2025 Report on the Mantle Cell Lymphoma Scientific Consortium and Workshop Hosted by the Lymphoma Research Foundation

The Past and the Future

The meeting began with the presentation of the Mantle Cell Lymphoma Leadership Award to Martin Dreyling, MD, PhD, an inaugural member of the Mantle Cell Lymphoma Consortium (MCLC) Executive Committee. Dreyling was recognized for his leadership in mantle cell lymphoma (MCL) research over the years, his role in establishing the European MCL Network, and his unwavering commitment to advancing progress for patients with MCL.

In his keynote address, Dreyling discussed the history of MCL research and how an improved understanding of the molecular mechanisms of pathogenesis has transformed the landscape of MCL treatment. The modern era of MCL care began in 1974 with the identification of the “cell of origin” in lymphoma. Still, diagnosis remained difficult, and the pathology of the disease was not always clear. In the 1990s, the identification of key MCL-specific alterations—including rearrangement of BCL1—opened the door to the characterization of MCL as a unique subset of disease, and improved diagnosis, and the identification of novel pathways involved in pathogenesis.^1,2 Additional research over the following decades revealed that MCL represents a spectrum of disease, ranging from indolent to classical to transformed, and that unique molecular features shape the progression of the disease.³ The goal of MCL care is therefore to tailor treatment appropriately based on individual risk, thereby improving outcomes and minimizing the burden of treatment-related adverse effects.^3,4

For many years, chemotherapy had been the standard in first-line treatment of MCL, but outcomes have remained limited. Over the years, initial treatment of MCL has evolved following a number of therapeutic advances—including the development of novel chemotherapeutic regimens, optimization of the use of autologous stem cell transplant (ASCT), and the introduction of maintenance rituximab therapy.^3,5,6 Such advancements have transformed the treatment of MCL such that it is now considered maintenance therapy and has resulted in prolonged survival outcomes for many patients. Still, there is room for improvement and an urgent need for novel therapies in the frontline setting, where there is the greatest opportunity to provide a meaningful benefit to patients.

A growing body of evidence suggests that Bruton tyrosine kinase inhibitors (BTKis) represent a promising option in early relapse, with improved tolerability and survival outcomes compared with chemotherapy.^7,8 More recently, the phase 3 TRIANGLE trial (NCT02858258) has investigated the use of BTKis in first-line treatment and has shown long-term benefits over immunochemotherapy alone with regard to both failure-free survival and overall survival (OS).⁹ Emerging evidence from TRIANGLE also provides insight into many important questions that remain unanswered in the treatment of MCL, including whether maintenance treatment is still needed (yes) and whether benefits are still observed with ASCT after BTK inhibition (some benefit is still observed for high-risk patients, but there is a need for larger studies).

Looking ahead, a variety of clinical trials are underway to refine the treatment of MCL, including the comparison of novel combination regimens (phase 1/2 OAsIs trial [NCT02558816]) and chimeric antigen receptor (CAR) T-cell therapies (phase 2 CARMAN trial [NCT06482684]) with current standard-of-care approaches, as well as optimization of treatment in patients based on age and underlying risk status. Significant improvements in survival have been observed over the past several decades, and progress continues to be made. Dreyling concluded his talk by challenging attendees to keep generating preclinical and clinical data that will offer new opportunities to improve outcomes and treatment experiences for people living with MCL.

Day 1

MCL Genetics and Biology

Ongoing research into the underlying biology and genetics of MCL is critical not only to better understand disease pathogenesis and progression but also to identify novel potential targets that can be leveraged in clinical care. In this session, investigators shared the latest research and advances in MCL genetics and biology.

The SOX11 Interactome Reveals the SOX11:SMARCA4 Complex as a Driver of Oncogenic Transcriptional Programs in Mantle Cell Lymphoma

To open the session, Virginia Amador, PhD, from the August Pi i Sunyer Biomedical Research Institute in Barcelona, Spain, described the identification of a novel molecular complex as a driver of oncogenic transcription in MCL.¹⁰ The transcription factor SOX11 is aberrantly expressed in conventional MCL, which exhibits an aggressive phenotype. SOX11 expression influences a variety of oncogenic factors, but the precise role in MCL pathogenesis remains unknown. To better understand this process, a proximity-labeling strategy was employed to identify SOX11 interacting partners, which revealed an interactome comprising 92 distinct proteins in MCL. Among these, the SMARCA4 catalytic subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) pathway was identified as a key interacting partner, with genomic co-occupancy of the SOX11:SMARCA4 complex demonstrated in nearly 60% of SOX11-specific binding regions. Expression of SMARCA4 was found to correlate with SOX11 expression in MCL cell lines, and degradation of SMARCA4 reduced binding of SOX11 to the DNA and resulted in altered expression of several genes within known oncogenic pathways in MCL. Given the identification of the SOX11:SMARCA4 complex as a key driver of oncogenic transcriptional programs in MCL, disruption of this complex may represent an innovative therapeutic approach for patients with aggressive MCL.

CEACAM1 Orchestrates Lipid Raft Dynamics and B-Cell Receptor Signaling in Mantle Cell Lymphoma

Next, Vu Nguyen Ngo, PhD, from City of Hope, described the role of CEACAM1 as a mediator of B-cell receptor (BCR) signaling in MCL.¹¹ In healthy B cells, BCR signaling is important for survival and antigen-mediated responses. Activation of BCR signaling has been found in many MCL cell lines and has been correlated with poor survival. While it is clear that BCR signaling is an oncogenic driver in MCL, the underlying mechanisms are poorly understood. The genetic alterations observed within this pathway in MCL are distinct from those seen in other disease states, suggesting an alternative role in pathogenesis. A genetic screen was therefore performed to identify the MCL-specific role of BCR signaling in oncogenesis. From this screen, CEACAM1 was identified as a key potential factor. Knockout of CEACAM1 in mantle cells resulted in reduced survival due to increased rates of apoptosis and defects in cell cycle progression.

Overexpression of CEACAM1 was observed in MCL cells, and knockdown in xenograft models of MCL was found to reduce tumor growth and increase survival. This activity correlated with the disruption of BCR signaling in both MCL and normal B cells. Additionally, CEACAM1 expression correlated with ibrutinib sensitivity, such that cells with the highest levels of CEACAM1 expression were the most sensitive to ibrutinib, whereas low expressers exhibited resistance. These results suggest that CEACAM1 plays a role in the development of MCL as a positive mediator of BCR signaling within a context-dependent manner, and that its expression may serve as a marker for understanding ibrutinib sensitivity.

A Single-Cell Atlas of Classical Mantle Cell Lymphoma Reveals Paired Tumor-Immune Malignant States Correlating With Prognosis

The next presentation, by Amira Marouf, MD, PhD, from Memorial Sloan Kettering Cancer Center, described the tumor and environmental drivers of immune evasion in MCL at single-cell resolution.¹² While risk stratification in MCL has historically been based on tumor-specific factors, there is increasing appreciation for the role of other factors within the tumor microenvironment (TME). Using single-cell technology, the goal of this study was to identify shared gene programs among malignant cells to identify cellular networks that contribute to immune evasion in MCL. Using topic modeling, 3 biologically relevant gene program “topics” were identified that correlated with cellular phenotypes: a “core-like” topic (which represented a potentially quiescent state), a “memory-like” topic, and a “proliferating-like” topic. Among these, the proliferating-like topic was predicted to represent an immune-evasive state; indeed, cells from patients with progressive disease within 24 months of first-line therapy (POD24) were found to express high levels of the proliferating-like topic, whereas those without POD24 expressed higher levels of the core-like and memory-like topics. Additionally, enrichment of the proliferating-like topic at the time of relapse suggests that memory- and proliferating-like phenotypes may be prognostically relevant. Although analyses of cell-cell interactions are ongoing, neighborhood analysis revealed proximity between proliferating-like tumor cells and macrophages/monocytes and fibroblasts, suggesting these cells may play an immunosuppressive role within the TME. Prognostically relevant gene programs also remain to be validated in an independent cohort.

Molecular Characterization of TP53-Altered Mantle Cell Lymphoma

Chengfeng Bi, MD, PhD, from the University of Nebraska Medical Center, then discussed the molecular characterization of TP53-altered MCL, TP53-MCL.¹³ TP53-MCL represents a therapeutic challenge, characterized by limited responses to rituximab-based immunotherapy. During the presentation, Bi discussed deep sequencing of 2 MCL cohorts (first by whole-exome sequencing, then validated with targeted sequencing), which revealed TP53-MCL as a genetically distinct entity from other genetic subtypes of MCL (eg, ATM-altered), with multiple nonoverlapping genetic alterations observed. Transcriptomic analysis revealed a highly proliferative expression signature in TP53-MCL, enriched for genes involved in cell cycle regulation, proliferation, and cell signaling. Characterization of the TME in TP53-MCL demonstrated increased recruitment of immune cells—particularly myeloid cells—related to other genetic subtypes, with a high degree of interaction between immune and tumor cells. Gene expression analysis revealed that these myeloid cells exhibit an immune-suppressive phenotype, suggesting a role in immune evasion. Additionally, functional analysis of TP53-knockout and overexpressing cell lines found that p53 acts as a repressor of BCR signaling, which is mediated through interactions with SHP-1. These results provide new insights into the molecular characteristics of TP53-MCL and reveal new potential targets for addressing this high-risk subtype of MCL.

MALAT1 Long-Non-Coding RNA Regulates SOX11 Expression in Mantle Cell Lymphoma

To close out the session, Lalit Sehgal, PhD, from The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, presented on the role of the long non-coding RNA (lncRNA) MALAT1 as a regulator of SOX11 expression in MCL.¹⁴ LncRNAs are found extensively throughout the genome and can fold into complicated 3D structures that interact with DNA, RNA, and protein to regulate gene expression.¹⁵ The role of lncRNAs as oncogenic mediators is an active area of research, but their activity in MCL remains unknown. In this study, differential expression of lncRNAs was compared between MCL cells and normal B cells, with 385 found to be upregulated and 387 downregulated. Among these, MALAT1 was one of the most significantly upregulated in MCL, and its expression was found to correlate strongly with the expression of cell cycle pathway genes. In subsequent experiments, loss of MALAT1 expression was associated with reduced expression of SOX11, a process mediated by the role of MALAT1 in regulating cell cycle progression. By defining the interactions and binding partners that regulate these activities, the investigators hope to identify novel strategies for the treatment of patients with MCL with SOX11 activity.

MCL Preclinical Data

Combinatorial Therapy of MCL-1i with CAR-T to Overcome Therapy Resistance and Reciprocally Enhance Treatment Efficacies Against Mantle Cell Lymphoma

Jing Gao, PhD, from the University of Virginia, began the next session with a presentation on the use of combination therapy with CAR T cells and an MCL-1 inhibitor (MCL-1i) to overcome therapeutic resistance and enhance treatment efficacy in MCL.¹⁶ This research builds on previous studies that point to MCL-1 as essential for the growth and survival of lymphoma cells.^17,18 Gao presented that MYC-expressing cell lines were found to be highly sensitive to MCL-1 inhibition, with the greatest sensitivity observed among cells with the highest MYC expression. In practice, MCL-1 inhibition is challenging, though, as tumor cells often develop resistance. Resistance to MCL-1 inhibition was found to correlate with downregulation of MYC and upregulation of STAT1, alongside activation of interferon 1 (IFN1) and inflammatory pathways. Using single-cell RNA sequencing, inhibition of MCL-1 was associated with enrichment of IFN1 response genes and a proinflammatory signature and remodeling of the TME, whereas untreated samples exhibited a strong MYC-related gene signature. A similar signature was observed in patients with nondurable responses to CAR T-cell therapy, suggesting these samples may be sensitive to MCL-1 inhibition. Indeed, CAR T–resistant cell lines were found to be sensitive to MCL-1 inhibition, and vice versa. When combined, synergistic killing of CAR T–resistant cell lines was observed with CD19 CAR T-cell therapy and MCL-1 inhibition, and combination treatment in animal models was associated with improved tumor clearance and prolonged survival over single-agent therapy. These results suggest that combination therapy with an MCL-1 inhibitor may represent an opportunity to overcome resistance to CAR T-cell therapy in patients with lymphoma.

CD24 CAR-T and Bispecific Antibody (BsAb) as a Next Generation of Immunotherapy of Mantle Cell Lymphoma (MCL)

Next, Qing Yin, PhD, from the University of Virginia, presented research on novel immunotherapies targeting CD24 for the treatment of MCL.¹⁹ CD24 is a marker that is overexpressed in a variety of tumors, including lymphomas, and correlates with more advanced pathological stages and poor clinical outcomes. It plays an important role in self-recognition, and CD24 blockade has been found to increase tumor cell recognition and immune clearance.²⁰ A CD24-engaging bispecific antibody and CAR T-cell construct were therefore generated and tested for their potential use in MCL. In both cell culture and animal models, these constructs exhibited potent antitumor activity and activation of the immune system. Additionally, cells resistant to CD19 CAR T-cell therapy remained sensitive to CD24 CAR T-cell treatment, suggesting CD24-targeted immunotherapy may represent an opportunity to overcome resistance. To test this, a CD19 CAR T-cell construct that secretes a CD24 bispecific T-cell engager (BiTE) was engineered and found to efficiently kill lymphoma tumor cells, including CD19-resistant cell models. Ongoing research aims to understand the safety and toxicity of these constructs, evaluating their potential use in MCL clinical trials.

Reduction of Glutathione Peroxidase 4 by High-Density Lipoprotein-Like Nanoparticles (Au-HDL NPs) Potently Induces Cell Death in Mantle Cell Lymphoma

Jonathan S. Rink, PhD, from Northwestern University, next discussed the use of high-density lipoprotein-like nanoparticles (HDL NPs) to induce ferroptosis in MCL.²¹ Ferroptosis is an iron-mediated cell death pathway, and a variety of lymphoma cell types have been found to be highly sensitive to its inhibition. Cell death in these models was found to correspond with an increase in lipid peroxide levels, suggesting a potential association between ferroptosis and cholesterol homeostasis. In this study, HDL NPs were generated to block the uptake of HDL cholesterol by inhibition of scavenger receptor class B type 1 (SR-B1). Treatment of SR-B1–expressing lymphoma cells, including MCL cell lines, with HDL NPs was found to potently induce cell death; this activity was associated with increased accumulation of lipid peroxidase, consistent with ferroptosis as the mechanism of cell death. In MCL cells, variability in HDL NP sensitivity was found to correlate with SR-B1 expression, with the highest expressors exhibiting the greatest sensitivity. In animal models, HDL NPs accumulated primarily in the liver (consistent with high SR-B1 expression in hepatocytes); the safety profile was mild, but continuing work will be aimed at understanding both the efficacy and safety of these HDL NPs in vivo.

CD74 CAR-T Cells Target Mantle Cell Lymphoma and Its Immunosuppressive Microenvironment

In the next presentation, Lapo Alinari, MD, PhD, from The Ohio State University The James Comprehensive Cancer Center, described the development of a novel CD74-targeting CAR T cell for MCL.²² CD74 is a surface marker abundantly expressed on malignant B cells that mediates prosurvival signaling pathways. A CD74-directed CAR-T cell agent (milatuzumab) was previously developed, showing promising results in preclinical models but modest clinical activity due to the rapid internalization of the antibody-CD74 complex. A second-generation CD74 CAR T cell was therefore generated, which was optimized for expansion, CD74 affinity, immune (CD69) activation, and cytotoxicity. This construct exhibited potent efficacy against MCL patient samples, which correlated strongly with CD74 surface density. In MCL animal models, treatment with this CD74 CAR T-cell therapy was associated with prolonged survival and significant reductions in tumor cell burden. For clinical use, a CAR-after-CAR strategy was proposed, in which the anti-CD74 agent would be used after the currently available CD19 CAR T-cell therapy. CD19-negative MCL cells abundantly express CD74, suggesting the potential to overcome resistance in patients who have been previously treated. CD74 is also expressed on immunosuppressive cells within the TME, which can be targeted and killed with CD74 CAR T-cell treatment. In animal models, minimal off-target toxicity is observed, suggesting this CD74 CAR T-cell construct represents a promising option for further investigation.

Inosine Monophosphate Dehydrogenase-2 (IMPDH2) Is a Novel Therapeutic Target in Mantle Cell Lymphoma

The session concluded with a presentation by Johnvesly Basappa, MSc, PhD, from Fox Chase Cancer Center, on inosine monophosphate dehydrogenase-2 (IMPDH2) as a novel therapeutic target in MCL.²³ IMPDH2 is an important regulator of purine synthesis that has been found to be upregulated and activated in a variety of cancers, including MCL. Purine nucleotides are vital for RNA and DNA synthesis and play important roles in cellular proliferation, growth signaling, and metabolism. Mycophenolic acid (MPA), an inhibitor of IMPDH2, was found to regulate the growth of MCL cells—including those with TP53 alterations and ibrutinib resistance—and was associated with increased apoptosis. Untargeted metabolomic analysis of MPA-treated cells revealed disruption of purine metabolism and nucleotide synthesis as well. As MPA is already an approved therapy in other indications, these results suggest that MPA may be repurposed for the treatment of MCL. In discussions, audience members also suggested that there may be potential to combine MPA treatment with purine analogues to enhance antitumor activity.

MCL Mechanisms of Resistance

Although a variety of novel therapies have emerged to improve outcomes in the initial treatment of MCL, many patients develop resistance or become refractory to treatment. An understanding of the mechanisms that underlie these processes is therefore important to help overcome resistance and improve long-term outcomes in MCL.

SOX11 Enhances Sensitivity to Cytarabine and DNA-Damaging Agents by Impairing SAMHD1 Activity

The session began with a presentation by Mohammad Morsy, PhD, from the Karolinska Institutet, in Stockholm, Sweden, on the role of SOX11 and SAMHD1 in the sensitivity of MCL to DNA-damaging agents.²⁴ SOX11 is a transcription factor that contributes to MCL pathogenesis via alteration of gene expression. It may have additional oncogenic effects as well, though, as low expression of SOX11 has been found to correlate with poor survival outcomes in patients who received high-dose cytarabine (a pyrimidine analogue).^25,26 In this study, co-immunoprecipitation revealed that SOX11 binds to SAMHD1 (a cytidine deaminase) in MCL, which was found to alter the tetramerization of SAMHD1 and disrupt its dNTPase activity.²⁷ SAMHD1 has previously been shown to play a role in homologous recombination (HR), and investigators here described that SOX11 may also regulate DNA damage responses such as HR. Across MCL cell lines, SOX11 expression correlated with response to the topoisomerase I inhibitor, camptothecin, and ectopic expression of SOX11 induced camptothecin sensitivity in previously resistant cells. Depletion of SAMHD1 in MCL cells partially mimicked the SOX11 effect observed in camptothecin response, suggesting that SOX11-mediated HR is at least partially mediated by inhibition of SAMHD1 activity. These results suggest that SOX11 expression may leave MCL cells vulnerable to DNA damage and that incorporation of DNA-damaging agents into treatment could enhance therapeutic responses.

Leveraging SMARCA4 Dependency of Mantle Cell Lymphomas to Overcome BTK Inhibitor Resistance

The next presentation was by Ji-Hye Paik, PhD, from Weill Cornell Medicine, who discussed leveraging SMARCA4 dependency to overcome BTKi resistance in MCL.²⁸ Alterations in SMARCA4 promote resistance to BTKis in MCL cell lines by blocking ferroptosis. Through analysis of gene expression, this activity was found to be mediated by the transcription factor MEF2B, the expression of which was determined to block ferroptosis by suppressing reactive oxygen species and labile iron levels. In cell culture, MCL cells showed dependency on SMARCA4, as inhibition of SMARCA4 reduced cell survival in a concentration-dependent manner. Additionally, treatment with FHD-286, a SMARCA2/4 inhibitor, potently induced ferroptosis in MCL cell lines. This activity was found to be correlated with attenuation of BCR signaling, and dual treatment with FHD-286 and a BTKi (pirtobrutinib) synergistically induced cytotoxicity in MCL cells. These results suggest SMARCA4 inhibition may represent an opportunity to overcome resistance to BTKis in MCL.

Cyclin-Dependent Kinase 5 (CDK5) Contributes to Bruton Tyrosine Kinase Inhibitor (BTKi) Resistance via IRE1α/Xbp1s Axis in Mantle Cell Lymphoma (MCL)

Andrew Chen, MS, from City of Hope, continued the discussion on BTKi resistance by describing the role of CDK5 in this process.²⁹ In this study, MCL cell lines JeKo-1, Mino, and Maver were found to be sensitive to the BTKi ibrutinib. These cells were continuously exposed to increasing concentrations of ibrutinib to generate models of acquired ibrutinib resistance, which were then subjected to RNA sequencing to compare gene expression between resistant and parental (sensitive) cell lines. This revealed enrichment of the unfolded protein response (UPR) pathway in resistant cells, with upregulation of CDK5 within this pathway confirmed at the transcript and protein level. Overexpression of CDK5—a regulator of cell cycle regulation, survival, and proliferation—in parental cells was found to confer resistance to ibrutinib, knockdown in ibrutinib-resistant models restored drug sensitivity, and ibrutinib-resistant cells were sensitive to CDK5 inhibition. Further analysis revealed that CDK5 acts as an activator of the UPR pathway in response to ibrutinib, which is mediated through interactions with the IRE1α/Xpb1s axis. As knockdown of CDK5 and Xpb1s can partially recover ibrutinib sensitivity, these proteins may represent promising targets for overcoming resistance to BTKis in MCL.

Multi-Omics Analyses Delineate Mechanisms of Resistance to Ibrutinib-Venetoclax Combination Therapy in Mantle Cell Lymphoma

The session continued with a presentation by Kevin Qiu, a medical student from the University of Virginia, who described the use of multiomics analyses to uncover mechanisms of resistance to ibrutinib/venetoclax combination therapy in MCL.³⁰ In this study, ibrutinib/venetoclax-resistant and sensitive cells were subjected to single-cell RNA sequencing and assessment of chromatin accessibility to characterize transcriptional and chromatin-level changes associated with treatment resistance. For many genes, dysregulation of expression in resistant cells was found to correlate with chromatin accessibility, suggesting that the development of resistance may be driven by epigenetic changes. Investigators further characterized a subset of drug-tolerant persister (DTP) cells of interest that were transcriptionally and epigenetically distinct from other cells in their respective samples and that exhibited hallmarks of both senescence and stemness. Pseudotime trajectory analysis revealed 3 modules of gene expression that were significantly increased in DTP and/or resistant cells. Module 1 within this analysis represented genes whose expression increased in DTP cells prior to the emergence of resistance, and which became further enriched as resistance developed. The investigators hypothesized that these genes may represent key drivers of resistance to ibrutinib/venetoclax. Network analysis revealed the histone modifiers EZH2 and KDM5B at the center of this gene module, and binding analysis for regulation of transcription confirmed both as key regulators of target genes in DTP and resistant cell lines. Inhibition of both EZH2 and KDM5B was found to exhibit a modest cytotoxic effect in MCL cells, suggesting they may be exploited as therapeutic targets to delay, prevent, or overcome resistance. Further research is aimed at uncovering additional drivers of resistance in MCL that can be targeted to improve treatment responses in the clinic.

Unlocking the Potential of CAR T-Cell Immunotherapy Targeting ROR1 in Combination With EZH2 Inhibition in Mantle Cell Lymphoma

Cosimo Lobello, PhD, from Fox Chase Cancer Center, concluded the session with a presentation on the use of EZH2 inhibition to improve outcomes with ROR1-directed CAR T-cell therapy in MCL.³¹ ROR1 is a tyrosine kinase–like receptor enriched on the surface of many cancer cells, including MCL. It plays an oncogenic role in MCL but is heterogeneously expressed in patients with MCL. Expression of ROR1 can be epigenetically boosted in MCL cells through inhibition of EZH2, and investigators hypothesized that EZH2 inhibition may enhance the effects of ROR1-targeting CAR T-cell therapy by upregulation of the target marker. An ROR1 CAR T-cell construct was developed and exhibited high specificity for ROR1 and potent anti-MCL activity. When used in combination with EZH2 inhibition, killing of MCL cells was enhanced; this effect was maintained across several combination approaches, including simultaneous treatment, pretreatment with washout, and pretreatment with continuous treatment. Pretreatment with an EZH2 inhibitor was found to confer the greatest CAR T–mediated cytotoxic effect and reduce the number of CAR T cells needed for efficient clearance of MCL cells. These results suggest that EZH2 inhibition may represent a promising option for improving responses to ROR1 CAR T-cell therapy.

MCL Retrospective Series

Validation of POD24 as a Robust Early Clinical Indicator of Poor Survival in Mantle Cell Lymphoma from 1280 Patients on Clinical Trials, a LYSA Study

Clémentine Sarkozy, MD, PhD, from the Curie Institute in Paris, France, began the next session with a discussion on the validation of POD24 as a robust early clinical predictor of poor survival in MCL.³² Progress has been made in the treatment of MCL and other lymphomas, such that earlier end points are now needed to predict survival in patients with indolent disease. Using data from a large cohort of patients with MCL in clinical trials, the predictive power of POD24 was assessed in diverse patient subgroups based on age, treatment history, and other disease factors.³³ Across groups, POD24 was associated with poor overall survival after second-line treatment (OS2), even in the post-BTKi era. POD24 remained strongly associated with OS after accounting for differences in baseline characteristics between POD24 and non-POD24 patients. No associations were observed with POD24 and either age (OR, 0.46; 95% CI, 0.1-2.4) or prior ASCT (OR, 0.64; 95% CI, 0.1-3.6); rituximab maintenance after ASCT was, however, found to be associated with lower risk for POD24, and this association persisted after multivariable analysis. These results suggest that POD24 is a robust indicator of poor survival in MCL, independent of clinical or treatment factors. POD24 may represent a promising option as an early end point or for risk stratification in future clinical trials. Results from this analysis also suggest that ASCT has no impact on the risk of early disease progression; however, the addition of rituximab maintenance after ASCT may reduce the risk of POD24.

Outcome of Pts With Mantle Cell Lymphoma After Failure of Anti-CD19 CAR T-Cell Therapy: A DESCAR-T Study by LYSA Group

Sarkozy continued the discussion with a presentation on outcomes in patients with MCL after CD19 CAR T-cell therapy failure using data from the French national DESCAR-T registry.³⁴ The analysis included data from 61 patients with relapsed MCL after brexucabtagene autoleucel (brexu-cel) therapy. Within this data set, 28% and 22% achieved a complete or partial response, respectively, as best response to brexu-cel; 2% had stable disease, and 6% had progressive disease. The median time to failure was 4.5 months, and 28% experienced relapse within 3 months. The median OS2 after brexu-cel failed the patient was 5.8 months, with a 1-year OS2 of 29.8%. OS2 was significantly reduced in patients with relapse within 3 months and nominally lower in patients with POD24. After multivariate adjustment, nonresponse to bridging therapy and ECOG performance status of 2 or more at infusion were significantly correlated with OS2. After brexu-cel failed patients, 80% of patients received salvage therapy; lenalidomide, immunochemotherapy, or BTKi-venetoclax therapy (alone or in combination) were the most common salvage strategies. Median progression-free survival 2 (PFS2) after salvage therapy was 2 months, and 1-year PFS2 was 20.8%. The objective response rate (ORR) to lenalidomide, immunochemotherapy, and BTKi-venetoclax salvage treatment was 18.8%, 23.1%, and 0%, respectively. An ORR of 43% was observed with BiTE salvage; in this group (n=7), 1-year PFS2 was 43% and 1-year OS2 was 57%.

Since these data were presented, complete and partial response rates increased to 46% and 36%, respectively. OS2 remained stable at 5.8 months, and PFS2 decreased to 1.8 months.³⁵ These results suggest that outcomes in MCL after brexu-cel failed patients are very poor. Salvage strategies remain largely unstandardized, though treatment with BiTE therapy may represent an opportunity to achieve durable responses in this population. Additional research is needed to understand how best to address this unmet clinical need.

Real World First-Line Treatment Strategies and Outcomes in TP53 Mutated and Unmutated Mantle Cell Lymphoma

Michael E. Williams, MD, ScM, FACP, from the University of Virginia Health, concluded the session with a description of real-world first-line treatment strategies and outcomes for patients with TP53-mutated and -unmutated MCL.³⁶ The analysis included data from 415 patients with wild-type (WT) TP53 and 230 with TP53-MCL from 19 institutions in the US. Patients with TP53-MCL tended to be older, have a higher Mantle Cell Lymphoma International Prognostic Index (MIPI) score, and were more likely to exhibit blastoid histology compared with the WT group. The most frequently used first-line treatment regimen in both groups was bendamustine-rituximab (BR), which was used in approximately 30% to 35% of patients. Among patients with TP53-MCL, 79% were identified prior to initiation of first-line therapy; selection of treatment was not found to be associated with TP53 mutation status. However, ASCT was used more frequently in the WT group (29% WT vs 17% TP53-MCL). Across all patients, and within the TP53-MCL group, PFS did not differ based on the type of treatment (BTKi, chemotherapy alone, or chemotherapy-free). Time to next treatment (TTNT) was the same in TP53-MCL regardless of treatment type, but was improved in the WT cohort with chemoimmunotherapy vs BTKi or chemotherapy-free treatment. OS was significantly reduced for patients with TP53-MCL relative to the WT group (8.3 vs 14.2 years), but was higher than previously reported for this high-risk subgroup (1-3 years), suggesting that even patients with TP53-MCL are surviving significantly better with modern treatment. OS was not associated with the first-line treatment approach or use of ASCT in either group. These results suggest that while OS is improving for patients with TP53-MCL, outcomes in this group remain poor, and there is no clear approach to first-line treatment. Williams noted that ongoing research aims to stratify patients based on specific TP53 alterations, as differences have been found in the clinical implications of various mutations.

CAR T-Cell Resistance in MCL

The first day of the workshop concluded with a discussion, led by Michael Wang, MD, from The University of Texas MD Anderson Cancer Center, on mechanisms of resistance to CAR T-cell therapy in MCL. A variety of factors have been linked to the development of CD19 CAR T-cell resistance in lymphoma, including antigen escape, loss of proapoptotic molecules within tumor cells, development of an immunosuppressive TME, T-cell exhaustion, and CAR T-cell dysfunction.^37,38 How these mechanisms contribute to CAR T-cell resistance in MCL has remained unclear, though. Overcoming CAR T-cell resistance in MCL is important, as results from the phase 2 ZUMA-2 trial (NCT02601313) demonstrate poor survival in patients who relapse after CAR T-cell therapy.³⁹

Single-cell RNA sequencing was used to identify potential resistance mechanisms in 39 longitudinally collected samples from 15 patients with MCL treated with brexu-cel. Compared with pretreatment and responsive stages of disease, brexu-cel–resistant fractions were found to exhibit a T-cell–exhausted and myeloid cell–enriched phenotype. Characterization of the cellular compartments corroborated these findings, showing enrichment of cytotoxic CD8-positive T cells at responsive stages and exhausted CD8-positive T cells at relapse. T-cell exhaustion markers, including TIGIT, were found to be upregulated in the latter population, particularly in exhausted populations observed at relapse. Acquisition of TIGIT expression after brexu-cel relapse was found to occur concomitantly with loss of expression of other immune genes, including CD19 and HLA-II molecules.

Multiplex cytokine profiling from 20 patients with MCL also revealed molecular reprogramming of cytokines, chemokines, and soluble receptor profiles after relapse, suggesting immunological remodeling of the soluble TME. These results suggest that acquired expression of TIGIT in cytotoxic lymphocytes as well as MCL cells is the central mechanism leading to therapeutic relapse to CAR T-cell therapies in MCL, and that the cotargeting of TIGIT may represent an opportunity to prevent relapse and improve long-term outcomes with CAR T-cell treatment.

In discussions, audience members talked about how to overcome resistance to CD19 CAR T-cell therapy in MCL. The identification of TIGIT as a mediator of resistance is promising, but some have noted that clinical targeting of this molecule will likely need to be done in the context of combination therapy, as research in other disease states reveals a high degree of immune adaptation. Others suggested that CAR T-cells may be modified to target 2 antigens (ie, CD19 and a separate, unique tumor marker), which would help overcome heterogenicity seen in tumor populations and may help reduce the tumor’s ability to evade treatment up front. However, others cautioned that combining treatments and enhancing immune suppression may have serious safety consequences, particularly about the risk for serious opportunistic infections. Collectively, based on the presentations seen throughout the day, attendees agreed that they expect to see differences in the mechanisms of relapse based on time to progression and were interested in understanding what other regulators may contribute to resistance in MCL as well.

Day 2

Clinical Trials

MCL Prospective Clinical Trials

Phase 1b/2 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed/Refractory (R/R) and Treatment-Naive (TN) Mantle Cell Lymphoma (MCL): Preliminary Analysis of Safety, Efficacy, and Minimal Residual Disease (MRD)

The second day began with a presentation from Christopher J. Melani, MD, from the National Cancer Institute, on the preliminary safety, efficacy, and minimal residual disease (MRD) status in a phase 1b/2 study (NCT03223610) of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed/refractory (R/R) and treatment-naive MCL.⁴⁰ The ViPOR regimen targets multiple key survival pathways in lymphoma and has previously been found to induce durable remissions in patients with R/R diffuse large B-cell lymphoma (DLBCL).⁴¹ In this study of patients with MCL, ViPOR was administered in time-limited, noncontinuous cycles to minimize potential toxicities. All agents were given for a fixed duration of 6 cycles (without maintenance or planned consolidation) with a 1-week break between cycles. Venetoclax was initiated on cycle 2 with 1 full cycle of iPOR alone to allow for tumor debulking and mitigate the risk for tumor lysis. A total of 39 patients were enrolled thus far in the study (19 with R/R MCL and 20 treatment-naive). High-risk disease was observed in 31% of patients by MIPI score and 20% by MCL35 proliferation signature; blastoid or pleomorphic histology was observed in 28% of patients, elevated Ki-67 in 37%, and 33% had a TP53 alteration. Hematologic adverse events (AEs) were the most common, with the majority being mild. The most common nonhematologic AEs were hypokalemia, diarrhea, and rash, with hypokalemia and rash being the only grade 3 nonhematologic toxicities observed in more than 10% of patients. No cases of tumor lysis syndrome or treatment-related mortality were observed. All patients experienced a reduction in tumor burden by CT, with all but 1 patient with R/R MCL achieving a complete response (CR). Among 37 evaluable patients off study therapy, the overall and CR rates were 100% and 97%, respectively, with a CR rate of 94% observed in patients with R/R disease. More than 80% of CRs were maintained up to 4 years of follow-up. The 2-year time to progression (TTP) was 95% in patients who were treatment-naive and 93% in patients with R/R disease. The 2-year PFS was 95% in treatment-naive patients and 67% in patients with R/R disease; there were 2 disease-related and 3 infection-related deaths in this group. Two-year TTP was inferior in patients with elevated (> 30%) Ki-67 levels (85% vs 100% for those with < 30% Ki-67) and blastoid or pleomorphic morphology (80% vs 100% for those with classic morphology). Among patients amenable to MRD monitoring, 94% of all patients and 97% of those in CR were MRD undetectable at the end of therapy; MRD undetectability rates increased to 97% among all evaluable patients (n = 36) upon updated analysis.⁴² All nonprogressing patients had persistently undetectable MRD. Enrollment for the study continues in phase 2 expansion cohorts, and a multicenter phase 2 study is in development to confirm the activity of fixed-duration ViPOR in patients with MCL.

MRD Analysis in Phase 2 Trial of Acalabrutinib and Lenalidomide Plus Rituximab (ALR) or Obinutuzumab (ALO) for Patients With Treatment-Naive Mantle Cell Lymphoma

The session continued with a presentation by Jia Ruan, MD, PhD, from Weill Cornell Medicine, on a phase 2 trial (NCT03863184) of MRD-driven, time-limited acalabrutinib and lenalidomide plus rituximab (ALR) or obinutuzumab (ALO) in treatment-naive MCL.⁴³ This study builds on previous work involving the use of lenalidomide plus rituximab in MCL to determine whether the addition of the next-generation BTKi acalabrutinib can improve response by targeting additional pathways that contribute to MCL pathogenesis and remodeling of the TME. The ALO cohort was also added to determine whether rituximab can be replaced with obinutuzumab, which may perform better in MCL. A total of 34 patients were enrolled in the study (24 in the ALR arm and 10 in the ALO arm); the study population was representative of MCL in community practice based on age, sex distribution, and high-risk status (TP53-MCL represented 20% to 30% of the study population). Patients received 12 cycles of induction ALR or ALO; maintenance ALR or ALO was continued until disease progression, with an opportunity for de-escalation of therapy based on MRD undetectability at week 25. A majority of patients achieved MRD undetectability within 12 cycles. Survival data demonstrated durable remissions in patients who received ALO, with higher relapse rates observed in the ALR treatment arm. In exploratory analyses, TP53 alteration status was the only factor that appeared to influence PFS with ALR, though the subset of patients with TP53-MCL was small, and a larger cohort is needed to confirm this trend. The results of this study provide support for the efficacy of the ALR and ALO regimens in patients who are treatment-naive with MCL, regardless of TP53 alteration status. Additionally, MRD analysis was found to represent a promising strategy for response-adapted treatment de-escalation to minimize toxicity with maintenance therapy.

A Phase I Study of Copanlisib and Venetoclax in Patients With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL)

Next, Paolo Lopedote, MD, from City of Hope, presented data on the use of copanlisib, a selective PI3K inhibitor, in combination with venetoclax in patients with R/R MCL.⁴⁴ Overexpression of PI3K p110 isoforms targeted by copanlisib is often observed at relapse in MCL, and their inhibition results in downregulation of apoptotic pathway proteins.⁴⁵ Upregulation of these proteins (ie, BCL-2, BCL-xL, and MCL-1) is implicated in resistance to BCL-2 inhibitors such as venetoclax; investigators therefore hypothesized that the use of copanlisib in combination with venetoclax may improve treatment responses to help induce lasting remission after relapse. The single-center phase 1/2 trial (NCT04939272) enrolled 8 patients with R/R MCL who received venetoclax and copanlisib for a median of 4 cycles of treatment. The median number of prior lines of therapy was 3; 88% were BTKi-exposed, and 62% were BTKi-refractory. The toxicity profile was like that observed with copanlisib monotherapy; grade 3 or higher AEs included hypertension, sepsis, tumor lysis syndrome, and decreased white blood cell counts. One dose-limiting toxicity (grade 5 sepsis) occurred in cycle 1. Among 7 evaluable patients, the ORR was 71% and the CR rate was 28%; 1 patient had stable disease, and 1 had progressive disease as the best response. Over a median of 12.6 months of follow-up, 2 patients died from disease progression. Median PFS was 3.9 months, median OS was 17.9 months, and the median duration of response was 2.8 months. Given the high overall response rate observed in the study, the investigators proposed that venetoclax/copanlisib combination therapy may represent a promising option for bridging therapy in patients with R/R MCL, including those who are heavily pretreated.

Multicenter Study of Mantle Cell Lymphoma (MCL) Outcomes Following First-Line (1L) Bendamustine-Rituximab (BR) and Second- line (2L) Bruton’s Tyrosine Kinase Inhibitor (BTKi) Therapy

Yucai Wang, MD, PhD, from Mayo Clinic, concluded the session by presenting modeling results on outcomes following first-line BR and second-line BTKi therapy in MCL.⁴⁶ The updated analysis included data for 755 patients who received front-line BR (with or without rituximab maintenance) in the phase 3 SHINE (NCT01776840) and ECHO (NCT02972840) trials.^47,48 Within this cohort, 263 subsequently received a BTKi after progression or relapse, or at retreatment (149 received ibrutinib, 84 received acalabrutinib, and 30 received zanubrutinib). Patients who did not receive second-line therapy or those who received a non-BTKi after progression or relapse were censored from the second-line analysis. In the entire cohort, the median event-free survival (EFS) was 34.2 months; median OS was 85.3 months; and the 7-year OS was 50.6%. Among patients who received second-line BTKi therapy, the median EFS after second-line treatment (EFS2) was 64.8 months from initiation of first-line BR. Across all groups, outcomes were improved in patients who received rituximab maintenance compared with those who did not. Median OS was 108.7 months in the maintenance group vs 77.2 months in the no maintenance group; EFS2 after BTKi therapy was 94.6 vs 58.8 months in the maintenance vs no maintenance groups, respectively. Results were moderately attenuated in patients 65 years or older, but similar trends persisted, and a benefit from rituximab maintenance in this population was still observed. Based on these observational data, the investigators believe that the results provide support for the sequential use of first-line BR and second-line BTKi therapy for patients with MCL, including older adults.

MCL Challenges and Opportunities

Kami J. Maddocks, MD, from The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, began the session with a discussion on how risk status should be handled and considered in MCL clinical trials. A variety of factors contribute to risk in MCL, including clinical (eg, MIPI score), biologic (eg, histology, proliferation by Ki-67), and genetic (eg, TP53 status) factors, as well as response to therapy. When trying to stratify patients based on risk factors, a number of challenges emerge. In many cases, patients with these risk factors represent a rare subset within an already rare disease, which makes it difficult to enroll for individual clinical trials; additionally, these features are not mutually exclusive, which may make it difficult to tease out the individual contribution to risk. As a result, there are varying levels of evidence from available clinical trials, which makes it difficult to make comparisons and impacts the timeliness and broad applicability to clinical practice. Among available clinical trials, the phase 2 study (NCT03824483) of zanubrutinib, obinutuzumab, and venetoclax (BOVen) provides the greatest opportunity to examine outcomes specifically in high-risk patients based on TP53 status, with 2-year PFS and OS rates of 72% and 75% observed, respectively.⁴⁹ These results are promising in light of emerging evidence that BTK inhibition alone is insufficient to overcome high-risk biology. Additional questions remain, though, such as whether time-limited approaches are appropriate in high-risk MCL. Available evidence, while limited, currently suggests that discontinuation of treatment in patients who are high-risk may pose a greater risk than benefit, but a clear signal has not emerged, and it is unclear what role MRD status can play in guiding these approaches.^50-52 A variety of clinical trials are currently underway that are specifically dedicated to understanding treatment outcomes in patients with high-risk disease, but definitions for high-risk are still inconsistent, making it difficult to translate the collective body of results into clinical practice. In discussions, attendees agreed that there is a need to define high-risk in MCL in a more uniform way, which will help clinicians better identify these patients and determine how best to move forward in future clinical trials.

Alexey Danilov, MD, PhD, from City of Hope, continued the session on challenges in MCL with a discussion on mechanisms of resistance to BTKi. Available evidence suggests that there is significant heterogeneity in the mechanisms of resistance to BTKi, both within and between patients, which can make it difficult to overcome. Transcriptomic analysis of individual patient data has revealed complex resistance mechanisms in MCL, with a great degree of heterogeneity and evolution over the course of the disease.⁵³ Many of the oncogenic pathways that have been identified as contributing to resistance in MCL remain untargetable with current therapies, but a variety of novel potential targets have emerged—such as NFkB, PI3K, SMARCA4, and MCL-1—that may represent new opportunities to help overcome resistance.^54-57 Likewise, novel immunotherapies, including CAR T-cell therapies and bispecific antibodies, may represent unique opportunities to address remodeling of the TME in MCL, the role of which remains unclear in BTKi resistance. As more data emerge in the coming years, Danilov suspects that combination approaches involving targeted and immunotherapies will likely play an important role in addressing the heterogeneity that contributes to BTKi resistance in MCL.

Andrew D. Zelenetz, MD, PhD, from Memorial Sloan Kettering Cancer Center, concluded the session with a discussion on the use of MRD in MCL. The definition of MRD remains a moving target as the efficacy of treatment and the sensitivity of testing continue to evolve. Although it is commonly used in practice, Zelenetz argued that the term MRD negativity is a misnomer, as the value is dependent on the limit of detection for the given assay. Instead, undetectable is the preferred terminology, presented in nominal sensitivity. A variety of testing strategies are available for the detection of MRD, with varying limitations and levels of sensitivity.⁵⁸ Immunosequencing, for example, has high sensitivity; however, this value is dependent on the input and may be limited by sample quality. Additional challenges arise with sequencing-based methods due to the limitations of available technology. In practice, the sensitivity of genomics often does not reach the theoretical limits, as the sequencing process itself is error-prone and introduces novel mutations that cannot be distinguished from true tumor markers. Phased sequencing strategies, such as phased variant sequencing and phased variant enrichment and detection sequencing, can help overcome the challenge of distinguishing true mutations from sequencing errors to improve sensitivity. However, their dependence on the identification of clustered genomic variants may limit the availability of informative loci for analysis. This is a particular concern in MCL, as phase variants have been found to occur less frequently (5- to 10-fold) in MCL compared with other lymphomas.⁵⁹ Beyond testing strategy, there is also a lack of consensus on the optimal target and whether cellular or cell-free options are preferred. As with testing strategy, each option has its own unique advantages and challenges, and it is important to consider how these compare in MCL. Circulating tumor DNA, for instance, has been shown to correlate closely with tumor burden in DLBCL but is less predictive in patients with MCL.^60-62 Kinetic assessment of MRD may be more helpful in MCL, according to available evidence, but more work is needed to understand the optimal strategy for MRD assessment in monitoring in this unique disease state.⁶² To better understand the optimal use of MRD in MCL, Zelenetz proposed that a collective effort is needed to gather data from available phase 2 and 3 studies to answer key questions regarding the appropriate methodology for assessment and clinical utility of MRD, with the ultimate goal of understanding whether MRD represents an early predictor of treatment response and if it may one day serve as a surrogate end point in MCL clinical trials. Zelenetz challenged attendees to include MRD as an end point in all ongoing and future clinical trials to help collect the data needed to support this effort.

Trial Design, Regulatory Pathways, and End Points

Panel Discussion

Next, a panel of MCL experts discussed considerations for clinical trial design, including key end points and regulatory approval pathways. Several approval pathways exist for new therapeutics, and the standards for each vary. Accelerated approval represents an important pathway in the treatment of lymphoma that not only accelerates access to treatment but also drives innovation that may otherwise not occur. Panelists and audience members questioned, though, how regulatory requirements for accelerated approval may change in light of recent failures that have been seen due to the emergence of toxicities in larger trials, and suggested that more rigor will be needed to reach the threshold for approval in this space. Citing experiences with BTKis, panelists suggested that earlier initiation of phase 3 studies will help to support this as well by revealing important safety signals in a timely manner.

The costs associated with phase 3 studies are high, though, and a large study population may be difficult to achieve given the relative rarity of MCL. Despite the availability of compelling data, many therapies may never make it to approval in MCL due to logistical challenges and barriers. Panelists discussed whether there is an opportunity to gather real-world data earlier in patients who receive off-label treatment with drugs approved in different settings. Panelists emphasized, though, that while navigating accelerated approval may be more challenging moving forward, this represents an important pathway for increasing treatment options in disease states such as MCL with limited effective therapies.

As outcomes in MCL improve, panelists also discussed the need for novel efficacy end points to support approval. Panelists and audience members agreed that while OS remains the standard and most relevant target for patients, it is becoming increasingly difficult to demonstrate improvements in OS within feasible clinical trial windows. Surrogate end points such as PFS are often used, but the clinical benefit of these end points in the absence of improvements in OS remains questionable to physicians if quality of life is compromised due to toxicities or treatment burden. Experts agreed that MRD is emerging as the most promising early predictor of OS benefit, and also that more data are needed to support its acceptance by regulatory agencies as a surrogate end point. While there are currently more data available in other disease states—such as multiple myeloma and acute myeloid leukemia—some experts felt strongly that concerted efforts by MCL physicians to show concordance with traditional survival outcomes will help support the acceptance of MRD as a surrogate end point to support approvals in the future.

In discussions of OS as the gold standard for efficacy, panelist John P. Leonard, MD, from NYU School of Medicine, also noted that there is a need to consider the international nature of many phase 3 trials. OS is influenced by the availability of downstream treatment options, which will vary among countries and regions. As a growing number of studies are conducted internationally, the availability of subsequent therapies may differ dramatically from patient to patient. Differences in the options available for treatment after progression will have an impact on OS and could influence outcomes based solely on geography, rather than treatment efficacy.

Panelists also agreed that there is an urgent need to define high-risk populations to allow for better comparisons across trials.

Addressing the Unmet Needs of MCL

Panel Discussion

In a discussion on the unmet needs in MCL, a panel of experts emphasized the need to optimize management of high-risk MCL. While the precise definition of high-risk remains to be clarified, many cancer centers have access to the diagnostic tools needed to stratify patients according to a variety of risk factors. In community settings, though, access is often more limited, and many patients within community health systems may be unaware of their risk status. In Europe and the US, testing for TP53 alteration status is not always done and may not be adequately characterized, despite stronger recommendations for testing in clinical guidelines. Panelists suggested there is an opportunity for education for patients and community physicians on the importance of genetic testing for TP53 alterations, including the types of mutations observed.

Panelists also agreed that there is a need for clinical trials specifically studying treatment strategies for patients with high-risk MCL to help optimize care.

For all patients, panelists expressed interest in a shift toward time-limited therapy in MCL. Treatment breaks offer a variety of benefits, including reduced clinical toxicity, decreased financial toxicity, and the potential avoidance of resistance mutations. The risk-benefit ratio is patient-specific, though, and it is important that any time-limited approaches be considered within the context of baseline factors, the specific treatment regimen, and the sensitivity of assays (eg, MRD) to measure response to treatment. The use of time-limited therapy may be less appropriate for high-risk patients; however, even within this group, panelists believe there may be an opportunity for individualizing the treatment approach.

Regarding the assessment of MRD, there is also a need to understand how to use the information to guide clinical practice. Physicians noted that many patients reach undetectable MRD, but that it is unclear if or how to adjust treatment once they reach that point. Likewise, it is not clear what it means when MRD detectability fluctuates, and an increasing number of patients are following their MRD status closely. While some physicians felt there may be an opportunity to use MRD to guide decision-making in the future, others questioned whether it would ever be a helpful clinical tool in MCL.

In Conclusion

MCL Clinical Trials in Europe and the US

To close the workshop, Mats Jerkeman, MD, PhD, from Lund University in Sweden, and Brad S. Kahl, MD, from Washington University Medicine, shared updates on ongoing MCL clinical trials in Europe and the US, respectively.

Jerkeman began with an update on results from the TRIANGLE trial, a phase 3 trial of ibrutinib with standard-of-care (SOC) immunotherapy, with or without ASCT in patients younger than 66 years with MCL.⁹ In this study, the addition of ibrutinib to SOC significantly improved 4-year OS regardless of ASCT. A trend toward superiority with ASCT was observed in patients with certain high-risk features (ie, blastoid cytology, high p53 expression, or elevated Ki-67 levels), but these trends were nonsignificant. Results from TRIANGLE also revealed significant benefits with rituximab maintenance therapy regardless of treatment arm. Compared with the TRIANGLE cohort, the phase 2/3 ENRICH trial (EudraCT 2015–000832–13) population was older (median age, 74 years).⁶³ In this study, ibrutinib/rituximab (IR) therapy was evaluated as an alternative to SOC immunochemotherapy in treatment-naive MCL. An advantage over immunochemotherapy was observed with IR regarding PFS over more than 7 years of follow-up, suggesting IR represents a new SOC for older patients with previously untreated MCL. In the phase 2 ALTAMIRA trial (NCT05214183)—a follow-up study to ENRICH—ibrutinib was replaced with acalabrutinib (AR), and a risk-adapted approach to treatment was explored. Older patients with high-risk disease received continuous treatment until progression; all others stopped acalabrutinib after achieving MRD undetectability after a minimum of 1 year. The AR regimen was safe and effective regardless of the low-risk group, with a 24-month PFS of 96%. PFS at 24 months was lower in the high-risk group (38%), suggesting the AR regimen is insufficient for patients with high-risk disease by TP53 status, blastoid histology, and Ki-67 expression. Finally, the phase 2 OASIS II trial (NCT04802590) estimated the rate of MRD undetectability in patients receiving ibrutinib plus a CD20 antibody (CD20Ab) with or without venetoclax.⁶⁴ MRD undetectability was achieved by 82.1% of patients who received venetoclax vs 53.8% of those who received ibrutinib-CD20Ab alone. Survival results (PFS and OS) are pending.

In the US, the National Clinical Trials Network continues to support collaborative clinical trial efforts led by SWOG, ECOG-ACRIN, ALLIANCE, and the Blood & Marrow Transplant Clinical Trials Network. Kahl began with an update on the phase 2 E1411 trial (NCT01415752) for older patients with MCL, which explored the use of BR, with or without bortezomib, plus rituximab-based maintenance therapy. With more than 8 years of follow-up, this study confirmed BR as an effective induction therapy in older patients with MCL, with a median PFS of more than 5 years with rituximab maintenance. No benefit was observed with the addition of bortezomib. Next, Kahl discussed the phase 2 EA4181 trial (NCT04115631)for patients 70 years or younger with untreated MCL.⁶⁵ The goal of this study is to determine whether high-dose cytarabine can be safely replaced by novel agents (BR and/or acalabrutinib) in SOC. In this study, the addition of acalabrutinib to a combination BR/cytarbine-rituximab approach added toxicity without improving efficacy. Although the study was closed early, BR-acalabrutinib exhibited lower toxicity than other treatment arms with similar toxicity, suggesting it may represent an appealing option to avoid high-dose cytarabine. Kahl concluded with a discussion of results from EA4151, a phase 3 trial (NCT03233350) of rituximab maintenance after ASCT in MRD undetectable MCL in complete remission.⁶⁶ Results from this study showed that patients with MCL in first CR with undetectable MRD6 did not benefit from consolidative ASCT. Benefits from ASCT may be observed in patients who remain MRD detectable after induction therapy, as patients who converted to undetectable MRD6 after ASCT had improved PFS and OS in exploratory analyses. Together with the results from TRIANGLE, this study suggests limited benefit from consolidative ASCT in younger patients with MCL.

Summary

The 2025 MCL Scientific Workshop covered recent advancements in our understanding of MCL biology and treatment. Ongoing efforts to understand MCL pathogenesis, TME remodeling, and the development of drug resistance have revealed a variety of novel targets in MCL. Preclinical studies have paved the way for clinical trials aimed at evaluating novel therapeutics, with efforts increasingly focused on improving outcomes for patients with BTKi-resistant and high-risk MCL.

Despite these efforts, many unmet needs remain in MCL.

A consensus definition for high-risk MCL is needed to inform clinical trial design and, in turn, guide treatment decision-making in the clinic. Experts agreed that TP53 alterations represent a good starting point, but that the relative impact of other conventional high-risk factors remains unclear.

Inclusion of MRD as an end point in clinical trials is an urgent need to help generate the data needed to evaluate its efficacy as a surrogate end point for OS. A call to action stating this is needed to gain broader support from the community and funding sources. Such a statement should also guide the recommended characteristics of testing, including approach, sensitivity, and compartment.

There is a role for the Lymphoma Research Foundation to participate in community outreach aimed at helping patients understand the need for molecular characterization and TP53 testing in MCL.

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