Bruton Tyrosine Kinase Inhibitor Ibrutinib Research Articles

Ibrutinib impairs IGF-1-dependent activation of intracellular Ca handling in isolated mouse ventricular myocytes.

The Bruton tyrosine kinase (BTK) inhibitor Ibrutinib is associated with a higher incidence of cardiotoxic side effects including heart failure (HF). Ibrutinib is capable of inhibiting PI3K/Akt signaling in neonatal rat ventricular cardiomyocytes when stimulated with insulin-like growth factor 1 (IGF-1). We therefore hypothesized that Ibrutinib might disrupt IGF-1-mediated activation of intracellular Ca handling in adult mouse cardiomyocytes by inhibiting PI3K/Akt signaling. Isolated ventricular myocytes (C57BL6/J) were exposed to IGF-1 at 10 nmol/L in the presence or absence of Ibrutinib (1 µmol/L) or Acalabrutinib (10 µmol/L; cell culture for 24 ± 2 h). Intracellular Ca handling was measured by epifluorescence (Fura-2 AM) and confocal microscopy (Fluo-4 AM). Ruptured-patch whole-cell voltage-clamp was used to measure ICa. Levels of key cardiac Ca handling proteins were investigated by immunoblots. IGF-1 significantly increased Ca transient amplitudes by ∼83% as compared to vehicle treated control cells. This was associated with unaffected diastolic Ca, enhanced SR Ca loading and increased ICa. Co-treatment with Ibrutinib attenuated both the IGF-1-mediated increase in SR Ca content and in ICa. IGF-1 treated cardiomyocytes had significantly increased levels of pS473Akt/Akt and SERCA2a expression as compared to cells concomitantly treated with IGF-1 and Ibrutinib. SR Ca release (as assessed by Ca spark frequency) was unaffected by either treatment. In order to test for potential off-target effects, second generation BTK inhibitor Acalabrutinib with greater BTK selectivity and lower cardiovascular toxicity was tested for IGF1-mediated activation of intracellular Ca handling. Acalabrutinib induced similar effects on Ca handling in IGF-1 treated cultured myocytes as Ibrutinib in regard to decreased Ca transient amplitude and slowed Ca transient decay, hence implying a functional class effect of BTK inhibitors in cardiac myocytes. Inhibition of BTK by Ibrutinib impairs IGF-1-dependent activation of intracellular Ca handling in adult ventricular mouse myocytes in the face of disrupted Akt signaling and absent SERCA2a upregulation.

Drug-drug interactions and dose management of BTK inhibitors when initiating nirmatrelvir/ritonavir (paxlovid) based on physiologically-based pharmacokinetic models

ObjectiveCo-administration of Bruton's tyrosine kinase (BTK) inhibitors with nirmatrelvir/ritonavir is challenging because of potential drug-drug interactions (DDIs). However, clinical trials specifically evaluating such DDIs are absent. To evaluate and quantify the DDIs between them and provide rational dose management strategies of BTK inhibitors, we conducted this study using physiologically-based pharmacokinetic (PBPK) models. MethodsPhysicochemical properties and pharmacokinetic parameters were acquired from the published literature and databases. The PBPK models were developed using Simcyp® software. These models were validated by comparing with published literature values. The successfully validated PBPK models were used to simulate the plasma concentration-time profiles and DDIs in a virtual healthy population receiving BTK inhibitors alone or with ritonavir. ResultsSimulated plasma concentration-time profiles and pharmacokinetic parameters of each drug were in agreement with clinically observed values from literatures. Ritonavir increased ibrutinib maximum plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC) 33- and 53.88-fold, respectively, increased zanubrutinib Cmax and AUC 2.57- and 3.18-fold, respectively, and increased acalabrutinib Cmax and AUC 3.85- and 6.54-fold, respectively. Based on our simulations, dose-adjustment strategies may consist of ibrutinib at 25 mg q48h, zanubrutinib at 80 mg twice-daily and acalabrutinib at 25 mg twice-daily with nirmatrelvir/ritonavir. ConclusionsThe PBPK models predicted the in vivo pharmacokinetics and the DDIs of BTK inhibitors and ritonavir. The prospective simulations not only provided scientific evidence regarding rational dosing management strategies when initiating nirmatrelvir/ritonavir therapy but also provided a reference for the design of clinical DDIs study that may save resources and time. SummaryPaxlovid could increase Cmax and AUC0-τ of BTK inhibitors (ibrutinib, zanubrutinib and acalabrutinib), and dose adjustment strategy of ibrutinib (25 mg q48h), zanubrutinib (80 mg q12h) and acalabrutinib (25 mg q12h) should be considered when combination with nirmatrelvir/ritonavir.

Treatment with idelalisib in patients with chronic lymphocytic leukemia – real world data from the registry of the German CLL Study Group

Idelalisib in combination with rituximab is an efficacious treatment for patients suffering from chronic lymphocytic leukemia (CLL) with known limitations due to toxicities. However, the benefit after prior Bruton tyrosine kinase inhibitor (BTKi) therapy remains unclear. For this analysis, 81 patients included in a non-interventional registry study of the German CLL study group (registered at www.clinicaltrials.gov as # NCT02863692) meeting the predefined criteria of a confirmed diagnosis of CLL and being treated with idelalisib containing regimens outside clinical trials were considered. 11 patients were treatment naïve (13.6%) and 70 patients (86.4%) pretreated. Patients had median of one prior therapy line (range 0–11). Median treatment duration with idelalisib was 5.1 months (range 0–55.0 months). Of 58 patients with documented treatment outcome, 39 responded to idelalisib containing therapy (67.2%). Patients treated with the BTKi ibrutinib as last prior treatment prior to idelalisib responded in 71.4% compared to a response rate of 61.9% in patients without prior ibrutinib. Median event free survival (EFS) was 15.9 months with a 16 versus 14 months EFS in patients with ibrutinib as last prior treatment or not, respectively. Median overall survival was 46.6 months. In conclusion, treatment with idelalisib appears to have a valuable impact in patients being refractory to prior ibrutinib therapy even though there are limitations in our analysis due to the low number of patients included.

Waldenström's macroglobulinemia - clinical symptoms and review of therapy yesterday, today and tomorrow.

Waldenström macroglobulinemia (WM) is a lymphoplasmocytic lymphoma with immunoglobulin M monoclonal protein. The incidence of this disease is very low (0.4/100,000), so that this disease can be regarded as an orphan's disease. It means that new drugs are often tested and registered for more frequent diseases. In this review we will focus on the efficacy of the new drugs for WM. The current treatment options for symptomatic WM patients include alkylating agent cyclophosphamide and anti-CD20 monoclonal antibodies. Therapy with rituximab and bendamustin resulted in longer therapeutic response then therapy with rituximab, cyclophosphamide and dexamethasone. Many drugs, used in multiple myeloma (MM), shoved promising results in WM patients. Bortezomib is effective in WM, but its neurotoxicity is higher in WM than in MM patients. Therefore, new proteasome inhibitors, carfilzomib and ixazomib, are better tolerated as documented in several studies. New types of antiCD20 antibody (obinutuzumab) can be used in patients with rituximab intolerance. in five of our patients with WM, obinutuzumab and bendamustin reached deeper responses than therapies administered in previous lines of therapy. Oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib alone and in combination with rituximab have extended the treatment options for WM patients. New BTK inhibitors (e. g. acalabrutinib, zanubrutinib, and vecabrutinib) were tested and their lower toxicity (atrial fibrillation) was documented. Moreover, the BCL2 inhibitor venetoclax is newly tested. New antiCD20 antibody (obinutuzumab) is of advantage in patients with WM with rituximab intolerance as well as bendamustin and new proteasome inhibitors (ixazomib and carfilzomib) or new BTK inhibitors with lower cardiotoxicity. Many of the abovementioned drugs do not have official registration for WM and can be administrated with the consent of the health care provider only. Thus, this work brings evidence of their efficacy.

The efficacy and safety of Bruton tyrosine kinase inhibitors as monotherapy in the treatment of newly diagnosed patients with Waldenström macroglobulinemia

Objective: To investigate the efficacy and safety of Bruton tyrosine kinase inhibitors (BTKi) ibrutinib or zanubrutinib monotherapy in newly diagnosed patients with Waldenström macroglobulinemia (WM) . Methods: The efficacy and adverse effects of 58 patients with newly diagnosed WM receiving BTKi monotherapy in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were analyzed retrospectively from January 2018 to August 2022. Results: The response of 55 patients may be examined. Forty patients received ibrutinib monotherapy for a median of 15 months, with an overall response rate (ORR) of 85%, a main remission rate (MRR) of 70%, and a very good partial remission (VGPR) rate of 10%. Fifteen patients received zanubrutinib monotherapy for a median of 13 months, with an ORR of 93%, an MRR of 73%, and a VGPR rate of 0%. For various reasons, 10 patients were converted from ibrutinib to zanubrutinib. Ibrutinib treatment lasted an average of 7.5 months before conversion. The median duration of zanubrutinib therapy after conversion was 3.5 months. The ORRs before and after conversion were 90% and 100%, MRRs were 80% and 80%, and VGPR rates were 10% and 50%, respectively. After a median of 16 months, the 24-month progression-free survival (PFS) rate of patients who received both BTKi was 86%. PFS did not differ statistically across individuals with low, medium, and high-risk ISS scores (P=0.998). All of the patients survived. The most common side effects of BTKi were neutropenia and thrombocytopenia, which occurred in 12% and 10% of all patients, respectively. Ibrutinib accounts for 5% of atrial fibrillation, and zanubrutinib has a 7% risk of bleeding. Conclusions: In treating WM, ibrutinib or zanubrutinib provides good efficacy and tolerable adverse effects.

Immunomodulating effects of antitumor drugs Bruton tyrosine kinase inhibitors and the possibility of their use in allergic and infectious diseases

Bruton's tyrosine kinase (BTK) inhibitors represent a class of drugs that have demonstrated their efficacy and safety in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphomas who were considered refractory to any previously used type of therapy. BTK plays a key role in all stages of B lymphocyte development, but in recent years, there have been data indicating that BTK is also involved in the activation of myeloid cells.The aim of this study is to analyze and systematize all published materials on the immunomodulatory effects of BTK inhibitors (ibrutinib, acalabrutinib, etc.).A systematic review of the scientific literature was performed using a step-by-step search process in electronic databases (PubMed, Web of Science, ScienceDirect, and Scopus). The following keywords were used in the database search: “CLL”, “BTK”, “ibrutinib”, “COVID-19”, “allergy”, “inflammation.” The search for studies was conducted from the time of the first BTK inhibitor drug (ibrutinib) appearance in 2009 until December 2022.The results of the study on the influence of BTK inhibitors on the functional state of B and T lymphocytes, neutrophils, and monocytes/macrophages are presented. The immunomodulatory effects of ibrutinib on adaptive and innate immune system cells, including CD4+ and CD8+T lymphocytes and NK cells, are described. Since BTK inhibitors alter the functional activity of phagocytic cells and the ratio of T cell populations, there is a suggestion about the possibility of using these drugs for the treatment of other nosological forms, not only B cell malignancies, which is currently being studied in clinical trials. Data on the use of BTK inhibitors to combat hyperacute inflammation and to suppress allergic reactions, including anaphylaxis, are summarized. In addition, the expediency of short-term use of BTK inhibitors to reduce the risk of side effects during oral immunotherapy and for desensitization to drugs is discussed.The presented data indicate that BTK inhibitors are promising drugs with immunomodulatory effects. However, BTK inhibitors need to increase selectivity to reduce off-target effects on other kinases.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Next-generation Bruton tyrosine kinase inhibitors (BTKis) acalabrutinib (acala) and zanubrutinib (zanu) were compared with the standard of care BTKi ibrutinib in relapsed/refractory chronic lymphocytic leukemia (RR CLL) in the head-to-head randomized clinical trials (RCTs) ELEVATE-RR and ALPINE, respectively. However, differences in these RCT’s populations prevent comparison of acala and zanu. ASCEND, another RCT assessing acala, had a similar population to ALPINE but a different comparator. Thus, we used unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala vs zanu using individual patient data (IPD) from ASCEND and published aggregate data from ALPINE. Methods: Acala IPD from ASCEND were weighted to match zanu baseline data from ALPINE. This reduced differences in variables that were prognostic/effect-modifying of progression-free survival (PFS) in an exploratory multivariate cox regression analysis of ASCEND. These included sex, ECOG PS, bulky disease, prior chemoimmunotherapy, del(11q), del(17p), TP53 without del(17p), IGHV status, region, age, prior lines of therapy and Rai stage. An efficacy analysis assessed investigator-assessed PFS (INV PFS) in randomized patients with baseline data (acala, n = 149; zanu, n = 327). Pseudo IPD for INV PFS for zanu were obtained from Kaplan-Meier curves. A safety analysis assessed odds ratios (ORs) of adverse events (AEs) in treated patients with baseline data (acala, n = 148; zanu, n = 324). To compare the incidence of AEs, an artificial data cut-off (Feb 21, 2020) was imposed for acala to match the zanu median treatment exposure (both 28.4 months). Results: After matching, the effective sample size of acala was 99 (66.6%; 65% male; median age 66 years). 12- and 24-month INV PFS are shown in Table 1. The MAIC hazard ratio (HR) for INV PFS is similar for acala vs zanu: HR 0.90, 95% confidence interval (CI) 0.60–1.36. The risk of having grade ≥3 AE (OR 0.66, 95% CI 0.41–1.05), atrial fibrillation (AF; OR 1.32, 95% CI 0.56–3.08), grade ≥3 AF/atrial flutter (OR 0.60, 95% CI 0.12–2.89), grade ≥3 hemorrhage (OR 0.61, 95% CI 0.19–2.03) or an AE leading to discontinuation (OR 1.14, 95% CI 0.61–2.13) was similar with acala vs zanu. The risk of having a serious AE (OR 0.61, 95% CI 0.39–0.97), hypertension (any grade: OR 0.18, 95% CI 0.09–0.37; grade ≥3: OR 0.22, 95% CI 0.09–0.54), any grade hemorrhage (OR 0.54, 95% CI 0.34–0.87) or an AE leading to dose reduction (OR 0.30, 95% CI 0.14–0.67) favored acala vs zanu. Conclusions: Acala and zanu have a similar efficacy in RR CLL, while acala has a lower risk of grade ≥3 hemorrhage, any grade and grade ≥3 hypertension and dose reduction due to AEs vs zanu. Limitations of MAICs mean results should be viewed as hypothesis-generating. Encore Abstract—previously submitted to ASCO 2023, EHA 2023 The research was funded by: AstraZeneca Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract P. Ghia Consultant or advisory role AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Research funding: AbbVie, AstraZeneca, Janssen, Roche A. Skarbnik Consultant or advisory role AstraZeneca, Abbvie, Genentech, Genmab, Novartis, Kite Pharma, Epizyme, Janssen, Morphosys, Pharmacyclcics, SeaGen, TG Therapeutics, Lilly (LOXO) Other remuneration: Speakers' Bureau: AstraZeneca, Abbvie, Beigene, Celgene, Genentech, Janssen, Kite Pharma, Pharmacyclics, SeaGen, TG Therapeutics M. Miranda Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca A. S. Yong Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Roos Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca Other remuneration: Patient/Royalties/Other Intellectual Property: CalciMedica R. Hettle Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca S. Palazuelos-Munoz Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca V. Shetty Employment or leadership position: AstraZeneca Stock ownership: Verona Pharma A. Kittai Consultant or advisory role Abbvie, AstraZeneca, Beigene, BMS, Eli Lilly, Janssen, KITE Research funding: AstraZeneca Other remuneration: Speaker's bureau: Beigene

Discovery of novel dual Bruton’s tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronically systemic autoimmune disorder, which is related with various cellular signal pathways. Both BTK (Bruton’s Tyrosine Kinase) and JAK3 (Janus Kinase 3) play important roles in the pathogenesis of rheumatoid arthritis. Herein, we reported the discovery of dual BTK/JAK3 inhibitors through bioisosterism and computer-aided drug design based on the structure of BTK inhibitor ibrutinib. We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, compound XL-12 (LD50 > 1600 mg/kg) exerted improved safety compared with ibrutinib (LD50 = 750 mg/kg). These results indicated that compound XL-12, the dual BTK/JAK3 inhibitor, might be a potent drug candidate for the treatment of RA.

Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy.

Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans. Heterobivalent BTK protein degraders are also in development, based on the premise that proteolysis targeting chimeras (PROTACs) may provide additional therapeutic benefits. However, most BTK PROTACs are based on the BTK inhibitor ibrutinib raising concerns about their selectivity profiles, given the known off-target effects of ibrutinib. Here, we disclose the discovery and in vitro characterization of BTK PROTACs based on the selective BTK inhibitor GDC-0853 and the cereblon recruitment ligand pomalidomide. PTD10 is a highly potent BTK degrader (DC50 0.5 nM) that inhibited cell growth and induced apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, and had improved selectivity compared to ibrutinib-based BTK PROTACs.

A Non-Canonical Role for the Glycosyltransferase Enzyme UGT2B17 as a Novel Constituent of the B Cell Receptor Signalosome.

In chronic lymphocytic leukemia (CLL), an elevated glycosyltransferase UGT2B17 expression (UGT2B17HI) identifies a subgroup of patients with shorter survival and poor drug response. We uncovered a mechanism, possibly independent of its enzymatic function, characterized by an enhanced expression and signaling of the proximal effectors of the pro-survival B cell receptor (BCR) pathway and elevated Bruton tyrosine kinase (BTK) phosphorylation in B-CLL cells from UGT2B17HI patients. A prominent feature of B-CLL cells is the strong correlation of UGT2B17 expression with the adverse marker ZAP70 encoding a tyrosine kinase that promotes B-CLL cell survival. Their combined high expression levels in the treatment of naïve patients further defined a prognostic group with the highest risk of poor survival. In leukemic cells, UGT2B17 knockout and repression of ZAP70 reduced proliferation, suggesting that the function of UGT2B17 might involve ZAP70. Mechanistically, UGT2B17 interacted with several kinases of the BCR pathway, including ZAP70, SYK, and BTK, revealing a potential therapeutic vulnerability. The dual SYK and JAK/STAT6 inhibitor cerdulatinib most effectively compromised the proliferative advantage conferred by UGT2B17 compared to the selective BTK inhibitor ibrutinib. Findings point to an oncogenic role for UGT2B17 as a novel constituent of BCR signalosome also connected with microenvironmental signaling.

Polatuzumab-bendamustine-rituximab as bridge to CD19-directed CAR T cells in mantle cell lymphoma refractory to ibrutinib and venetoclax.

Polatuzumab-bendamustine-rituximab as bridge to CD19-directed CAR T cells in mantle cell lymphoma refractory to ibrutinib and venetoclax.

Abstract 5866: Mavorixafor enhances apoptosis of tumor cells treated with ibrutinib or venetoclax in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia

Abstract Despite advances in therapies for B-cell lymphoma, patients may still develop resistance and often relapse. Contributing factors may include interactions between lymphoma cells (LCs) or leukemia cells and bone marrow microenvironment (BMM). Overexpression of CXCR4WT and its ligand CXCL12 promote LC-BMM interactions, contributing to disease severity in lymphomas or leukemia such as diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Mavorixafor is an investigational oral CXCR4 antagonist being evaluated in combination with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in patients with Waldenström’s macroglobulinemia (WM). In preclinical models of MYD88L265P CXCR4WT WM, mavorixafor restored sensitivity of WM cells to B-cell-targeted therapies in coculture of WM cells and bone marrow stromal cells (BMSCs); however, the effects of mavorixafor on other lymphomas with CXCR4WT have not been evaluated. We report the effects of mavorixafor alone or in combination with B-cell─targeted therapies on LCs in an in vitro preclinical model and assess the role of BMM in the pathogenesis of B-cell lymphomas in an in vitro coculture model of LCs and BMSCs. Bioinformatic analysis of publicly available gene expression datasets GSE11318 and GSE32918 showed patients with DLBCL and CXCR4hi have significantly inferior survival probability compared with those with CXCR4low (P<.001 and P<.05, respectively). In vitro studies assessing effects of targeting CXCR4 with mavorixafor showed apoptosis of CXCR4+ LCs OCILY19 (DLBCL), MEC1 (CLL), MINO (MCL), and DOHH2 (FL) cells increased by ≈10%─60%. The apoptosis of LCs was further enhanced by ≈5%─60% when treated with mavorixafor in combination with ibrutinib or venetoclax compared to ibrutinib or venetoclax alone. Coculture of LCs with BMSCs reduced the sensitivity of LCs to apoptosis-inducing effects of ibrutinib and venetoclax. Combining mavorixafor with ibrutinib or venetoclax restored sensitivity of LCs to apoptosis-inducing effects of the tested B-cell─targeted inhibitors. Mavorixafor also inhibited migration of LCs toward CXCL12, suggesting prevention of the homing of LCs to protective niche. Overall, our findings suggest the contribution of CXCR4WT to pathogenicity of LCs. This is the first in vitro study to show that reduced sensitivity of LCs against B-cell-targeted therapies conferred by BMSCs can be overcome by inhibition of the CXCL12-CXCR4 axis with mavorixafor. Our study provides supporting evidence for further exploration of mavorixafor alone or in combination with other B-cell-targeted therapies in the treatment of lymphomas and leukemias. Further studies using additional LC lines and/or primary patient cells are warranted to support these findings. Citation Format: Tom Kruitwagen, Thalia Martins Rebelo, Barbara Maierhofer, Gerwin Heller, Halenya Monticelli, Arthur G. Taveras, Chi Nguyen. Mavorixafor enhances apoptosis of tumor cells treated with ibrutinib or venetoclax in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5866.

Bruton's tyrosine kinase inhibition suppresses neutrophilic inflammation and restores histone deacetylase 2 expression in myeloid and structural cells in a mixed granulocytic mouse model of asthma.

Asthmatic inflammation is not a single homogenous inflammation but may be categorized into several phenotypes/endotypes. Severe asthma is characterized by mixed granulocytic inflammation in which there is increased presence of neutrophilic numbers and unresponsiveness to corticosteroids. Neutrophilic oxidative stress and histone deacetylase 2 (HDAC2) dysregulation in the pulmonary compartment are thought to lead to corticosteroid insensitivity in severe asthma with mixed granulocytic inflammation. Bruton's tyrosine kinase (BTK) is a no-receptor tyrosine kinase which is expressed in innate immune cells such as neutrophils and dendritic cells (DCs) where it is incriminated in balancing of inflammatory signaling. We hypothesized in this study that BTK inhibition strategy could be utilized to restore corticosteroid responsiveness in mixed granulocytic asthma. Therefore, combined therapy of BTK inhibitor (ibrutinib) and corticosteroid, dexamethasone was administered in cockroach allergen extract (CE)-induced mixed granulocyte airway inflammation model in mice. Our data show that CE-induced neutrophilic inflammation was concomitant with HDAC2 expression and upregulation of p-NFkB expression in airway epithelial cells (AECs), myeloid cells and pulmonary tissue. Further, there were increased expression/release of inflammatory and oxidative mediators such as MUC5AC, TNF-α, GM-CSF, MCP-1, iNOS, nitrotyrosine, MPO, lipid peroxides in AECs/myeloid cells/pulmonary tissue. Dexamethasone alone significantly attenuated eosinophilic inflammation and inflammatory cytokines but was not able to control oxidative inflammation. Ibrutinib alone markedly reduced neutrophilic infiltration and oxidative inflammation, and restored HDAC2 without having any significant effect on eosinophilic inflammation. These data suggest that BTK inhibition strategy may be used in conjunction with dexamethasone to treat both neutrophilic and eosinophilic inflammation, i.e. mixed granulocytic asthma.

Arrhythmogenic Cardiotoxicity Associated With Contemporary Treatments of Lymphoproliferative Disorders.

Background There are limited data on risk of arrhythmias among patients with lymphoproliferative disorders. We designed this study to determine the risk of atrial and ventricular arrhythmia during treatment of lymphoma in a real-world setting. Methods and Results The study population comprised 2064 patients included in the University of Rochester Medical Center Lymphoma Database from January 2013 to August 2019. Cardiac arrhythmias-atrial fibrillation/flutter, supraventricular tachycardia, ventricular arrhythmia, and bradyarrhythmia-were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes. Multivariate Cox regression analysis was used to assess the risk of arrhythmic events with treatments categorized as Bruton tyrosine kinase inhibitor (BTKi), mainly ibrutinib/non-BTKi treatment versus no treatment. Median age was 64 (54-72) years, and 42% were women. The overall rate of any arrhythmia at 5 years following the initiation of BTKi was (61%) compared with (18%) without treatment. Atrial fibrillation/flutter was the most common type of arrhythmia accounting for 41%. Multivariate analysis showed that BTKi treatment was associated with a 4.3-fold (P<0.001) increased risk for arrhythmic event (P<0.001) compared with no treatment, whereas non-BTKi treatment was associated with a 2-fold (P<0.001) risk increase. Among subgroups, patients without a history of prior arrhythmia exhibited a pronounced increase in the risk for the development of arrhythmogenic cardiotoxicity (3.2-fold; P<0.001). Conclusions Our study identifies a high burden of arrhythmic events after initiation of treatment, which is most pronounced among patients treated with the BTKi ibrutinib. Patients undergoing treatments for lymphoma may benefit from prospective focused cardiovascular monitoring prior, during, and after treatment regardless of arrhythmia history.

Pirtobrutinib (Jaypirca): A Fourth Bruton's Tyrosine Kinase Inhibitor for Mantle Cell Lymphoma

The Bruton's tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca – Lilly) has received accelerated approval from the FDA for treatment of relapsed or refractory mantle cell lymphoma (MCL) in adults who received ≥2 prior lines of systemic therapy, including a BTK inhibitor. Accelerated approval was based on the response rate. The BTK inhibitors ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) are also approved for treatment of MCL.

In Brief: Zanubrutinib (Brukinsa) for CLL or SLL

The Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa), which was previously approved by the FDA for treatment of mantle cell lymphoma, Waldenström's macroglobulinemia, and relapsed or refractory marginal zone lymphoma, has now been approved for treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults. The BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence) were approved earlier for treatment of CLL and SLL.

Tyrosine Kinase Inhibitors in the Treatment of Steroid Refractory Chronic Graft Versus Host Disease

Introduction: Different novel drugs have been investigated for steroid-refractory chronic graft versus host disease (SR-cGVHD). Despite Rixulotinib approval, the need for more therapeutic options is still warranted. Tyrosine kinase (TK) inhibitors are known to inhibit pathways involved in cGVHD pathophysiology, including transforming growth factor (TGF)-β and platelet-derived growth factor receptor (PDGF-r) signaling pathways. Therefore, this drug class is currently under investigation in treating SR cGVHD. Methods: A comprehensive search was conducted across various data sets, including PubMed, Cochrane, and Embase. A review of the most recent data is summarized in this abstract. Results: Results from a randomized single-arm multicenter study highlighted the efficacy of Bruton's TK inhibitor ibrutinib with an acceptable safety profile. Similarly, multiple pilot studies show Imatinib, BCR/ABL TK inhibitor, as a suitable alternative treatment for steroid-refractory cGVHD. One study shows higher efficacy of Imatinib when combined with mycophenolate. A single phase I/II study highlighted the potential role of nilotinib. A list of complete and partial response rates of these studies with their most common adverse effects are listed in the table. 1. A cumulative analysis of these studies showed that overall these three tyrosine kinase inhibitors showed a median complete response (CR) rate of 3.85% with ranges from 0 to 36.80% and a median partial response (PR) rate of 55.50% with ranges of 25-80%. These results, although not groundbreaking but still are encouraging. Conclusion Tyrosine kinase inhibitors are promising results in treating patients with SR cGVHD with a good side effect profile. More research is warranted to explore this drug class in this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessing the Burden of Adverse Events in a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia (CLL)

Background: In a previously reported phase 3 head-to-head trial of the Bruton tyrosine kinase (BTK) inhibitors acalabrutinib (Acala) and ibrutinib (Ibr) (NCT02477696), Acala demonstrated noninferiority to Ibr and an improved safety profile with statistically fewer atrial fibrillation/flutter (afib/flutter) events (9% vs 16%) and numerically fewer discontinuations due to adverse events (AEs; 15% vs 21%) vs Ibr in patients (pts) with previously treated CLL (Byrd et al. J Clin Oncol 2021;39:3441-52). To further characterize differences in the safety profile between Acala and Ibr, we conducted a post hoc analysis of AEs using a recently developed, novel statistical method (Ruppert et al. Leukemia 2021;35:2854-61), which considers measures not captured by incidence alone, such as event duration, recurrence, and grade weighting. Methods: Pts with previously treated CLL and del(17p) or del(11q) received oral Acala 100 mg twice daily or Ibr 420 mg daily until disease progression or unacceptable toxicity. Any-grade AE incidence was reported overall and for AEs commonly associated with BTK inhibitors. An AE burden score was adapted from Ruppert et al and calculated as the sum of the products of the AE duration and AE severity grade (weight) recorded for each all-cause AE, divided by duration of the evaluable treatment-emergent period for each pt. Grade 1-4 AEs were weighted according to their CTCAE severity grades; grade 5 AEs were weighted as 10 to reflect the fatal outcome. Pts with no AE had a score of 0. Separate scores were calculated for grade 1-4 AEs and grade 1-5 AEs. Results: In total, 529 pts (Acala, n=266; Ibr, n=263) received study treatment; median number of prior therapies was 2 in both arms. Median total treatment exposures were 38.3 and 35.5 mo, respectively, at the September 15, 2020 data cutoff. While the frequency of experiencing any AE was similar between Acala (98%) and Ibr (97%), the overall AE burden score considering all AEs was higher for Ibr vs Acala, with (P=0.0006) or without (P=0.0016) grade 5 events included (Figure). The overall AE burden score was higher with Ibr vs Acala in certain pt subgroups, including age <65 y, age ≥65 y, and 1-3 prior therapies; there was no statistical difference among pts with ≥4 prior therapies (Figure). AE incidences and AE burden scores for events of clinical interest (ECIs) and selected AEs are shown in the Table. Among ECIs, the afib/flutter AE burden score P=0.0201and event incidence (P) were higher with Ibr than Acala. The AE burden score for cardiac events overall was numerically higher for Ibr vs Acala, even when including grade 5 events; the incidence rate was also numerically higher for Ibr. For hypertension and hemorrhage, AE burden scores (P<0.0001 and P=0.0007, respectively) and event incidences (P<0.0001 and P=0.0020, respectively) were higher with Ibr; no difference was observed for major hemorrhage. Neither the incidence nor AE burden score for infections was different between treatment arms. Among notable symptomatic AEs, the incidence and AE burden score of fatigue was similar between Acala and Ibr. Diarrhea was more frequent among Ibr-treated pts (P=0.0075); however, the AE burden score was higher with Acala (P=0.0114). Headache was more frequent with Acala (P=0.0002), with a higher AE burden score vs Ibr (P=0.0002). The AE burden score for musculoskeletal events was higher with Ibr (P=0.0229). Conclusions: The results of this novel analysis using methodology that incorporates event duration and severity weighting further support the superior tolerability of Acala compared with Ibr and confirm the safety differences that have been reported previously between the two drugs. The AE burden score was lower with Acala vs Ibr overall as well as for afib/flutter, hypertension, hemorrhage, and musculoskeletal events, while it was greater with Acala for diarrhea and headache. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Pilot Study Evaluating Acalabrutinib for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphomas

Background: Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes, and/or spinal cord without evidence of systemic disease. While frontline PCNSL is potentially curable, relapsed PCNSL has a dismal prognosis, particularly if the relapse is within 1 year of frontline therapy. Secondary central nervous system lymphoma (SCNSL) is defined as systemic NHL that has CNS involvement either concurrently or at relapse. There is no standard of care for relapsed CNS lymphoma. Recently, though, novel targeted agents have shown promise. Bruton's tyrosine kinase (BTK) is a key enzyme in the B-cell receptor (BCR) signaling pathway. In some B-cell NHL, BTK is essential for proliferation and survival. The BTK inhibitor (BTKi) ibrutinib is effective for the treatment of both primary and secondary CNS lymphomas with response rates of 68% (CR=45%) and 56% (CR=17%), respectively. Acalabrutinib is an irreversible BTKi that has been evaluated in NHL. Phase 2 trials of acalabrutinib in relapsed/refractory MCL reported an ORR of 80.6% with a CR rate of 39.5%. Importantly, there were no cases of atrial fibrillation and only 1 case of grade 3 or higher gastrointestinal hemorrhage. We hypothesize that acalabrutinib, a more selective BTKi, may be an effective treatment for relapsed CNS lymphomas with fewer complications. Study Design/Methods: This is a multicenter, open-label, single-arm, pilot study designed to investigate the antitumor effects of acalabrutinib in subjects with relapsed PCNSL or SCNSL that is open to accrual (NCT04548648). All subjects receive acalabrutinib 100mg every 12 hours until progression or discontinuation of treatment due to an adverse event. Prophylactic administration of the antifungal agent isavuconazole will be mandatory while subjects receive acalabrutinib. This decision is based on cases of invasive aspergillosis in studies evaluating ibrutinib. As a moderate CYP3A4 inhibitor, isavuconazole may increase acalabrutinib levels. Pharmacokinetic studies have shown that coadministration may increase acalabrutinib dosing 2- to 3-fold. We feel that this possible increase in concentration is reasonable given the need for blood-brain-barrier penetration. During the study, 15 evaluable subjects will be enrolled and treated. Response will be assessed via brain magnetic resonance imaging (MRI) after 2, 4, 6, 9, 12, 18 and 24 months. After 24 months, patients will require yearly MRIs for response assessment. The primary endpoint is overall response rate (ORR) at 2 months of therapy. Secondary endpoints include toxicity, complete response (CR) rate, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Key inclusion criteria include: biopsy (can be from initial diagnosis) or MRI findings consistent with B-cell NHL in CNS; ocular and CSF involvement are allowed but there must be a parenchymal mass as well; at least one prior line of therapy; no systemic involvement; ECOG performance status < 2. Key exclusion criteria include: previous BTKi exposure; anticoagulation with warfarin; strong CYP3A4 inhibitor that cannot be stopped; severe hepatic insufficiency; inability to take oral medication. Correlative studies include blood and CSF pharmacokinetic studies of acalabrutinib and its active metabolite, ACP-5862 (collected on day 1 and 8 of cycle 1). Molecular testing will be performed on biopsy samples to evaluate the presence of mutations in the MYD88 and CXCR4 genes. Additionally, the utility of 82Rubidium as a positron emission tomography-radiotracer will be evaluated (at screening and prior to cycle 3 and cycle 7) in the first five subjects at the University of North Carolina who consent to this scan. Mental status and cognitive function will be evaluated with the mini-mental status examination (MMSE) at screening then every 6 months. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genomic Characterization of Patients in a Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients with Relapsed/Refractory B-Cell Malignancies

Background/Introduction: Targeting Bruton tyrosine kinase (BTK) to inhibit B-cell receptor signaling is an effective way to treat B-cell malignancies. However, some patients (pts) have experienced toxicities to BTK inhibitors ibrutinib (ibr) and acalabrutinib (acala), which lead to dose reduction or treatment discontinuation. Zanubrutinib (zanu) is a potent and selective next-generation BTK inhibitor (Blood. 2021;138[suppl 1]:1410). BGB-3111-215 (NCT04116437) is an ongoing, phase 2 study of the safety and efficacy of zanu monotherapy in pts with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL) who discontinued ibr, acala, or acala and ibr because of intolerance. Here, we present the gene mutation profile of pts in this study to demonstrate the mutational landscape of pts intolerant to ibr or acala and to explore the association between gene mutations and response to zanu in ibr- and acala- intolerant pts. Methods: Peripheral blood from pts was collected before treatment and at or after the time of disease progression. Genomic DNA was isolated from peripheral blood mononuclear cells or plasma, and the mutational status of targeted genes was assessed using a targeted 106-gene next-generation sequencing (NGS) panel (PredicineHEMETM, Predicine). Samples were sequenced to a median depth of >20,000 reads, with a validated sensitivity of 0.25% mutant allele frequency for all genomic regions. Results: Samples from 63 pts were analyzed, including 63 at baseline and 5 at or after progressive disease (PD). There were 41 pts with CLL, 6 with SLL, 10 with WM, 3 with MCL, and 3 with MZL. The most common mutations at baseline were TP53 (31.7%), SF3B1 (22.2%), ATM (17.5%), NOTCH1 (17.5%), CHEK2 (14.3%), and KRAS (12.7%). Copy number variants were detected, including deletions at ATM locus (9.5%) and RB1 locus (9.5%) and amplifications at CCND2 locus (6.3%). For CLL/SLL, the frequencies of TP53 (27.7%), NOTCH1 (21.3%), SF3B1 (25.5%), ATM (21.3%), and BIRC3 (10.4%) mutations were comparable to those in other studies with high-risk relapsed/refractory CLL pts (Leukemia. 2018;32:3-91; Blood. 2014;123:3247-3254; Leuk Lymphoma. 2018;59[10]:2318-26). For WM, 5 of 10 (50%) samples harbored TP53 mutations, and 4 of 10 samples had MYD88 mutations; all harbored the L265P mutation. Among the 4 pts with MYD88 mutation, CXCR4 gene mutation was detected in 1 case. All 6 pts with MYD88 wild type also had CXCR4 wild type gene, consistent with published data (N Engl J Med. 2015;373:584-6). Baseline mutations were available for the 10 pts with PD, including 8 CLL, 1 SLL, and 1 MCL. Compared to pts without PD, pts with PD had increased frequency of certain mutations: TP53 (60%, P=0.071), ATM (50%, P=0.017), SF3B1 (50%, P=0.035), RB1 (40%, P=0.009), SETD2 (40%, P=0.009), and CDKN2A (30%, P=0.011). This finding suggests that these particular baseline mutations are associated with resistance to zanu. Five pts also had mutations detected at or after PD. Of these, 3 pts had BTK or PLCG2 mutations (submitted). One patient with CLL and without BTK or PLCG2 mutations had ATM and FBXW7 mutations (variant allele frequencies were 86% and 50%, respectively), suggesting DNA damage pathway mutations and NOTCH1 dysregulations may have contributed to disease progression in this patient. Conclusion: Exploratory analysis results confirmed that cell cycle, DNA damage, and NOTCH1 pathway genes were frequently mutated in pts with B-cell malignancies on study BGB-3111-215 (pts intolerant to ibr and/or acala). Pts with mutations associated with poor prognosis at baseline were more likely to develop PD.