Our previous study has suggested a favorable progression-free survival (PFS) with zanubrutinib over orelabrutinib in patients with relapsed or refractory mantle cell lymphoma (R/R MCL). Here, we conducted an updated analysis to indirectly compare the long-term efficacy between zanubrutinib and orelabrutinib in patients with R/R MCL.

Individual patient data from the zanubrutinib study were adjusted to match the patient population profile of the orelabrutinib study. An unanchored matching-adjusted indirect comparison (MAIC) was performed to adjust for effect modifiers and prognostic variables. The efficacy outcomes included investigator-assessed PFS, overall survival (OS), and overall response rate (ORR). Response evaluations were only computed tomography (CT)-based assessments in the orelabrutinib study, while positron emission tomography (PET)- and CT-based assessment were both performed in the zanubrutinib study. The comparison of PFS assessed by CT between zanubrutinib and orelabrutinib was the primary result.

After matching, the baseline characteristics were balanced between zanubrutinib and orelabrutinib, with an effective sample size of 70 in the zanubrutinib study. PFS assessed by CT was significantly longer in the zanubrutinib study vs. the orelabrutinib study (median PFS, not reached vs. 22.0 months; hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.34-0.86; P = 0.009). With longer follow-up, OS continued to trend favorably for zanubrutinib, with OS rate at 24 months numerically higher (83.7% vs. 74.3%); no statistical difference was observed (HR 0.68, 95% CI 0.36-1.27; P = 0.223). ORR was numerically higher in the zanubrutinib study (85.5% vs. 82.1%; odds ratio 1.28, 95% CI 0.56-2.94; P = 0.556).

MAIC results demonstrated that zanubrutinib had significantly longer PFS compared with orelabrutinib in the treatment of patients with R/R MCL.

Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis and limited treatment options. We respectively reviewed 38 patients with R/R PCNSL treated with zanubrutinib-based regimens in our center. The overall response rate, complete response rate and disease control rate were 76.3%, 47.4% and 92.1%, respectively. The median progression-free survival (PFS) was 31.0 months, the median overall survival (OS) was not reached. Unitivariate analysis by Cox's proportional hazards model revealed that overall response (vs. no response, HR = 0.18, 95%CI:0.07,0.48, p = 0.001), long duration of zanubrutinib (≥6months vs 2-5 months, HR = 0.20, 95%CI:0.06,0.63, p = 0.006) were independent factors for prolonged PFS. The log-rank analysis indicated a prolongation of PFS among patients exhibiting a higher Tumor mutational burden (TMB, ≥14.75muts/Mb) following zanubrutinib-based treatment (p = 0.016). Our data showed promising efficacy with tolerable safety of zanubrutinib-based therapies in patients with R/R PCNSL. Long duration of zanubrutinib may be associated with prolonged PFS.

MCL remains incurable, and patients who relapse post BTK inhibitors have poor outcomes. BsAbs and CAR T cell therapy are novel strategies to treat patients with R/R MCL. These therapies exhibit favorable outcomes and side effect profiles in a previously dismal space. This review looks to detail the current data available for BsAbs and CAR T cell therapy in R/R MCL, and how are current treatment paradigm is shifting to incorporate these novel agents.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

Mantle cell lymphoma (MCL) is a rare, incurable B-cell non-Hodgkin lymphoma and over half of patients affected are older adults (≥65 years of age). New targeted treatments for MCL have emerged over the past two decades. Nonetheless, MCL-specific death rates for older adults remain elevated compared with younger adults, demonstrating the challenge of treating this population. The older adult population is at risk for overtreatment or undertreatment. Clinicians must be mindful of how to optimize the holistic care of older adults receiving treatment for MCL. Evaluating fitness through a geriatric assessment (GA) is an important step when choosing therapy. The treatment armamentarium includes both chemotherapy and non-chemotherapy options and toxicities must be considered in the context of the patient's GA and proactively managed. Herein, the treatment of MCL in older adults is reviewed and strategies for choosing treatment are offered to assist in treatment decision-making for this challenging population.

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma, often characterized by a pattern of continued relapse after front-line chemoimmunotherapy. Although patients are usually able to regain durable disease control with covalent Bruton's tyrosine kinase inhibitors (cBTKi) at first relapse, it is now appreciated that such responses are often not sustained and the management of such patients represents a significant area of unmet need. There is an imperative to better understand resistance mechanisms and identify high-risk subsets of patients for whom cBTKi responses may be particularly short. Allogeneic stem cell transplant has an established role in appropriate candidates; however, contemporary consensus is to preferentially offer chimeric antigen receptor (CAR) T-cell therapy. In this Review, we consider the available data on both existing and emerging treatment options, including non-covalent BTK inhibitors, bispecific antibodies, antibody-drug conjugates and Bcl-2 inhibitors, and propose a treatment strategy, prioritizing clinical trials where available.

Mantle cell lymphoma is still a lymphoma subtype with productive clinical research. Recent published data on Bruton kinase inhibitors have changed the management of patients.

This review summarizes the most important trials evaluating the different treatment options in mantle cell lymphoma in the frontline and the relapsed/refractory setting in young and older patients, focusing on the role of Bruton kinase inhibitors in improving disease outcome and omitting consolidative autologous stem cell transplantation.

Following the results of the TRIANGLE trial, the addition of ibrutinib to the induction and maintenance treatment should be considered and the omission of autologous stem cell transplantation is questionable in all patients. Minimal residual disease is a promising biomarker that would dictate our decision making especially in the maintenance setting. CAR-T cells remain the best option in the relapsed/refractory patients after Brutonkinase inhibitors.

Advancements in mantle cell lymphoma (MCL) have illuminated the disease's molecular diversity, leading to a wide variation in the outcomes observed in MCL. Current prognostic risk scores are continuously revised to incorporate new updates in the mechanistic or biologic understanding of MCL. Nevertheless, key high-risk features of MCL associated with rapid disease progression and poor survival, such as TP53 mutations, complex karyotypes, and blastoid or pleomorphic morphologies, remain absent from available prognostic tools. The greater accessibility of genomic technologies, such as next-generation sequencing (NGS), has enabled clinicians to identify specific genetic alterations that serve as prognostic signals and disease monitoring parameters, cultivating accurate risk profiling that is illustrative of MCL heterogeneity. Through an increased understanding of distinct MCL behaviors, novel therapies that mechanistically target disease biology, including Bruton's tyrosine kinase inhibitors, BCL-2 inhibitors, ROR1 inhibitors, and bispecific T-cell engagers, have broadened the treatment armamentarium for relapsed/refractory MCL cases. These interventions, in addition to chemoimmunotherapy and autologous stem cell transplantation mainstays, confer the individualization of treatment and improved survival outcomes. Further exploration of the considerable biological heterogeneity of MCL can enhance knowledge, management, and the treatment of this rare lymphoma subtype.

Significant progress in determining the molecular origins and resistance mechanisms of mantle cell lymphoma (MCL) has improved our understanding of the disease's clinical diversity. These factors greatly impact the prognosis of patients with MCL. Given the dynamic alterations in MCL clones and disease evolution, it is crucial to recognize high-risk prognostic factors at diagnosis and relapse. Clinical factors include a high MCL International Prognostic Index score with a high Ki-67 proliferation index, early disease progression within 24 months of first-line treatment, >3 previous lines of therapy at relapse, and an aggressive (blastoid or pleomorphic) histology. Molecular aberrations include dysregulated cyclin D1, an aberrant SOX11-CD70 axis, upregulated Musashi-2, MYC rearrangement, metabolic reprogramming, and epigenetic changes. Other factors that contribute to high-risk MCL include an immune-depleted microenvironment and clone adaptability with complex chromosomal anomalies and somatic mutations in TP53, NSD2, CCND1, CDKN2A, BIRC3, SP140, KMT2D, NFkBIE, SMARCA4, and NOTCH2. Ultra-high-risk MCL is indicated by the coexistence of multiple high-risk prognostic factors in the relapse setting and can portend very short progression-free survival. As MCL treatments advance toward cellular therapies, resistance to anti-CD19 chimeric antigen receptor T-cell therapy is also observed. These findings necessitate revisiting the prognostic impact of high-risk factors, current management strategies, new bi- and trispecific T-cell engagers, combination therapies, novel therapeutic targets, and next-generation clinical trials for patients with high-risk MCL. This article provides a comprehensive update on recognizing and managing high-risk MCL and encompass current practices and future directions.

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that is clinically characterized by its heterogeneous behavior, with courses ranging from indolent to highly aggressive cases with limited prognosis. Targeted treatment alternatives in first-line and relapse settings are more and more shaping the therapeutic landscape of MCL. The development and implementation of new targeted and immunotherapeutic approaches have already improved outcomes for patients with MCL with refractory or relapsed disease. However, long-term prognosis is still limited, and patients with relapsed/refractory (R/R) disease, especially those failing Bruton tyrosine kinase (BTK) inhibitor treatment, usually have a dismal outcome. This review summarizes the current and emerging treatment options for R/R MCL, focusing on the implementation of combined targeted treatment strategies such as BTK inhibitors and BCL2 inhibitors, as well as immune-therapeutic approaches including chimeric antigen receptor T cells and bispecific antibodies.

Zanubrutinib has been demonstrated to have significant response rates and promising survival data in clinical trials. However, real-world adverse events still need to be ameliorated to facilitate rational clinical drug use.

Adverse incident reports from October 2019 to March 2024 were extracted from the FDA's Adverse Event Reporting System (FAERS) database. Zanubrutinib-related adverse events were obtained after data cleaning and analysis with SAS 9.4. Four methods were utilized to calculate disproportionality and evaluate AE signals of zanubrutinib.

At the system organ class (SOC) level, one SOC met the criteria of the four algorithms. At the preferred term (PT) level, most AEs are those already included in the product monograph, and no unexpected safety signals have been identified. Furthermore, the average time to onset of adverse events was 134.8 days, with a median time of 16.5 days. Adverse events occurred in 57.96% of cases within 1 month.

Compared to the adverse events reported in clinical trials and drug labels, no unreported signals were identified. This finding will provide clinicians with a more comprehensive understanding of the clinical application of zanubrutinib and provide valuable insights for future investigations.

The combination of ibrutinib and venetoclax leverages complementary mechanisms of action and has shown promising clinical activity in mantle cell lymphoma (MCL). This study evaluated the efficacy and safety of ibrutinib-venetoclax compared with ibrutinib-placebo in patients with relapsed or refractory MCL.

SYMPATICO is a multicentre, randomised, double-blind, placebo-controlled, phase 3 study performed at 84 hospitals in Europe, North America, and Asia-Pacific. Eligible patients were adults (aged ≥18 years) with pathologically confirmed relapsed or refractory MCL after one to five previous lines of therapy and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients were randomly assigned (1:1) to receive oral ibrutinib 560 mg once daily concurrently with oral venetoclax (5-week ramp-up to 400 mg once daily) or placebo for 2 years, then single-agent ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. Randomisation and treatment assignment occurred via interactive response technology using a stratified permuted block scheme (block sizes of 2 and 4) with stratification by ECOG performance status, previous lines of therapy, and tumour lysis syndrome risk category. Patients and investigators were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03112174, and is closed to enrolment.

Between April 26, 2018, and Aug 28, 2019, 267 patients were enrolled and randomly assigned; 134 to the ibrutinib-venetoclax group and 133 to the ibrutinib-placebo group. 211 (79%) of 267 patients were male and 56 (21%) were female. With a median follow-up of 51·2 months (IQR 48·2-55·3), median progression-free survival was 31·9 months (95% CI 22·8-47·0) in the ibrutinib-venetoclax group and 22·1 months (16·5-29·5) in the ibrutinib-placebo group (hazard ratio 0·65 [95% CI 0·47-0·88]; p=0·0052). The most common grade 3-4 adverse events were neutropenia (42 [31%] of 134 patients in the ibrutinib-venetoclax group vs 14 [11%] of 132 patients in the ibrutinib-placebo group), thrombocytopenia (17 [13%] vs ten [8%]), and pneumonia (16 [12%] vs 14 [11%]). Serious adverse events occurred in 81 (60%) of 134 patients in the ibrutinib-venetoclax group and in 79 (60%) of 132 patients in the ibrutinib-placebo group. Treatment-related deaths occurred in three (2%) of 134 patients in the ibrutinib-venetoclax group (n=1 COVID-19 infection, n=1 cardiac arrest, and n=1 respiratory failure) and in two (2%) of 132 patients in the ibrutinib-placebo group (n=1 cardiac failure and n=1 COVID-19-related pneumonia).

The combination of ibrutinib-venetoclax significantly improved progression-free survival compared with ibrutinib-placebo in patients with relapsed or refractory MCL. The safety profile was consistent with known safety profiles of the individual drugs. These findings suggest a positive benefit-risk profile for ibrutinib-venetoclax treatment.

Pharmacyclics (an AbbVie Company) and Janssen Research and Development.

Bruton tyrosine kinase (BTK), the primary target of BTK inhibitors, is a key enzyme in the proliferation and survival pathway of neoplastic B-cells. BTK inhibitors are approved in many hematologic malignancies: chronic lymphocytic leukaemia, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinaemia and follicular lymphoma. Second-generation BTK inhibitors display high target selectivity thus resulting in a reduction in off-target and off-tissue effects, better therapeutic index and improved tolerability. This paper summarizes the mechanisms of action of first and second generation BTK inhibitors and elucidates results in any disease setting, with a precise focus on zanubrutinib.

TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. We conducted a multicenter, phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated patients with MCL with a TP53 mutation. Patients initially received 160 mg zanubrutinib twice daily and obinutuzumab. Obinutuzumab at a dose of 1000 mg was given on cycle 1 day 1, 8, and 15, and on day 1 of cycles 2 to 8. After 2 cycles, venetoclax was added with weekly dose ramp-up to 400 mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease (uMRD) using an immunosequencing assay, treatment was discontinued. The primary end point was met if ≥11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with a TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD at a sensitivity level of 1 × 10-5 and uMRD at a sensitivity level of 1 × 10-6 at cycle 13 was 95% (18/19) and 84% (16/19), respectively. With a median follow-up of 28.2 months, the 2-year progression-free, disease-specific, and overall survival were 72%, 91%, and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy end point in TP53-mutant MCL. These data support its use and ongoing evaluation. This trial was registered at www.ClinicalTrials.gov as #NCT03824483.

Double-expressor lymphoma (DEL) has a poorer prognosis than other subtypes of diffuse large B-cell lymphoma (DLBCL). This study is a multicenter, prospective, single-arm, phase 2 clinical study initiated by investigators to evaluate the efficacy and safety of combined zanubrutinib with R-CHOP, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with DEL (stage II or more), as well as to explore factors related to efficacy preliminarily.

From November 2020 to July 2022, 48 newly diagnosed patients were enrolled. All patients received twice-daily oral zanubrutinib (160 mg) for 6 months and standardized R-CHOP regimen for six to eight cycles.

The objective response rate (ORR) was 89.6%, with a complete response rate (CRR) of 83.3%. The median follow-up was 29.3 months. The median progression-free survival (PFS) and overall survival (OS) were not reached. The PFS and OS were 81.25% and 93.75% at 2 years, respectively. Grade ≥3 adverse events (AEs) were reported in 23 of 48 (47.9%) patients. Next-generation sequencing (NGS) results of 33 patients showed that TP53, MYD88, and PIM1 were the most common mutated gene. Multivariate analysis revealed that BCL-6 gene rearrangement was an adverse prognostic factor for both PFS (hazard ratio [HR], 0.247; 95% confidence article [CI], 0.068-0.9; p = .034) and OS (HR, 0.057; 95% CI, 0.006-0.591; p = .016), whereas the number of extranodal involvements also significantly influenced OS (HR, 15.12; 95% CI, 1.07-213.65; p = .044).

Zanubrutinib in combination with R-CHOP is an effective option for DEL patients, and the toxicity of zanubrutinib is entirely acceptable for patients.

B-cell depleting therapy (BCDT) has revolutionised the treatment of B-cell malignancies and autoimmune diseases by targeting specific B-cell surface antigens, receptors, ligands, and signalling pathways. This narrative review explores the mechanisms, applications, and complications of BCDT, focusing on the therapeutic advancements since the introduction of rituximab in 1997. Various monoclonal antibodies and kinase inhibitors are examined for their roles in depleting B cells through antibody-dependent and independent mechanisms. The off-target effects, such as hypogammaglobulinemia, infections, and cytokine release syndrome, are discussed, emphasising the need for immunologists to identify and help manage these complications. The increasing prevalence of BCDT has necessitated the involvement of clinical immunologists in addressing treatment-associated immunological abnormalities, including persistent hypogammaglobulinemia and neutropenia. We highlight the importance of considering underlying inborn errors of immunity (IEI) in patients presenting with these complications. Furthermore, we discuss the impact of BCDT on other immune cell populations and the challenges in predicting and managing long-term immunological sequelae. The potential for novel BCDT agents targeting the BAFF/APRIL-TACI/BCMA axis and B-cell receptor signalling pathways to treat autoimmune disorders is also explored, underscoring the rapidly evolving landscape of B-cell targeted therapies.

Mantle cell lymphoma (MCL) is a clinically heterogeneous B-cell neoplasm with unique clinicopathological features, accounting for 5% of all non-Hodgkin lymphoma. Although for many chemoimmunotherapy can lead to durable remissions, those with poor baseline prognostic factors, namely blastoid morphology, TP53 aberrancy and Ki67 >30%, will have less durable responses to conventional therapies. With this in mind, clinical trials have focused on novel targeted therapies to improve outcomes. This review details the recent advances in the understanding of MCL biology and outlines the recommended diagnostic strategies and evidence-based approaches to treatment.

Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and Results: Alisertib, an AK-A inhibitor, has anti-tumor activity in relapsed/refractory (r/r) MCL patients. We evaluated alisertib plus ibrutinib in MCL to abrogate ibrutinib resistance. Alisertib plus ibrutinib was therapeutically synergistic on both Granta-519 insensitive to ibrutinib and JeKo-1 cells sensitive to ibrutinib. Alisertib decreased PI-3K, BTK, p38, HCK, and RSK kinases, indicative of its multipotent effect on cellular proliferation and growth. A mouse xenograft model of Granta-519 demonstrated that alisertib plus ibrutinib had a comparable anti-tumor response to ibrutinib plus rituximab. However, alisertib plus ibrutinib plus rituximab demonstrated significantly stronger tumor growth inhibition than the doublets. Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL.

Historically considered a lymphoma with limited treatment options and poor outcomes, the treatment landscape in mantle cell lymphoma (MCL) has evolved remarkably in the last decade. Chemoimmunotherapy (CIT) remains the primary frontline treatment for most patients with MCL, typically with an intensive approach in younger and fit patients. The role of consolidative autologous stem cell transplantation remains controversial, with recent data further questioning its benefit. Novel agents have shown promising results in recent frontline clinical trials and challenge the current paradigm in MCL, particularly in high-risk patients who generally have poor outcomes with CIT. Risk stratification is key to incorporating novel agents in the frontline treatment of MCL, identifying patients who do not benefit from or could be spared CIT, guiding treatment intensity and duration, and improving overall outcomes, including safety and quality of life. The MCL International Prognostic Index and Ki-67 play an important role in identifying patients with high-risk MCL. TP53 aberrations, particularly mutations, currently identify patients with the highest risk, limited benefit from CIT, and greatest need for novel therapies. Other genetic aberrations and biological clusters are being identified but currently have limited clinical utility.

Mantle cell lymphoma (MCL) is a heterogenous disease that is one of the most challenging blood cancers due to its poor prognosis, high risk of relapse and drug resistance. Recent researches have brought significant changes in MCL patients outcomes and new clinical. Bruton's Tyrosine Kinase (BTK), a key kinase in the B-cell antigen receptor (BCR) signaling pathway, is a clinical research hot spot and plays a major role in the survival and spread of malignant B cells. The first generation of BTK inhibitors, led by ibrutinib, have shown promising results in targeted treatment. Meanwhile, several inhibitors have entered clinical studies and demonstrated outstanding therapeutic activity in clinical trials for MCL, indicating a good prospect for development. Despite these encouraging findings, the duration of response is limited, and resistance to BTK inhibitors develops in a portion of individuals. This review summarizes the pathogenesis of MCL and targeted BTK inhibitors and provides an overview of the mutations that can lead to resistance to BTK inhibitors. The purpose of this article is to review the literature describing these selective therapies and provides perspectives for their further development.

The B cell receptor (BCR) signalling pathway has an integral role in the pathogenesis of many B cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma, diffuse large B cell lymphoma and Waldenström macroglobulinaemia. Bruton tyrosine kinase (BTK) is a key node mediating signal transduction downstream of the BCR. The advent of BTK inhibitors has revolutionized the treatment landscape of B cell malignancies, with these agents often replacing highly intensive and toxic chemoimmunotherapy regimens as the standard of care. In this Review, we discuss the pivotal trials that have led to the approval of various covalent BTK inhibitors, the current treatment indications for these agents and mechanisms of resistance. In addition, we discuss novel BTK-targeted therapies, including covalent, as well as non-covalent, BTK inhibitors, BTK degraders and combination doublet and triplet regimens, to provide insights on the best current treatment paradigms in the frontline setting and at disease relapse.

Lymphoma is the sixth most prevalent cancer globally. Non-Hodgkin's lymphomas are the majority group of lymphomas, with B cells accounting for approximately 95% of these lymphomas. A key feature of B-cell lymphoma is the functional perturbations of essential biological pathways caused by genetic aberrations. These lead to atypical gene expression, providing cells with a selective growth advantage. Molecular analysis reveals that each lymphoma subtype has unique molecular mutations, which pose challenges in disease management and treatment. Substantial efforts over the last decade have led to the integration of this information into clinical applications, resulting in crucial insights into clinical diagnosis and targeted therapies. However, with the growing need for more effective medication development, we anticipate a deeper understanding of signaling pathways and their interactions to emerge. This review aims to demonstrate how the BCR, specific signaling pathways like PI3K/AKT/mTOR, NF-kB, and JAK/STAT are diverse in common types of B-cell lymphoma. Furthermore, it offers a detailed examination of each pathway and a synopsis of the approved or in-development targeted therapies. In conclusion, finding the activated signaling pathways is crucial for developing effective treatment plans to improve the prognosis of patients with relapsed or refractory lymphoma. Trial Registration: ClinicalTrials.gov identifier: NCT02180724, NCT02029443, NCT02477696, NCT03836261, NCT02343120, NCT04440059, NCT01882803, NCT01258998, NCT01742988, NCT02055820, NCT02285062, NCT01855750, NCT03422679, NCT01897571.

Mantle cell lymphoma (MCL) is a challenging B-cell non-Hodgkin lymphoma with a poor prognosis and frequent relapses. While treatment advancements such as rituximab and Bruton tyrosine kinase inhibitors (BTKi) like ibrutinib have improved outcomes, novel treatments are continually sought. Zanubrutinib, a second-generation BTKi, promises reduced side effects due to its high selectivity and reduced off-target inhibition. This paper presents a novel case of simultaneous radiotherapy and zanubrutinib treatment in a patient with MCL. We describe a 76-year-old female with a history of MCL treated with zanubrutinib. The patient presented with a metastatic lesion in the parotid gland, which emerged from a previously treated spinocellular carcinoma. She underwent parotidectomy followed by adjuvant radiotherapy while continuing zanubrutinib. The combination was well-tolerated with minimal side effects, including grade 1 dermatitis and grade 2 mucositis, neither of which progressed significantly. Hematological parameters monitored during treatment showed delayed, transient lymphopenia and neutropenia, which resolved post-therapy. No dose adjustment was necessary. The safety and efficacy of concurrent radiotherapy and zanubrutinib treatment in MCL patients are largely unexplored in clinical literature. This case represents the first documented instance of concurrent radiotherapy and zanubrutinib treatment. Our case suggests a favorable safety profile with manageable adverse effects, contrasting with concerns about increased toxicity with other tyrosine kinase inhibitors and radiotherapy combinations. These results indicate the feasibility of this approach with minimal adverse effects. Future studies should explore the broader applicability and efficacy of this treatment strategy, focusing on long-term outcomes and the interplay between BTKi therapy and radiotherapy response.

To explore the safety and efficacy of Bruton's tyrosine kinase inhibitor (BTKi) combined with immunological therapy in untreated patients with aggressive mantle cell lymphoma. A retrospective study was conducted on 9 previously untreated patients who received BTKi combined with immunological therapy, which means using immunological therapy and BTKi at the same time. The median age of the patients was 61 years, 7 were males, and the median follow-up time was 14 months. Among the 7 evaluable patients, the median follow-up was 14 months, and the objective remission rate was 100% (complete remission rate 86%, partial remission rate 14%), while the median progression-free survival and overall survival were not achieved. No patients were dead. The progression-free survival rate of 6 patients in the low-risk group was 100%. The combination of BTKi and chemoimmunotherapy has shown excellent therapeutic results in untreated patients of aggressive mantle cell lymphoma. At the same time, it also can prolong the survival time of high-risk patients. The combined therapy has acceptable safety in previously untreated patients. Hematological toxicity is the most common side effect and infection is the second one. A rash reaction was seen occasionally. There are no heart-related adverse events in the study. There are no new adverse effects caused by the combined treatment.

B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTKi. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.

Clinical bleeding events are reported here from 773 patients with B-cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT-E], n = 216; antithrombotic nonexposed [AT-NE], n = 557). Among the AT-E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any-grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3-51.5) in the AT-E cohort and 181 patients (32.5%; 95% CI, 28.6-36.4) in the AT-NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT-E: 65.4%; AT-NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT-E: 22.7%; AT-NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT-E cohort and 11 patients (2.0%) in the AT-NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT-E and AT-NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT-E cohort, and one patient (0.2%) in the AT-NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies.

Mantle cell lymphoma (MCL) is an uncommon non-Hodgkin lymphoma that is generally considered incurable. Covalent BTK inhibitors (cBTKi) are the cornerstone of treatment for relapsed or refractory (R/R) MCL, but treatment options are limited and prognosis is poor after cBTKi failure. Pirtobrutinib is a non-covalent BTK inhibitor that has demonstrated excellent efficacy and safety and represents an important new treatment in the evolving treatment landscape of R/R MCL.

This review will provide an overview of the therapeutic landscape of R/R MCL, characteristics of pirtobrutinib, and efficacy and safety data of pirtobrutinib in R/R MCL from pivotal clinical trials. PubMed and major hematology conference proceedings were searched to identify relevant studies involving pirtobrutinib.

For patients with R/R MCL that has progressed after treatment with cBTKi, pirtobrutinib is an important and efficacious treatment that confers favorable outcomes. In the post-cBTKi setting, when chimeric antigen receptor (CAR) T-cell therapy is not available or feasible, pirtobrutinib is the preferred treatment for R/R MCL. How to sequence or combine pirtobrutinib with CAR T-cell therapy and other available or emerging therapies requires further investigation. Future studies should also explore the role of pirtobrutinib in earlier lines of therapy for MCL.

Blastoid variant-mantle cell lymphoma (BV-MCL) represents an aggressive subset of patients with no established standard of care treatment approach.

We performed a retrospective analysis of the clinical characteristics and outcomes of 17 de novo BV-MCL patients treated at our institution between May 2009 and September 2023. In addition, we reviewed the literature supporting 2nd/3rd generation Bruton's Tyrosine-kinase (BTKi)-based therapies for upfront management.

The complete response rate to frontline and salvage therapy was 66.7% and 25%, respectively. Two-year overall survival (OS) was low at 62.5% (95% CI, 34.7%-81.1%). Variables associated with higher OS included receipt of consolidative HSCT (p = 0.017), TP53-wild type (p = 0.031), intermediate- versus high-risk Mantle Cell Lymphoma Prognostic Index score (p = 0.026), and achieving complete response with induction therapy (p = 0.027).

Treatment outcomes with chemo-immunotherapy in BV-MCL patients are poor, especially among TP53-mutated patients. Recent findings describing positive outcomes with novel BTKi-based therapies are encouraging and should be considered in this high-risk population.

Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3-5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib-lenalidomide-dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12-month overall survival (12-month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow-up of 2.37 months (95% CI 0.92-6.47), the 12-month OS was 13%. The rate of grade 3-4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced-stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic.

T-cell engaging-therapies have transformed the treatment landscape of relapsed and refractory B-cell non-Hodgkin lymphomas by offering highly effective treatments for patients with historically limited therapeutic options. This review focuses on the advances in chimeric antigen receptor-modified T cells and bispecific antibodies, first providing an overview of each product type, followed by exploring the primary data for currently available products in large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. This review also highlights key logistical and sequencing considerations across diseases and product types that can affect clinical decision-making.

Bruton tyrosine kinase (BTK) is a kinase expressed by various immune cells and is often activated under proinflammatory states. Although the majority of BTK-related research has historically focused on B cells, understanding the role of BTK in non-B cell populations is critical given myeloid cells also express BTK at comparable levels. In this study, we investigated and compared how BTK inhibition in human and murine myeloid cells alters cell phenotype and function. All experiments were performed using two BTK inhibitors (evobrutinib and tolebrutinib) that are currently in late-stage clinical trials for the treatment of multiple sclerosis. Assays were performed to assess the impact of BTK inhibition on cytokine and microRNA expression, phagocytic capacity, and cellular metabolism. In all cells, both evobrutinib and tolebrutinib significantly decreased phosphorylated BTK and LPS-induced cytokine release. BTK inhibition also significantly decreased the oxygen consumption rate and extracellular acidification rate in myeloid cells, and significantly decreased phagocytosis in murine-derived cells, but not human macrophages. To further elucidate the mechanism, we also investigated the expression of microRNAs known to impact the function of myeloid cells. BTK inhibition resulted in an altered microRNA expression profile (i.e., decreased miR-155-5p and increased miR-223-3p), which is consistent with a decreased proinflammatory myeloid cell phenotype. In summary, these results provide further insights into the mechanism of action of BTK inhibitors in the context of immune-related diseases, while also highlighting important species-specific and cell-specific differences that should be considered when interpreting and comparing results between preclinical and human studies.

Despite recent therapeutic advancements in the general field of non-Hodgkin lymphoma, effective treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL) remains a challenge. The development of Bruton tyrosine kinase (BTK) inhibitors has revolutionized the field and these agents are now the mainstay of R/R MCL management. However, BTK inhibitors are not curative, and as they are increasingly being incorporated into frontline regimens, the shifting treatment landscape for R/R disease presents new challenges. Here we review data for commonly employed treatment strategies including BTK inhibitors, the BCL2-inhibitor venetoclax, lenalidomide-based regimens, and chimeric antigen receptor T-cell therapy. We additionally review data for promising novel agents including antibody-drug conjugates and bispecific antibodies before highlighting some emerging targeted agents that continue to bring promise for improved outcomes in R/R MCL.

In the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival (OS) was 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95% CI, 37-79), with 4 experiencing disease recurrence. Two of 3 reattained CR on retreatment. Time-to-treatment failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7 years for responders. Beyond 56 weeks, grade ≥3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries.