Relapsed Mantle Cell Lymphoma Research Articles

TARMAC trial—a new path for chimeric antigen receptor (CAR) T in relapsed mantle cell lymphoma (MCL)?

TARMAC trial—a new path for chimeric antigen receptor (CAR) T in relapsed mantle cell lymphoma (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.

Relapsed mantle cell lymphoma with parenchymal central nervous system involvement successfully treated with chimeric antigen receptor T-cell therapy—a case report

Relapsed mantle cell lymphoma with parenchymal central nervous system involvement successfully treated with chimeric antigen receptor T-cell therapy—a case report

Efficacy and safety of brexucabtagene autoleucel CAR T-cell therapy with BTK inhibitors in the treatment of relapsed mantle cell lymphoma with central nervous system involvement.

Efficacy and safety of brexucabtagene autoleucel CAR T-cell therapy with BTK inhibitors in the treatment of relapsed mantle cell lymphoma with central nervous system involvement.

Development and Clinical Validation of an Ultra-Fast CAR-T Manufacturing Platform Enabling Production of CAR-T Cells in Less Than 1 Day

Recently, the use of CAR-T cells has made a major impact on the therapy for a subset of hematologic malignancies including non-Hodgkin lymphoma (NHL) and multiple myeloma. In relapsed/refractory NHL where historically most patients did not respond to chemotherapy, CAR-T cell therapy can lead to initial remission rates >50%. Despite promising outcomes, there are major unmet needs to develop rapid, cost-effective, and scalable CAR-T manufacturing platforms that lead to efficacious and affordable autologous CAR-T cell products. Major barriers to widespread access to CAR-T cell therapy include weeks to months long delays from time of prescription to infusion that leads to disease progression in a significant subset of patients, very elevated costs that preclude access for a majority of patients world-wide, and high relapse rates (~estimated 30-60% within one year) in patients who initially achieve remission. To help address these barriers, we developed an ultra-fast CAR-T manufacturing platform (UF-CAR) that allows production of highly cost-effective CAR-T product in less than 24 hours. The manufacturing workflow was specifically designed to be simple, low cost and rapid to enable its formulation in healthcare facilities without sophisticated equipment or personnel expertise. In addition, we hypothesized that this manufacturing workflow would generate a product that demonstrates dramatically improved efficacy and CAR-T expansion in vivo. Using a BCMA CAR we manufactured CAR-T cell product using both our ultra-fast manufacturing workflow and a traditional 9-day CAR-T cell manufacture workflow. Both workflows led to nearly identical levels of CAR surface expression on the T cells (67% and 66% CAR expression on the UF-BCMA product and 9-day product respectively). To compare the activity of the products, we injected immunodeficient mice intravenously with luciferase labelled MM1.s cells followed by a single intravenous injection of CAR-T cells on day 0. As seen in figure 1A, both products demonstrated efficacy, but the UF-BCMA product induced durable disease control while disease progression started to occur with the 9-day product on day 29 after CAR-T injection. Consistent with the improved efficacy, circulating levels of the UF-BCMA CAR-T cells in the mouse blood were found to be up to 100x higher than the levels of the 9-day BCMA CAR-T product (Figure 1B). Similar increased potency and marked increases in circulating CAR-T cells were observed in a mouse model of human lymphoma when comparing a CD19 CAR manufactured using the UF-CAR workflow as compared to a standard CAR-T manufacturing process. To assess the safety and clinical potential of CAR-T products manufactured with the UF-CAR platform, a phase 1 trial was recently initiated using a CD19 CAR-T product (UF-Kure19). This trial that is open to patients with relapsed/refractory NHL completed treatment of its first patient who had relapsed mantle cell lymphoma. UF-Kure19 product was manufactured successfully in less than 1 day and demonstrated CAR expression of 41%. The product passed all release criteria for infusion and was administered to the patient after lymphodepletion with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 daily for 3 days. UF-Kure19 cells expanded robustly in the patient and peaked around day 10 (23% of circulating CD3) with a strong skewing of CD4/CD8 cells (93% CD8+ T cells on day 10). The patient was found to be in complete metabolic remission by day 28 and ongoing remission was confirmed on day 60. We have developed an ultra-fast CAR-T cell manufacturing platform that enables low-cost production in less than one day. In vitro and animal data suggest this fast-manufacturing platform leads to potent CAR-T cells. Early human testing indicates CAR-T cells generated using this novel system have clinical activity against hematologic malignancies.

Predicting CAR-T Response in Mantle Cell Lymphoma Using Deep Neural Network Models on Single-Cell RNA Sequencing Data

Introduction The approval of CD19 chimeric antigen receptor (CAR) T therapy by the FDA for relapsed mantle cell lymphoma (MCL) represents a significant advancement. However, patients are resistant or experience relapse after receiving CAR T therapy. High degree of transcriptomic heterogeneities among MCL tumor cells makes it challenging to predict response to CAR-T therapy. In this study, we employed deep learning models in conjunction with single-cell RNA sequencing data to predict the response to CAR-T therapy in MCL patients. Methods In this study, we collected and analyzed 39 patient samples treated with CAR-T therapy, of which 30 were sensitive and 9 were resistant to the treatment. Single-cell RNA sequencing was performed on these samples, and downstream analysis was conducted using the Seurat R package (version 4.3.0.1), including dimension reduction and cell type annotation. B cells were isolated in-silico, followed by differential gene expression analysis using the Wixcoxon rank sum test. The identified differentially expressed genes were then used as inputs for deep learning neural networks to predict the response to CAR-T therapy (Figure 1A). We applied a multilayer perceptron (MLP) network as the binary classifier for response prediction. The model consists of four fully connected layers, including one input layer, two intermediate hidden layers, and one output layer. The number of neurons in the input layer corresponds to that of the differentially expressed genes. The two hidden layers have 64 and 16 neurons, respectively, each followed by one activation layer using rectified linear unit (ReLU) and one dropout layer with dropout rate of 0.4. The features from the latter hidden layer were extracted for embedding plots. The output layer has two neurons with activation function of Softmax, each neuron representing the probability of categorical patient response labels. A leave-one-sample-out approach was employed to calculate the prediction accuracy. Results A total of 49,112 cells passed the quality control criteria, with 15,322 identified as tumor B cells (31.19%, Figure 1B). We observed a high level of transcriptomic heterogeneity among tumor cells in patients. Differential expression analysis revealed 1,236 genes with significantly different expression between sensitive and resistant samples (adjusted p-value < 0.05). To evaluate the predictive performance of our model, we employed a leave-one-sample-out approach and achieved an average accuracy of 90.07%. For instance, when sample K0 was used as the test dataset and all other samples were used as the training dataset, 91.49% of cells from sample K0 were accurately predicted to be sensitive (Figure 1C). Further, visualization of the hidden layer using the Uniform Manifold Approximation (UMAP) embedding plot demonstrated that sample K0 fell into the same area as other sensitive samples. Conclusion In conclusion, our study highlights the potential of deep learning models and single-cell RNA sequencing data in predicting the response to CAR-T therapy in MCL. These findings hold promise for clinical applications and may contribute to the development of personalized treatment strategies for MCL patients.

A Multicenter Phase 2 Trial of Zanubrutinib, Obinutuzumab, and Venetoclax (BOVen) in Patients with Treatment-Naïve, TP53-Mutant Mantle Cell Lymphoma

Background: TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with chemoimmunotherapy (Eskelund, Blood 2017) with median progression-free survival (PFS) of 0.9 years and median overall survival (OS) of 1.8 years. There is no standard frontline treatment for this high-risk subset. The combination of Bruton's tyrosine kinase (BTK) inhibition and BCL2 inhibition were synergistic and active in relapsed, refractory MCL, including in patients with TP53 mutation (Tam, NEJM 2018). Obinutuzumab, ibrutinib, and venetoclax were well tolerated and efficacious in relapsed and untreated MCL patients (Le Gouill, Blood 2021). We hypothesized that treatment with zanubrutinib (Zanu), Obinutuzumab (Obin), and venetoclax (Ven) (BOVen) would be well-tolerated and efficacious in untreated TP53-mutant MCL. Methods:In this multicenter, investigator-initiated phase 2 trial (NCT03824483), eligible patients had previously untreated MCL with TP53 mutation (of any variant allele frequency) and ECOG PS ≤2, ANC >1, PLT >75, HGB ≥9 (unless if due to MCL). BOVen is administered in 28-day cycles: Zanu 160 mg PO BID starting D1; Obin 1000 mg IV D1 or split D1-2, 8, 15 of C1, D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg QD). Treatment duration is 2 years at minimum and the primary endpoint is 2-year PFS. Response was assessed using Lugano criteria (Cheson, JCO 2014). PFS and OS were estimated using the Kaplan-Meier method. Peripheral blood minimal residual disease (PB-MRD) assessment was performed using the Adaptive clonoSEQ ® assay. After 24 cycles, Zanu and Ven can be discontinued if MRD undetectable (<10 -6) complete remission (CR) is achieved. With subsequent PB-MRD monitoring, patients can be retreated if clinical progression or MRD detectability (>10 -6). Adverse events (AE) were assessed per CTCAE v5. Results: All 25 planned patients have been enrolled (May 15, 2023 data cut). The median age on study was 65 years (range 29 - 82); 76% were male (19/25); various histologic subtypes were included (15 conventional MCL, 5 non-nodal leukemic, and 5 blastoid variant); 100% stage IV (25/25); by MIPI: 68% high risk (17/25), 28% intermediate (7/25), and 4% low risk MIPI score (1/25); 67% Ki67 ≥30% (14/21); 33% Ki67≥50% (7/21); 100% TP53 mutation, and 48% 17p deletion (12/25). Treatment was overall well-tolerated. The most common treatment-related AEs (≥20%) were predominantly low-grade and manageable, including diarrhea (52%), neutropenia (28%), infusion-related reaction (24%), bruising (20%), COVID-19 infection (20%), nausea (20%), thrombocytopenia (20%), and rash (20%). The grade 3 or higher treatment-related AEs were neutropenia (12%), infusion-related reaction (8%), COVID-19 (8%), diarrhea (4%), transaminitis (4%), thrombocytopenia without bleeding (4%), and rash (4%). Detailed toxicity data will be presented in future. Median follow-up was 16.1 months. There were 5 progressions and 4 deaths on study (2 COVID-related, 1 post-operative aspiration pneumonia, 1 unknown cause), see Figure 1. All deaths occurred in patients who were in ongoing response at time of death. The best overall response rate was 95% (24/25) with 88% (22/25) achieving a CR. At C3 post Zanu-Obin, 68% (n=17/25) achieved PET-CR and post cycle 3, 5 patients converted to a PET-CR (Figure 1). The 1-year PFS and overall survival (OS) were 84% (95% CI: 71%, 100%) and 96% (95% CI: 89%, 100), respectively. The 16-month PFS and OS were 75% (95% CI: 60%, 95%) and 87% (95% CI: 75%, 100%), respectively. The 16-month PFS and OS for patients less than 65 years of age (n=9) were both 100%. Seven patients completed 24 treatment cycles. Of these, 71% (5/7 pts) were in CR and MRD undetectable (treatment discontinued) and 29% (2/7 pts) were in CR and MRD detectable (continued treatment). Outcomes post C24 will be presented in future. At 10 -6 MRD sensitivity level, 7 (28%) of 23 patients had undetectable MRD at C3 and 16 (100%) of 16 patients at C13. Conclusions:BOVen is a well-tolerated, outpatient regimen associated with high response rates and high rates of undetectable MRD in untreated TP53-mutant MCL. The early PFS and OS estimates with BOVen compare favorably with historical outcomes of chemoimmunotherapy in this high-risk subset of MCL. Based on this data, BOVen emerges as a promising treatment option for TP53-mutant MCL and, therefore, the study was expanded to include an additional 25 (total 50) TP53-mutant MCL patients.

Outcomes of Bridging and Salvage Radiotherapy in Relapsed or Refractory Mantle Cell Lymphoma Patients Undergoing CD19-Targeted CAR T-Cell Therapy.

We sought to describe our early experience of using bridging and salvage radiation therapy (RT) in patients with relapsed/refractory mantle cell lymphoma (MCL) undergoing CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. A retrospective study was conducted for consecutive MCL patients who were treated with commercially available CD19-targeted CAR T-cell therapy between 2020 and 2022 at a single institution. Patients who received RT pre-and post-CAR T-cell therapy were identified and analyzed using descriptive and statistical analysis. Overall survival (OS) from the date of CAR T infusion was estimated with the Kaplan-Meier method. The duration of local control (LC) was defined as the time between the start date of RT and the date of in-field progression/relapse. Response to RT was analyzed based on the total number of irradiated sites. A total of 21 patients with MCL who received CD19-targeted CAR T-cell therapy were identified (17 brexu cel, 3 tisa-cel, and 1 liso-cel) with a median follow-up of 15.3 months (24 days-36.2 months). The median age was 65 years at time of apheresis (43-83 years). The median OS for the entire cohort following CAR T-cell therapy was 17 months (95% CI: 14.2 months-not reached). Of the 21 patients, 1 patient received bridging RT prior to CAR T infusion, 1 patient received RT pre-and post-CAR T, and 5 patients received salvage RT post-CAR T with a total of 23 irradiated sites. Sites of RT include: extremities (10), central nervous system (3), pelvis/groin (3), head and neck (3), chest (2), abdomen (1), and multiple sites (1). The median dose/fractionation were 16.5 Gy (range, 3.6-45 Gy) and 5.5 fractions (range, 2-16 fractions)- radiation data was incomplete only for 1 patient who received RT at an outside institution. The in-field responses of the 21 evaluable sites were as follows: complete response (CR) (n = 18, 86%) and partial response (PR) (n = 3, 14%), translating into an LC rate of 100%; the remaining 2 sites were not evaluable since the patient died shortly after receiving RT due to progressive lymphoma. Notably, there was no correlation between RT dose and LC; 9 sites received low-dose RT (3.6-6 Gy) with responses as follows: CR (n = 6, 67%) and PR (n = 3, 33%). Only 1 patient experienced grade 3-4 RT-related toxicities. At the time of the last follow-up, 4 patients remained alive, and 3 patients succumbed to progressive lymphoma. As no studies exclusively focusing on CAR T-cell therapy and bridging or salvage RT have been published among relapsed/refractory MCL patients, our early experience underlines that using RT as a bridging and salvage approach is associated with excellent in-field control and limited toxicity in the peri-CAR T setting. Low-dose RT for MCL appears to be very effective in this highly refractory population and warrants further investigation.

The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer.

The ubiquitin-proteasome system (UPS) is an intracellular organelle responsible for targeted protein degradation, which represents a standard therapeutic target for many different human malignancies. Bortezomib, a reversible inhibitor of chymotrypsin-like proteasome activity, was first approved by the FDA in 2003 to treat multiple myeloma and is now used to treat a number of different cancers, including relapsed mantle cell lymphoma, diffuse large B-cell lymphoma, colorectal cancer, and thyroid carcinoma. Despite the success, bortezomib and other proteasome inhibitors are subject to severe side effects, and ultimately, drug resistance. We recently reported an oncogenic role for non-ATPase members of the 19S proteasome in chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and several different solid tumors. In the present study, we hypothesized that ATPase members of the 19S proteasome would also serve as biomarkers and putative therapeutic targets in AML and multiple other cancers. We used data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) available at UALCAN and/or GEPIA2 to assess the expression and prognostic value of proteasome 26S subunit, ATPases 1-6 (PSMC1-6) of the 19S proteasome in cancer. UALCAN was also used to associate PSMC1-6 mRNA expression with distinct clinicopathological features. Finally, cBioPortal was employed to assess genomic alterations of PSMC genes across different cancer types. The mRNA and protein expression of PSMC1-6 of the 19S proteasome were elevated in several cancers compared with normal controls, which often correlated with worse overall survival. In contrast, AML patients demonstrated reduced expression of these proteasome subunits compared with normal mononuclear cells. However, AML patients with high expression of PSMC2-5 had worse outcomes. Altogether, our data suggest that components of the 19S proteasome could serve as prognostic biomarkers and novel therapeutic targets in AML and several other human malignancies.

Outcomes of Bridging and Salvage Radiotherapy in Relapsed or Refractory Mantle Cell Lymphoma Patients Undergoing CD19‐Targeted CAR T‐Cell Therapy

Outcomes of Bridging and Salvage Radiotherapy in Relapsed or Refractory Mantle Cell Lymphoma Patients Undergoing CD19‐Targeted CAR T‐Cell Therapy

BV6, AN ANTAGONIST OF INHIBITOR OF APOPTOSIS PROTEINS, SENSITIZES RESISTANT MANTLE CELL LYMPHOMA CELLS TO VENETOCLAX

Introduction: Although Bruton’s tyrosine kinase inhibitors (BTKi) and CAR T-cell therapy have achieved remarkable efficacy in the treatment of mantle cell lymphoma (MCL), it remains incurable due to the inevitable development of therapeutic resistance. The BCL-2 inhibitor venetoclax is effective in many relapsed MCL patients, including those who progressed on BTKi, but subsequent relapse to venetoclax yields poor clinical outcomes. Hence, novel therapeutics and combination therapies are required to tackle the clinical challenges. Here, we investigated BV6, an antagonist of inhibitor of apoptosis proteins (IAPs), alone and in combination with venetoclax in multiple therapy-resistant MCL models. Methods: We performed single-cell RNA-seq to assess gene expression in ibrutinib-sensitive, ibrutinib-resistant, and dual ibrutinib-/CAR T-resistant MCL patients. Cell lines with acquired resistance to ibrutinib or venetoclax, as well as primary tumor cells from patients who relapsed after multiple therapies, were used as models of MCL resistance. CellTiter-Glo® luminescent assay was used to measure cell viability; annexin V/PI staining was used to measure the induction of apoptosis; and western blotting was used to assess IAP and apoptosis signaling protein expression across MCL cell lines after drug treatment. Results: The single-cell RNA-seq analysis demonstrated that IAP gene expression was not influenced by patient response to ibrutinib and CAR T-cell therapy, and western blotting showed that IAP proteins were broadly expressed across all MCL cell lines. To determine the on-target effects of BV6, we treated JeKo-1, JeKo-IBN-R, Mino, and Mino-VEN-R cells with BV6 and examined the expression of IAPs. BV6 treatment for 4h markedly reduced c-IAP1 and c-IAP2 expression, and moderately reduced XIAP expression. BV6 inhibited cell viability in both ibrutinib- and venetoclax-resistant cell lines, and BV6 treatment for 24 h dose-dependently induced apoptosis in MCL cells, including not only cell lines with acquired resistance but also patient primary cells, independent of their resistance to ibrutinib, venetoclax, and CAR T-cell therapy. We observed a striking and significant synergy in the cell viability assay when ibrutinib- or venetoclax-resistant cells were treated with BV6 combined with venetoclax (combination index < 1), and a dramatic enhancement of apoptosis (p < 0.001). The combination eradicated c-IAP1 and c-IAP2 expression, while XIAP was synergistically diminished. This was accompanied by strong caspase-3 activation and PARP cleavage. This combination therapy is currently under evaluation in venetoclax-resistant mouse model in vivo. Conclusions: Our findings indicate that a combination of IAP antagonists with apoptosis inducers can be exploited as a rational strategy to overcome therapeutic resistance in MCL. This study was supported by philanthropic funds from the Kimmel Research fund and various donor funds. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.

Abstract 6208: Targeting DNA polymerase theta and ATM leads to synergistic killing of mantle cell lymphoma cells

Abstract Introduction: Rapid cell proliferation requires intact and faithful DNA damage repair mechanisms. DNA polymerase theta (POLQ) plays a key role in repairing DNA double-strand breaks through the microhomology-mediated end-joining (MMEJ), which is one of the three main pathways involved in repairing replication-induced double-strand breaks. Limited data have suggested that concurrent depletion of POLQ and ataxia-telangiectasia mutated (ATM) could be embryonic lethal. Hence, this phenomenon has the potential to be exploited for therapeutic benefit in cancers where ATM mutations are commonly seen. Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma marked by (11;14) translocation with ATM alterations seen in 40-50% of patients. There is an unmet need to find novel therapeutic strategies, especially in relapsed and/or refractory (R/R) MCL. Here, we investigated whether targeting POLQ and ATM could be a potential therapeutic strategy in MCL. Methods: In vitro studies were conducted by using MCL cell lines. CRISPR-Cas9 system was used to genetically deplete POLQ and ATM genes and sgRNAs co-expressing fluorescence markers were used to track the cell population with respective genotypes over time. Cell viability was assessed by CellTiter-Glo assay and flow cytometry. All cell lines were profiled for ATM expression and activity. A p-value of &amp;lt; 0.05 was considered statistically significant. The combination index of &amp;lt;1 was defined as synergistic. Results: CRISPR-Cas9-mediated depletion of POLQ significantly decreased cell proliferation in multiple MCL cell lines. In particular, Granta-519, which possesses a single copy of kinase-dead ATM that is reduced in expression, was most sensitive to POLQ depletion. Concurrent genetic depletion of ATM and POLQ resulted in a synergistic antiproliferative effect in ATM-proficient MCL cell lines. Subsequently, this cellular phenotype caused by the genetic intervention was recapitulated by using two POLQ inhibitors (novobiocin and ART558) and an ATM inhibitor (AZD0156). In vitro, single-agent treatment with novobiocin or ART558 caused a significant cytotoxic effect at physiologically relevant concentrations in ATM-deficient cells and co-treatment of novobiocin or ART558 with AZD0156 was synergistic in killing ATM-proficient MCL cells. Importantly, POLQ inhibitors significantly decreased the cell viability of MCIR1, which is an ibrutinib-resistant MCL cell line. Mechanistically, novobiocin or ART558 treatment induced gH2AX and cleaved PARP upregulation, which was further enhanced by ATM depletion, suggesting that co-inhibition of POLQ and ATM caused apoptosis due to the accumulation of unrepaired DNA damage. Conclusion: POLQ is a promising target in MCL, especially in ATM-deficient setting. In ATM-proficient MCL, targeting ATM and POLQ is synergistic. Our data has the potential to uncover novel biomarker-driven drug therapy of POLQ inhibitors in R/R MCL. Citation Format: Jithma Prasad Abeykoon, Shuhei Asada, Kalindi Parmar, Xiaosheng Wu, Thomas Witzig, Geoffrey Shapiro, Alan D. D'Andrea. Targeting DNA polymerase theta and ATM leads to synergistic killing of mantle cell lymphoma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6208.

Abstract 1422: Fibroblast growth factor receptor-1 is a novel therapeutic target in mantle cell Lymphoma

Abstract Cell cycle dysregulation and significant enrichment of E2F1 target genes are hallmarks of MCL, and the inability to directly target E2F1-dependent processes is a clinical hindrance. Despite several treatment options, mantle cell lymphoma is associated with poor clinical outcomes and the development of resistance. We identified Fibroblast Growth Factor Receptor-1 is upregulated in relapsed mantle cell lymphoma patients and high FGFR-1 expression in MCL correlates with poor overall and progression-free survival. Genetic ablation of FGFR1 in MCL cells induced cell cycle arrest, and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. Functionally, FGFR1 loss upregulates the expression of the cell-cycle dependent Kinase inhibitor 1C (CDKN1C) through epigenetic repression via EZH2. CDKN1C binds to E2F1 and regulates the transactivation of its target genes, including CDK1. CDK1 further stabilizes MYC and positively regulates the expression of EZH2, activating the feed-forward loop to promote cell survival. Conversely, losing FGFR1 disrupts this feed-forward loop in malignant cells. This is the first report establishing FGFR1 as a novel therapeutic target and providing a rationale to target FGFR1 to treat Mantle cell lymphoma and disrupt the feed-forward loops contributing to the survival of malignant cells. Citation Format: Anuvrat Sircar, Satishkumar Singh, Ken H. Young, Narendranath Epperla, Lalit Sehgal. Fibroblast growth factor receptor-1 is a novel therapeutic target in mantle cell Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1422.

Isolation and characterization of pseudo degradation products of acalabrutinib using ESI-HRMS/MS and NMR: Formation of possible geometrical isomers

A forced degradation study of acalabrutinib (ACB), used to treat relapsed mantle cell lymphoma, was performed to identify and characterize all possible major degradation products formed under different stress conditions. The degradation products (DP) were separated using reverse phase UHPLC system on Kinetex EVO C18 column. Major DPs formed were isolated using semi-preparative HPLC and characterized by LC-ESI-HRMS/MS and NMR. ACB degraded to form seven major degradants (DP-I to DP-VII). DP-I and DP-V were formed under alkaline stress condition, whereas DP-II, DP-III, DP-VI and DP-VII were formed under both acidic and basic conditions. Further, DP-IV was formed when ACB drug was exposed to hydrogen peroxide stress condition. ACB was found to be stable when subjected to aqueous (neutral pH), thermal and UV radiation of 254 nm, as it has not shown any significant degradation under these conditions. Interestingly, two pairs of pseudo geometrical isomeric DPs (DP-II and DP-III, DP-VI and DP-VII) were observed. The plausible degradation pathway of ACB and fragmentation patterns of both ACB and major DPs were discussed.

Aggressive, early resistant and relapsed mantle cell lymphoma distinct extrinsic microenvironment highlighted by transcriptome analysis.

Immunotherapy strategies relying on innate or adaptive immune components are increasingly used in onco-haematology. However, little is known about the infiltrated lymph nodes (LN) or bone marrow (BM) landscape of mantle cell lymphoma (MCL). The original transcriptomic approach of reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was applied here to explore the expression of 24 genes of interest in MCL at diagnosis (21 LN and 15BM) or relapse (18 LN). This allowed us to identify that at baseline, samples from MCL patients with an aggressive morphology (i.e. blastoid or pleomorphic) or a high proliferative profile, displayed significantly higher monocyte/macrophage-associated transcripts (CD14 and CD163) in LN and BM. Regarding T-cells, aggressive MCL forms had significantly lower amounts of LN CD3E transcripts, yet an increased expression of cytotoxic markers in LN (CD8) and BM (CD94). A very high-risk group with early treatment resistance displayed, at diagnosis, high proliferation (KI67) and high macrophages and cytotoxic transcript levels. Post-immunochemotherapy relapsed samples revealed lower levels of T- and natural killer-cells markers, while monocyte/macrophage markers remained similar to diagnosis. This study suggests that rapid analysis of MCL microenvironment transcriptome signatures by RT-MLPA could allow for an early distinction of patient subgroups candidates for adapted treatment strategies.

Experiences with Glofitamab Administration following CAR T Therapy in Patients with Relapsed Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare type of B-cell Non-Hodgkin lymphoma (NHL) affecting predominantly male patients. While complete remissions following first-line treatment are frequent, most patients ultimately relapse, with a usually aggressive further disease course. The use of cytarabine-comprising induction chemotherapy and autologous stem cell transplantation, Rituximab maintenance, Bruton’s tyrosine kinase (BTK) inhibitors and CAR T therapy has substantially improved survival. Still, options for patients relapsing after CAR T therapy are limited and recommendations for the treatment of these patients are lacking. We report two cases of patients with mantle cell lymphoma who relapsed after CAR T therapy and were treated with the bispecific CD20/CD3 T cell engaging antibody glofitamab. Both patients showed marked increases of circulating CAR T cells and objective responses after glofitamab administration. Therapy was tolerated without relevant side effects in both patients. One patient completed all 12 planned cycles of glofitamab therapy and was alive and without clinical progression at the last follow-up. The second patient declined further treatment after the first cycle and succumbed to disease progression. We review the literature and investigate possible mechanisms involved in the observed responses after administration of glofitamab, such as proliferation of CAR T cells, anti-tumor effects of the bispecific antibody and the role of other possibly contributing factors. Therapy with bispecific antibodies might offer an effective and well-tolerated option for patients with mantle cell lymphoma relapsing after CAR T therapy.

CAR-T therapy in mantle cell lymphoma: a review of the current literature

Mantle cell lymphoma (MCL) is a rare lymphoma derived from mature B cells with the presence of translocation t(11;14) resulting in cyclin D1 overexpression, with a variety of clinical symptoms and a variable course. Despite better understanding regarding its pathogenesis, and the use of aggressive immunochemotherapy with autologous bone marrow transplantation, this disease is still considered incurable, with median overall survival of five years. Patients with refractory and relapsed disease have a poor prognosis and the traditional cytotoxic therapy is insufficiently effective in this group of patients. New therapies such as Bruton’s tyrosine kinase inhibitors (BTKi), B-cell lymphoma-2 (BCL-2) inhibitors, and immunomodulatory drugs have produced high response rates, but the duration of response is limited, and patients can have another relapse diagnosed. Recently adopted immunotherapy with chimeric antigen receptor (CAR) T-cells directed against the CD19 receptor on lymphoma cells seems to be promising in the population of refractory and relapsed MCL patients. In July 2020, the United States Food and Drug Administration approved brexucaptagene autoleucel CAR-T product for patients with MCL after two lines of therapy and treatment with Bruton kinase inhibitors. In this review, we briefly discuss the treatment options in patients with refractory and relapsed MCL, focusing on BTKi treatment as the targeted therapy required before CAR-T treatment. We summarize our knowledge of CAR-T cell therapy for MCL in clinical trials and real-world clinical practice, and consider the place of CAR-T in future MCL therapy.

Mantle Cell Lymphoma: the Role of Risk-Adapted Therapy and Treatment of Relapsed Disease.

In this review, the current treatment strategies are recapped, evolving agents are discussed, and we provide guidance in treating R/R MCL. There has been an advancement in treatment using targeted therapy, cellular therapies including chimeric antigen receptor (CAR) T cell therapy and hematopoietic stem cell transplantation (HSCT) and novel therapeutic agents including non-covalent BTKis, bispecific antibodies, and antibody-drug conjugates for treatment of refractory and relapsed mantle cell lymphoma. Mantle cell lymphoma (MCL) is a mature B-cell lymphoma that is associated with a poor prognosis. Current treatments include immunochemotherapy, chemotherapy and autologous stem cell transplantation (SCT) which place patients in remission but result in relapse. Chemoimmunotherapy uses chemotherapeutic agents paired with rituximab in patients who have chemo-sensitive disease with prolonged remission of at least > 2years and/or have contraindications to chemotherapy that serve as bridges to more definitive treatment. Additional therapies including proteosome inhibitor-based therapies and immunomodulators, like bortezomib and lenalidomide, can be used as single agents or in combination with others. Bruton's tyrosine kinase (BTK) inhibitors including ibrutinib, acalaburtinib, and zanubrutinib have also been proven effective for the treatment of (R/R) disease. Another agent is Venetoclax, a robust drug that can be used in MCL after progression or intolerance to BTKi. Newer advances in the management of MCL have led to the utilization of cellular therapies including chimeric antigen receptor (CAR) T cell therapy and SCT that are options for healthy young (< 65years old) who have progressed through several lines of therapies. With progression of disease, mutations are acquired that cause therapy resistance. Novel therapeutic agents such as non-covalent BTKis, bispecific antibodies, and antibody-drug conjugates are paving the way for advancements in treatment for R/R MCL. R/R MCL is a complex disease with many therapeutic options none of which has been proven superior in head-to-head comparison. In this review, the current treatment strategies are recapped, evolving agents are discussed, and we provide guidance in treating R/R MCL.

Cost-effectiveness and value of information analyses of Bruton's tyrosine kinase inhibitors in the treatment of relapsed or refractory mantle cell lymphoma in the United States.

BACKGROUND: Ibrutinib, acalabrutinib, and zanubrutinib have shown improvements in efficacy and safety over conventional chemoimmunotherapy in refractory or relapsed mantle cell lymphoma (R/R MCL). OBJECTIVE: To evaluate the comparative cost-effectiveness of the Bruton's tyrosine kinase inhibitors (BTKIs) and estimate the expected value of (partial) perfect information (EV[P]PI) in terms of net health benefits (NHBs) and net monetary benefits (NMBs) forgone. METHODS: Using a two-state Markov model (progression-free; progression or death), we estimated in base-case and probabilistic sensitivity analyses (PSAs) the incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) of, respectively, progression-free survival (PFS) life-years (PFLYs) and PFS quality-adjusted LY (PFQALY) gained (g) against 3-year and 5-year time horizons. A willingness-to-pay threshold of $150,000/PFQALY was used to assess the probability of being cost-effective in the PSA. EVPI was calculated from the respective NHBs and NMBs. RESULTS: Compared with ibrutinib, acalabrutinib yielded a 3-year ICER of $90,571 (PSA = $88,588)/PFLYg and ICUR of $117,098 ($110,063)/PFQALYg, whereas zanubrutinib yielded a 3-year ICER of $58,422 ($58,907)/PFLYg and ICUR of $73,027 ($73,634)/PFQALYg. The corresponding 5-year estimates were ICER of $73,918 ($74,189)/PFLYg and ICUR of $90,512 ($90,844)/PFQALYg for acalabrutinib and ICER of $48,641 ($48,732)/PFLYg and ICUR of $61,612 ($63,727)/PFQALYg for zanubrutinib. Compared with zanubrutinib, treatment with acalabrutinib yielded a 3-year ICER of $144,633 ($134,964)/PFLYg and ICUR of $197,227 ($166,109)/PFQALYg; the corresponding 5-year estimates were $117,579 ($118,161)/PFLYg and $136,144 ($136,818)/PFQALYg. The EVPI/patient was an NHB of 0.036 PFQALYs and NMB of $3,602 forgone, resulting in a population EVPI of $134,766,957 forgone. The EVPPIs/patient for effectiveness were NHB of 0.015 PFQALYs and NMB of $1,479, with corresponding values of 0.032 and $3,187 for costs and 0.015 and $1,519 for health-related quality of life forgone. CONCLUSIONS: This early cost-effectiveness analysis based on phase I/II clinical trials of BTKIs in R/R MCL suggests an additional PFS benefit for second-generation BTKIs compared with ibrutinib. However, the relative uncertainty due to the lack of direct trial evidence may lead to an opportunity cost or lost health benefits if the current evidence is adopted to compare between these products. Additional evidence is needed to address the relative efficacy of the BTKIs. DISCLOSURES: A. McBride serves on speakers bureaus for Coherus BioSciences and Merck. He is now at Bristol-Myers Squibb in a position unrelated to this study. I. Abraham is joint equity owner in Matrix45. By company policy, owners and employees are prohibited from owning equity in client and sponsor organizations (except through mutual funds or other independently administered collective investment instruments), contracting independently with client and sponsor organizations, or receiving compensation independently from such organizations. Matrix45 provides similar services to biopharmaceutical, diagnostics, and medical device companies on a nonexclusivity basis. Of relevance to this article, Matrix45 has not provided any services to this study. I. Abraham is the quantitative methods editor of JAMA Dermatology and deputy editor-in-chief of the Journal of Medical Economics. The remaining authors have no relevant financial or nonfinancial interests to disclose.

Successful treatment of second-time CAR-T 19 therapy after failure of first-time CAR-T 19 and ibrutinib therapy in relapsed mantle cell lymphoma.

A patient with relapsed mantle cell lymphoma (MCL) showed stable disease after receiving ibrutinib therapy as a salvage therapy, after the failure of his first chimeric antigen receptor (CAR)-T 19 cell therapy. The combined effects of CAR-T 19 cells from the patient and ibrutinib on JeKo-1 cell were explored in vitro and in vivo. The expression of programmed death-1 (PD-1) receptor on CD3+ T cells in the peripheral blood decreased from 82.95% in the first CAR-T 19 cell therapy to approx. 40% after 14 months of ibrutinib therapy. When the disease progressed again during the ibrutinib therapy, the patient was enrolled into the same clinical trial of CAR-T 19 cell therapy. The efficacy of CAR-T 19 cells increased after the ibrutinib therapy. The mRNA expression level of PD-1 in CAR-T 19 cells after ibrutinib therapy was lower than in CAR-T 19 cells before the ibrutinib therapy. Nevertheless, CAR-T 19 cell therapy combined with ibrutinib had no synergistic effect in a short term in vitro and in the JeKo-1 cell mouse model. We expect our results to provide evidence for the combination treatment of ibrutinib for MCL or even other types of B-cell lymphomas. Moreover, the improvement in CAR-T 19 cell function was based on long-term ibrutinib therapy.