Outcome In Mantle Cell Lymphoma Research Articles

Characteristics, treatment, and outcomes of mantle cell lymphoma with cutaneous involvement: a decade-long study at MD Anderson cancer center

Characteristics, treatment, and outcomes of mantle cell lymphoma with cutaneous involvement: a decade-long study at MD Anderson cancer center

Genomic and transcriptomic profiling reveals distinct molecular subsets associated with outcomes in mantle cell lymphoma.

Genomic and transcriptomic profiling reveals distinct molecular subsets associated with outcomes in mantle cell lymphoma.

MiR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma.

B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. We revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.

Dissecting the Single Cell Landscape of Leukemic Mantle Cell Lymphoma

Introduction: Resistance to therapy remains a major challenge for Mantle Cell Lymphoma (MCL) patients, despite a diverse and expanding treatment landscape. There is thus a major need to better understand the mechanistic underpinnings of therapy resistance in order to optimize treatment selection. Given the advent of immunotherapies in recent years, there has been increasing evidence that not only tumor-intrinsic factors affect therapy resistance, but that tumor-immune cell interactions are an additional major contributor. In the context of MCL, such interactions have been poorly characterized, but hold the promise of identifying novel treatment approaches and better understanding resistance mechanisms to commonly applied therapies such as BTK inhibition. Methods: This study aimed to investigate the single-cell landscape of leukemic MCL using single-cell profiling of 26 patients and 10 healthy donors. In addition, we performed in vitro drug testing on a subset of patient samples (n=12; 6 treatments) to understand the effects of drugs on both tumor and immune cells in MCL . To comprehensively characterize the phenotypic and functional features of immune and tumor cells within a single-cell landscape, we employed high-dimensional full-spectrum cytometry. Therefore, we developed 5 high-dimensional panels covering markers to deeply interrogate T and NK cells, immune evasion and immune checkpoints, cytokines and cytotoxicity, cellular trafficking and intracellular signaling/phosphoproteome (covering >120 proteins). We combined this with single-cell RNA sequencing and a scalable and reproducible bioinformatics pipeline. To assess the disease specificity of the immune landscape, we also obtained single-cell data from other B-NHL including MZL and CLL (n=60 patients). Results: Our data indicate profound changes in the immune landscape, in particular in the T cell compartment of MCL patients. In this regard, multi-omics factor analysis (MOFA) confirmed a highly distinct T cell landscape in MCL patients, characterized by higher effector marker expression in conventional CD4+ and CD8+ T cells in addition to higher fraction of effector and effector memory T cells compared to healthy donors (Fig. 1A and B). Moreover, our analysis revealed a pronounced expansion of highly suppressive regulatory T cells (~5% of T cells) (Fig.1B). The emergence of this effector Treg (eTreg) subset in MCL patients might limit efficient anti-tumor immunity of CD8+ and conventional CD4+ T cells. Consistent with this, we observed a high fraction of several dysfunctional CD8+ T cells subsets. Notably, we found a remodeling of this eTreg subset in patients undergoing ibrutinib treatment leading to a less pronounced suppressive phenotype and concomitantly observed an increase of proteins crucial for cytotoxic function such as Granzyme B and Interferon-γ in effector T cells. We further sought to link tumor cell signatures with the healthy immune cell signatures in order to assess potential interactions and mechanisms of immune escape. As such, the tumor cell compartment (MCL cells) displayed high-expression of inhibitory immune checkpoint ligands such as PVR, HLA-G, CD70 and PD-L1 and antiphagocytic proteins such as CD47 and CD24, which may contribute to the dysfunctional T cell compartment. In line with this, our analysis revealed that high expression of the immune checkpoint ligand CD70 on malignant B cells was inversely associated with an activation module in CD4+ T cells, providing a potential axis contributing to immune escape, which may be leveraged for future therapeutic use. Finally, we identified tumor and immune cell signatures associated with in vitro drug response that may not only be useful for improving treatment selection, but also offer novel biological insights into potential mechanisms of treatment resistance. Conclusion: This study provides valuable insights into the single-cell landscape of leukemic MCL, offering crucial understanding of how tumor-immune cell interactions may contribute to disease progression and treatment resistance. The findings hold potential for therapeutic exploitation to eventually improve patient outcomes in Mantle Cell Lymphoma.

Ki-67 Expression of 50% Is the Optimal Cut-Off to Predict Survival Outcomes in Mantle Cell Lymphoma (MCL): A Pooled Analysis from CALGB 50403 (Alliance) and MCL Real-World Study Cohort

Introduction The Ki-67 index has been previously shown to be prognostic, wherein the cut-off of 30% was associated with inferior survival outcomes (Determann O et al, Blood 2008) in newly diagnosed MCL patients (pts). However, this cut-off determination was made in pts treated with CHOP/R-CHOP as the first-line treatment, controlled only for MIPI, and predates the advent of novel agents. Short diagnosis to treatment interval (DTI ≤ 14 days) was recently shown to be prognostic in newly diagnosed MCL but its association with Ki-67 is unknown. We sought to determine the optimal Ki-67 cut-off in MCL and its prognostic relevance in the modern era. Methods This is a pooled analysis of 2 large datasets, one prospective (CALGB 50403) and one retrospective (MCL real world study [MCL-RWS]). CALGB is now part of the Alliance for Clinical Trials in Oncology. CALGB 50403 is a phase II randomized study wherein newly diagnosed MCL pts received intensive induction chemoimmunotherapy (IIC) followed by autologous transplant, and posttransplant rituximab. The MCL-RWS included adult pts (≥18 years [yrs]) with MCL treated from 2000 to 2017 at 12 participating US sites. Pts from sites in the MCL-RWS that enrolled on CALGB 50403 were excluded. Ki-67 was scored by central review in 10% increments in the CALGB 50403 and per institutional standard in the MCL-RWS. We assessed Ki-67 as a continuous variable and used a restricted quadratic spline fit to find an optimal cut-off. We looked at the associations between Ki-67 and other known/ established MCL prognostic markers including MIPI and DTI. The outcome parameters were PFS and OS. Time-to-event endpoints were evaluated by Kaplan-Meier and Cox proportional hazard methods. Results Among the 793 pts (n=666, MCL-RWS and n=127, CALGB 50403) in the pooled analysis, Ki-67 was available in 385 pts (311 from MCL-RWS and 74 from CALGB 50403). The median OS (mOS) and PFS (mPFS) in the entire cohort (n=793) was 11.8 years and 4.7 years, respectively. The two groups (gps), those with and without Ki-67 data, were well balanced including MIPI and DTI. The median age was 62 yrs (range, 32-88), 81% males, 94% with ECOG performance status (PS) 0-1 and 84% with stage 4. We found a Ki-67 cut-off of 50% to be optimal as the relative hazard of death rises after 50%. Pts in the Ki-67 >50% gp had significantly higher proportion with short DTI (36% vs 17%, p<0.001), ECOG PS ≥2 (12% vs 5%, p=0.02), elevated LDH (58% vs 39%, p=0.005), and MIPI ≥6.2 (38% vs 20%, p=0.007) compared to Ki-67 of ≤50%. Ki-67 >50% was associated with significantly inferior PFS with a hazard ratio (HR) of 2.10 (95%CI 1.50-2.92) compared to Ki-67 ≤50% with a mPFS of 2.1 vs 5.3 yrs, respectively, regardless of the age (young [≤65 yrs], 2.6 vs 5.3 yrs or old [>65 yrs], 1.1 vs 5.4 yrs) or receipt of IIC (2.2 vs 5.9 yrs). Figure 1 shows the statistically significant difference in PFS between the Ki-67 gps of ≤10%, >10% to <30%, ≥30 to ≤50%, and >50%. Ki-67 >50% remained prognostic for PFS in multivariable analysis (MVA) after adjusting for significant variables in univariable analysis (UVA) including short DTI, ECOG PS ≥2, stage 4, elevated LDH, and MIPI ≥6.2 with adjusted HR (aHR) 2.19, 95%CI 1.38-3.48, p <0.001. Ki-67 >50% was associated with significantly inferior OS with a HR of 2.10 (95%CI 1.33-3.32) compared to Ki-67 ≤50% with a mOS of 9.4 yrs vs not reached (NR), respectively, regardless of the age or receipt of IIC. Figure 2 shows the statistically significant difference in OS between the Ki-67 gps of ≤10%, >10% to <30%, ≥30 to ≤50%, and >50%. Ki-67 >50% was not prognostic for OS in MVA after adjusting for significant variables in the UVA (MIPI and sex), aHR 1.79, 95% CI 0.92-3.49, p=0.08. Similar findings were seen in multivariable analysis with Ki-67 >30%, which showed no prognostic significance (aHR 1.46, 95%CI 0.82-2.58, p=0.19). Because of disparate datasets, we performed sensitivity analysis looking at the prognostic relevance of in individual datasets (CALGB 50403 and MCL-RWS) and found Ki67 >50% was prognostic for PFS and OS in both of the datasets consistent with the primary analysis. Conclusions This study evaluating the optimal Ki-67 cut off for pts with newly diagnosed MCL in the modern era found that Ki-67 > 50% was prognostic for PFS but not OS in MVA. A potential reason for the lack of prognostic relevance for OS in this more recent dataset is the availability of effective options at relapse. We also found that short DTI was associated with high Ki-67 gp which is a novel finding.

An International Multicohort Study of Conditional Survival and Cause of Death after Achieving Event-Free Survival at 24 Months in Patients with Mantle Cell Lymphoma

Background: Event-free survival at 24 months (EFS24) after frontline immunochemotherapy (IC) is an important endpoint in diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 have similar survival compared to age- and sex-matched general population. The role of EFS24 in predicting subsequent survival has not been established in mantle cell lymphoma (MCL), possibly due to perceived poor survival historically. In the last decade, the outcomes of MCL are improving in the evolving treatment landscape. In this international multicenter study, we investigated conditional survival and cause of death in patients with MCL who achieved EFS24 after frontline IC in the older and more recent eras. Methods: Outcomes after frontline IC were evaluated in 5 independent cohorts that included over 3000 patients in total: Mayo/Iowa MER prospective cohort, BC Cancer retrospective population-based cohort, US 12-center retrospective cohort, Swedish Lymphoma Registry, and Danish National Lymphoma Registry. For each cohort, 2 treatment eras were defined based on cohort-specific shifts in treatment patterns (Table 1). Overall survival (OS) after diagnosis and after achieving EFS24 were compared to the background age- and sex-matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model. Results: In the MER cohort, patients treated in Era M1 (2002-2009; n=147) and Era M2 (2010-2015; n=153) both had inferior OS compared to the general US population. A lower SMR in Era M2 vs M1 (2.25 vs 3.46) suggests a narrower gap in OS compared to the general US population. Lymphoma was the leading cause of death in both eras. In Era M1, patients who achieved EFS24 still had inferior OS compared to the general US population (SMR=2.40, 95% CI 1.76-3.19), and lymphoma remained the leading cause of death. For patients in Era M2 who achieved EFS24, the difference in OS compared to the general US population was not statistically significant with current follow-up (SMR=1.43, 95% CI 0.93-2.09), and lymphoma was no longer the leading cause of death (Table 2). In the BC cohort, patients treated in Era B2 (6/2013-2019; n=188) vs Era B1 (2003-5/2013; n=250) had a narrower gap in OS compared to the general British Columbia population (SMR 4.53 vs 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 vs B1 (SMR 3.56 vs 4.99). After achieving EFS24, lymphoma was the single leading cause of death for patients in Era B1 but not in Era B2 (Table 2). In the US 12-center cohort, patients treated in Era U1 (2002-2011; n=312) and Era U2 (2012-2016; n=417) both had inferior OS compared to the general US population (SMR 2.68 and 2.92, respectively). In patients who achieved EFS24, with current follow up, the difference in OS compared to the general US population was statistically significant in Era U1 (SMR=2.01, 95% CI 1.50-2.64) but not in Era U2 (SMR=1.44, 95% CI 0.82-2.34). Lymphoma was not the leading cause of death after achieving EFS24 (Table 2). In the Swedish cohort, the gap in OS compared to the general Swedish population was narrower in Era S2 (2013-2018; n=439) vs S1 (2006-2012; n=442), both after frontline IC (SMR 4.8 vs 5.4) and after achieving EFS24 (SMR 2.6 vs 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Table 2). In the Danish cohort, patients treated in Era D2 (2014-2020; n=370) vs Era D1 (2004-2013; n=461) had a slightly narrower gap in OS compared to the general Danish population (SMR 1.90 vs 2.10). For patients who achieved EFS24, those in Era D1 still had inferior OS compared to the general Danish population (SMR=1.44, 95% CI 1.22-1.68), but the OS difference compared to the general Danish population in Era D2 was not statistically significant (SMR=1.27, 95% CI 0.92-1.72) with current follow-up (Table 2). Cause of death data were not available in this cohort. Conclusion: Survival in patients with MCL who achieved EFS24 after frontline IC improved in the more recent treatment era and moved closer to the background expected survival. After achieving EFS24, lymphoma-related mortality was no longer the leading cause of death in the more recent era. EFS24 following frontline treatment may become a critical endpoint for predicting subsequent outcomes in patients with MCL in the modern era.

Post-CAR-T Minimal Residual Disease (MRD) Monitoring in Mantle Cell Lymphoma Enables Early Relapse Detection

INTRODUCTION: Over 40% of patients with mantle cell lymphoma (MCL) will progress within 1 year after treatment with brexucabtagene autoleucel (Brexu-cel)(Michael Wang et al. ZUMA-2 NEJM 2020). Monitoring minimal residual disease (MRD) of circulating tumor cells (CTC) via next-generation sequencing of the immunoglobulin sequences (IgHTS) with a sensitivity of 1 in million (ClonoSeq, Adaptive Biotechnologies) has previously been shown to identify patients at high risk of MCL relapse (Simone Ferrero et al. Blood 2022). However, there is a limited understanding of MRD monitoring after Brexu-cel. A sub-analysis of 27 patients post-Brexu-cel in ZUMA-2 showed predictive performance of MRD measured at months 1, 3, and 6 in estimating relapse potential. METHODS: Clonotypes were identified from paraffin-embedded tissues and underwent PCR amplification of the IgH, IgH-DJ, and Ig Kappa/lambda regions. CTC MRD assessments were monitored at 1, 3, 6, and 12 months (if applicable) following standard-of-care brexu-cel infusion in all patients with MCL at our center who had at least 3 months of follow-up. PFS and overall survival (OS) were determined by Kaplan-Meier analysis and significance by log-rank test. The comparison between the two groups was conducted using a two-tailed Mann-Whitney test. Significances were calculated using a Fisher exact test between two categorical variables or as otherwise specified. Statistical analysis and plots were generated using Prism 8.4.1 (GraphPad) RESULTS: Between January 2020 and December 2022, all treated patients (n=34) were analyzed. 3 patients were excluded as they were unable to reach day 28 (D28) assessments due to death, progressive disease, or refusal of CAR-T infusion. 5 patients were excluded due to a follow-up of <3 months. The median follow-up time for the 26 included patients was 18.9 months. The median age was 68, 73% were male and 27% were female, 4 median lines of therapy prior, including AutoHSCT (34.6%) or BTKi (92%). The best overall response rate at D28 was 100% with a CR rate of 73% which was similar to ZUMA-2. The median OS was 18.9 months and the median PFS was 15.3 months. We chose to analyze the Day 28 MRD assessment and found 17 of 23 patients (74%) had undetectable MRD and 6 patients had detectable MRD (26%). Due to the relatively small sample size, no significant differences were found between Age, Gender, Pre-treatment LDH, MIPI score, Ki-67, TP53 mutational status, and probability of Day 28 undetectable MRD. Notably, however, 3 of the 6 patients with TP53 mutations had detectable Day 28 MRD. Those patients with detectable MRD compared with those with undetectable MRD had a lower median PFS of 10.74 months vs 17.69 months (p-value= 0.21, Figure 1); although the median OS was similar of 17.69 and 17.84 months, (p-value= 0.75) respectively. 88% of patients (15 out of 17) with undetectable MRD on Day 28 not only maintained this status at 6 months but also showed no radiological disease progression in 93% (14 out of 15) of cases at the time of longest follow-up. A total of 7 patients relapsed during follow-up. MRD predicted 6 impending relapses earlier than PET CT with a median of 294 days (range 15-332 days) prior to progression (Figure 2). CONCLUSION: Evidence from the ZUMA-2 study and our study highlights the significance of early post-CAR-T MRD as an independent prognostic marker for predicting disease recurrence and durable remissions in MCL. Combining MRD measurements with PET-CT at months 1, 3, and 6 after CAR-T therapy can effectively identify high-risk patients for disease progression, offering promising potential to improve outcomes in MCL.

Outcomes in Mantle Cell Lymphoma with Central Nervous System Involvement - a Dual Center Study

Background Central nervous system (CNS) involvement is a rare complication (<5% of cases) of mantle cell lymphoma (MCL) and is associated with poor outcomes, highlighting the need for novel treatment approaches. We report the outcomes of a large cohort of patients (pts) with CNS MCL from Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC). Methods MCL pts with CNS involvement seen at Mayo Clinic and MSKCC between 1/2000-1/2021 were included. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcomes. First-line MCL chemotherapy was categorized into higher intensity chemotherapy (i.e., anthracycline-based +/- high-dose cytarabine), moderate intensity chemotherapy (i.e., bendamustine-based regimens or single agent chemotherapy), and other. CNS treatment regimens were categorized as intrathecal (IT) therapy alone, systemic therapy (with CNS penetration such as IV cytarabine or IV methotrexate) with/without IT therapy, regimens with Bruton's tyrosine kinase inhibitors (BTKi), chimeric antigen receptor T cell (CAR-T) therapy, or radiation alone. Kaplan-Meier method was used for time to event analysis. Forest plots were developed using univariable Cox proportional hazards models. Results Seventy patients were included in the cohort, 34 from MSKCC and 36 from Mayo Clinic. Median age at MCL diagnosis was 65 years (range 56-72) and 52 were male (74%). MIPI score was available in 60 pts: low (n=10, 17%), intermediate (n=20, 33%), and high (n=30, 50%) risk. First line therapy included: higher intensity chemotherapy (n=42, 60%), moderate intensity chemotherapy (n=25, 36%) and other (n=3, 4%). Twenty-five (36%) pts underwent autologous hematopoietic cell transplantation in CR1. Median time from initial MCL diagnosis to CNS involvement was 24 months (m) (range 0-167). Four (6%) pts had CNS involvement at initial diagnosis. Abnormal CNS imaging was reported in 53 (76%) pts: leptomeningeal (n=37), leptomeningeal and parenchymal (n=4), parenchymal (n=8), orbital (n=4). The most common regimen following CNS diagnosis was systemic therapy with or without IT therapy (n=34, 54%) followed by treatment including BTKi (n=13, 21%), IT alone (n=10, 16%), radiation alone (n=3, 5%), and treatment including CAR-T (n=3, 5%). Three patients elected hospice care and four patients had missing/unknown CNS treatment. The overall CNS response to therapy was available in 54 patients: CR in 22 (41%) pts, PR in 8 (15%), SD in 11 (20%), and PD in 13 (24%) pts. Of the 70 patients, 63 died. Median follow up was 6.9 years (range: 1.6-11.2) from initial MCL diagnosis and 2.1 years from CNS diagnosis (range: 0.4-7.9). Median OS from MCL diagnosis was 3.4 years (95% CI: 2.4-4.6). In univariable Cox models, sex, stage, performance status, Ki67, or first line systemic chemotherapy type were not significantly associated with OS from MCL diagnosis. Low risk MIPI score (score < 5.7) was associated with favorable OS (HR 0.31, 94% CI: 0.12-0.77; p value 0.01) compared to high risk. First-line treatment and treatment intensity were not associated with a significant difference in OS. Median PFS for the first CNS-directed therapy was 2.4 m (95% CI: 1.7-4.3). Cause of death was disease-related in a majority (n=49, 78%) of pts and therapy-related in 10% (n=6). The remaining 8 deaths had cause of death reported as missing or other (13%). Median OS from CNS involvement was 5.1 m (95% CI: 3.3-10.0) (Figure 1). When assessing OS from time of CNS diagnosis, treatment regimens incorporating BTK inhibitors were associated with a more favorable OS compared to systemic therapy +/- IT therapy (HR=0.37, 95% CI: 0.16-0.89, p value=0.03) (Figure 2). Conclusions Our dual center series confirms patients with CNS involvement by MCL have poor outcomes. When evaluating OS from the time of CNS diagnosis, novel therapies, including BTKi and CAR-T, may be more effective than CNS-penetrant chemotherapy for treatment of CNS relapse suggesting newer therapeutic approaches are required to improve outcomes.

Multicenter Study of Mantle Cell Lymphoma Outcomes Following First-Line Bendamustine-Rituximab and Second-Line Bruton's Tyrosine Kinase Inhibitor Therapy

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.

MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 - a Nordic Lymphoma Group study.

The transcription factor MYC is a well-described oncogene with an important role in lymphomagenesis, but its significance for clinical outcome in mantle cell lymphoma (MCL) remains to be determined. We performed an investigation of the expression of MYC protein in a cohort of 251 MCL patients complemented by analyses of structural aberrations and mRNA, in a sub-cohort of patients. Fourteen percent (n=35) of patients showed high MYC protein expression with >20% positive cells (MYChigh), among whom only one translocation was identified, and 86% (n=216) of patients showed low MYC protein expression. Low copy number gains of MYC were detected in ten patients, but with no correlation to MYC protein levels. However, MYC mRNA levels correlated significantly to MYC protein levels with a R2 value of 0.76. Patients with a MYChigh tumor had both an independent inferior overall survival and an inferior progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% CI]: 1.2-3.4 and HR=2.2, 95% CI: 1.04-4.6, respectively) when adjusted for additional high-risk features. Patients with MYChigh tumors also tended to have additional high-risk features and to be older at diagnosis. A subgroup of 13 patients had concomitant MYChigh expression and TP53/p53 alterations and a substantially increased risk of progression (HR=16.9, 95% CI: 7.4-38.3) and death (HR=7.8, 95% CI: 4.4-14.1) with an average overall survival of only 0.9 years. In summary, we found that at diagnosis a subset of MCL patients (14%) overexpressed MYC protein, and had a poor prognosis but that MYC rearrangements were rare. Tumors with concurrent MYC overexpression and TP53/p53 alterations pinpointed MCL patients with a dismal prognosis with a median overall survival of less than 3 years. We propose that MYC needs to be assessed beyond the current high-risk factors in MCL in order to identify cases in need of alternative treatment.

Impact of diagnosis to treatment interval in patients with newly diagnosed mantle cell lymphoma.

The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2)patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worseeastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCLInternational Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p<0.0001) and overall survival (7.8 years vs. 11.8 years, p<0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided.

Treatment outcomes of mantle cell lymphoma in real-world practice: analysis of forty-one patients.

Treatment outcomes of mantle cell lymphoma in real-world practice: analysis of forty-one patients.

Exploring Splicing Factor Aberrations As a Therapeutic Target in Mature B-Cell Malignancies

Objectives Cancers originating from mature B cells at various stages of terminal differentiation represent a diverse set of cancers. There are numerous pathological subtypes, each comprising genetically and clinically heterogeneous malignancies with distinct biology and clinical outcomes. We have previously identified the recurrence of mutations in splicing factor HNRNPH1 in mantle cell lymphoma (MCL), which were associated with inferior outcomes. Based on growing evidence for the role of splicing factors in mature B cell neoplasms, we sought to extend our characterization of splicing factor aberrations across additional B cell malignancies. We hypothesize that regulation of alternative splicing is essential for B cell differentiation and maturation, and aberrations of splicing factors in B cell malignancies are related to these normal patterns of alternative splicing. Ultimately, we are pursuing alternative splicing as a potential novel therapeutic vulnerability common among mature B cell neoplasms. Methods We leveraged whole genome, exome, and RNA sequencing data from 2999 tumors assembled from controlled-access repositories and ongoing projects at BC Cancer as part of our Genomic Analysis of Mature B-cell Lymphomas (GAMBL) project. RNA-seq data was aligned with STAR and splicing events were quantified with RMATS. Novel splicing events were quantified following de novo transcriptome assembly with StringTie. Simple somatic mutations were detected using a workflow comprised of four algorithms to identify high-confidence variants. We used additional RNA-seq data from distinct B-cell maturation states (naïve, centroblast, centrocyte, memory, bone marrow plasma, and tonsillar plasma cells) to identify annotated and novel splicing events which are differentially regulated throughout B cell maturation. Annotated and novel events were subsequently used to query alternative splicing in a subset of tumor samples using a combination of Illumina-based and Oxford Nanopore sequencing. Results More than 30% of patient samples harboured somatic mutations in at least one of 67 queried splicing factors. HNRNPU, PCBP1, SF3B1, DAZAP1, and HNRNPH1 were most commonly mutated, 13% of cases (Figure 1A). Although only reported in MCL thus far, we noted an abundance of HNRNPH1 mutations in DLBCL showing the same pattern of non-coding mutations, most commonly in the activated B cell subgroup. In non-malignant samples, we identified 129 known and 267 novel splicing events which display differential regulation during B cell maturation and warrant further investigation within subtypes of B cell malignancies (Figure 1B). Based on this observation, we hypothesize that the RNA isoform repertoire may vary across B cell differentiation states and its perturbation may contribute to oncogenesis in a context-dependent manner. Furthermore, the importance of alternative splicing during B cell maturation implies that perturbation of splicing in B cell malignancies could play a role in pathogenesis. We previously demonstrated that non-coding mutations in HNRNPH1 contribute to overexpression of the hnRNP H protein and are associated with poor patient outcomes in MCL. Based on the predominance of these mutations in DLBCL, we sought to evaluate hnRNP H overexpression as a potential therapeutic target. We identified a putative exonic splicing enhancer (ESE) with minimal secondary structure in the essential exon of HNRNPH1 using ESEfinder and designed locked nucleic acid antisense oligos (ASOs) complementary to the ESE. Using ddPCR, we showed that the ESE ASO can effectively decrease the proportion of the productive HNRNPH1 splice variant at nanomolar concentrations in HEK cells; however, a splice site ASO does not display the same efficacy. Conclusions We have identified a growing number of splicing factors in mature B cell malignancies as recurrently mutated, indicating that deregulation of the RNA isoform repertoire in B cells can contribute to oncogenesis. Characterizing the landscape of alternative splicing in normal and malignant B cells will allow us to identify opportunities to exploit this reliance in the development of novel therapeutic strategies. Our data highlight antisense oligonucleotides as a promising therapeutic avenue for targeting splicing aberrations caused by common mutations in B cell malignancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rituximab Maintenance (RM) after First-Line (1L) Treatment Is Associated with a Lower Risk of Early-POD in Patients with Mantle Cell Lymphoma (MCL)

Background RM after 1L immunochemotherapy has improved the Progression-Free Survival (PFS) and Overall Survival (OS) in MCL in phase III clinical trials and in real-life patients. Early progression/relapse (E-POD) after 1L has been significantly associated with a shorter OS in younger patients with MCL after intensive 1L and autologous stem-cell transplantation (ASCT), although these patients did not receive RM (Visco et al, BJH 2019). The aim of our study was to analyze the impact of the use of RM on the risk of early-POD in a real-life cohort of patients with MCL. Methods We retrospectively reviewed all patients diagnosed with MCL between January 2000 and December 2021 at 6 tertiary centers. Only patients receiving 1L at diagnosis and achieving complete (CR) or partial response (PR) were eligible for maintenance and therefore included in this analysis. Patients were categorized as "RM” if they had received RM after 1L or as "non-RM” if they had not. Relapse/progression after 1L occurring before or after the first 24 months (m) from diagnosis was considered early or E-POD and late or L-POD, respectively (Visco et al, BJH 2019). Patients not relapsing after 1L were considered L-POD only if their follow-up time (FU) from diagnosis was 24 months or longer. Patient's characteristics, biological risk factors at diagnosis, as well as the type of 1L were recorded (intensive immunochemotherapy with high-dose cytarabine -HiDAC- or standard immunochemotherapy without HiDAC -non-HiDAC-), with or without ASCT consolidation. The duration of response (DOR) after 1L, PFS and OS were also analyzed for all patients. Statistical analyses were performed with the R-4.1.0 software. Univariate logistic regression was carried out to study the association between E-POD and maintenance. Survival analysis (DOR, PFS and OS) were calculated using the Kaplan-Meier method and the univariate Cox was used for statistical comparison. Results Out of 212 patients attaining CR or PR after 1L, 87 (41%) received maintenance therapy (RM group) whereas 125 patients (59%) did not (non-RM group). The RM regimens administered were: rituximab monotherapy (R)/8 weeks (wk) x 2 years (N=41), R/8 wk x 3 years (N=27) and other R-based regimens (with BTK inhibitors, N=7; other R schedules, N=12). Except for a higher percentage of patients older >65 years at diagnosis in the RM group (51.7% RM vs. 37.6% non-RM, p=0.042), the rest of baseline characteristics were well balanced between the two groups (Table 1). Regarding 1L, more patients in the full cohort had received a non-HiDAC regimen [120 pts (56.6%) non-HiDAC vs. 92 pts (43.4%) HiDAC], but the proportion of patients receiving RM was similar after both types of 1L. Only 22 out of the 87 patients in the RM group (25.3%) had undergone previous ASCT consolidation (Table 1). With a median follow-up of 72.8 months (51.52 m and 92.65 m in the RM and non-RM groups, respectively), median PFS was 44.39 m (36.11-55.46), with a significant advantage for the RM group (61.04 m vs. 32.82 m, HR=1.7 [1.15-2.51], p=0.01) (Figure 1). Moreover, median DOR was 30.03 m (26.02-42.94), also significantly longer in the RM group (53.88 m vs. 24.21 m, HR=1.61 [1.12-2.3], p=0.01). Median OS was 12.18 yrs (8.66-NR) in the full cohort, with no significant differences between the two groups (14.03 yrs vs. 11.48 yrs, HR=1.34 [0.74-2.45], p=0.34). Regarding POD24, a statistically significant association was observed between not receiving RM and early-POD: 49 patients (40.5%) were E-POD in the non-RM group compared with only 19 (24.4%) in the RM group (OR=2.11 [1.14-4.04], p=0.020) (Table 1). Conclusions Only 41% of our real-life cohort received RM despite it being considered a safe and effective strategy for MCL patients. In line with previous studies, in our series RM after 1L is associated with a significant advantage in terms of PFS and DOR, although it did not have impact on OS. In our cohort, RM is significantly associated with a lower risk of early-POD, in all age groups and regardless of the 1L induction strategy, therefore confirming the benefit of this strategy in the management and outcomes of MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluating real-world treatment patterns and outcomes of mantle cell lymphoma

AbstractMantle cell lymphoma (MCL) is considered incurable with the available chemoimmunotherapy approaches, and therefore, newer effective targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors are increasingly used in MCL as chronic suppressive therapy, especially in the elderly. We aimed to describe the treatment patterns in MCL at different lines of therapy with a focus on BTK inhibitor use and compare outcomes with known prognostic factors using a nationwide Flatiron Health electronic health record–derived de-identified database. We analyzed patient-level data from the period of 2011 to 2021. In this study of 4336 patients with MCL, we found that bendamustine plus rituximab chemotherapy was the most commonly used frontline regimen (42%). Maintenance rituximab or consolidative autologous stem cell transplant (ASCT) was administered to 31% of all patients. Also, for patients who received ASCT as consolidation therapy, only 34% subsequently received rituximab maintenance. BTK inhibitors were the most preferred agents in second or later lines of therapy (n = 933, 57%), followed by bortezomib, lenalidomide, and venetoclax, respectively. Among patients treated with BTK inhibitors, the median real-world overall survival (rwOS) was 35 months (95% confidence interval [CI], 27-50), 24 months (95% CI, 22-30), and 18 months (95% CI, 14-21) for first line, second line, and third or later line of therapy, respectively. Patients with a deletion 17p/TP53 mutation and blastoid variant MCL had poor outcomes; however, BTK inhibitors appeared to mitigate the negative influence of del17p/TP53-mutated MCL with a hazard ratio of 1.17 (95% CI, 0.88-1.55) on multivariable analysis.

Circulating tumor DNA predicts therapeutic outcome in mantle cell lymphoma

AbstractMantle cell lymphoma (MCL) is biologically and clinically heterogeneous and would benefit from prognostic biomarkers to guide management. Circulating tumor DNA (ctDNA) is a novel prognostic biomarker in diffuse large B-cell lymphoma that may have applicability in MCL. We analyzed ctDNA dynamics in previously untreated patients with MCL who received induction therapy with bortezomib and DA-EPOCH-R for 6 cycles followed by random assignment to observation or bortezomib maintenance in responding patients in a prospective phase 2 study. Most patients also underwent initial treatment window of bortezomib alone prior to induction. Serum was collected pretreatment, after the window, after cycles 1 and 2, at the end of induction, and at each follow-up visit along with restaging computed tomography scans. Next-generation sequencing was used to identify and quantify ctDNA encoding the immunoglobulin receptor sequences in serum as markers of minimal residual disease. Fifty-three patients were enrolled, with a median follow-up of 12.7 years. Patients without detectable ctDNA after 2 cycles of induction had longer progression-free survival (PFS) and overall survival (OS) compared with those with detectable ctDNA (median PFS, 2.7 vs 1.8 years; overall P = .005; median OS, 13.8 vs 7.4 years; overall P = .03). Notably, in vivo assessment of ctDNA dynamics during the bortezomib window was not prognostic, and there was no difference in PFS or OS with bortezomib maintenance. ctDNA monitoring after induction showed that molecular relapse preceded clinical relapse in some cases. In conclusion, interim ctDNA negativity strongly correlates with improved survival and supports the investigation of response-adapted strategies. This trial was registered at www.clinicaltrials.gov as #NCT00114738.

Survival of Mantle Cell Lymphoma in the Era of Bruton Tyrosine Kinase Inhibitors: A Population-Based Analysis

Survival of Mantle Cell Lymphoma in the Era of Bruton Tyrosine Kinase Inhibitors: A Population-Based Analysis

Disparities in Mantle Cell Lymphoma Outcomes in Hispanics: A Population Based Analysis in Texas and Florida

Disparities in Mantle Cell Lymphoma Outcomes in Hispanics: A Population Based Analysis in Texas and Florida

Phase 1/2 Trial of IL7/IL15-Expanded Bispecific LV20.19 CAR T-Cells for Relapsed, Refractory B-Cell Non-Hodgkin Lymphoma

Phase 1/2 Trial of IL7/IL15-Expanded Bispecific LV20.19 CAR T-Cells for Relapsed, Refractory B-Cell Non-Hodgkin Lymphoma

Event-Free Survival at 24 Months (EFS24) Becomes an Important Clinical Endpoint in Newly Diagnosed Mantle Cell Lymphoma in the New Era

Event-Free Survival at 24 Months (EFS24) Becomes an Important Clinical Endpoint in Newly Diagnosed Mantle Cell Lymphoma in the New Era