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PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

Treatment with covalent Bruton tyrosine kinase inhibitors (BTKi) represents an important advance in the management of relapsed or refractory mantle cell lymphoma, but these treatments are not curative and many patients ultimately relapse. Pirtobrutinib, a highly selective, non covalent (reversible) BTKi, inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients with poor prognosis B-cell malignancies following prior therapy, including covalent BTKi. This phase III, head-to-head, randomized study (NCT04662255) will evaluate whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naive mantle cell lymphoma.MCL is an uncommon type of B-cell non-Hodgkin lymphoma, a cancer of the immune system. It starts in the part of the lymph node called the mantle zone, where unusual B cells gather and crowd out healthy B cells in the lymph nodes, spleen, bone marrow and/or other organs. MCL can be caused by inappropriate cell signaling. BTK has been identified as a key driver of unusual cell signaling and blocking BTK has been shown to help kill the cancer cells. Covalent (not reversible) BTK inhibitors have advanced the treatment of MCL, but the effectiveness of these treatments is limited by side effects and treatment resistance. Pirtobrutinib, a non covalent (reversible) BTK inhibitor, has been shown to have manageable side effects and to be effective in patients with MCL following previous treatment, including treatment with covalent BTK inhibitors. The BRUIN MCL-321 study compares pirtobrutinib with three currently approved covalent BTK inhibitors (ibrutinib, acalabrutinib or zanubrutinib), in patients with MCL who have never received any form of BTK inhibitor. This trial will look at how many people live with the disease without it getting worse. Like other cancer treatments, pirtobrutinib may affect both healthy cells and tumor cells, which can result in side effects that will also be looked at in this study. This study is active and currently recruiting new patients who have received at least one previous therapy for MCL and have never been treated with a BTK inhibitor.

Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed.Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group.Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

PURPOSE Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent (c) BTKi pre-treated mantle cell lymphoma (MCL), a population with poor prognosis. PATIENTS AND METHODS Patients with cBTKi pre-treated relapsed/refractory MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 trial (BRUIN, NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR) and safety. RESULTS Median patient age was 70 years (range, 46-87), median prior lines of therapy 3 (range, 1-8), 82.2% had discontinued a prior cBTKi due to disease progression, and 77.8% had intermediate or high risk sMIPI score. The ORR was 57.8% (95% CI, 46.9-68.1), including 20.0% complete responses (n=18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5-not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n=164), the most common treatment-emergent adverse events (TEAE) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAE of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib due to a treatment-related AE. CONCLUSION Pirtobrutinib is a first-in-class novel non-covalent (reversible) BTKi, and the first BTKi of any kind to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated relapsed/refractory MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation due to toxicity.

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell-lymphoma patient cohort from five centers in Germany and the United States (Germany, N=66; US, N=106, Total, N=172), we demonstrate that wide-spectrum antibiotics treatment (‘high-risk antibiotics’) prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely confounded by an increased pre-treatment tumor burden and systemic inflammation in high-risk antibiotics-pre-treated patients. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were uncovered between pre-CAR-T-infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-months survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine-learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also associating with pre-infusion peripheral T cell levels in these patients. Collectively, we uncover conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.

The field of mantle cell lymphoma (MCL) has witnessed remarkable progress due to relentless advances in molecular pathogenesis, prognostication, and newer treatments. MCL consists of a spectrum of clinical subtypes. Rarely, atypical cyclin D1-negative MCL and in situ MCL neoplasia are identified. Prognostication of MCL is further refined by identifying somatic mutations (such as TP53, NSD2, KMT2D), methylation status, chromatin organization pattern, SOX-11 expression, minimal residual disease (MRD), and genomic clusters. Lymphoid tissue microenvironment studies demonstrated the role of B-cell receptor signaling, nuclear factor kappa B (NF-kB), colony-stimulating factor (CSF)-1, the CD70-SOX-11 axis. Molecular mechanism of resistance, mutation dynamics, and pathogenic pathways (B-cell receptor (BCR), oxidative phosphorylation, and MYC) were identified in mediating resistance to various treatments (bruton tyrosine kinase (BTK) inhibitors [ibrutinib, acalabrutinib]. Treatment options range from conventional chemoimmunotherapy and stem cell transplantation (SCT) to targeted therapies against BTK (covalent and noncovalent), Bcl2, ROR1, cellular therapy such as anti-CD19 chimeric antigen receptor therapy (CAR-T), and most recently bispecific antibodies against CD19 and CD20. MCL patients frequently relapse. Complex pathogenesis and the management of patients with progression after treatment with BTK/Bcl2 inhibitors and CAR-T (triple-resistant MCL) remain a challenge. Next-generation clinical trials incorporating newer agents and concurrent translational and molecular investigations are ongoing.

Epstein-Barr virus–positive (EBV-positive) B-cell lymphomas are common in immunocompromised patients and remain an unmet medical need. Here we report that MDM2 inhibitors (MDM2is) navtemadlin and idasanutlin have potent in vivo activity in EBV-positive B-cell lymphoma established in immunocompromised mice. Tumor regression was observed in all 5 EBV-positive xenograft–associated B-cell lymphomas treated with navtemadlin or idasanutlin. Molecular characterization showed that treatment with MDM2is resulted in activation of p53 pathways and downregulation of cell cycle effectors in human lymphoma cell lines that were either EBV-positive or had undetectable expression of BCL6, a transcriptional inhibitor of the TP53 gene. Moreover, treatment with navtemadlin resulted in tumor regression and prevented systemic dissemination of EBV-positive lymphoma derived from 2 juvenile patients with posttransplant lymphoproliferative diseases, including 1 whose tumor was resistant to virus-specific T-cell therapy. These results provide proof-of-concept for targeted therapy of EBV-positive lymphoma with MDM2is and the feasibility of using EBV infection or loss of BCL6 expression to identify responders to MDM2is.

PURPOSE Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years). METHODS We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial ( NCT01880567 ). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed. RESULTS The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response. CONCLUSION IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

B cell malignancies pose challenges due to therapeutic resistance and repeated relapse. Advances in adoptive cellular therapies including chimeric antigen receptor (CAR)-T cells have the potential to transform the treatment landscape in hematological and solid tumor cancers. Improvements in constructs of CAR-T have improved specificity in targeting malignant cells. Multiple clinical trials have demonstrated the efficacy of CAR-T and other cellular treatments. In spite of advances in cellular therapies, hurdles in managing toxicities and lingering resistance remain. This review aims to summarize current innovations in adoptive cellular therapies and introduces future paths of discovery that will enhance these therapies in the era of precision oncology.

Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but many patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type and C481-mutated BTK with equal low nM potency.Determine whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naïve MCL.BRUIN MCL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated, BTKi-naïve MCL. Approximately 500 patients will be randomized 1:1. Randomization will be stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2).Global; community hospitals, academic medical centers.Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL who received ≥ 1 prior line of systemic therapy for MCL that did not include a prior BTKi. Patients must have measurable disease per Lugano criteria and must have progressed on or relapsed following the most recent line of therapy prior to study enrollment. Key exclusion criteria include a history of current or prior CNS involvement, significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of randomization, and allogeneic stem cell transplant (SCT), autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization.Pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy.The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee, with the goal of demonstrating the superiority of pirtobrutinib over the investigator's choice of covalent BTKi. Secondary endpoints include overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04662255).Trial in Progress.Trial in Progress.

Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but most patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild-type and C481-mutated BTK with equal low nM potency.To evaluate pirtobrutinib safety and efficacy in patients with MCL.BRUIN is an ongoing multicenter phase 1/2 study (NCT03740529) of pirtobrutinib monotherapy.Global; community hospitals, academic medical centers.Patients with advanced B-cell malignancies.Oral pirtobrutinib, phase 1 dose-escalated in a standard 3+3 design, phase 2 continuous therapy, 28-day cycles.The primary phase 1 objective was to determine the recommended phase 2 dose (RP2D) and the primary phase 2 objective was overall response rate (ORR); secondary objectives included duration of response, progression-free survival, overall survival, safety/tolerability, and pharmacokinetics.As of 27 September 2020, 323 patients (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL) were treated on 7 dose levels (25-300mg QD). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in10% of patients. The most common adverse event of grade ≥3 was neutropenia (10%). Five (1%) patients discontinued due to treatment-related adverse events. 52 prior BTKi treated MCL patients were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%]), 11 PD [21%] and 5 [10%] discontinued prior to first response assessment). Median follow-up was 6 months (0.7-18.3+). Responses were observed in 9/14 patients (64%) with prior autologous or allogeneic stem cell transplant, and 2/2 with prior CAR-T cell therapy.Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new patients with MCL and an additional 10 months since the prior data-cut will be presented.

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma in which immunochemotherapy, with or without high-dose therapy, and autologous stem cell transplantation remain standard frontline therapies. Despite their clear efficacy, patients inevitably relapse and require subsequent therapy. In this review, we discuss the key therapeutic approaches in the management of relapsed MCL, covering in depth the data supporting the use of covalent Bruton tyrosine kinase (BTK) inhibitors at first or subsequent relapse. We describe the outcomes of patients progressing through BTK inhibitors and discuss the mechanisms of covalent BTKi resistance and treatment options after covalent treatment with BTKi. Options in this setting may depend on treatment availability, patient’s and physician’s preference, and the patient’s age and comorbidity status. We discuss the rapid recent development of anti-CD19 chimeric antigen receptor T-cell therapy, as well as the utility of allogenic stem cell transplantation and novel therapies, such as noncovalent, reversible BTK inhibitors; ROR1 antibody drug conjugates; and bispecific antibodies.