgG1 and the constant domains of kappa light chain. ChAbMT99/3 was expressed in the stable human expression system based on HEK293T cells. ChAbMT99/3 was purified from the culture supernatant of ChAbMT99/3-expressing HEK293T cells using Protein G chromatography. The purity and structure of ChAbMT99/3 were verified by SDS-PAGE and western blotting. The binding specificity and activity were determined by staining with cells expressing recombinant and native human CD99. The anticancer activity of ChAbMT99/3 in mediating the ADCP mechanism against MCL cell line Z138 using human monocytederived macrophages was evaluated. Results: We successfully constructed the plasmid to produce ChAbMT99/3. Human HEK293T cells stably expressing ChAbMT99/3 were established. The ChAbMT99/3- expressing HEK293T cells could secrete ChAbMT99/3 into the culture supernatant. The high purity and complete IgG structure of ChAbMT99/3 were obtained from the purification process. Crucially, this chimeric antibody retained its binding reactivity to recombinant and native human CD99. In addition, the produced ChAbMT99/3, upon binding to MCL cells, significantly enhanced ADCP against MCL cell line Z138 in a dose-dependent manner. Conclusion: The production of a mouse/human chimeric antibody against human CD99 derived from mouse mAb MT99/3 was successful. The engineered antibody could mediate ADCP activity against MCL cells. The produced ChAbMT99/3 might be a promising therapeutic candidate for MCL treatment.

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

BackgroundWith 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.MethodsHematologists 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.ResultsFour 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.ConclusionsThis 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.

Paraneoplastic glomerulonephritis and kidney infiltration by mantle cell lymphoma: A diagnostic challenge.

Mantle cell lymphoma (MCL) is a rare and aggressive type of lymphoma that can affect the kidneys. The disease can lead to kidney impairment, and glomerulonephritis (GN) is a rare but serious complication of MCL. We report a case of MCL with kidney interstitial infiltration and membranoproliferative glomerulonephritis with focal and segmental glomerulosclerosis. A 75-year-old man presented recurrent acute kidney failure and worsening of nephrotic syndrome. Kidney biopsy revealed membranoproliferative glomerulonephritis presented immunoglobulin and complement deposition, focal and segmental glomerulosclerosis of not otherwise specified type, and infiltration by mantle cell lymphoma. Bone marrow biopsy and PET/CT scan confirmed the diagnosis of mantle cell lymphoma. The patient was treated with R-CHOP21 chemotherapy with cyclophosphamide dose adjustment for nephroprotection. He achieved complete remission with normalization of hematological parameters, improvement of kidney function, and reduction of proteinuria and albuminuria. This case shows the importance of considering alternative diagnoses in patients with recurrent chronic kidney disease and worsening nephrotic syndrome. Early diagnosis and treatment of mantle cell lymphoma can lead to favorable outcomes.

Insight into Mantle Cell Lymphoma Pathobiology, Diagnosis, and Treatment Using Network-Based and Drug-Repurposing Approaches.

Mantle cell lymphoma (MCL) is a rare, incurable, and aggressive B-cell non-Hodgkin lymphoma (NHL). Early MCL diagnosis and treatment is critical and puzzling due to inter/intra-tumoral heterogeneity and limited understanding of the underlying molecular mechanisms. We developed and applied a multifaceted analysis of selected publicly available transcriptomic data of well-defined MCL stages, integrating network-based methods for pathway enrichment analysis, co-expression module alignment, drug repurposing, and prediction of effective drug combinations. We demonstrate the "butterfly effect" emerging from a small set of initially differentially expressed genes, rapidly expanding into numerous deregulated cellular processes, signaling pathways, and core machineries as MCL becomes aggressive. We explore pathogenicity-related signaling circuits by detecting common co-expression modules in MCL stages, pointing out, among others, the role of VEGFA and SPARC proteins in MCL progression and recommend further study of precise drug combinations. Our findings highlight the benefit that can be leveraged by such an approach for better understanding pathobiology and identifying high-priority novel diagnostic and prognostic biomarkers, drug targets, and efficacious combination therapies against MCL that should be further validated for their clinical impact.

Real-world adherence and healthcare resource utilization of Bruton tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma.

e19048 Background: This study aimed to examine treatment adherence and healthcare resource utilization (HCRU) of BTKi treatment in mantle cell lymphoma (MCL). Methods: The Symphony Integrated Dataverse (IDV) was used to conduct a retrospective observational study. Adult patients with MCL initiating their first BTKi or second BTKi (after ibrutinib) between 01/2020 and 10/2023 were included in the study. The index was defined as the date of BTKi initiation. Patients without 30 days of continuous enrollment pre- and post-index date were excluded. Patients were followed until the end of the study period or lost to follow-up. Adherence was evaluated by compliance and persistence. Compliance was calculated as the proportion of days covered >0.80 using 30-day intervals from initiation to 1 year. Persistence was measured as the proportion of patients who remained in treatment among patients with sufficient follow-up periods. HCRU was measured by all-cause outpatient visits, inpatient services, and other medical/hospital services per-patient-per-month (PPPM) during BTKi treatment. Results: Among 2,122 patients who were first-time BTKi users, there were significant differences for mean age at index (acalabrutinib=70; ibrutinib=68; zanubrutinib=70, P<.0001), commercial insurance (acalabrutinib=34%; ibrutinib=42%; zanubrutinib=47%, P<.0001), and baseline atrial fibrillation (acalabrutinib=1.94%; ibrutinib=1.24%; zanubrutinib=3.47%, P=0.0232). A total of 228 patients switched from ibrutinib to acalabrutinib or zanubrutinib. Adherence results suggested zanubrutinib had numerically better 1-year compliance ( P=0.2176) and treatment persistence at 1 and 2 years ( P=0.2687; P=0.6270) for patients who switched from ibrutinib to zanubrutinib or acalabrutinib (Table). HCRU showed that the mean (SD) outpatient visits (1.12 [1.67] vs 1.62 [3.17]; P=0.1755) and inpatient services (0.22 [0.68] vs 0.68 [3.12]; P=0.1693) were lower in patients switched from ibrutinib to zanubrutinib than acalabrutinib. Conclusions: In this study, zanubrutinib was associated with a trend towards improved compliance, persistence, and HCRU when used as the first BTKi and after prior ibrutinib. [Table: see text]

Targeted Therapies in the Treatment of Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a rare, heterogeneous B-cell non-Hodgkin's lymphoma. The standard front-line treatment utilizes chemotherapy, often followed by consolidation with an autologous hematopoietic cell transplant; however, in most patients, the lymphoma will recur and require subsequent treatments. Additionally, mantle cell lymphoma primarily affects older patients and is frequently chemotherapy-resistant, which has further fostered the necessity for new, chemotherapy-free treatment options. In the past decade, targeted therapies in mantle cell lymphoma have been practice-changing as the treatment paradigm shifts further away from relying primarily on cytotoxic agents. Here, we will review the pathophysiology of mantle cell lymphoma and discuss the emergence of targeted, chemotherapy-free treatments aimed at disrupting the abnormal biology driving its lymphomagenesis. Treatments targeting the constitutive activation of NF-kB, Bruton's Tyrosine Kinase signaling, and anti-apoptosis will be the primary focus as we discuss their clinical data and toxicities. Our review will also focus primarily on the emergence and use of targeted therapies in the relapsed/refractory setting but will also discuss the emergence of their use in front-line therapy and in combination with other agents.

Front-line and second-line treatment for mantle cell lymphoma in clinical practice: A multicenter retrospective analysis.

There are few reports of clinical practice treatment patterns and efficacy in mantle cell lymphoma (MCL). We retrospectively studied a large, multicenter, cohort of patients with MCL diagnosed between 2000 and 2020 in eight institutions. 536 patients were registered (73% male, median of 70 years). Front-line treatment was based on high-dose cytarabine, bendamustine, and anthracyclines in 42%, 12%, and 15%, respectively. The median PFS for all patients was 45 months; 68, 34, and 30 months for those who received high-dose cytarabine-based, bendamustine-based and anthracycline-based therapy. 204 patients received second-line. Bendamustine-based treatment was the most common second-line regimen (36% of patients). The median second-line PFS (sPFS) for the entire cohort was 14 months; 19, 24, and 31 for bendamustine-, platinum-, and high-dose cytarabine-based regimens, with broad confidence intervals for these latter estimates. Patients treated with cytarabine-based therapies in the front-line and those with front-line PFS longer than 24 months had a substantially superior sPFS. Front-line treatment in this cohort of MCL was as expected and with a median PFS of over 3.5 years. Second-line treatment strategies were heterogeneous and the median second-line PFS was little over 1 year.

Abstract CT145: The final results of a phase I study using velcade (bortezomib), cladribine, and rituximab (VCR) in treating elderly patient with mantle cell lymphoma

Abstract Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium size B cell lymphoma. In this phase 1 study, we evaluated the safety and efficiency of Valcade, Cladribine, and Rituximab (VCR) combination treatment in MCL. Patients and Methods: This is a single arm, open label, investigator-initiated Phase 1 study. This study employed a standard 3+3 dose escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. The treatment scheme and Cladribine dose escalation levels (1, 2, and 3) are as follows: the therapy consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles, Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 35 mg/m2 (3 mg/m2 for level 1, 4 mg/m2 for level 2, and 5 mg/m2 for level 3) infusion was given on days 1 to 5 for 6 cycles. If the patient was older than 70 years old, Cladribine was only given on days 1 to 3 of each cycle. Velcade 1.6 mg/m2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1 to 3, then Day 5 and 19 during Cycles 4 to 6, then once per month as maintenance therapy until toxicity or progression of the disease. The primary endpoint of this study was to investigate the dose limiting toxicity (DLT), safety, and efficiency of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression free survival (PFS) and overall survival (OS). This study is registered with clinicaltrials.gov (NCT01439750). Results: No subject experienced dose limited toxicity (DLT) at either level 1 or 2, one possible DLT (infectious colitis) was observed on a subject during 2nd cycle at level 3. Then no additional DLTs were seen in 3 subjects added to level 3. Overall, this study recruited 13 subjects, with a median age of 64 years old (range from 55 to 83), and a total of 11 male and 2 females. Ten subjects were never previously treated, while 3 either relapsed or failed previous treatments. The majority of subjects tolerated this regimen well. Two relapsed patients experienced disease progression after received two cycles of treatments and died in 5 and 7 months after initiating the treatment. Another patient died 15 months after starting treatment. The overall remission (OR) rate was 77% (10/13) and complete remission (CR) rate was 85% (10/13). In newly diagnosed subject cohort, the RR and OS rates were 90% (9/10), PFR was 80% (8/10), and CR rate was 100% (10/10), of which 3 patients have been followed for more than 4 years, 3 other patients for more than 3 years, and 3 others for over 2 years. However, in relapsed/refractory subject cohort, 1 subject achieved CR for 7 months but then relapsed, 2 subjects had no response. There were 2 blastoid subjects, one was newly diagnosed and achieved CR.No severe systemic toxicity was observed in this study. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Conclusions: The VCR combination is a well-tolerated, low toxicity and effective regimen for for untreated MCL. Cladribine 5 mg/m2 is a tolerable dose with manageable toxicity. Citation Format: Jeffrey J. Pu, Kristin Berger, David Claxton, Joseph Drabick, Thomas Loughran, Elliot Epner. The final results of a phase I study using velcade (bortezomib), cladribine, and rituximab (VCR) in treating elderly patient with mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT145.

Abstract 676: The integrated stress activator BTM-3566 overcomes therapeutic resistance in mantle cell lymphoma

Abstract Successive generations of BTK inhibitors and CAR T-cell therapy have transformed the treatment of mantle cell lymphoma (MCL). However, treatment resistance has inevitably emerged, creating significant medical need. Recently a novel, clinical stage small molecule, BTM-3566, has been described that targets a mitochondrial process essential for Diffuse Large B-cell lymphoma (DLBCL) survival. BTM-3566 activates the mitochondrial protease OMA1, triggering the ATF4 integrated stress response (ISR). BTM-3566 has robust in vitro efficacy in DLBCL cell lines irrespective of genomic background and elicits complete tumor regression in multiple CDX and PDX mouse models of DLBCL. Based on the activity observed in DLBCL, we further explored the effectiveness of BTM-3566 in MCL models in vitro and in xenograft mouse models in vivo. BTM-3566 inhibited cell proliferation across a panel of MCL cell lines, irrespective of resistance status to ibrutinib and venetoclax (IC50s of 142.5-687.6 nM). Following a 24-hour treatment with BTM-3566, a dose-dependent increase in apoptosis was observed in four tested MCL cell lines—JeKo-1, JeKo-IBN-R, Mino, and Mino-VEN-R, as determined by increased caspase-3 activation and PARP cleavage. Similarly, western blot analysis revealed dose-dependent reductions in MCL-1 and c-MYC, accompanied by an increase in the transcription factor ATF4, indicative of activation of the stress response. We evaluated the in vivo efficacy of BTM-3566 in the JeKo-CDX mouse model. Daily oral administration of BTM-3566 at 10, 20 and 30 mg/kg (n = 5 for each group) in a 5-day on and 2-day off schedule resulted in tumor regression at all three doses (Treatment vs. Vehicle, p < 0.01). We expanded our investigation to PDX mouse models, including those derived from patients resistant to multiple therapies. Four PDX models encompassing naive, rituximab-resistant, BTKi-CAR T dual-resistant and BTKi-VEN-CAR T triple-resistant models were evaluated. BTM-3566 treatment results in nearly complete tumor growth inhibition associated with robust reductions in tumor burden in treated mice across all four PDX models (reduction in tumor weight at the study endpoint, p < 0.001). Notably, no toxicity was observed during the treatment period. In summary, BTM-3566 is effective in treating MCL in vitro and in vivo in preclinical studies. Citation Format: Yang Liu, Heng-Huan Lee, Joseph McIntosh, Yijing Li, Tianci Zhang, Wei Wang, Matthew J. Kostura, Michael Wang. The integrated stress activator BTM-3566 overcomes therapeutic resistance in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 676.

Abstract 6044: EPriL: A platform for the rapid identification of degraders of inhibitor-resistant kinases

Abstract Heterobifunctional kinase degraders (HKDs) are an important new class of therapeutic modalities, of which the first have recently entered clinical trials. HKDs are small molecules that comprise a kinase-of-interest binding moiety and an E3 ligase binding moiety connected via a spacer. HKDs are excellently suited to target kinases that have a scaffolding function, or that are resistant against conventional inhibitors. A HKD brings a kinase and an E3 ligase in proximity forming a ternary complex leading to ubiquitin-dependent catalytic degradation of the kinase of interest. This ternary complex formation is unique for each kinase which can make HKDs highly specific. To discover novel HKDs, we have developed a platform called Energetically Privileged Ligands (EPriLs), which is based on a macrocycle scaffold that binds non-covalently in the kinase ATP pocket with near-covalent affinity, and allows binding to kinases that have acquired known inhibitor resistance mutations. The macrocyclic structure allows attachment of E3 ligase ligands with multiple exit vectors. With the EPriL platform, we have developed novel HKDs for various clinically relevant kinase targets, including Bruton’s Tyrosine Kinase (BTK). BTK inhibitor drugs are used as first line treatment for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM) and as second line treatment for mantle cell lymphoma (MCL). Despite their great success in the clinic, many patients on BTK inhibitors relapse eventually, mostly because of the emergence of resistance mutations in the BTK protein. These include BTKC481S, which abrogates binding of covalent drugs, and BTKT474I, BTKL528W and BTKV416L which preclude binding of non-covalent inhibitors like pirtobrutinib. HKDs can combat resistance by degrading such BTK variants, and by removing the scaffold function of BTK. BTK degraders such as NX-5948 and NX-2127 are currently in clinical Phase 1. To show the applicability of the EPriL platform for the discovery of novel BTK degraders, we screened a library of more than 100 EPriL HKDs for biochemical binding to BTK, and tested their propensity to induce degradation of HiBiT-tagged BTKWT, BTKC481S and BTKT474I in HEK293 cell lines. The degrading activity of hits was verified through western blot on the BTK-dependent DLBCL cell line TMD8. The best degraders - based on potency and efficacy - were tested in cell proliferation assays on a panel of TMD8 BTK mutant cell lines. In these lines, endogenous BTK was mutated by CRISPR to BTKC481S, BTKT474I, BTKL528W or BTKV416L. Several BTK degraders had potent (< 20 nM IC50) antiproliferative activity on most TMD8 lines, including difficult-to-target variants such as BTKV416L and BTKL528W. The unique binding mode of the EPriL scaffold thus translates to broad activity on resistance variants, while its selectivity ensures minimal degradation of off-target tyrosine kinases as observed for other degraders. Citation Format: Michelle Muller, Jos de Man, Joost C. Uitdehaag, Freek van Cauter, Sander van Gemert, Milan Hoffmann, Yvonne G. van Mil, Winfried R. Mulder, Martine B. Prinsen, Jan Gerard Sterrenburg, Diep Vu, Joeri de Wit, Erik Ensing, Rogier C. Buijsman. EPriL: A platform for the rapid identification of degraders of inhibitor-resistant kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6044.

Simultaneous Determination of Ibrutinib, Dihydroxydiol Ibrutinib, and Zanubrutinib in Human Plasma by Liquid Chromatography-Mass Spectrometry/Mass Spectrometry.

Ibrutinib and zanubrutinib are Bruton tyrosine kinase inhibitors used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Dihydroxydiol ibrutinib (DHI) is an active metabolite of the drug. A liquid chromatography-tandem mass spectrometry method was developed to detect ibrutinib, DHI, and zanubrutinib in human plasma. The method involved a protein precipitation step, followed by chromatographic separation using a gradient of 10 mM ammonium acetate (containing 0.1% formic acid)-acetonitrile. Ibrutinib-d5 was used as an internal standard. Analytes were separated within 6.5 minutes. The optimized multiple reaction monitoring transitions of m/z 441.1 → 304.2, 475.2 → 304.2, 472.2 → 455.2, and 446.2 → 309.2 were selected to inspect ibrutinib, DHI, zanubrutinib, and the internal standards in positive ion mode. The validated curve ranges included 0.200-800, 0.500-500, and 1.00-1000 ng/mL for ibrutinib, DHI, and zanubrutinib, respectively. The precisions of the lower limit of quantification of samples were below 15.5%, the precisions of the other level samples were below 11.4%, and the accuracies were between -8.6% and 8.4%. The matrix effect and extraction recovery of all compounds ranged between 97.6%-109.0% and 93.9%-105.2%, respectively. The selectivity, accuracy, precision, matrix effect, and extraction recovery results were acceptable according to international method validation guidelines. A simple and rapid method was developed and validated in this study. This method was used to analyze plasma concentrations of ibrutinib and zanubrutinib in patients with mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, or diffuse large B-cell lymphoma. The selected patients were aged between 44 and 74 years.

Empowering macrophages: the cancer fighters within the tumour microenvironment in mantle cell lymphoma.

In Mantle Cell Lymphoma (MCL), the role of macrophages within the tumour microenvironment (TME) has recently gained attention due to their impact on prognosis and response to therapy. Despite their low absolute number in MCL tumour tissue, recent findings reveal an association between the levels of macrophages and prognosis, consistent with trends observed in other lymphoma subtypes. M2-like macrophages, identified by markers such as CD163, contribute to angiogenesis and suppression of the immune response. Clinical trials with MCL patients treated with chemoimmunotherapy and targeted treatments underscore the adverse impact of high levels of M2-like macrophages. Immunomodulatory drugs like lenalidomide reduce the levels of MCL-associated CD163+ macrophages and enhance macrophage phagocytic activity. Similarly, clinical approaches targeting the CD47 "don't eat me" signalling, in combination with the anti-CD20-antibody rituximab, demonstrate increased macrophage activity and phagocytosis of MCL tumour cells. Cell-based therapies such as chimeric antigen receptor (CAR) T-cell have shown promise but various challenges persist, leading to a potential interest in CAR-macrophages (CAR-M). When macrophages are recruited to the TME, they offer advantages including phagocytic function and responsiveness to microenvironment alterations, suggesting their potential as a manipulable and inducible alternative when CAR T-cell therapies fails in the complex landscape of MCL treatment.

Disruption of cyclin D1 degradation leads to the development of mantle cell lymphoma

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers. Here, we demonstrated that cyclin D1 is SUMOylated, and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1. We generated cyclin D1 mutant mice with mutations in the SUMOylation site, phosphorylation site, or both sites of cyclin D1, and found that double mutant mice developed a Mantle cell lymphoma (MCL)-like phenotype. We showed that arsenic trioxide (ATO) enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes, leading to MCL cell apoptosis. Treatment of severe combined immunodeficiency (SCID) mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth. In this study, we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.

A306 A CASE OF SCLEROSING CHOLANGITIS AS A COMPLICATION OF CAR-T THERAPY

Abstract Background Chimeric antigen receptor T-cell (CAR-T) therapy is a novel immunotherapy for treating hematological malignancies. CAR-T therapy starts with the collection of T-cells from patients. Then, receptors on the T-cell membrane are re-engineered to become chimeric antigen receptors that specifically target antigens on the surface of malignant cells. These engineered cells are grown ex vivo and infused back into the patient, leading to a targeted immune response against cancer. While CAR-T therapy has shown promising results in treating malignancies refractory to conventional treatment, there have also been reports of complications from unwanted off-target effects with CAR-T therapy. Aims We report a case of sclerosing cholangitis secondary to CAR-T therapy for the treatment of mantle cell lymphoma. Methods Case report. Results A 67-year-old male with refractory stage IVB mantle cell lymphoma underwent CAR-T therapy. His lymphoma was first diagnosed in 2011 and previous treatment included R-CHOP followed by autologous stem cell transplant. He had disease progression despite rituximab maintenance therapy and was switched to ibrutinib therapy with good response until 2023. In 2023, he was noted to have progression of his lymphoma. He subsequently underwent CAR-T therapy. His treatment was complicated by grade 2 cytokine release syndrome requiring two doses of tocilizumab. Other complications included immune effector cell-associated neurotoxicity syndrome leading to status epilepticus. He was intubated and required monitoring in the ICU however he was not in shock, nor did he require vasopressors. Post-CAR-T therapy he developed an increase of his liver enzymes in a cholestatic pattern. Magnetic resonance cholangiopancreatography (MRCP) showed irregular biliary dilation with beading suggestive of sclerosing cholangiopathy. He subsequently underwent multiple endoscopic retrograde cholangiopancreatography (ERCP) with stent insertions but there were no improvements in his liver enzymes and jaundice. A liver biopsy was performed which showed large bile duct obstruction with extensive cholestasis and some evidence of non-caseating granulomatous inflammation. Given the timing of new sclerosing cholangiopathy post-CAR-T therapy along with multiple other complications related to CAR-T therapy, it was thought this patient developed sclerosing cholangitis secondary to CAR-T therapy. Due to worsening clinical status along with progression of mantle cell lymphoma, he was transitioned to comfort care. Conclusions CAR-T therapy is a novel immunotherapy for the treatment of refractory hematological malignancies. However, complications from the off-target effects of CAR-T therapy can occur. This case highlighted a rare side effect associated with CAR-T therapy. In the future, more research will be needed to further characterize the risks associated with CAR-T therapy. Cholangiogram showing no visible filling defects or obstructive lesion. Funding Agencies None

Evaluation of second-generation Bruton's tyrosine kinase inhibitors for the treatment of mantle cell lymphoma.

Second-generation Bruton's tyrosine kinase (BTK) inhibitors, acalabrutinib and zanubrutinib, are preferred agents for the treatment of relapsed and/or refractory mantle cell lymphoma (MCL) over first-generation BTK inhibitor, ibrutinib. The comparative safety and efficacy of these two agents have not been studied. Currently, the decision between using one second-generation BTK inhibitor over the other is largely dependent on provider preference, cost, organ dysfunction, presence of drug-drug interactions, adherence considerations, and theorized differences in safety outcomes due to the lack of head-to-head trials in MCL. This retrospective, observational study seeks to provide real-world data on the safety and efficacy of second-generation BTK inhibitors in the setting of relapsed and/or refractory MCL. Thirty-eight patients treated with a second-generation BTK inhibitor were evaluated. Ten percent of patients experienced a select adverse drug event (ADE) in the acalabrutinib group that included hypertension and major hemorrhage with no patients experiencing a select ADE in the zanubrutinib group. Results support historical data that acalabrutinib and zanubrutinib have a more favorable safety profile compared to ibrutinib in MCL.

Twenty Years of Advancing Discoveries and Treatment of Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14) chromosomal translocation, which leads to the dysregulation of the cell cycle through overexpression of cyclin D1. Although advances in treatment have improved outcomes, in particular the introduction of Bruton tyrosine kinase inhibitors to the treatment armamentarium and more recently chimeric antigen receptor T-cell therapy, MCL often rapidly develops resistance and has a high rate of relapse. In addition, MCL is clinically heterogeneous. Response to treatment can vary, making it difficult to establish a standard treatment approach. Thus, there remains a significant need for more research on MCL biology, including those molecular mechanisms underpinning treatment response or lack thereof, so that novel agents may be identified and/or the use of existing agents may be optimized. At the Lymphoma Research Foundation's 20th MCL Scientific Consortium and Workshop, researchers gathered to discuss recent developments in both basic scientific and clinical research to continue to develop an understanding of MCL and improve outcomes for patients. This report, which includes a summary of each presentation, reviews the findings presented at the workshop and highlights opportunities, open questions, and areas for future study that would pave the way for a cure for this disease in the coming decades.

Patient perspectives on treatment for mantle cell lymphoma and chronic lymphocytic leukemia in Japan.

The increasing number of treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in Japan underscores the critical need to comprehend their treatment preferences. In this study, individual semi-structured interviews with 20 Japanese patients with diagnosis of MCL or CLL/SLL were conducted and qualitatively analyzed to elicit concepts important for patients regarding treatment selection. Although effectiveness and safety were imperative for treatment selection, convenience and quality of life were also reported as important attributes. Over the course of their disease journey, patients reported diverse and changing preferences in terms of treatment characteristics. Additionally, there was a discrepancy between their desired and actual levels of involvement in shared decision-making with physicians about treatment choices. Optimal personalized care for better outcomes of patients with MCL and CLL/SLL hinges on healthcare professionals acknowledging individual patient needs and preferences within their cultural, societal and personal context.

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.

Ion Trap LC/MS reveals the generation of reactive intermediates in acalabrutinib metabolism: phase I metabolic profiling and bioactivation pathways elucidation.

Acalabrutinib (CALQUENCE; ACB) is a Bruton tyrosine kinase inhibitor (BTKI) used to treat mantle cell lymphoma, small lymphocytic lymphoma (SLL), and chronic lymphocytic leukemia (CLL). On 21 November 2019, ACB was approved by the U.S. FDA for the use as a single therapy for the treatment of CLL/SLL. In silico studies were first done to propose vulnerable sites of metabolism and reactivity pathways by StarDrop software and Xenosite online software; respectively. ACB metabolites and stable adducts were characterized in vitro from rat liver microsomes (RLMs) using Ion Trap LC/MS. Generation of reactive intermediates (RIs) in the in vitro metabolism of ACB was investigated using glutathione, potassium cyanide, and methoxylamine as trapping nucleophiles for the RIs including iminopyridinone, iminium, and aldehyde, respectively, to form stable adducts that can be identified and characterized by Ion Trap LC/MS. Five phase I metabolites, seven 6-iminopyridin-3(6H)-one and five aldehyde RIs of ACB were identified. Based on literature reviews, the generation of RIs of ACB, and the subsequent drug-induced organ toxicity (DIOT) reactions may provide an explanation of ACB ADRs. Additional drug discovery investigations can be performed to facilitate the creation of novel medications with improved safety characteristics.

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.