Bruton's Tyrosine Kinase Inhibitor Research Articles

Monitoring Response and Resistance to Treatment in Chronic Lymphocytic Leukemia.

The recent evolution in chronic lymphocytic leukemia (CLL) targeted therapies led to a progressive change in the way clinicians manage the goals of treatment and evaluate the response to treatment in respect to the paradigm of the chemoimmunotherapy era. Continuous therapies with BTK inhibitors achieve prolonged and sustained control of the disease. On the other hand, venetoclax and anti-CD20 monoclonal antibodies or, more recently, ibrutinib plus venetoclax combinations, given for a fixed duration, achieve undetectable measurable residual disease (uMRD) in the vast majority of patients. On these grounds, a time-limited MRD-driven strategy, a previously unexplored scenario in CLL, is being attempted. On the other side of the spectrum, novel genetic and non-genetic mechanisms of resistance to targeted treatments are emerging. Here we review the response assessment criteria, the evolution and clinical application of MRD analysis and the mechanisms of resistance according to the novel treatment strategies within clinical trials. The extent to which this novel evidence will translate in the real-life management of CLL patients remains an open issue to be addressed.

Treatment Sequencing in Chronic Lymphocytic Leukemia in 2024: Where We Are and Where We Are Headed.

As treatments with BTK inhibitors and BCL2 inhibitors have replaced the use of chemoimmunotherapy in CLL in both first-line and relapsed patients, it becomes critical to rationalize their use and exploit the full potential of each drug. Despite their proven, robust, and manifest efficacy, BTKis and BCL2is fail to provide long-term disease control in some categories of patients, and to date this is an unmet clinical need that is critical to recognize and address. Ongoing clinical trials are evaluating new treatment algorithms and new molecules to progressively thin this population. In this review for each category of patients we explicate the different possible patterns of treatment sequencing based on currently available evidence, starting from the frontline to currently ongoing trials, in order to optimize therapies as much as possible.

Ibrutinib followed by ofatumumab consolidation in previously untreated patients with chronic lymphocytic leukemia (CLL): GELLC-7 trial from the Spanish group of CLL (GELLC)

BTK inhibitors have been concurrently administered with anti-CD20 monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL). However, the optimal regimen for combining these two drugs remains pending. This multi-center phase 2 study aimed to analyze whether consolidation with ofatumumab improved the response in patients with CLL receiving front-line treatment with ibrutinib. Patients received 12 cycles of ibrutinib monotherapy. Those who achieved CR after this induction were maintained on ibrutinib. Conversely, those who did not attain CR continued with ibrutinib in addition to a consolidation, which involved 7 doses of ofatumumab. The primary objective was the complete response (CR) rate at cycle 20. This study is registered within the EU Clinical Trials Register (EudraCT 2016-004937-26). Between September 8, 2017, and May 21, 2018, 84 patients (median age, 69 years) were included. After completion of 12 cycles of ibrutinib (n=80), 4 patients (5%) were in CR, 67 (84%) in partial response (PR), and 6 patients (7%) had a PR with lymphocytosis (PRL). After consolidation with ofatumumab, 20 patients improved the response from PR to CR and 6 patients with PRL obtained a PR. Seventy-one patients (85%) completed 20 cycles of treatment, with a CR rate of 24/71 (34%). According to the intention-to-treat analysis at cycle 20, the ORR was 69/84 (82.2%), with a CRR of 24/84 (28.6%). Progression-free survival and overall survival at 48-months were 89.9% (CI: 82.4-95.5) and 92.2% (CI: 85.3-97.1), respectively. These findings underscore the potential for a consolidation strategy in CLL, wherein the addition of a mAb in patients with low tumor burden might enhance the quality of the response. The study was funded by Janssen that also supplied ibrutinib, whereas ofatumumab was supplied by Novartis.

Chronic Lymphocytic Leukemia: Management of Adverse Events in the Era of Targeted Agents.

The treatment landscape for CLL has undergone a profound transformation with the advent of targeted agents (TAs) like Bruton's Tyrosine Kinase inhibitors (BTKis) and BCL-2 inhibitors (BCL-2is). These agents target crucial cellular pathways in CLL, offering superior efficacy over traditional chemo-immunotherapy, which has led to improved progression-free and overall survival rates. This advancement promises enhanced disease control and potentially normal life expectancy for many patients. However, the journey is not without challenges, as these TAs are associated with a range of adverse events (AEs) that can impact treatment efficacy and patient quality of life. This review focuses on detailing the various AEs related to TA management in CLL, evaluating their frequency and clinical impact. The aim is to present a comprehensive guide to the effective management of these AEs, ensuring optimal tolerability and efficacy of TAs. By reviewing the existing literature and consolidating findings, we provide insights into AE management, which is crucial for maximizing patient outcomes in CLL therapy.

Targeting the tumor microenvironment for treating double-refractory chronic lymphocytic leukemia

AbstractThe introduction of BTK inhibitors and BCL2 antagonists to the treatment of chronic lymphocytic leukemia (CLL) has revolutionized therapy and improved patient outcomes. These agents have replaced chemoimmunotherapy as standard of care. Despite this progress, a new group of patients is currently emerging, which has become refractory or intolerant to both classes of agents, creating an unmet medical need. Here, we propose that the targeted modulation of the tumor microenvironment provides new therapeutic options for this group of double-refractory patients. Furthermore, we outline a sequential strategy for tumor microenvironment-directed combination therapies in CLL that can be tested in clinical protocols.

#1261 A small-molecule inhibitor of Bruton's tyrosine kinase reduces production of galactose-deficient IgA1 in IgA nephropathy

Abstract Background and Aims IgA nephropathy (IgAN) is a chronic kidney disease characterized by glomerular immunodeposits that contain aberrantly glycosylated IgA1, i.e., IgA1 with some hinge-region O-glycans deficient in galactose (galactose-deficient IgA1; Gd-IgA1). These immunodeposits originate from circulating immune complexes that contain Gd-IgA1 bound by IgG autoantibodies. Consistent with this hypothesis, serum levels of Gd-IgA1 and IgG autoantibodies independently predict disease progression in IgAN patients. Biochemical studies using IgA1-secreting cell lines derived from peripheral blood of IgAN patients and healthy controls have revealed that Gd-IgA1 production is driven by altered biosynthetic pathways of IgA1 O-glycans. Specifically, cell lines from IgAN patients have altered expression and activity of several glycosyltransferases, C1GalT1 and ST6GalNAc2, and a C1GalT1-specific chaperone, C1GalT1C1. Genetic studies have shown that serum levels of Gd-IgA1 are genetically co-determined and genome-wide association studies (GWAS) identified genetic variations that impact the expression C1GALT1 and C1GALT1C1 genes. Moreover, macroscopic hematuria during an upper-respiratory-tract infection is common at the clinical onset of IgAN and during episodes of accentuated disease activity, indicating a connection between IgAN and mucosal inflammation. Notably, a pro-inflammatory cytokine interleukin-6 (IL-6), enhances production of Gd-IgA1 exclusively in the cell lines derived from IgAN patients. Leukemia inhibitory factor (LIF) has similar effects. LIF-induced effects are mediated by abnormal STAT1 signaling and pathways that include Lyn, a Src-family kinase. The corresponding gene, LYN, was recently identified in one of the 16 new IgAN-associated GWAS loci. Lyn, together with spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk), is involved in B-cell-receptor (BCR)-signaling pathways that include activation and inhibitory signals. The aim of this study was to assess if Btk may be involved in Gd-IgA1 production in IgAN. Method IgA1-producing cell lines were cloned by limiting dilution of Epstein-Barr-virus-immortalized peripheral-blood B cells from patients with IgAN (n = 5) and healthy controls (n = 5). Cell signaling, induced by LIF or by BCR crosslinking with anti-IgA antibody, was assessed by flow cytometry or SDS-PAGE/immunoblotting using antibodies for specific phosphorylated sites of selected proteins. Data were normalized using antibodies for specific proteins. Total IgA and Gd-IgA1 were quantified in cell-culture medium using standard ELISA and lectin-ELISA, respectively. Gd-IgA1, normalized to IgA, was expressed in Units (U) of standard Gd-IgA1 protein. Results IgA1-producing cell lines from patients with IgAN and healthy controls secreted similar amounts of total IgA (17.2 ± 9.3 ug/ml vs. 14.6 ± 9.5 ug/ml), but the cells from IgAN patients secreted more Gd-IgA1 (24.2 ± 7.5 U vs. 15.5 ± 2.7 U; p < 0.05). Baseline phosphorylation of Btk (Y223), but not Syk (Y551), was higher in the cells from patients with IgAN than in those from healthy controls. We used an IgA1-secreting cell line from an IgAN patient to confirm that BCR crosslinking with F(ab’)2 anti-IgA antibody in IgA + CD19+ cells lines induced phosphorylation of Btk (Y223). Conversely, anti-IgM antibody, used as a negative control, did not activate Btk. LIF stimulation did not affect phosphorylation of Btk or Syk. A Btk inhibitor, PCI-32765 (ibrutinib), reduced Gd-IgA1 production in a dose-dependent fashion exclusively in the IgAN-derived cells. Notably, 1 uM PCI-32765 reduced Gd-IgA1 production to that for healthy controls (25.7 ± 1.2 U to 17.3 ± 1.8 U; p < 0.01). Conclusion Inhibition of Btk with a small-molecule inhibitor normalized Gd-IgA1 production in IgA1-secreting cells from patients with IgAN, revealing a previously unknown role of Btk in aberrant O-glycosylation of IgA1. Btk may thus represent a potential new target for disease-specific therapy of IgAN.

Low Cell Bioenergetic Metabolism Characterizes Chronic Lymphocytic Leukemia Patients with Unfavorable Genetic Factors and with a Better Response to BTK Inhibition.

Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role of cell metabolism, which is able to influence the outcome of treatments, in other neoplasms, we aimed to assess its prognostic role in CLL patients by determining the ex vivo bioenergetic metabolic profile of CLL cells, evaluating the correlation with the patient clinical/biological characteristics and the in vivo response to BTK inhibitor treatment. Clustering analysis of primary samples identified two groups, characterized by low (CLL low) or high (CLL high) bioenergetic metabolic rates. Compared to the CLL high, CLL with lower bioenergetic metabolic rates belonged to patients characterized by a statistically significant higher white blood cell count and by unfavorable molecular genetics. More importantly, patients in the CLL low cluster displayed a better and more durable response to the BTK inhibitor ibrutinib, thus defining a bioenergetic metabolic subgroup that can benefit the most from this therapy.

The impact of Bruton's tyrosine kinase inhibitor treatment on COVID-19 outcomes in Chinese patients with chronic lymphocytic leukemia.

Impact of B-cell depletion following treatment with Bruton tyrosine kinase-inhibitors (BTKi) on the outcome of SARS-CoV-2 infection in chronic lymphocytic leukemia (CLL) patients remain controversial. We investigated the impact of BTKi on susceptibility and the severity of COVID-19 in Chinese patients with CLL during the first wave of COVID-19 (Omicron variant). CLL patients (n=171) visiting the Institute of Hematology, Peoples' Hospital, China (November 15, 2022- January 20, 2023) were included in the study. Seventeen patients receiving BTKi and venetoclax with or without obinutuzumab were excluded. Data from 117 patients receiving treatment with BTKi were collected using a standardized questionnaire through telephone interviews. Thirty-four patients without CLL-specific treatment served as controls. The data was analysed using IBM SPSS Software version 21 and a P value of <0.05 was considered statistically significant. The median age of patients was 67 years and majority were males (n=100). Treatment with BTKi was not associated with higher incidence of COVID-19 (74% [95% Confidence Interval (CI) 60%, 92%]) versus 74% (CI 48%, 100%) without any treatment (P=0.92). Hypoxemia was reported by 45% (32%, 61%) and 16% (4%, 41%) (P=0.01). BTKi was the only independent risk factor of hypoxemia (Hazard Ratio [HR], 4.22 [1.32, 13.50]; P = 0.02). Five (5.7%) patients with COVID-19 under BTKi required ICU admission; 4 of them died. No ICU admissions/deaths were observed in the control group. In Chinese patients with CLL and treated with BTKi experienced more severe lung disease and ICU admissions due to COVID-19 than patients without CLL therapy. Frequency of infections with SARS-CoV-2, however, was not different in patients with or without BTKi treatment.

Meta-analysis of the efficacy and adverse effects of acalabrutinib in the management of relapsed/refractory chronic lymphocytic leukemia

The advent of Bruton tyrosine kinase inhibitor (BTKi) therapy with ibrutinib introduced a highly effective targeted therapy in the management of chronic lymphocytic leukemia (CLL). However, due to the adverse effect profile some patients cannot tolerate this novel therapy. Newer, more potent and targeted BTK inhibitors such as acalabrutinib have been developed. Acalabrutinib is an irreversible and second generation BTKi that covalently inhibits BTK with greater selectivity than ibrutinib. As novel BTKis are developed, a greater understanding of their efficacy and adverse effect rates can assist clinicians and patients in the shared clinical decision-making process. A search was conducted using the PICOS model and PRISMA guidelines. PubMeb, Embase, and Cochrane Library databases were searched using the keywords: Acalabrutinib, Acalabrutinib Monotherapy, Tyrosine Kinase Inhibitor, and Relapsed/Refractory (R/R) CLL. After initial literature review 12 studies were chosen for evaluation in this meta-analysis. Meta-analysis and follow up meta-regression models were completed. The results were as follows: ORR 82% (95% CI 74%–90%, I2 = 84.14%, p < 0.01), CR 4% (95% CI 2%–6%, I2 = 0.00%, p = 0.99), mortality rate 12% (95% CI 6%–19%, I2 = 87.23%, p < 0.01), mortality rate due to adverse effect 7% (95% CI 3%–10%, I2 = 67.67%, p = 0.01), mortality due to pneumonia 2% (95% CI 1%–3%, I2 = 0.00%, p = 0.43), mortality due to CLL progression 4% (95% CI 2%–6%, I2 = 61.03%, p = 0.04), neutropenia (≥ grade 3) 18% (95% CI 15%–20%, I2 = 0.00%, p = 0.70), thrombocytopenia (≥ grade 3) 7% (95% CI 4%–11%, I2 = 54%, p = 0.09), anemia (≥ grade 3) 9% (95% CI 6%–12%, I2 = 36.93%, p = 0.18), pneumonia (≥ grade 3) 10% (95% CI 6%–14%, I2 = 66.37%, p = 0.02) and atrial fibrillation 7% (95% CI 3%–11%, I2 = 80.13%, p = 0.00). The results demonstrate that acalabrutinib shows efficacy in the treatment of R/R CLL with tolerable adverse reaction rates.

Racial and Ethnic Characteristics and Outcomes of Patients Diagnosed with CLL/SLL in the USA.

This study was designed to compare outcomes among patients by race and ethnicity in the post-covalent Bruton tyrosine kinase inhibitor (cBTKi) treatment era. A nationwide electronic health record (EHR)-derived de-identified database was utilized that included patients diagnosed with CLL from 2013 to 2022 who received systemic therapy for their disease. Use of cBTKi therapy, time to next treatment or death (TTNT-D), and overall survival (OS) were compared by race in unadjusted (Kaplan-Meier method) and adjusted analyses (Cox proportional hazards regression). This study included 4,572 White (71.8%) and 558 Black (8.8%) patients with CLL; 270 were Hispanic or Latino (4.2%). Patients who were Black were significantly younger, more were female, had later stage disease, were of lower socioeconomic status (SES), and were more likely to have unmutated immunoglobulin heavy chain gene (IGHV) and to have received cBTKi therapy than White patients (all p ≤ 0.002). SES was also significantly different by ethnicity. TTNT-D and OS were not different by race in either unadjusted or adjusted analyses (all p &gt; 0.05). In unadjusted and adjusted analyses, TTNT-D and OS were not different by race. These data did not identify racial healthcare disparities in the era following the introduction of cBTKi therapy despite differences in baseline characteristics.

Clinical characteristics and prognosis of patients with newly diagnosed primary central nervous system lymphoma: a multicentre retrospective analysis.

Bruton's tyrosine kinase inhibitors (BTKi) exhibit superior efficacy in relapsed/refractory primary central nervous system lymphoma (PCNSL), but few studies have evaluated patients with newly diagnosed PCNSL, and even fewer studies have evaluated differences in efficacy between treatment with BTKi and traditional chemotherapy. This study retrospectively analyzed the clinical characteristics of 86 patients with PCNSL and identified predictors of poor prognosis for overall survival (OS). After excluding patients who only received palliative care, 82 patients were evaluated for efficacy and survival. According to the induction regimen, patients were divided into the traditional chemotherapy, BTKi combination therapy, and radiotherapy groups; the objective response rates (ORR) of the three groups were 71.4%, 96.2%, and 71.4% (P = 0.037), respectively. Both median progression-free survival and median duration of remission showed statistically significant differences (P = 0.019 and P = 0.030, respectively). The median OS of the BTKi-containing therapy group was also longer than that of the traditional chemotherapy group (not reached versus 47.8 (32.5-63.1) months, P = 0.038).Seventy-one patients who achieved an ORR were further analyzed, and achieved an ORR after four cycles of treatment and maintenance therapy had prolonged OS (P = 0.003 and P = 0.043, respectively). In conclusion, survival, and prognosis of patients with newly diagnosed PCNSL are influenced by the treatment regimen, with the BTKi-containing regimen showing great potential.

Outcomes of younger patients with mantle cell lymphoma experiencing late relapse (>24 months): the LATE-POD study

AbstractPatients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are the established standard treatment at first relapse, but their effectiveness compared with chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes among patients at first, late POD beyond 24 months. The primary objective was progression-free survival from the time of second-line therapy (PFS-2) of BTKi vs CIT. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 years (range, 19-70), and 77% were male. Median follow-up from the time of second-line therapy was 53 months (range, 12-144). Overall, 114 patients had second-line BTKi, whereas 271 had CIT, consisting of rituximab-bendamustine (R-B; n = 101), R-B and cytarabine (R-BAC; n = 70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone]- or platinum-based; n = 100). The 2 groups were balanced in clinicopathological features and median time to first relapse. Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT (not reached [NR] vs 26 months, respectively; P = .0003) and overall survival (NR and 56 months, respectively; P = .03). Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio, 0.41 for R-B and 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in patients with BTKi-naïve MCL.

Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib

AbstractChronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from patients with relapsed/refractory CLL in ELEVATE-RR (NCT02477696; median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up, 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 acalabrutinib-treated (66%) and 11 ibrutinib-treated patients (37%; median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, whereas neither mutation occurred with ibrutinib. L528W and A428D comutations presented in 1 ibrutinib-treated patient. Preexisting TP53 mutations were present in 25 acalabrutinib-treated (53.2%) and 16 ibrutinib-treated patients (53.3%) at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF, 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and 1 ibrutinib-treated patient had emergent TP53/BTK comutations. Emergent PLCG2 mutations occurred in 3 acalabrutinib-treated (6%) and 6 ibrutinib-treated patients (20%). One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 comutations. Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population. The trial was registered at www.clinicaltrials.gov as #NCT02477696.

Multi-phased Kinetics and Interaction of Protein Kinase Signaling in Glycoprotein VI-Induced Platelet αIIbβ3 Integrin Activation and Degranulation.

Platelet glycoprotein VI (GPVI) stimulation activates the tyrosine kinases Syk and Btk, and the effector proteins phospholipase Cγ 2 (PLCγ2) and protein kinase C (PKC). Here, the activation sequence, crosstalk, and downstream effects of this Syk-Btk-PKC signalosome in human platelets were analyzed. Using immunoblotting, we quantified 14 regulated phospho-sites in platelets stimulated by convulxin with and without inhibition of Syk, Btk, or PKC. Convulxin induced fast, reversible tyrosine phosphorylation (pY) of Syk, Btk, LAT, and PLCγ2, followed by reversible serine/threonine phosphorylation (pS/T) of Syk, Btk, and downstream kinases MEK1/2, Erk1/2, p38, and Akt. Syk inhibition by PRT-060318 abolished all phosphorylations, except Syk pY352. Btk inhibition by acalabrutinib strongly decreased Btk pY223/pS180, Syk pS297, PLCγ2 pY759/Y1217, MEK1/2 pS217/221, Erk1/2 pT202/Y204, p38 pT180/Y182, and Akt pT308/S473. PKC inhibition by GF109203X abolished most pS/T phosphorylations except p38 pT180/Y182 and Akt pT308, but enhanced most Y-phosphorylations. Acalabrutinib, but not GF109203X, suppressed convulxin-induced intracellular Ca2+ mobilization, whereas all three protein kinase inhibitors abolished degranulation and αIIbβ3 integrin activation assessed by flow cytometry. Inhibition of autocrine ADP effects by AR-C669931 partly diminished convulxin-triggered degranulation. Kinetic analysis of GPVI-initiated multisite protein phosphorylation in human platelets demonstrates multiple phases and interactions of tyrosine and serine/threonine kinases with activation-altering feedforward and feedback loops partly involving PKC. The protein kinase inhibitor effects on multisite protein phosphorylation and functional readouts reveal that the signaling network of Syk, Btk, and PKC controls platelet granule exocytosis and αIIbβ3 integrin activation.

A Review of Resistance Mechanisms to Bruton's Kinase Inhibitors in Chronic Lymphocytic Leukemia.

Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.

Zanubrutinib is effective in non-germinal-center B-cell-like diffuse large B-cell lymphoma with mutated CD79B, high TCL1A expression, or over- expressed MYC/BCL-2

To evaluate the effects of gene mutations on Bruton tyrosine kinase inhibitor, zanubrutinib’s effectiveness in patients with diffuse large B-cell lymphoma (DLBCL), we examined pooled data from four single-arm studies (BGB-3111-AU-003 [NCT02343120], BGB-3111-207 [NCT03145064], BGB-3111_GA101_Study_001 [NCT02569476], BGB-3111-213 [NCT03520920]; n = 121). Objective response rate (ORR) was higher, though not statistically significant, in patients with activated B-cell-like (ABC)- and unclassified DLBCL (42.9% [21/49]) versus those with germinal-center B-cell-like DLBCL (14.3% [1/7]; p = 0.15). Patients with CD79B mutations had better ORR (60%) versus patients with wild-type alleles (25.9%, p < 0.01). Higher TCL1A expression correlated with better zanubrutinib response (p = 0.03), longer progression-free survival (p = 0.01), and longer overall survival (p = 0.12). TCL1A expression was higher in ABC-DLBCL (p < 0.001) and MYD88/CD79B-mutated subtypes (p < 0.0001). Eighteen patients with high MYC/BCL-2 expression responded better to zanubrutinib (ORR = 61 vs. 29%, p = 0.02). Our results support assessing CD79B mutations, co-expressor DLBCL, and TCL1A expression status to identify patients with DLBCL who will benefit from zanubrutinib.

A New Scoring System for the Evaluation of Ibrutinib-Associated Arrhythmias in Chronic Lymphocytic Leukemia: The ACEF Score

Bruton tyrosine kinase inhibition in cardiac tissue causes inhibition of the PI3K-AKT signaling pathway, which is responsible for protecting cardiac tissue during stress. Therefore, there is an increase in the risk of arrhythmia. This study explores the prediction of that risk with the Age-Creatinine-Ejection Fraction (ACEF) score as a simple scoring system based on the components of age, creatinine, and ejection fraction. Patients diagnosed with chronic lymphocytic leukemia (CLL) and receiving ibrutinib treatment for at least 1 year were evaluated with echocardiography and Holter electrocardiography and the results were compared with a control group of CLL patients who had not received treatment. ACEF score was calculated with the formula age/left ventricular ejection fraction+1 (if creatinine >2.0 mg/dL). When the arrhythmia development of the patients was evaluated, no statistically significant difference was found between the control and ibrutinib groups in terms of types of arrhythmias other than paroxysmal atrial fibrillation (PAF). PAF was found to occur at rates of 8% versus 22% (p=0.042) among ibrutinib non-users versus users. For patients using ibrutinib, an ACEF score of >1.21 predicted the development of PAF with 77% sensitivity and 75% specificity (area under the curve: 0.830, 95% confidence interval: 0.698-0.962, p<0.001). The ACEF score can be used as a risk score that predicts the development of PAF in patients diagnosed with CLL who are scheduled to start ibrutinib.

Cardio-Oncology: A New Discipline in Medicine and Its Relevance to Hematology.

Cardio-oncology, a burgeoning subspecialty, addresses the complex interplay between cardiology and oncology, particularly in light of increased cardiovascular (CV) disease mortality in cancer patients. This review provides a comprehensive overview of cardio-oncology with a focus on the therapies used in hematological malignancies. We explore the bidirectional relationship between heart failure and cancer, emphasizing the need for collaborative care. The review discusses risk stratification, highlighting the importance of baseline CV risk assessment and personalized surveillance regimens. Primary and secondary prevention strategies, including pharmacological interventions, are outlined. The review also delves into the cardiotoxicity associated with hematological cancer therapies, focusing on anthracyclines, Bruton kinase inhibitors, BCR-ABL tyrosine kinase inhibitors, CAR-T cell therapy, immune checkpoint inhibitors, multiple myeloma treatments, and hematopoietic stem cell transplantation. We then highlight the high risk of venous and arterial thromboembolisms in cancer patients and the challenges of anticoagulation management in cardio-oncology. Finally, the review touches on the importance of long-term follow-up and appropriate screening in cancer survivors at high risk of CV morbidity and mortality, based on their CV risk profile and the type and dose of cardiotoxic therapies they received such as anthracyclines or high radiation doses.

BTK inhibitor-induced defects in human neutrophil effector activity against Aspergillus fumigatus are restored by TNF-α.

Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal infections, although the mechanism is poorly understood. Neutrophils are the primary line of defense against these infections; therefore, we examined the effect of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNF-α fully compensated for defects imposed by IBT and newer-generation BTK inhibitors and restored the ability of neutrophils to contain A. fumigatus hyphal growth. Blocking TNF-α did not affect ROS production in healthy neutrophils but prevented exogenous TNF-α from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNF-α was independent of transcription. Moreover, the addition of TNF-α immediately rescued ROS production in IBT-treated neutrophils, indicating that TNF-α worked through a BTK-independent signaling pathway. Finally, TNF-α restored effector activity of primary neutrophils from patients on IBT therapy. Altogether, our data indicate that TNF-α rescued the antifungal immunity block imposed by inhibition of BTK in primary human neutrophils.

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.