Mantle Cell Lymphoma Relapse Research Articles

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.

A Novel Machine-Learning Model to Predict Early Relapse in Mantle Cell Lymphoma (MCL)

Background MCL is currently an incurable disease. Although survival has greatly improved due to the advent of more effective treatments, early relapse or refractoriness after the first-line treatment (1L) is independently associated with a dismal outcome (Visco et al, BJH 2019). An early identification of these higher-risk patients would allow to optimize their management strategies and, possibly, to improve their outcome. The purpose of this study was to develop a novel prognostic model index that could predict, from the time of diagnosis, the risk of early relapse. Methods Patients diagnosed with MCL from 6 Spanish centers between January 2000 and December 2021 and treated with ≥1 lines were retrospectively analyzed (training population). An external cohort from an additional Spanish hospital was used to further validate the score (test cohort). Patients were classified as early-POD (E-POD: refractory to 1L or relapsing ≤24 m from diagnosis) or late-POD (L-POD: relapse after 1L beyond 24 m from diagnosis or absence of relapse at data cut-off). All patients had a follow-up (FU) ≥24 m from diagnosis to be evaluable for POD24, except those dying from MCL <24m, who were included as E-POD. The LASSO method with the minimum lambda was used to identify the most relevant variables affecting POD24. Missing variables in the training cohort were imputed so as not to lose patients. To enhance the predictive performance, a multimodal approach was adopted. First, a random forest survival (RFS) model was constructed using the variables selected by LASSO to predict Overall Survival (OS). Subsequently, a gradient-boosting (GB) model was developed to predict POD24, incorporating both the LASSO-selected variables and the risk predictions derived from the RFS model. Results The training cohort included 231 patients, 99 (43%) E-POD and 132 (57%) L-POD, and the test cohort 38 patients, 12 (32%) E-POD and 26 (68%) L-POD. Table 1 shows the baseline characteristics of both cohorts. Median FU was 97.12 m (86.93 -113.45) for the training cohort and 120.44 m (103.69 -144.82) for the test cohort. Among the variables associated with the risk of E-POD in the univariate analysis (age>65 years, no previous transplant, advanced stage, high-risk MIPI, Ki67≥30% and blastoid morphology), the LASSO method selected a total of 4: age at diagnosis, stage (I-II vs. III-IV), MIPI group (low, intermediate or high risk) and morphologic variant (classic vs. blastoid/pleomorphic). These variables, adjusted for POD24 as the endpoint, were first included in the RFS model to estimate the OS of each patient, obtaining a c-index of 0.78 in both the training and the validation cohorts. Then, we performed a GB model to predict the risk of E-POD, by including the same LASSO-selected variables in addition to the risk prediction of survival obtained with the RFS model, with relative weights of 9.86% (age), 0.38% (stage), 14.34% (MIPI), 16.18% (morphology) and 59.25% (estimated OS). The resulting model showed an AUC (area under the curve) of 0.82 and 0.75 in the training and test cohorts, respectively, and the calibration curves for the prediction model in both cohorts are shown in Figure 1. Our model identifies 3 tertile groups with differentiated risk of E-POD: high, intermediate and low risk with an accuracy of 81% and 74%, sensitivity 81% and 70%, specificity 81% and 76%, positive predictive value 78% and 64% and negative predictive value 85% and 81% for the training and validation cohorts, respectively. Since Gradient Boosting models are an ensemble of multiple decision trees and their predictions are made by combining the outputs of these trees using weighted averaging, rather than using a fixed mathematical formula with coefficients as in traditional linear models, a formula cannot be provided. Therefore, an online application is currently under construction to make the calculation of this E-POD index score widely applicable. Conclusion This new index score can predict the risk of E-POD at diagnosis, allowing for an earlier identification of this high-risk patient subset in need of more effective treatment strategies. External validation of this E-POD index score in a larger cohort is warranted to allow a wider application of this prognostic tool.

Sequencing-based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy.

Our knowledge of genetic aberrations, that is, variants and copy number variations (CNVs), associated with mantle cell lymphoma (MCL) relapse remains limited. A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole-exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: TP53, ATM, KMT2D, CCND1, SP140, and LRP1B. The most frequent CNVs at diagnosis and at relapse included TP53 and CDKN2A/B deletions, and PIK3CA amplifications. The mean count of mutations per patient significantly increased at relapse (n = 34) compared to diagnosis (n = 27). The most frequent newly detected variants at relapse, LRP1B gene mutations, correlated with a higher mutational burden. Variant allele frequencies of TP53 variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with CDKN2A/B deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.

Long-Term Survival of Patients with Mantle Cell Lymphoma after Total Body Irradiation, High-Dose Chemotherapy and Stem Cell Transplantation: A Monocenter Study.

In patients with mantle cell lymphoma (MCL), long-term remissions can be achieved by stem cell transplantation (SCT). Different conditioning treatment protocols exist with or without total body irradiation (TBI). There are few data published on the role of TBI before autologous stem cell transplantation (autoSCT) or allogenic stem cell transplantation (alloSCT). We report on the long-term survival data of patients treated by TBI prior to autologous or allogenic SCT at our center. In a retrospective analysis, the data of patients treated at the University Hospital of Muenster from May 2004 to February 2015 were collected and evaluated. For the analysis, all data of patients who were histopathologically diagnosed with MCL and underwent TBI prior to stem cell transplantation (SCT) were evaluated. A total of 22 patients (19 men and 3 women) were treated with a TBI-based conditioning prior to SCT. The median age at initial diagnosis was 57.5 years (38-65 years). Seventeen patients had Ann Arbor stage IV, two patients had Ann Arbor stage III, and three patients Ann Arbor stage II disease. AutoSCT was performed in 19 patients and alloSCT was performed in 3 patients. In 18 patients, autoSCT was applied as part of first-line therapy, and in one patient after relapse. Two patients received alloSCT after relapse of MCL, and one patient received alloSCT during first-line therapy after an inadequate treatment response. TBI was performed in 12 patients with 10 Gy and in 6 patients with 12 Gy, these patients subsequently received autoSCT. In the group of four patients who received TBI with four Gy, four patients subsequently received alloSCT and one patient received autoSCT. Median overall survival after autoSCT and previous TBI was 11.4 years (142 months). In total, 11 out of 19 patients treated with autoSCT lived longer than 6.8 years (82-202 months). After alloSCT and previous TBI, the median overall survival was 3.25 years (14-59 months). A large proportion of patients with advanced MCL survived remarkably longer than 11.4 years after high-dose chemotherapy, TBI, and SCT. The present results of multimodal treatment support the published reports that TBI-based high-dose therapy followed by autoSCT is highly effective in this prognostically unfavorable disease situation.

Unusual solitary rectal relapse of mantle cell lymphoma after second remission

Mantle cell lymphoma is a rare type of B cell non-Hodgkin's lymphoma (NHL) comprising only 3%–6% of all NHL. It is aggressive and prone to relapse. Around 15%–30% of the patients present with gastrointestinal tract involvement. Solitary rectal mantle cell lymphoma is rare and there are very few reports of the same. Till date, there is no report of a solitary rectal relapse of mantle cell lymphoma occurring after second remission. We report a relapse of solitary rectal mantle cell lymphoma presenting with rectal bleeding after second remission in primary gastric mantle cell lymphoma.

Survival of patients with mantle cell lymphoma in the rituximab era: Retrospective binational analysis between 2000 and 2020.

Mantle cell lymphoma (MCL) is a rare peripheral B-cell lymphoma characterised by eventual relapse and progression towards a more aggressive disease biology. With the introduction of rituximab- and cytarabine-based immunochemotherapy regimens, the prognosis of the disease has changed dramatically over the last two decades. To assess the real-world survival of patients with MCL, we used a population-based cohort of 564 patients with MCL who were diagnosed and treated between 2000 and 2020. Patient data were collected from seven Finnish treatment centres and one Spanish treatment centre. For the entire patient population, we report a 2-year overall survival (OS) rate of 77%, a 5-year OS of 58%, and a 10-year OS of 32%. The estimated median OS was 80 months after diagnosis. MCL is associated with increased mortality across the entire patient population. Additionally, we assessed the survival of patients after MCL relapse with the aim of establishing a cut-off point of prognostic significance. Based on our statistical analysis of survival after the first relapse, disease progression within 24 months of the initial diagnosis should be considered as a strong indicator of poor prognosis.

Favorable Overall Survival Following First and Second Relapse of MCL with Availability of Novel Therapies: Results from the Lion Prospective Observational Registry

Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma (NHL) associated with a high rate of relapse following frontline treatment, but with expanding treatment options for relapsed/refractory (RR) disease. Historically, outcomes for RR MCL have been unfavorable compared with indolent NHL subtypes, however survival data with more recently approved therapies is less well characterized. We report survival data following 2nd and 3rd line therapy for RR MCL in a large contemporary prospective cohort. Methods: We included patients (pts) with RR MCL enrolled in the Lymphoma Innovations ORIEN Network (LION) prospective observational registry at one of seven participating centers. The LION Cohort is a 7-center cohort project which enrolls patients with relapsed/refractory NHL. All patients signed written consent. Clinical data were abstracted from medical records using a standardized protocol. Event free survival was estimated using the method of Kaplan-Meier and defined as time from start of 2nd (EFS2) or 3rd (EFS3) line treatment until progression, subsequent treatment, or death censoring pts alive and without further treatment or relapse at last follow-up. Overall survival was estimated using Kaplan-Meier and defined as time from start of 2nd (OS2) or 3rd (OS3) line treatment until death, censoring pts alive at last follow-up. Comparisons of EFS and OS were performed using the log-rank test. Results: A total of 128 eligible pts with RR MCL consented between 2/5/2020 and 7/8/2022. Pts received 2nd line treatment between 2002- 2021; 84% (107/128) after November 2013. Baseline characteristics included male sex in 95 pts (77%), stage III/IV disease in 110 pts (91%), progression within 24 months (mo) of initial treatment (POD24) in 43 pts (34%). Median age at first relapse was 65 years. Second line treatments included BTK inhibitors (BTKi) in 61 pts (50%), bendamustine based therapy in 14 pts (12%), lenalidomide and/or bortezomib based therapy in 14 pts (12%), venetoclax in 3 pts (3%), and other classes of treatment in 30 pts (25%). After a median follow-up of 45 mo, the estimated median EFS2 was 26 mo (95% confidence interval [CI] 15-38), with a 24-month estimated EFS2 of 51% (95% CI 41-60) and 5-year estimated EFS2 of 24% (95% CI 14-34). The estimated 24-month OS2 was 91% (95% CI 84-96) and 5-year estimated OS2 was 84% (95% CI 74-90). Third line treatments included BTKi in 36 pts (47%), chimeric antigen receptor T-cell (CAR-T) in 10 pts (13%), bendamustine based therapy in 5 (7%), venetoclax in 3 (4%), lenalidomide and/or bortezomib in 3 (4%), and other treatments in 20 (26%). After a median follow-up of 34 mo from 2nd relapse, the estimated median EFS3 was 19 mo (95% CI 12-49), with a 24-month EFS3 of 47% (95% CI 34-58) and 5-year EFS3 of 29% (95% CI 16-43). The estimated 24-mo OS3 was 84% (95% CI 72-91) and 5-year estimated OS3 of 73% (95% CI 57-84). POD24 was associated with inferior EFS2, with estimated median EFS2 9.7 mo (95% CI 5.1-23.6) vs 34.4 mo (95% CI 18.4-45.9) for non-POD24 pts (p=0.0025). POD24 from frontline treatment was also associated with inferior EFS3 among pts with indexed third line therapy with median EFS3 15.6 mo (95% CI 8-37) for POD24 and 49.1 mo (95% CI 11-84) for non-POD24 pts (p=0.04). No significant differences were observed in EFS2 between pts treated with BTKi, with median EFS2 21 mo (95% CI 10-34), compared with other classes of second-line treatment with median EFS2 of 35 mo (95% CI 14-46, p=0.37). Likewise, EFS3 was not significantly different between patients treated with third-line BTKi with estimated median EFS3 of 54 mo (95% CI 11-not reached) compared to CAR-T with estimated median EFS3 of 9 mo (95% CI 3-19), compared to other third line treatments with median EFS3 of 20 mo (95% CI 10-49, p=0.4). Conclusions: We observed a median EFS2 of 26 mo and median EFS3 of 19 mo in a contemporary prospective cohort of pts with RR MCL. We did not observe an association between class of treatment received and EFS2 or EFS3, but observed inferior EFS2 and EFS3 for patients with POD24 following frontline therapy compared with patients with later first relapse highlighting the higher risk nature of this population. The observed OS2 and OS3 outcomes in this prospective cohort exceed historical estimates for relapsed MCL prior to availability of newer therapies, provide context for interpreting single arm trial results, and may inform future clinical trial design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Is There Still a Role for Transplant for Patients with Mantle Cell Lymphoma (MCL) in the Era of CAR-T Cell Therapy?

Opinion statementFor years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton’s tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies.

RITUXIMAB INDUCED LUNG DISEASE IN A MANTLE CELL LYMPHOMA PATIENT RECEIVING MAINTENANCE: CASE PRESENTATION

Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough but no clear evidence of infection. We describe the clinical presentation, management, and response to rechallenge in one mantle cell lymphoma patient who developed R-ILD during maintenance rituximab. Case report 66 years old male with history of mantle cell lymphoma (MCL), who had been treated with RCHOP and underwent autologous stem cell transplantation (ASCT), was diagnosed with relapse 5 years after ASCT. Six courses of rituximab-bendamustine resulted in 2nd complete response and 2-monthly rituximab maintenance was initiated.10 days after 3rd rituximab , he presented with a 1 week history of progressive exertional dyspnea and cough. He was tachypneic and hypoxemic. Thorax HRCT showed peripheral bilateral patchy ground glass opacities and nodular opacities. Bronchoalveolar lavage identified no bacterial,viral or fungal pathogen. With presumptive diagnosis of late R-ILD, methylprednisolone(MP) 1 mg/kg/day was started. In absence of rapidly progressing respiratory failure and fever, the patient was evaulated as non severe R-ILD. Thus, rechallenge with rituximab is being considered due to the risk of relapse of MCL. Discussion: Reported rate of possible R-ILD is <0.03% in over 540,000 patients. Pulmonary complications of rituximab are hypersensitivity pneumonitis, ARDS, interstitial pneumonitis, organizing pneumonia, pulmonary fibrosis, and alveolar haemorrhage. Symptoms of R-ILD are dyspnea, fever, and hypoxemia and HRCT findings include focal alveolar densities, ground glass opacities and alveolar opacification. Time to symptom onset ranges from 1 day to several weeks after 1st infusion with mean mean duration of 3 months. Our patient had received rituximab prior to relapse and developed R-ILD after 9 doses of rituximab for relapse, which is a rare finding. All other causes of potential lung injury had to be meticulously excluded. ILD is a rare but potentially fatal pulmonary toxicity due to rituximab. As the symptoms at presentation are nonspecific, physicians must maintain a high index of suspicion to recognize it early and initiate treatment to avoid severe morbidity and mortality.

TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma.

BackgroundChimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the only CAR T-cell therapy approved by the FDA for MCL. However, development of relapses to BA is recognized with poor patient outcomes. Multiple CAR T-cell therapies have been approved for other lymphomas and the resistance mechanisms have been investigated. However, the mechanisms underlying BA relapse in MCL have not been investigated and whether any previously reported resistance mechanisms apply to BA-relapsed patients with MCL is unknown.MethodsTo interrogate BA resistance mechanisms in MCL, we performed single-cell RNA sequencing on 39 longitudinally collected samples from 15 BA-treated patients, and multiplex cytokine profiling on 80 serial samples from 20 patients.ResultsWe demonstrate that after BA relapse, the proportion of T cells, especially cytotoxic T cells (CTLs), decreased among non-tumor cells, while the proportion of myeloid cells correspondingly increased. TIGIT, LAG3, and CD96 were the predominant checkpoint molecules expressed on exhausted T cells and CTLs; only TIGIT was significantly increased after relapse. CTLs expanded during remission, and then contracted during relapse with upregulated TIGIT expression. Tumor cells also acquired TIGIT expression after relapse, leading to the enhanced interaction of tumor cell TIGIT with monocyte CD155/PVR. In myeloid cells, post-relapse HLA-II expression was reduced relative to pretreatment and during remission. Myeloid-derived suppressor cells (MDSCs) were enriched after relapse with elevated expression of activation markers, including CLU (clusterin) and VCAN (versican). Extracellular chemokines (CCL4, CXCL9, CXCL13), soluble checkpoint inhibitors (sPD-L1, sTIM3, s4-1BB), and soluble receptors (sIL-2R, sTNFRII) were decreased during remission but elevated after relapse.ConclusionsOur data demonstrate that multiple tumor-intrinsic and -extrinsic factors are associated with T-cell suppression and BA relapse. Among these, TIGIT appears to be the central player given its elevated expression after BA relapse in not only CTLs but also MCL cells. The acquisition of TIGIT expression on tumor cells is MCL-specific and has not been reported in other CAR T-treated diseases. Together, our data suggest that co-targeting TIGIT may prevent CAR T relapses and thus promote long-term progression-free survival in MCL patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12943-022-01655-0.

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

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

Ibrutinib improves survival compared with chemotherapy in mantle cell lymphoma with central nervous system relapse

AbstractCentral nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood–brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Deep Neural Networks and Machine Learning Radiomics Modelling for Prediction of Relapse in Mantle Cell Lymphoma.

Simple SummaryMantle cell lymphoma (MCL) is an aggressive lymphoid tumour with a poor prognosis. There exist no routine biomarkers for the early prediction of relapse. Our study compared the potential of radiomics-based machine learning and 3D deep learning models as non-invasive biomarkers to risk-stratify MCL patients, thus promoting precision imaging in clinical oncology. Mantle cell lymphoma (MCL) is a rare lymphoid malignancy with a poor prognosis characterised by frequent relapse and short durations of treatment response. Most patients present with aggressive disease, but there exist indolent subtypes without the need for immediate intervention. The very heterogeneous behaviour of MCL is genetically characterised by the translocation t(11;14)(q13;q32), leading to Cyclin D1 overexpression with distinct clinical and biological characteristics and outcomes. There is still an unfulfilled need for precise MCL prognostication in real-time. Machine learning and deep learning neural networks are rapidly advancing technologies with promising results in numerous fields of application. This study develops and compares the performance of deep learning (DL) algorithms and radiomics-based machine learning (ML) models to predict MCL relapse on baseline CT scans. Five classification algorithms were used, including three deep learning models (3D SEResNet50, 3D DenseNet, and an optimised 3D CNN) and two machine learning models based on K-nearest Neighbor (KNN) and Random Forest (RF). The best performing method, our optimised 3D CNN, predicted MCL relapse with a 70% accuracy, better than the 3D SEResNet50 (62%) and the 3D DenseNet (59%). The second-best performing method was the KNN-based machine learning model (64%) after principal component analysis for improved accuracy. Our optimised CNN developed by ourselves correctly predicted MCL relapse in 70% of the patients on baseline CT imaging. Once prospectively tested in clinical trials with a larger sample size, our proposed 3D deep learning model could facilitate clinical management by precision imaging in MCL.

Exploration of residual disease in stem cell products from mantle cell lymphoma using next-generation sequencing

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become a treatment option for fit patients with mantle cell lymphoma (MCL). However, these patients often relapse within few years, potentially caused by contaminating lymphoma cells within the reinfused stem cell product (SCP). Studies have shown that measurable residual disease, also termed minimal residual disease (MRD), following ASCT predicts shorter survival. Using next-generation sequencing, we explore whether the diagnostic MCL clonotype is present within the infused SCP. MRD was detected in 4/17 of the SCPs, ranging 4–568 clonal cells/100,000 cells. With a median survival of 17 months, 3/4 of patients with MRD+ graft succumbed from MCL relapse versus 2/13 in the MRD– fraction. Patients receiving MRD+ grafts had increased risk of mortality, and thus screening of SCPs may be important for clinical decision-making.

Analysis of Outcomes and Predictors of Response in Patients with Relapsed Mantle Cell Lymphoma Treated with Brexucabtagene Autoleucel

Analysis of Outcomes and Predictors of Response in Patients with Relapsed Mantle Cell Lymphoma Treated with Brexucabtagene Autoleucel

Bispecific CD19-CD20 and CD19-CD22 CAR-T Cells with Glycogen Synthase Kinase (GSK)-3β Inhibitor TWS119 Treatment Have Superior Therapeutic Effects on Mantle Cell Lymphoma

Introduction: Chimeric antigen receptor (CAR) - expressing T cells have shown breakthrough clinical successes to hematological malignancies such as diffuse large B cell lymphoma. Intensive development on CAR-T cell therapies are being developed in many common lymphomas. However, the development of CAR-T cell therapies in mantle cell lymphoma (MCL), a rare lymphoma has lagged behind. So far only CD19 CAR-T has been applied to MCL treatment, and MCL frequent relapse from prior CD19 CAR-T therapy with CD19 antigen loss. Bispecific CAR-T cells target two tumor antigens at once could reduce the risk of relapse. In addition, immune checkpoint blockade such as GSK3β and PD-1inhibition has been successfully used to enhance CAR-T cell therapies. Therefore, we attempt to develop a dual CAR for mantle cell lymphoma with checkpoint blockade.Methods: CD19-CD20 and CD19-CD22 bispecific CAR-T constructs were generated by subcloning the fragments in-frame into the pSFG retroviral vector. The BiCAR-T cells were cultured with/without a small molecule GSK3β inhibitor TWS119. Then, we performed a serial of experiments using CARs. 1, We assayed the CAR expression and cell expansion rates in vitro. 2, We assessed the tumor-killing capacity in vitro using MCL cell lines and primary MCL patient samples. 3, We performed phenotypic analyses by determination of proteins expression profiles of exhaustion markers and stem cell markers by flow cytometry. 4, We examined in vivo antitumor efficacy using preclinical models of MCL cell line-derived xenograft (CDX) .Results: Firstly, we found CD19-CD20 and CD19-CD22 bispecific CAR-T cells showed similar CAR expression levels (55%-72% CAR+ ) and similar expansion rate as single CD19 or CD20 CAR. Secondly, bispecific CAR- T cells potently and specifically lysed tumor cells in vitro, and showed the better killing of MCL tumor than CD19 or CD20 single CAR after challenge with MCL cell lines in vitro. Finally, we also confirmed these effects in CDX mice models derived from MCL cell line, Jeko-1 in vivo. CD19-CD20 and CD19-CD22 bispecific CAR successfully eliminated MCL tumor, showed better antitumor efficacy, and prolonged mouse survival than single CAR treated groups (P < 0.001). We also found that CD19-CD20 and CD19-CD22 bispecific-CAR T cells treated with TWS119 express significantly fewer exhaustion markers, such as PD-1 (P < 0.001), and LAG3 (P < 0.001), and showed better antitumor efficacy than the nontreated control group and single CAR groups in vivo. Furthermore, CAR-T cells expressing bispecific CD19-CD20 and CD19-CD22 CAR with TWS119 treatment had superior anti-MCL activity in vitro. In total, significantly better anti-MCL effects were observed for CD19-CD20 and CD19-CD22 bispecific CARs than single CAR. Their anti-MCL functions were further improved by TWS119 treatment.Conclusion: Altogether, these findings suggest that bispecific CD19-CD20 and CD19-CD22 CAR-T cells are potent for treating MCL relapse and drug resistant patients. In addition, bispecific CD19-CD20 and CD19-CD22 CAR-T cells with TWS119 treatment will further bring up the full power of CARs. These data support the therapeutic potential of bispecific CARs in patients with MCL. DisclosuresWang: Newbridge Pharmaceuticals: Honoraria; Moffit Cancer Center: Honoraria; BGICS: Honoraria; Bayer Healthcare: Consultancy; Hebei Cancer Prevention Federation: Honoraria; Clinical Care Options: Honoraria; Lilly: Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Mumbai Hematology Group: Honoraria; Epizyme: Consultancy, Honoraria; Dava Oncology: Honoraria; Chinese Medical Association: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Molecular Templates: Research Funding; Imedex: Honoraria; Physicians Education Resources (PER): Honoraria; VelosBio: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Genentech: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; CStone: Consultancy; Scripps: Honoraria; OMI: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding; Oncternal: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; CAHON: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding.

Noninvasive Monitoring of Mantle Cell Lymphoma by Immunoglobulin Gene Next-Generation Sequencing in a Phase 2 Study of Sequential Chemoradioimmunotherapy Followed by Autologous Stem-Cell Rescue

BackgroundMinimal residual disease (MRD) monitoring has been used to identify early molecular relapse and predict clinical relapse in mantle cell lymphoma (MCL). Few published data exist in MCL on the performance of next-generation sequencing–based assay of immunoglobulin gene rearrangements for MRD assessment. Patients and MethodsIn a prospective clinical trial (NCT01484093) with intensive induction chemotherapy and autologous stem-cell transplantation, posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with an earlier version of the Adaptive Biotechnologies MRD assay. ResultsOf the 7 patients whose disease remained in remission, the MRD test remained negative in 5 (71%). Of the 9 patients who experienced relapse, the MRD test was positive at least 3 months before relapse in 6 patients (67%) and positive at the time of relapse in 1 patient (11%). All patients with at least 2 positive MRD tests experienced relapse. ConclusionThe next-generation sequencing–based MRD assay identified early molecular relapse, and we observed more sensitivity in the cellular (circulating leukocytes) versus acellular (plasma cell-free DNA) compartment. This observation may be due to availability of tumor target or a limitation of the assay.

Safety and Preliminary Efficacy in Patients with Relapsed/Refractory Mantle Cell Lymphoma Receiving Lisocabtagene Maraleucel in Transcend NHL 001

Safety and Preliminary Efficacy in Patients with Relapsed/Refractory Mantle Cell Lymphoma Receiving Lisocabtagene Maraleucel in Transcend NHL 001

Recurrent mantle cell lymphoma in the uterine cervix: a case report

BackgroundMantle cell lymphoma is one of several subtypes of non-Hodgkin lymphoma. Cervical relapse of non-Hodgkin lymphoma is a very rare condition that has a variable and nonspecific presentation and may resemble other neoplastic or inflammatory conditions.Case presentationOur patient was a 58-year-old Caucasian woman who experienced relapse of mantle cell lymphoma with cervical localization. She complained of postmenopausal vaginal bleeding, bladder pressure, and rapid growth of a cervical lesion. An irregular tumor mass of the cervix was visualized during gynecological examination, with findings highly suggestive of locally advanced cervical cancer. Surprisingly, the biopsies showed an extra nodal relapse of mantle cell lymphoma in the cervix. The rarity of this presentation and the scarcity of clinical studies make this type of recurrence very aggressive and difficult to treat.ConclusionsObtaining a definitive histological diagnosis by biopsy or surgical resection and starting appropriate therapy are essential for recovery and treatment of these patients, even if the prognosis is poor.

Rapidly Progressive Dementia as a Manifestation of Relapse in Mantle Cell Lymphoma: Experience in Diagnosis and Treatment

Rapidly progressive dementia is an entity that has a multiple and heterogeneous etiology. It is characterized by the alteration of two or more cognitive domains in a period of less than 1 to 2 years. The involvement of the central nervous system attributed to mantle cell lymphoma is rare with a poor prognosis in the short term and mainly debuts in the late stages of the disease as a relapse. A 61-year-old male with a history of mantle cell lymphoma who presents a relapse of the central nervous system, given by a clinical course compatible with a rapidly progressive dementia and which is confirmed by flow cytometry studies in cerebrospinal fluid, which show a 53 , 8% of mature lymphoid population: CD45, CD19, CD20, HLA-DR, BCL2. It presents an adequate response to management with a tyrosine kinase inhibitor (Ibrutinib), resolving clinical symptoms and imaging findings.