Bruton's Tyrosine Kinase Inhibitor Research Articles

Evidence-based expert consensus on clinical management of safety of Bruton's tyrosine kinase inhibitors (2024).

Bruton's tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of B-cell lymphomas. However, safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy. A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment. A multidisciplinary consensus working group was established, comprising 35 members from the fields of hematology, cardiovascular disease, cardio-oncology, clinical pharmacy, and evidence-based medicine. This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method. The Joanna Briggs Institute Critical Appraisal (JBI) tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach were used to rate the quality of evidence and grade the strength of recommendations, respectively. This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains, including the management of common adverse drug events such as bleeding, cardiovascular events, and hematological toxicity, as well as the management of drug-drug interactions and guidance for special populations. This multidisciplinary expert consensus could contribute to promoting a multi-dimensional, comprehensive and standardized management of BTKis.

Waldenström Macroglobulinemia - A State-of-the-Art Review: Part 1: Epidemiology, Pathogenesis, Clinicopathologic Characteristics, Differential Diagnosis, Risk Stratification, and Clinical Problems.

Waldenström macroglobulinemia (WM) is an infrequent variant of lymphoma, classified as a B-cell malignancy identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the MYD88 L265P mutation, which is observed in over 90% of cases. The direct invasion of the malignant cells into tissues like lymph nodes and spleen, along with the immune response related to IgM, can also lead to various health complications, such as cytopenias, hyperviscosity, peripheral neuropathy, amyloidosis, and Bing-Neel syndrome. Chemoimmunotherapy has historically been considered the preferred treatment for WM, wherein the combination of rituximab and nucleoside analogs, alkylating drugs, or proteasome inhibitors has exhibited notable efficacy in inhibiting tumor growth. Recent studies have provided evidence that Bruton Tyrosine Kinase inhibitors (BTKI), either used independently or in conjunction with other drugs, have been shown to be effective and safe in the treatment of WM. The disease is considered to be non-curable, with a median life expectancy of 10 to 12 years.

Cryptococcosis associated with biologic therapy – a narrative review

Abstract Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and prevention of transplant rejection, which may affect human defence mechanisms against cryptococcosis. In this review, we comprehensively investigated the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affects the Th1/macrophage activation pathways, such as tumour necrosis factor-α (TNF- α) antagonists, Bruton tyrosine kinase (BTK) inhibitors, fingolimod, JAK/STAT inhibitors, and monoclonal antibody against CD52. Other risk factors, such as age, underlying condition, and concurrent immunosuppressants especially corticosteroids, should also be taken into account during risk stratification.

Efficacy and Safety of Upadacitinib or Elsubrutinib Alone or in Combination for Systemic Lupus Erythematosus: A Phase 2 Randomized Controlled Trial.

The 48-week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (Janus kinase inhibitor) and elsubrutinib (Bruton's tyrosine kinase inhibitor) alone or in combination (ABBV-599) in adults with moderately to severely active systemic lupus erythematosus (SLE). Patients were randomized 1:1:1:1:1 to once-daily (QD) ABBV-599 high dose (HD; elsubrutinib 60mg + upadacitinib 30mg), ABBV-599 low dose (LD; elsubrutinib 60mg + upadacitinib 15mg), elsubrutinib 60mg, upadacitinib 30mg, or placebo. The primary endpoint was the proportion of patients achieving both SLE Responder Index-4 (SRI-4) and glucocorticoid dose ≤10mg QD at week 24. Additional assessments through week 48 included British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS) responses, number of flares, time to first flare, and adverse events. The study enrolled 341 patients. The ABBV-599LD and elsubrutinib arms were discontinued after a planned interim analysis showed lack of efficacy (no safety concerns). More patients achieved the primary endpoint with upadacitinib (54.8%; P=0.028) and ABBV-599HD (48.5%; P=0.081) versus placebo (37.3%). SRI-4, BICLA, and LLDAS response rates were higher for both upadacitinib and ABBV-599HD versus placebo at weeks 24 and 48. Flares were reduced and time to first flare through week 48 was substantially delayed with both upadacitinib and ABBV-599HD versus placebo. No new safety signals were observed beyond those previously reported for upadacitinib or elsubrutinib. Upadacitinib 30mg alone or in combination with elsubrutinib (ABBV-599HD) demonstrated significant improvements in SLE disease activity, reduced flares and were well tolerated through 48 weeks.

Early reappearance of intraclonal proliferative subpopulations in ibrutinib-resistant chronic lymphocytic leukemia.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib represents an effective strategy for treatment of chronic lymphocytic leukemia (CLL), nevertheless about 30% of patients eventually undergo disease progression. Here we investigated by flow cytometry the long-term modulation of the CLL CXCR4dim/CD5bright proliferative fraction (PF), its correlation with therapeutic outcome and emergence of ibrutinib resistance. By longitudinal tracking, the PF, initially suppressed by ibrutinib, reappeared upon early disease progression, without association with lymphocyte count or serum beta-2-microglobulin. Somatic mutations of BTK/PLCG2, detected in 57% of progressing cases, were significantly enriched in PF with a 3-fold greater allele frequency than the non-PF fraction, suggesting a BTK/PLCG2-mutated reservoir resident within the proliferative compartments. PF increase was also present in BTK/PLCG2-unmutated cases at progression, indicating that PF evaluation could represent a marker of CLL progression under ibrutinib. Furthermore, we evidence different transcriptomic profiles of PF at progression in cases with or without BTK/PLCG2 mutations, suggestive of a reactivation of B-cell receptor signaling or the emergence of bypass signaling through MYC and/or Toll-Like-Receptor-9. Clinically, longitudinal monitoring of the CXCR4dim/CD5bright PF by flow cytometry may provide a simple tool helping to intercept CLL progression under ibrutinib therapy.

Impaired Cardiac AMPK (5'-Adenosine Monophosphate-Activated Protein Kinase) and Ca2+-Handling, and Action Potential Duration Heterogeneity in Ibrutinib-Induced Ventricular Arrhythmia Vulnerability.

We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear. The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times-to-peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, P<0.05) in hearts from ibrutinib-treated rats. VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.

The role of Bruton's tyrosine kinase in pathogenesis of chronic spontaneous urticaria and the prospects for the use of new treatment

Chronic spontaneous urticaria is a fairly common disease with an unpredictable course, burdensome symptoms and a significant negative impact on patients` quality of life. Despite the established stepwise approach to treatment with antihistamines in standard and increased dosages, anti-IgE therapy, there remains a portion of patients with unsatisfactory control of urticaria symptoms, with the need to develop drugs that target new therapeutic targets. Mast cells, basophils and B cells are key cells involved in the pathogenesis of urticaria; activation, differentiation, proliferation, cytokine secretion and degranulation in all three types of cells is regulated via Bruton's tyrosine kinase signalling pathway through FcεRI and BCR receptors respectively. Inhibition of Bruton's tyrosine kinase is being developed as a new therapeutic strategy for chronic spontaneous urticaria. Here we present overview of the current understanding of chronic spontaneous urticarial`s pathogenesis, the role of Bruton's tyrosine kinase, the history of medical use of Bruton's tyrosine kinase inhibitors, as well as clinical data on the use of new Bruton's tyrosine kinase inhibitors in patients with chronic spontaneous urticaria who have not achieved adequate disease control with antihistamines.

EE506 Clinical Consequences and Associated Costs of Treating Patients With Waldenström Macroglobulinemia in the First-Line Setting With Bruton Tyrosine Kinase Inhibitors

EE506 Clinical Consequences and Associated Costs of Treating Patients With Waldenström Macroglobulinemia in the First-Line Setting With Bruton Tyrosine Kinase Inhibitors

Lysosome-Disrupting Agents in Combination with Venetoclax Increase Apoptotic Response in Primary Chronic Lymphocytic Leukemia (CLL) Cells Mediated by Lysosomal Cathepsin D Release and Inhibition of Autophagy.

Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the combination could be immunosuppressive. Lysosomes have previously been identified as a target for obinutuzumab cytotoxicity in CLL cells, but the mechanism remains unclear. In addition, studies have shown that lysosomotropic agents can cause synergistic cell death in vitro when combined with the BTK inhibitor, ibrutinib, in primary CLL cells. This indicates that targeting lysosomes could be a treatment strategy for CLL. In this study, we have shown that obinutuzumab induces lysosome membrane permeabilization (LMP) and cathepsin D release in CLL cells. Inhibition of cathepsins reduced obinutuzumab-induced cell death in CLL cells. We further determined that the lysosomotropic agent siramesine in combination with venetoclax increased cell death in primary CLL cells through an increase in reactive oxygen species (ROS) and cathepsin release. Siramesine treatment also induced synergistic cytotoxicity when combined with venetoclax. Microenvironmental factors IL4 and CD40L or incubation with HS-5 stromal cells failed to significantly protect CLL cells from siramesine- and venetoclax-induced apoptosis. We also found that siramesine treatment inhibited autophagy through reduced autolysosomes. Finally, the autophagy inhibitor chloroquine failed to further increase siramesine-induced cell death. Taken together, lysosome-targeting drugs could be an effective strategy in combination with venetoclax to overcome drug resistance in CLL.

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors

In this editorial, we offer a summary of the risk associated with hepatitis B reactivation (HBVr) in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase (BTK) inhibitors, with insights derived from current studies. Furthermore, we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments. This framework is essential for identifying those at increased risk of HBVr, enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

Cardiovascular events of Bruton's tyrosine kinase inhibitors: A real-world study based on the United States Food and Drug Administration Adverse Event Reporting System database.

Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs. Across all indications of three FDA-approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD). A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13-2.93]), pulmonary oedema (ROR = 2.15 [1.19-3.88]), ventricular extrasystoles (ROR = 5.18 [2.15-12.44]), heart rate irregular (ROR = 3.05 [1.53-6.11]), angina pectoris (ROR = 3.18 [1.71-5.91]) and cardiotoxicity (ROR = 25.22 [17.14-37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications. Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Bruton's tyrosine kinase inhibitor-related cardiotoxicity: The quest for predictive biomarkers and improved risk stratification.

Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable responses and prolonging survival, roughly 20-25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation. While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.

BGB-11417-203: An ongoing, phase 2 study of sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, in patients with Waldenström macroglobulinemia.

TPS7090 Background: Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 antibody-based systemic therapy are included within the preferred treatment algorithms for Waldenström macroglobulinemia (WM). However, to date, no treatments have been approved for patients with WM that is refractory to both BTK inhibitors and anti-CD20 therapy. Venetoclax, the first-generation BCL2 inhibitor, has demonstrated clinical activity in patients with relapsed/refractory (R/R) WM (Castillo et al. J Clin Oncol. 2022), but it has no regulatory approvals in WM. Sonrotoclax, a next generation BCL2 inhibitor, is more selective and a more pharmacologically potent inhibitor of BCL2 than venetoclax. In a phase 1 trial, sonrotoclax monotherapy was well tolerated at all dose levels tested up to 640 mg and showed promising evidence of antitumor activity in patients with R/R WM (Soumerai et al. Blood. 2022). Based on the data from these earlier studies, a phase 2 study of sonrotoclax monotherapy in patients with WM has been initiated and is currently recruiting. Methods: BGB-11417-203 (NCT05952037) is an open-label, international, phase 2 study. Eligible patients have histologically confirmed WM that is R/R to both BTK inhibitor therapy and anti-CD20–based systemic therapy combined with chemotherapy or a proteasome inhibitor (PI; Cohort 1); R/R to anti-CD20–based systemic therapy combined with chemotherapy or a PI and who are intolerant to BTK inhibitor therapy (Cohort 2); or R/R to a BTK inhibitor and who are unsuitable for chemoimmunotherapy (Cohort 3). Patients who have received previous treatment with a BCL2 inhibitor are ineligible. Approximately 85 patients will be enrolled across cohorts and will receive sonrotoclax until disease progression, death, unacceptable toxicity, patient withdrawal, loss to follow-up, or study termination. The primary endpoint is major response rate (MRR; defined as partial response or better) in Cohort 1 per IWWM-11 criteria, as assessed by independent review committee (IRC). Key secondary endpoints include MRR assessed by investigator (INV) in Cohort 1 and by IRC and INV in both Cohorts 2 and 3; overall response rate, duration of response, and progression-free survival by IRC and INV; overall survival; and safety and tolerability. Patient recruitment is ongoing in Australia, the US, China, and Europe. Clinical trial information: NCT05952037 .

Real-world risk of bleeding events in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) treated with BTKi.

7052 Background: Bruton tyrosine kinase inhibitors (BTKis) are effective treatments for various B-cell malignancies including CLL/SLL but are known to be associated with increased bleeding risk. Current evidence indicating this association has largely been demonstrated in clinical trial research. However, bleeding risk in real-world CLL/SLL patients, who are often sicker with more comorbidities requiring anticoagulant (AC) or antiplatelet (AP) use is not well described. This study aimed to assess the prevalence of AC/AP use and explore risk factors for bleeding among real-world CLL/SLL patients receiving BTKi therapies. Methods: We conducted a retrospective cohort study using the claims-linked Premier PINC AI Healthcare Database of patients aged ≥18 years with a diagnosis of CLL/SLL from July 1, 2016 to March 31, 2022. Patients were followed from first BTKi prescription fill (index date) to earliest of BTKi discontinuation, death, or end of the study period. Patient comorbidities, treatments, and bleeding events were assessed using diagnosis and procedure codes and prescription claims. Multivariable-adjusted risk for bleeding events was assessed with Cox proportional-hazards regression. Results: Among 2091 patients with CLL/SLL receiving BTKi therapies, mean age was 65.7 years, 61.8% were men, and 77.7% were White. BTKi treatments included ibrutinib (86.3%), acalabrutinib (13.1%), and zanubrutinib (&lt;1%). Overall, 4.3% of patients switched BTKis during follow-up; 615 (29.4%) had AC/AP use at any time during the study period, of whom 411 (66.8%) started after BTKi initiation. Bleeding events occurred in 526 (25.2%) patients during a mean BTKi exposure of 14.2 months, with an incidence of 26.6 per 100 person-years (PYs) overall, and 37.2 and 22.0 per 100 PYs in patients with and without any prescription AC/AP use, respectively. The proportion of patients with fatal bleeding was &lt;0.3%. In adjusted models, risk of first bleeding event was higher for AC use (HR [95% CI] 2.33 [1.83–2.98]), age ≥65 years (1.32 [1.14–1.53]), women (1.28 [1.10–1.48]), and history (during 90 days prior to BTKi start) of bleeding (2.27 [1.87–2.76]), ulcers (2.21 [1.06–4.63]) or myocardial infarction (MI) (1.74 [1.31–2.33]) (all P≤0.05). Prescription AP use, race/ethnicity, and history of chronic kidney disease or thrombocytopenia were not statistically significant. Conclusions: In this large real-world study of bleeding risk in patients receiving BTKis, bleeding events occurred in 26.6 per 100 patients per year, with higher risk in AC users, women, and patients with history of bleeding, ulcers, or MI. However, the risk of fatal bleeding was low.

Real-world adherence and healthcare resource utilization of Bruton tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma.

e19048 Background: This study aimed to examine treatment adherence and healthcare resource utilization (HCRU) of BTKi treatment in mantle cell lymphoma (MCL). Methods: The Symphony Integrated Dataverse (IDV) was used to conduct a retrospective observational study. Adult patients with MCL initiating their first BTKi or second BTKi (after ibrutinib) between 01/2020 and 10/2023 were included in the study. The index was defined as the date of BTKi initiation. Patients without 30 days of continuous enrollment pre- and post-index date were excluded. Patients were followed until the end of the study period or lost to follow-up. Adherence was evaluated by compliance and persistence. Compliance was calculated as the proportion of days covered &gt;0.80 using 30-day intervals from initiation to 1 year. Persistence was measured as the proportion of patients who remained in treatment among patients with sufficient follow-up periods. HCRU was measured by all-cause outpatient visits, inpatient services, and other medical/hospital services per-patient-per-month (PPPM) during BTKi treatment. Results: Among 2,122 patients who were first-time BTKi users, there were significant differences for mean age at index (acalabrutinib=70; ibrutinib=68; zanubrutinib=70, P&lt;.0001), commercial insurance (acalabrutinib=34%; ibrutinib=42%; zanubrutinib=47%, P&lt;.0001), and baseline atrial fibrillation (acalabrutinib=1.94%; ibrutinib=1.24%; zanubrutinib=3.47%, P=0.0232). A total of 228 patients switched from ibrutinib to acalabrutinib or zanubrutinib. Adherence results suggested zanubrutinib had numerically better 1-year compliance ( P=0.2176) and treatment persistence at 1 and 2 years ( P=0.2687; P=0.6270) for patients who switched from ibrutinib to zanubrutinib or acalabrutinib (Table). HCRU showed that the mean (SD) outpatient visits (1.12 [1.67] vs 1.62 [3.17]; P=0.1755) and inpatient services (0.22 [0.68] vs 0.68 [3.12]; P=0.1693) were lower in patients switched from ibrutinib to zanubrutinib than acalabrutinib. Conclusions: In this study, zanubrutinib was associated with a trend towards improved compliance, persistence, and HCRU when used as the first BTKi and after prior ibrutinib. [Table: see text]

Cardiotoxicity from bruton tyrosine kinase inhibitors (BTKi)—an analysis of an administrative health claims database

BackgroundFirst generation Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib have been associated with cardiovascular toxicities. Newer generation BTKi (e.g.,acalabrutinib and zanabrutinib) have been associated with lower incidence of cardiotoxicity in clinical trials.ObjectiveGiven paucity in real-world data on the overall cardiac risk factor profile, especially with the newer BTKi, our study evaluated the incidence of cardiotoxicity with various BTKi among a large, commercially insured population of patients.MethodsWe performed a retrospective cohort analysis of all adults with a diagnosis of B-cell malignancy undergoing treatment with BTKi acalabrutinib and ibrutinib between January 2018 and June 2020 using Optum’s de-identified Clinformatics® Data Mart Database. We then identified patients who had pre-existing cardiac disease one year prior to starting BTKi. New incidence of atrial fibrillation/flutter, hypertension, bleeding, ventricular tachycardia/fibrillation and sudden cardiac death from the time of index presciption were compared with standard Chi Square or Student t-test where appropriate. Multivariate logistic regression models were also estimated to evaluate for confounding.ResultsA total of 1691 patients were included in the final analysis. 1595 (94%, median age 75 (19–90) years, 61% male gender) patients received ibrutinib, and 96 (6%, median age 73.5 (32–90) years, 62.5% male gender) patients received acalabrutinib. The median duration of drug exposure of ibrutinib was 238 (2-1084) days vs. 150 (30–870) days for acalabrutinib. There was lower new incidence of atrial fibrillation/flutter (4.6%-vs-17%, p = 0.013), hypertension (6.3%-vs-25%, p = NS), sudden cardiac arrest/death (0% vs. 1.5%, p = NS) in the acalabrutinib group compared to ibrutinib, of which only the lower incidence of atrial fibrillation/flutter was statistically significant. This was despite the finding of a higher prevalence of atrial fibrillation/flutter at baseline in patients receiving acalabrutinib.ConclusionsThere was lower incidence of new atrial fibrillation/flutter with acalabrutinib when compared to ibrutinib in a real-world cohort of patients.

Real-world treatment switching and sequencing to next line of therapy of zanubrutinib, acalabrutinib, and ibrutinib in CLL/SLL.

e19022 Background: Evaluating use of Bruton tyrosine kinase inhibitors (BTKis) for the treatment of CLL/SLL is crucial to understand real-world outcomes of these therapies in diverse populations. The objective of this study was to evaluate real-world switching and sequencing to next line of therapy in patients (pts) initiating BTKis as first-line (1L) or second-line (2L) CLL/SLL treatment. Methods: A retrospective study was conducted using IntegraConnect PrecisionQ to identify adult pts with ≥1 diagnosis for CLL/SLL initiating zanubrutinib (zanu), acalabrutinib (acala), or ibrutinib (ibru) in 1L or 2L between 1/1/2020-2/28/2023 (index period). Index date was defined as date of BTKi initiation. Pts were required to be continuously enrolled for ≥30 days pre- and post-index date. Treatment switching was measured as pts initiating another treatment within same line or advancing to next line of therapy within 90 days. Sequencing to next line of therapy was calculated from time to next treatment Kaplan-Meier curve, censoring patients at end of follow-up, and reported as proportion of pts receiving next line of therapy at 180 days. Results: 2,816 pts initiated a 1L BTKi (zanu=157; acala=1,238; ibru=1,421) and 1,253 initiated a 2L BTKi (zanu=107; acala=672; ibru=474). No major differences were observed in baseline demographic and clinical characteristics among 1L and 2L BTKi cohorts. Median follow-up in 1L was 123 days for zanu, 406 days for acala, and 637 days for ibru. Regardless of line of therapy, switching rate at ≤60 days and 61-89 days was statistically significantly lower for pts receiving zanu vs acala and ibru (P&lt;0.0001, both 1L and 2L) (Table). Proportion of pts receiving next line of therapy at 180 days was lower for zanu vs acala and ibru (1L P=0.2958; 2L P&lt;0.0001) (Table). Conclusions: Zanu pts had significantly lower switching rate within 90 days and lower proportion of pts receiving next line of therapy at 180 days when compared with acala and ibru in 1L and 2L. Longer follow-up and larger zanu sample size are required for a comprehensive assessment of treatment outcomes associated with use of BTKis in CLL/SLL. [Table: see text]

Real-world understanding of the unmet need for treatment of non-covalent BTKi in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

e19028 Background: Non-covalent (nc) Bruton Tyrosine Kinase inhibitors (BTKi) for the treatment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (CLL/SLL) provide patients with a new treatment option after resistance to on-target BTK mutations or PLCγ2 mutations that bypass BTK inhibition. Given the December 1, 2023 accelerated FDA approval for pirtobrutinib, a nc-BTKi, in the treatment of CLL/SLL for treatment of patients who have received at least two prior lines of therapy with a covalent (c) BTKi and a B-Cell Lymphoma 2 Protein Inhibitor (BCL2i), we sought to understand the addressable population for treatment with nc-BTKI therapy in a real-world database of CLL/SLL patients. Methods: We used the Integra Connect PrecisionQ real-world de-identified database of over 3 million cancer pts across 500 sites of care to identify CLL/SLL pts for the analysis. The CLL patients included for the analysis were on a treatment in 2023 and must have had either &gt;5 CLL/SLL diagnosed visits or more CLL/SLL visits than non-CLL/SLL visits if &lt;5 CLL/SLL diagnosed visits. Descriptive analyses were used for this study. Results: Of the 6,992 patients treated for CLL/SLL in 2023, the median age at treatment start was 71, 62% were male, 65% identified as White, 6% as African American, and 29% as Other. Of the pts, 12% received a c-BTKi and BCL2i, 64% received a c-BTKi only, and 12% received a BCL2i only. Of the 12% of pts who received a c-BTKi and BCL2i, 191 pts started a subsequent line of therapy. Among pts who received a c-BTKi and BCL2i, 79% received a BTKi therapy first, 10% received a BCL2i therapy first, and 12% had a line of therapy with both a BTKi and BCL2i. We found 59 pts who received nc-BTKi; among those pts, 51% received a c-BTKi and BCL2i prior to initiation of nc-BTKi. The median age at first treatment for CLL/SLL was 71.7 for those who received a c-BTKi, 71.1 for those who received a BCL2i, and 70.8 for those who received nc-BTKi. The median age at first diagnosis for CLL/SLL was 68 for those who received a c-BTKi, 66 for those who received a BCL2i, and 63 for those who received nc-BTKi. The median time to first treatment was 470 days for pts treated with a c-BTKi, 507 days for pts treated with BCL2i, and 587 days for pts treated with nc-BTKi. Conclusions: We found that among nearly 7,000 treated patients in the database, 12% were treated with both a c-BTKi and BCL2i; of those, just 23% started a subsequent treatment. Among patients who were treated with a nc-BTKi we found their median age at treatment start and diagnosis was lower than those who received a c-BTKi or BCL2i respectively.