Search Results (53)

Pediatric-onset multiple sclerosis (POMS) is a rare yet increasingly recognized demyelinating disease of the central nervous system, characterized by a highly inflammatory disease course and an elevated relapse rate compared to adult-onset MS (AOMS). Given the unique immunopathogenesis of POMS, recent therapeutic strategies have shifted toward early initiation of high-efficacy disease-modifying therapies (DMTs) to minimize irreversible neurological damage. Among these, B-cell-targeting therapies, particularly anti-CD20 monoclonal antibodies, have shown efficacy in adult MS and are emerging as promising candidates for POMS treatment. The present review summarizes the current knowledge of the role of B-cells in POMS pathophysiology and evaluates the therapeutic potential of anti-CD-20 agents. It also highlights ongoing clinical trials and future perspectives, including novel B-cell-directed approaches such as anti-CD19 therapies, Bruton’s tyrosine kinase (BTK) inhibitors, and BAFF-targeting agents. Full article

Background/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) MCL. We recently reported that a novel oral formulation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we investigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 inhibitor Venetoclax (VEN) and/or the oral BTKi Acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R/R disease subtype. Methods: We performed in vitro analyses using MTS viability and Annexin V/PI apoptosis assays. For the in vivo studies, all treatments were administered via oral gavage in xenograft mouse models. Therapeutic efficacy was evaluated by monitoring tumor growth and survival. Results: BEN induced significant cytotoxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrated limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN ± ACAL further improved survival outcomes. Conclusions: Our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents. Full article

Background: The treatment of chronic lymphocytic leukemia (CLL) has advanced considerably in recent years. Bruton’s tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is) such as venetoclax have largely supplanted chemoimmunotherapy for both frontline and relapsed CLL. With the introduction of additional innovative agents and regimens, the clinical role of measurable residual disease (MRD) has become complicated. Methods: In this article, we will review the existing literature on MRD and its utility in the management of CLL. We will review the definitions of MRD, review MRD detection methods, and discuss the use of MRD in the current CLL treatment landscape. In doing so, we will clarify the present and conceivable future roles of MRD for the treatment of CLL. Conclusions: MRD is a powerful tool to assess response to CLL therapies, and can be prognostic with certain treatment regimens, such as fixed-duration venetoclax-based treatment. While we do not recommend MRD testing in routine clinical practice, we believe it has an important role in assessing treatment response and will be utilized routinely in the future. Further studies to incorporate MRD into treatment strategies for CLL are ongoing and will help to inform how we utilize it in clinical practice. Full article

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The therapeutic landscape for MS has evolved significantly since the 1990s, with the development of more than 20 different disease-modifying therapies (DMTs). These therapies effectively manage relapses and inflammation, but most have failed to meaningfully prevent disease progression. While classically understood as a T cell-mediated condition, the most effective DMTs in slowing progression also target B cells. Novel classes of MS therapies in development, including anti-CD40L monoclonal antibodies, CD19 chimeric antigen receptor (CAR) T cells, and Bruton’s tyrosine kinase (BTK) inhibitors show greater capacity to target and eliminate B cells in the brain/CNS, as well as impacting T-cell and innate immune compartments. These approaches may help tackle the disease at its immunopathological core, addressing both peripheral and central immune responses that drive MS progression. Another emerging therapeutic strategy is to use bispecific antibodies, which have the potential for dual-targeting various disease aspects such as immune activation and neurodegeneration. As such, the next generation of MS therapies may be the first to reduce both inflammatory demyelination and disease progression in a clinically meaningful way. Their ability to target specific immune cell populations while minimizing broad immune suppression could also lead to better safety profiles. Here, we explore the biological rationale, advantages, limitations, and clinical progress of these emerging immunotherapies for relapsing–remitting and progressive forms of MS. Full article

In the recent 2024 ESMO guidelines, the combination of venetoclax and ibrutinib was listed as one of the first-line treatment options for CLL patients. These drugs were first-in-class medicines that revolutionized CLL management, extending patients’ overall survival even in cases refractory to immunochemotherapy. However, since the approval of both compounds, more and more Bruton Tyrosine Kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is) have been discovered. Their efficacy and safety are the reasons for their use in monotherapy among both treatment-naïve and relapsed patients with CLL. Currently, several ongoing clinical trials are investigating the rationale for the combination of BCL2is and BTKis. In this review, we discuss the recent advancements in the field of co-therapy with BTKis and BCL2is. Full article

Chronic lymphocytic leukemia (CLL) cells depend on microenvironment niches for proliferation and survival. The adhesion of tumor cells to stromal cells in such niches triggers the activation of signaling pathways crucial for their survival, including B-cell receptor (BCR) signaling. While inhibitors of Bruton’s tyrosine kinase (BTKi) have shown efficacy in patients with CLL by disrupting these interactions, acquired resistance and toxicity remain a challenge during long-term therapy. Thus, identifying additional therapeutic modalities is important. Previously, we demonstrated that 5-lipoxygenase (5-LOX) pathway inhibitors reduced mantle cell lymphoma (MCL) cell adhesion to stromal cells, motivating us to investigate their potential in the context of CLL. We employed an ex vivo co-culture model to study CLL cell adhesion to stromal cells in the absence and presence of 5-LOX pathway inhibitors (zileuton and MK886) as well as the BTKi ibrutinib that was included for comparative purposes. Our findings demonstrated that different CLL samples adhere to stromal cells differentially. We observed a variable decrease in CLL cell adhesion to stromal cells following the inhibition of the 5-LOX pathway across a spectrum of patient samples that was distinct to the spectrum for ibrutinib. Positive and negative correlations were shown between the clinical and genetic features of the CLL samples and their level of adherence to stromal cells in both the absence and presence of the tested inhibitors. These results suggest the 5-LOX pathway as a candidate for assessment as a new therapeutic target in CLL. Full article

Background: The long-term follow-up of clinical trials of novel first-line (1L) therapies for chronic lymphocytic leukemia (CLL) demonstrates 6–10-year progression-free survival. We describe the effectiveness of 1L CLL treatments in real-world settings, with an emphasis on the important real-world outcome of time to next treatment or death (TTNT-D). Methods: This retrospective, observational study utilized de-identified electronic health records from the ConcertAI RWD360™ database with linked administrative open claims. Adults with CLL who initiated an approved 1L CLL therapy (June 2019–March 2023) were included. Duration of therapy (DoT), TTNT-D, and overall survival were assessed. Results: At 1L, 39.8% of 1843 patients received first-generation covalent Bruton tyrosine kinase inhibitors (cBTKis), 23.0% second-generation cBTKis, 12.4% venetoclax-obinutuzumab (VenO), 7.4% chemotherapy/chemoimmunotherapy (CT/CIT), and 17.4% anti-CD20 monotherapy. Median (range) follow-up in months was 24.9 (13.1–36.6) for first-generation cBTKis, 13.4 (7.3–21.7) for second-generation cBTKis, 16.0 (8.4–27.8) for VenO, 21.8 (11.2–32.7) for CT/CIT, and 19.7 (10.0–33.4) for anti-CD20 monotherapy. Median (range) DoT was 11.5 (4.2–25.0) and 8.6 (3.0–16.1), 9.1 (5.9–12.2), 5.6 (3.2–5.8), and 1.6 (1.6–4.5) months for first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively. Regarding TTNT-D, at 2 years’ follow-up, 69.1%, 82.5%, 86.3%, 79.1%, and 53.0% of patients treated with first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively, had not initiated subsequent treatment or experienced death. Conclusions: TTNT-D is an important real-world outcome in CLL. Our findings demonstrated the utility of time-limited VenO, with potentially more time off treatment, relative to continuous 1L cBTKi therapies. Full article

Effective available treatment options for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who relapse after becoming refractory to both a covalent Bruton Tyrosine Kinase inhibitor (cBTKi) and a B cell leukemia/lymphoma 2 inhibitor (BCL2i) remain limited, and prognosis is very poor. Emerging areas of drug development include cellular therapies such as chimeric antigen receptor T-cell therapy and bispecific antibodies. However, cost, accessibility, toxicity, and the need for either prolonged or repeated hospitalization prevent universal application of these therapies. Given this area of unmet clinical need, we present this review article on Bruton Tyrosine Kinase (BTK) degraders in patients with CLL/SLL. We focus on their development as a drug class, the up-to-date clinical data available, as well as future directions. BTK protein degraders are a novel drug class with an alternate mechanism of action (MOA), compared to cBTKis and non-covalent BTKis (ncBTKis), causing ubiquitination of BTK, thereby leading to its degradation through the proteasome. Encouraging pre-clinical data show that this MOA allows BTK protein degraders to overcome common BTK mutations. We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Preliminary data suggest a comparable safety and toxicity profile between agents across this drug class with many patients on phase 1 trials deriving durable clinical benefit. Optimal sequencing of BTK degraders in the therapeutic landscape of CLL/SLL treatment is yet to be established. Further trials investigating these agents in combination with other targeted CLL agents may help to further understand their applicability. An effective, tolerable oral class of drugs would be invaluable in the treatment of patients with multiply relapsed CLL/SLL. Full article

The proliferation and survival of chronic lymphocytic leukemia (CLL) cells are heavily dependent on B-cell receptor (BCR) signaling and resistance to apoptosis. Approvals of multiple covalent Bruton’s tyrosine kinas inhibitors (cBTKis) as well as the B-cell lymphoma-2 inhibitor (BCL2i) venetoclax targeting these pathways have revolutionized the treatment of CLL and small lymphocytic lymphoma (SLL). The superiority of these treatments over chemoimmunotherapy has been proven in phase III studies in both treatment-naïve and relapsed refractory settings, leading to the majority of patients with CLL being treated sequentially with cBTKis and the BCL2i venetoclax as their first- and second-line therapies. While most patients with CLL respond for many years to these sequenced treatments, they are unfortunately not curative. There remains an unmet need for effective treatment options for patients who progressed after treatment with both cBTKis and BCL2i, also referred to as double refractory patients. Treatment options for double refractory CLL has improved recently with the approval of the non-covalent BTK inhibitor (ncBTKi) pirtobrutinib as well as the CD19 targeted chimeric antigen receptor T-cell (CAR T-cell) therapy lisocabtagene maraleucel (liso-cel). These recently approved treatment options for patients with CLL with at least two prior lines of therapy have fortunately demonstrated efficacy for double refractory CLL. Additionally, there are several novel treatment options in clinical development, including bi-specific antibodies, second-generation BCL2is, new ncBTKis, and BTK degraders. Understanding resistance mechanisms to existing cBTKis and venetoclax can potentially inform us of the best utilization of available treatment options for double refractory CLL and provide a personalized approach for these patients. In this review, a challenging example of a double refractory patient with CLL will serve as the basis for a review of available literature on the treatment of double refractory CLL/SLL. Full article

Background: Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia among adults, particularly in Western nations. The introduction of Bruton’s tyrosine kinase (BTK) inhibitors as a treatment of CLL, namely, ibrutinib, which is a first-generation BTK inhibitor, has significantly improved the treatment landscape for CLL. However, ibrutinib has been associated with an increased risk of atrial fibrillation (AF) and hypertension. Real-world studies that compare the cardiovascular safety of ibrutinib with bendamustine plus anti-CD20 monoclonal antibody are not widely available. Methods: A retrospective cohort analysis using the TriNetX platform identified two patient groups: one treated with ibrutinib and the other with bendamustine and an anti-CD20 antibody. Propensity score matching balanced their demographic and clinical characteristics. The outcomes evaluated included the all-cause mortality and new-onset AF/flutter, hypertension, heart failure, ventricular arrhythmias, and bleeding. Results: No significant difference was observed in the all-cause mortality between the two cohorts. However, ibrutinib was associated with a higher risk of AF/flutter (HR 1.89, 95% CI 1.36–2.62; p < 0.05) and hypertension (HR 1.22, 95% CI 1.01–1.47; p = 0.04). Other outcomes, such as heart failure, ventricular arrhythmias, and bleeding, were not different between the cohorts. Conclusions: Ibrutinib remains a valuable option for the treatment of CLL, but is associated with significant cardiovascular risks, leading to it being superseded by the newer generation of BTKis, which offer less cardiovascular toxicities. These results highlight the TriNetX platform’s reliability as a real-world data source for validating clinical trial findings and highlight the importance of incorporating cardio-oncology into treatment plans for CLL patients with significant comorbidities. Full article

Bruton’s tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a pivotal role in B cell biology and function. As an essential component of the B cell receptor (BCR) signaling pathway, BTK is expressed not only in B cells but also in myeloid cells, including monocytes/macrophages, dendritic cells, neutrophils, and mast cells. BTK inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and other B cell malignancies. Besides their well-characterized role in inhibiting BCR signaling, BTKis also exert significant immunological influences outside the tumor cell that extend their therapeutic potential and impact on the immune system in different ways. This work elucidates the immunomodulatory mechanisms associated with BTK inhibition, focusing on CLL and other clinical contexts. We discuss how BTK inhibition affects various immune cells, including B cells, T cells, and macrophages. The effects of BTKis on the profiles of cytokines, also fundamental parts of the tumor microenvironment (TME), are summarized here as well. This review also appraises the implications of these immunomodulatory actions in the management of autoimmune diseases and infections. Summarizing the dual role of BTK inhibition in modulating malignant lymphocyte and immune cell functions, this paper highlights the broader potential clinical use of compounds targeting BTK. Full article

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. Full article

Background: Bruton tyrosine kinase inhibitors (BTKis) represent an advancement in chronic lymphocytic leukemia; however, these agents are administered continuously until disease progression or unacceptable toxicity, raising concerns about their affordability. Venetoclax in combination with obinutuzumab (VO) is a fixed-duration (12-month) treatment, approved in Canada in 2020. This study estimated the total cumulative cost of different treatment sequences and evaluated the economic impact of introducing treatment sequences with/without VO, from a Canadian health care system perspective. Methods: A 10-year partitioned survival model was developed, considering key clinical parameters and direct medical costs. Results were stratified by TP53 aberration. Results: Treatment sequences starting with first-line (1L) VO resulted in lower 10-year cumulative costs compared to sequences starting with BTKis administered until disease progression, across both TP53 aberration subgroups. With a maximum of three lines of treatment over a 10-year period, cumulative costs were largely determined by the first two lines of treatment. When comparing sequences with the same 1L treatment, sequences with BTKis in second-line incurred greater costs compared to fixed-duration regimens. Conclusions: Overall, the economic impact of treating all patients with VO led to 10-year cumulative savings of CAD 169,341 and CAD 293,731 per patient, without and with TP53 aberration, respectively. These savings are mainly due to reductions in treatment costs associated with fixed treatment duration. Full article

Introduction: Hairy-cell leukemia (HCL) is a rare B-cell chronic lymphoproliferative disorder (B-CLPD), whose favorable prognosis has changed with the use of purine nucleoside analogs (PNAs), such as cladribine (CDA) or pentostatin (P). However, some patients eventually relapse and over time HCL becomes resistant to chemotherapy. Many discoveries have been made in the pathophysiology of HCL during the last decade, especially in genomics, with the identification of the BRAF^V600E mutation and cellular biology, including the importance of signaling pathways as well as tumor microenvironment. All of these new developments led to targeted treatments, especially BRAF inhibitors (BRAFis), MEK inhibitors (MEKis), Bruton’s tyrosine kinase (BTK) inhibitors (BTKis) and recombinant anti-CD22 immunoconjugates. Results: The following major changes or additions were introduced in these updated guidelines: the clinical relevance of the changes in the classification of splenic B-cell lymphomas and leukemias; the increasingly important diagnostic role of BRAF^V600E mutation; and the prognostic role of the immunoglobulin (IG) variable (V) heavy chain (H) (IGHV) mutational status and repertory. We also wish to insist on the specific involvement of bones, skin, brain and/or cerebrospinal fluid (CSF) of the disease at diagnosis or during the follow-up, the novel targeted drugs (BRAFi and MEKi) used for HCL treatment, and the increasing role of minimal residual disease (MRD) assessment. Conclusion: Here we present recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients as well as for HCL-like disorders including HCL variant (HCL-V)/splenic B-cell lymphomas/leukemias with prominent nucleoli (SBLPN) and splenic diffuse red pulp lymphoma (SDRPL). Full article

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton’s tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague–Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca²⁺ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca²⁺ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca²⁺ leak and Ca²⁺ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca²⁺ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics. Full article