Generation Bruton Tyrosine Kinase Inhibitor Research Articles

Bruton's tyrosine kinase (BTK) inhibitors alter blood glucose and insulin in obese mice but reduce inflammation independent of BTK.

Obesity is associated with metabolic inflammation, which can contribute to insulin resistance, higher blood glucose, and higher insulin indicative of prediabetes progression. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a metabolic danger sensor implicated in metabolic inflammation. Many features of metabolic disease can activate the NLRP3 inflammasome; however, it is not yet clear which upstream triggers to target, and there are no clinically approved NLRP3 inflammasome inhibitors for metabolic disease. Bruton's tyrosine kinase (BTK) mediates activation of the NLRP3 inflammasome. Ibrutinib is the most-studied pharmacological inhibitor of BTK, and it can improve blood glucose control in obese mice. However, inhibitors of tyrosine kinases are permissive, and it is unknown if BTK inhibitors require BTK to alter endocrine control of metabolism or metabolic inflammation. We tested whether ibrutinib and acalabrutinib, a new generation BTK inhibitor with higher selectivity, require BTK to inhibit the NLRP3 inflammasome, metabolic inflammation, and blood glucose in obese mice. Chronic ibrutinib administration lowered fasting blood glucose and improved glycemia, whereas acalabrutinib increased fasting insulin levels and increased markers of insulin resistance in high-fat diet-fed CBA/J mice with intact Btk. These metabolic effects of BTK inhibitors were absent in CBA/CaHN-Btkxid/J mice with mutant Btk. However, ibrutinib and acalabrutinib reduced NF-κB activity, proinflammatory gene expression, and NLRP3 inflammasome activation in macrophages with and without functional BTK. These data highlight that the BTK inhibitors can have divergent effects on metabolism and separate effects on metabolic inflammation that can occur independently of actions on BTK.NEW & NOTEWORTHY Bruton's tyrosine kinase (BTK) is involved in immune function. It was thought that BTK inhibitors improve characteristics of obesity-related metabolic disease by lowering metabolic inflammation. However, tyrosine kinase inhibitors are permissive, and it was not known if different BTK inhibitors alter host metabolism or immunity through actions on BTK. We found that two BTK inhibitors had divergent effects on blood glucose and insulin via BTK, but inhibition of metabolic inflammation occurred independently of BTK in obese mice.

Comparison of zanubrutinib (zanu) and acalabrutinib (acala) in B-cell malignancies: An adverse event (AE)-based analysis.

e19049 Background: Acala and zanu are 2nd generation Bruton tyrosine kinase inhibitors (BTKis) that have demonstrated improved safety profiles vs 1st generation BTKi ibrutinib in clinical trials. While head-to-head comparison of zanu vs acala is lacking, a recent meta-analysis of clinical trials provided a comprehensive, indirect comparison of the AE profiles in B-cell malignancies (Hwang, Hemasphere. 2023;7(S3):1134). This study aims to evaluate costs and impacts on quality of life (QoL) for zanu vs acala using their AE profiles. Methods: A health economic model was developed to determine cost and QoL associated with AE management for zanu and acala. The incidence rates ( IRs) of all grade and grade ≥3 AEs of interest (n=21, including bleeding events, hypertension, atrial fibrillation, cytopenias, infections, headache, arthralgia, diarrhea) were taken from the meta-analysis. Additional model inputs, such as disutility, average duration of AE, and unit cost of each AE were sourced from published literature and publicly available cost databases in consultation with clinical experts. The model was developed from the US perspective, considering Medicare costs, inflated to 2023 USD. Model outcomes were AE management cost (= IR * unit cost) and quality-adjusted life years (QALYs) lost due to AE (= IR * Disutility * Duration/365.25). Results: In the base-case scenario (considering all AEs), treating a hypothetical cohort of 1000 patients (pts) with zanu instead of acala yielded cost savings of $124K and 3.7 QALY gains (i.e., 3.7 years extra in full health). Subgroup analysis for severe (grade ≥3) and non-severe AEs (grade 1-2) demonstrated similar trends. A sensitivity analysis limited to AEs significantly different between zanu and acala (n=13) yielded consistent results. Additionally, a probabilistic sensitivity analysis, conducted with 1000 iterations to account for uncertainty in model parameters, confirmed robustness of the model, indicating stable conclusions across a wide range of parameter uncertainties. Conclusions: This analysis suggested that zanu is cost-saving and associated with added health benefits compared to acala in terms of AE management in pts with B-cell malignancies. Should these results derived from meta-analysis of clinical trial data be applicable to real-world pt populations across different indications, the potential cost savings could be considerable. These results could be further improved if the differences in efficacy of zanu vs acala are also incorporated. [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.

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.

Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).

Bruton's tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant B-cells in chronic lymphocytic leukemia (CLL). Small molecule BTK inhibitors were designed to bind BTK's active site and block downstream signaling. These drugs have now been used in the treatment of thousands of patients with CLL, the most common form of leukemia in the western hemisphere. However, adverse effects of early generations of BTK inhibitors and resistance to treatment have led to the development of newer, more selective and non-covalent BTK inhibitors. As the use of these newer generation BTK inhibitors has increased, novel BTK resistance mutations have come to light. This review aims to discuss previously known and novel BTK mutations, their mechanisms of resistance, and their relationship with patient treatment. Also discussed here are future studies that are needed to investigate the underlying cause allowing these mutations to occur and how they incite resistance. New treatments on the horizon that attempt to maneuver around these resistance mutations can be met with new resistance mutations, creating an unmet need for patients with CLL. Novel therapies and combinations that address all forms of resistance are discussed.

CXCR4 S338X Promotes Resistance to Second Generation BTK Inhibitor and BCL-2 Inhibitor in WM Cells

Introduction: Waldenström macroglobulinemia (WM) is an IgM-secreting lymphoplasmacytic lymphoma. CXCR4 somatic mutations are common in WM and are associated with clinical resistance to Bruton's tyrosine kinase (BTK) inhibitors and other therapeutic agents. CXCR4 mutations occur nearly exclusively with MYD88 L265Pmutation, with CXCR4 S338X constituting the most common in WM patients. The aim of this study was to further investigate the effect of CXCR4 S338X on BTK inhibitors (ibrutinib and zanubrutinib) and a BCL-2 inhibitor (venetoclax) resistance. Methods: MWCL-1 cells were transfected with scramble, CXCR4 or CXCR4 S338Xplasmids using Lipofectamine 3000 followed by neomycin selection. CXCR4 expression was confirmed using qPCR and flow cytometry. Transfected cells were cultivated in presence of ibrutinib (5μΜ), zanubrutinib (5μΜ) and venetoclax (1μΜ) for 48 hours. Proliferation was estimated using CCK-8 colorimetric assay while cell cycle was evaluated by propidium iodide staining and flow cytometry. Apoptosis was estimated by Annexin V/7-AAD staining and flow cytometry while the expression of apoptotic genes was determined by qPCR. The statistical analysis was performed using Student's t-test and Graphpad Prism. Results: Drug-induced cytotoxicity was observed only in the case of venetoclax in CXCR4 S338X transfectedcells (p= 0.0007) while increased cytotoxicity was noted in the presence of ibrutinib, zanubrutinib and venetoclax in the case of scramble-transfected cells (p=0.038, p=0.006 and p=0.0006, respectively). Moreover, no significant difference in proliferation rate was noted between CXCR4 S338Xtransfectedcells treated with the therapeutic agents and CXCR4 S338X untreated cells, underlining the S338X role to promote cell proliferation. Interestingly, CXCR4 S338X transfectedcells exhibited apoptosis resistance not only compared to scramble-transfected cells but also in comparison with CXCR4-transfected cells, associated with resistance to all three drug agents (p=0.004, p=0.003 and p=0.034, respectively). In the case of scramble-transfected cells, an increase in apoptosis was demonstrated in parallel with an increase in caspases 8, 9 and 3 in presence of ibrutinib (p=0.006, p=0.0001 and p=0.025, respectively) and zanubrutinib (p=0.027, p=0.007 and p=0.052, respectively), whereas no statistically significant increase in caspase gene expression was observed in the case of CXCR4 S338Xtransfectedcells, highlighting S338X role in the inhibition of intrinsic and extrinsic apoptosis pathways. Lastly, the presence of S338X mutation acted as a mitotic promoting factor when cells treated with the aforementioned drugs showed a high proportion of cells in G2/M phases of cell cycle compared to scramble and CXCR4 controls. Conclusions: The above data demonstrate the role of CXCR4 S338X mutation in drug resistance and suggest the necessity to develop therapeutic strategies to address this issue and overcome this therapeutic barrier in WM. Data on more cell lines and downstream signaling will be presented at the meeting.

Safety Profile in Patients with Chronic Lymphocytic Leukemia Undergoing Treatment with 1st and 2nd Generation Bruton Tyrosine Kinase Inhibitors: Multicentric Real-World Experience

INTRODUCTION Chronic lymphocytic leukemia (CLL) is the most frequent leukemia, being more frequent in older adults. Bruton's tyrosinkinase inhibitors (BTKi) have revolutionized the treatment, displacing immunochemotherapy treatment in all patient profiles. The selectivity profile in the action of these drugs means that the toxicity of first and second generation BTKi is different, resulting in higher rates of atrial fibrillation and arterial hypertension, mainly in patients treated in the second line or later, while maintaining their efficacy. Real-life studies are needed to be able to demonstrate the effects in first-line treatment in a more heterogeneous patient profile, without the strict exclusion and inclusion criteria used in clinical trials. METHODS An observational, retrospective, multicenter, retrospective study was performed. Patients with in treatment with Ibrutinib or Acalabrutinib in first line or later were included. Demographic data, comorbidity, cytogenetic and mutational disease data, adverse effect profile, comprehensive geriatric assessment (if applicable) and treatment response evaluation data are collected. RESULTS A total of 91 patients were included with a median age of 73.22 years SD 11.06. Fifty-three (58.2%) were male. Fifty-three (58.2%) were treated in frontline, 31.9% (29) in second line and 9.9% (9) in subsequent lines. Acalabrutinib was used in 25 (27.5%) patients and Ibrutinib in 66 (72.5%). Patient characteristics are shown in Table 1. Differences were revealed between these two BTKis in terms of line of treatment, with the majority being treated first (P=0.006) and Rai stage, with Rai II predominating (P=0.014). No differences were found between the two BTKis according to the rest of the characteristics. In terms of toxicity, 14 (15.4%) of patients treated with Ibrutinib developed arterial hypertension, compared to no patients in the Acalabrutinib arm (p=0.009). With respect to the development of cardiac toxicity, 19 (20.9%) patients suffered some cardiotoxic event, 3 (3.3%) in patients on acalabrutinb and 16 (17.6%) on ibrutinib, with no significant differences found between the two drugs (p=0.2). No significant differences were found with respect to other toxicities (hematologic, digestive, bleeding and infections). Table 2 No differences were found in terms of progression-free survival or overall survival. CONCLUSIONS The iBTKs have changed the treatment of CLL, although the second-generation iBTKs have a safer cardiovascular profile and are just as effective in our cohort, even in the frontline.

ONO-7018, a First-in-Class MALT1 Inhibitor, Provides Novel Therapeutic Strategies for B Cell Malignancies: Overcoming BTK Inhibitor Acquired Resistance and Enhancing the Antitumor Effect of BTK Inhibitors

Introduction: B cell receptor (BCR) signaling plays a crucial role in promoting survival and growth in B cell malignancies, and several compounds targeting the signaling pathways have been approved. Bruton's tyrosine kinase (BTK) is a key molecule in BCR signaling pathways and BTK inhibitors are one of the essential treatment options for chronic lymphocytic leukemia (CLL) and certain subtypes of B cell Non-Hodgkin Lymphoma. However, there are issues that acquired resistance mutations in the BTK kinase domain and gain of function mutation of its downstream molecules, which lead to BTK inhibitor resistance and limit its efficacy. For example, BTK C481S mutation is well known as a resistant mutation to covalent BTK inhibitors and several mutations of BTK (such as T474I and L528W mutation) have recently been reported in relapsed or refractory CLL patients with acquired resistance to pirtobrutinib, a non-covalent BTK inhibitor. In addition, there are unmet medical needs to improve the duration of response of current standard therapies including BTK inhibitors for B cell malignancies. Therefore, therapeutic strategies to overcome the BTK inhibitor resistance and novel combination therapies to enhance the efficacy of BTK inhibitors are required. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is known as a key growth and survival regulator in BCR signaling and an emerging therapeutic target. ONO-7018 (formerly known as CTX-177), a potent and selective MALT1 inhibitor, demonstrated preclinical efficacy in several lymphoma models. Aim: Firstly, to explore the potential of ONO-7018 to overcome BTK inhibitor acquired resistance, we tested the antitumor effects of ONO-7018 on cell lines harboring BTK inhibitor-resistant mutations. Secondly, we examined the combination antitumor efficacy of ONO-7018 and tirabrutinib, a second generation BTK inhibitor in vitro and in vivo. Methods: Diffuse large B-cell lymphoma (DLBCL) cell lines harboring BTK inhibitor-resistant mutations (BTK T474I, C481S, or L528: PLCG2 R665W) were generated by continuous passage with BTK inhibitor or CRISPR-Cas9 gene editing followed by single cell cloning. In in vivo study, human DLBCL cell line, TMD8 cells were subcutaneously implanted in immune deficient mice. ONO-7018 and tirabrutinib were orally administered to the mice twice a day. Results: Anti-proliferative activities of ONO-7018 on these BTK inhibitor resistant cell lines were evaluated in vitro. ONO-7018 inhibited the proliferation of these cells with comparable IC 50 values to the parent cell line. Anti-proliferative activities of ONO-7018 alone or in combination with tirabrutinib on DLBCL and mantle cell lymphoma (MCL) cell lines were evaluated in vitro. ONO-7018 exhibited synergistic effects with tirabrutinib in both DLBCL and MCL cell lines. In addition, combination treatment of ONO-7018 with tirabrutinib strongly inhibited the expression of interferon regulatory factor 4, which is a downstream signal molecule in BCR signaling pathways, compared to their single treatment. We then evaluated the antitumor effects of ONO-7018 in combination with tirabrutinib in the xenograft model. Combination treatment of ONO-7018 with tirabrutinib showed dramatic antitumor effect with tumor regression. These results suggest that ONO-7018 could demonstrate antitumor effect on patients with B cell malignancies harboring BTK inhibitor acquired resistant mutations and synergistic antitumor effect with BTK inhibitors in clinic. Conclusion: ONO-7018 would provide novel therapeutic strategies to overcome the BTK inhibitor acquired resistance and enhance the antitumor effect of BTK inhibitors in clinic. Phase 1 study of ONO-7018 (NCT05515406) is currently ongoing.

Meta-Analysis of the Efficacy and Adverse Effects of Acalabrutinib in the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia

Background Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia and is characterized by the accumulation of small and mature appearing lymphocytes in blood, lymphoid tissue, and bone marrow. Chemoimmunotherapy and targeted therapies can improve overall survival and the duration of remission; however, CLL is prone to relapse, therefore identifying new therapeutic targets has been an important aspect of CLL research and management. B-cell receptor signaling serves an integral role in the pathogenesis of CLL and kinases involved in the BCR pathway are targets of novel therapies. The Bruton tyrosine kinase (BTK) that is immediately downstream of the B-cell receptor is a mediator of cell signaling involved in B cell survival and proliferation. Moreover, BTK is involved in CLL interaction with the tumor microenvironment. Targeting BTK with ibrutinib was a transformative advance in CLL treatment and has become a front-line therapy in the management of CLL. In recent years, newer generations of Bruton tyrosine kinase inhibitors (BTKi) have been approved in the management of CLL. Acalabrutinib is an irreversible, second generation BTKi that is more selective and potent than ibrutinib. This meta-analysis investigated the efficacy, outcomes, and hematologic adverse effects of acalabrutinib in the treatment of relapsed/refractory CLL. Methods A search was conducted using the PICOS model and PRISMA guidelines to retrieve outcome, efficacy, and adverse effect data. 12 studies were chosen after literature review and screening. In the event a study was an abstract or paper providing updated data on the same patient population of a previously published study, the most up to date information was used for analysis. The random effect meta-analysis model was used for analyses. Variables for analysis were: Overall Response Rate (ORR), Overall Discontinuation Rate, Death Rate, and Discontinuation due to Adverse Effects. Grade 3 Hematologic adverse reactions were analyzed: Anemia, Neutropenia, Thrombocytopenia. Results The analysis included a total of 796 patients (450 Males &amp; 200 females; sum discrepancy due to absence of certain demographic information in particular studies). ORR pooled estimate: 82% (95% CI [0.82,0.75]; p&amp;lt;.001, I 2=81.96%), death rate: 12% (95% CI [0.06,0.19]; p&amp;lt;.001, I 2=87.23%), overall discontinuation rate: 35% (95% CI [0.20, 0.30]; p&amp;lt; .001, I 2=98.84%), discontinuation due to adverse effect: 13% (95% CI [0.10,0.15]; p=0.6, I 2=0.00), neutropenia: 18% (95% CI [0.15,0.20]; p=0.70), anemia: 9% (95% CI [0.06,0.12];p=0.18), thrombocytopenia: 7% (95% CI [0.04,0.11];p=0.09). Discussion BTK inhibitors have significantly changed the management of CLL and are utilized as either as frontline or as salvage treatment. Although, ibrutinib has shown efficacy in management of CLL, off-target toxicities and treatment resistance has been demonstrated with its use. Therefore, a greater understanding of second generation BTK inhibitors such as acalabrutinib will offer clinicians perspective in choosing a CLL management strategy. Our meta-analyses noted an ORR pooled estimate of 82% with a death rate of 12%. Deaths in the literature typically occurred either from disease progression or adverse effects. Similarly, discontinuation typically occurred due to progressive disease or adverse events. The Grade 3 hematologic adverse effects most frequently reported were anemia, thrombocytopenia, neutropenia. Clinical Grade 3 adverse effects (e.g. pneumonia, cardiac events) and baseline characteristics will be focused on in a future analysis.

A Randomized, Open-Label, Phase 3 Study of Acalabrutinib in Combination with Rituximab and Reduced Dose CHOP (R-miniCHOP) in Older Adults with Untreated Diffuse Large B-Cell Lymphoma (ARCHED / GLA 2022-1)

Background Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and its incidence increases with age. Approximately 40% of patients with DLBCL are older than 70 years. Since the addition of the anti-CD20 antibody rituximab to CHOP regime (cyclophosphamide, doxorubicin, vincristine, and prednisone) prognosis in elderly patients has improved but still remains worse compared to their younger counterparts. Adequate dosage of chemotherapy in older adults is limited by comorbidities/frailty, especially in patients &amp;gt;80 years of age. An attenuated chemotherapy regimen, R-miniCHOP, has been evaluated in prospective trials and seems to provide a good balance between safety and efficacy in this vulnerable patient population (Peyrade et al, 2011). However, even with this regime, outcomes remain modest with 2-year overall survival at 50-60%, underlining the need for more effective treatment in this population. Acalabrutinib is a selective, irreversible, second-generation small molecule inhibitor of Bruton Tyrosine Kinase (BTK) with a more favorable safety profile compared to first generation BTK inhibitors. Although, not yet approved for the treatment of DLBCL, acalabrutinib showed promising results both as a single agent (Strati et al, Haematologica 2021) and in combination with full dose R-CHOP (Davies et al, ASH 2022), in patients aged up to 80 years. Furthermore, acalabrutinib carries the potential of improved efficacy in specific subgroups. The activated B-cell like (ABC) DLBCL subtype has been shown to depend on chronic active B-cell receptor signaling involving many downstream kinases including BTK. Additionally, the genetically defined subgroups MCD/C5, N1, and BN2/C1 and also may serve as potential predictive biomarkers for acalabrutinib. Study design and endpoints ARCHED is an investigator initiated, randomized, multicenter, open-label, phase III trial of R-miniCHOP with or without acalabrutinib in older adults with untreated DLBCL. Patients in the standard arm will receive 6 cycles of R-miniCHOP every 21 days followed by 2 cycles of rituximab alone, while patients in the experimental arm will receive the same regimen and additionally acalabrutinib 100 mg p.o. twice daily from day 1 to day 21 for 8 cycles (Figure 1). The primary endpoint of the study is investigator assessed progression-free survival (PFS). Secondary endpoints include overall survival, PFS per blinded independent review, event-free survival, outcomes according to cell of origin and molecular genotype, response rates, duration of response, progression, relapse and central nervous system (CNS) relapse rates as well as toxicity. Key eligibility criteria Patients are eligible for enrolment if they are &amp;gt;80 years old or &amp;gt;60 years old and ineligible for full-dose R-CHOP according to investigator assessment after standardized simplified geriatric evaluation and are diagnosed with untreated CD20+ DLBCL according to the 2017 WHO classification. Primary mediastinal lymphoma, high grade B-cell lymphoma and follicular lymphoma 3B as well as concurrent diagnosis of indolent lymphoma is allowed, but Richter's transformation is an exclusion criterion. Ann Arbor stage I patients can be included only in the presence of concomitant bulky disease (≥ 7.5 cm). Further exclusion criteria are CNS involvement, stroke or intracranial hemorrhage in the past 6 months and relevant organ dysfunction. An ECOG performance status score of 0 - 2 is required for enrolment but an ECOG score of 3 is acceptable if lymphoma associated. Statistical analysis With an expected 5% drop out rate, we aim to recruit 330 patients (165 in each arm) to achieve 80 % power at a 5 % significance level (two-sided) to observe a PFS difference of 15 % in favor of the experimental arm. An interim analysis for efficacy comparing PFS between the two treatment arms will be performed with n=200 patients and 1 year follow-up for the last patient, with approximately 50% of events. Additionally, an interim analysis for safety regarding treatment completion rates and all-cause mortality will take place when 92nd patient in each group has completed the sixth R-mini-CHOP cycle or died. ARCHED is an academic study of the German Lymphoma Alliance and is coordinated by the Saarland University Clinical Trials Unit. This study is funded by AstraZeneca GmbH. The trial is approved in the EU and is open for recruitment in Germany. (EU-CTN: 2022-501187-18-00, NCT05820841).

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.

Cardiovascular adverse events associated with second generation Bruton tyrosine kinase inhibitor therapy: A systematic review and meta-analysis.

e15109 Background: Cardiovascular adverse events (CVAE) is a frequent adverse effect of first-generation bruton tyrosine kinase inhibitor (BTKi) that significantly reduce the usage of these medications. This led to the development of second-generation BTKi (acalbrutinib and zanubrutinib) that are more selective and potent with presumably better safety profile than first-generation. CVAE associated with second-generation BTKis in the clinical practice has been sporadically reported. Hence, we attempted to pool the reported CVAE in this meta-analysis. Methods: Systematic searches of PubMed, PubMed Central, Cochrane library for clinical trials, Scopus, and Embase were conducted from inception until January 14, 2023. This meta-analysis performed per PRISMA protocol and registered in PROSPERO database (CRD42023392406). All randomized clinical trials including acalabrutinib or zanabrutinib in treatment arm with standard of care as control arms were included. The literature found from search engines were imported in the covidence platform and screened independently by 2 reviewers in title/abstract and full text phase. Conflicts were resolved by a third reviewer. Included studies were thoroughly reviewed by all reviewers and data from them extracted in a Microsoft Excel. Analysis performed using RevMan 5.4 meta-analysis software. Odds ratio was used as an effect measure with 95% confidence intervals (CI) using random effect model. Results: A total of ten trials (with 3048 patients, 1710 in treatment arm) were included in this meta-analysis. Cardiovascular events leading to death were reported in 4 studies. In the second generation BTKis group cardiovascular death was 0.94% (7/744), while in the control group it was 1.7% (12/705). Using the random effect model, a pooled analysis on death due to cardiovascular events were statistically insignificant across two groups (OR 0.46, 95% CI 0.19 to 1.11; n = 2039; I2 = 57%). Similarly, pooled analysis for any bleeding/hemorrhage from eight studies (OR 2.12, 95% CI 0.91 to 4.97; n = 2611; I2 = 93%), major bleeding from seven studies (OR 1.12; 95% CI 0.66 to 1.89, n = 2658, I2 = 28%), acute coronary syndrome from four studies (OR 3.13; 95% CI 0.65 to 15.13, n = 1585, I2 = 0%) were also statistically not significant. Conclusions: Treatment with acalabrutinib and zanabrutinib did not show any significant differences in cardiovascular events between the group when compared with standard treatment as a control group, meta-analyzing the data from published trials. As there is no evidence of worse cardiovascular outcomes or superiority of the second-generation BTKis compared to standard treatments in terms of safety based on available evidence, further large-scale controlled trials are required to support that new-generation BTKis are superior in safety and better tolerated.

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

Introduction: R-CHOP remains the standard of care in DLBCL yet for up to 40% of patients (pts.) it fails either through refractory lymphoma or relapse after achieving an initial remission. In the phase Ib/II ACCEPT study (NCT03571308), acalabrutinib (A), a second generation Bruton Tyrosine Kinase inhibitor with enhanced kinase selectivity and a potential for better tolerability, was assessed in combination with R-CHOP in patients with de novo DLBCL. There were no dose-limiting toxicities and the maximum tolerated dose was not reached, At the recommended phase II dose of A 100 mg bd, R-CHOP+A demonstrated a 95% 24 month progression-free survival (PFS). In older patients there was no difference in safety and no compromise of delivery of full course R-CHOP. Efficacy was preserved across cell-of-origin and genomic sub-groups. The REMoDL-A study now builds upon these findings to examine efficacy of R-CHOP+A against R-CHOP. Methods: REMoDL-A is a stratified open-label, multicentre, randomised phase II study. Eligible patients have untreated histologically confirmed DLBCL requiring full course R-CHOP. All patients receive 1 cycle of R-CHOP chemotherapy. FFPE diagnostic pathology blocks have molecular profiling and are assigned subtype Germinal Centre B-cell, Activated B-Cell, Molecular High Grade, Unclassifiable, or failed RNA extraction (GEP Fail). Patients whose biopsies are successfully sub-typed are randomised 2:1 between R-CHOP+A (Arm B) or R-CHOP for a further 5 cycles (Arm A). The randomisation is stratified by molecular subtype, International Prognostic index and age. The primary endpoint for the study is progression free survival (PFS) in the modified intention to treat (ITT) population (non-Fail ITT population). Secondary endpoints include PFS related to the cell of origin and genomic subtypes, duration of response, overall survival, event free survival, toxicity and quality of life. Exploratory analyses will investigate how dynamic molecular (including CTDNA) and PET based biomarkers predict risk and can be incorporated into a dynamic risk prediction model. An early interim analysis is planned to explore safety in the ≥65 years population. The trial is powered to detect a hazard ratio of 0.668 with 90% power with 1-sided significance level of 20%. The number of patients to be randomised is 453 (302:151 per arm). To date 155 patients have been recruited. Of the FFPE diagnostic pathology blocks that have undergone molecular profiling, failed RNA extraction (GEP fail) has occurred in only 4 patients. This is a UK National Cancer Research Institute multicentre trial coordinated by Southampton Clinical Trials Unit. Molecular profiling is performed in HMDS, Leeds. Trial registration: ISRCTN14251143/ NCT04546620 The trial has been supported by an investigator initiated grant and drug access from AstraZeneca (ESR-19-20180) and has endorsement from Cancer Research UK (CRUKE/19/017). Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract G. P. Collins Honoraria: Roche, AstraZeneca C. Fox Consultant or advisory role Abbvie, AstraZeneca, Atarabio, BMS, GenMab, Gilead/Kite, Incyte, Lilly, Morphosys, Ono, Roche, Takeda Research funding: Beigene Educational grants: Roche, BMS G. Griffiths Honoraria: AstraZeneca P. Johnson Honoraria: Takeda, InCyte, Genmab, Epizyme A. J. Davies Consultant or advisory role Celgene, Roche, Kite, Takeda, Incyte Honoraria: Celgene, Roche, Kite, Takeda Research funding: Celgene, Roche, Kite, Takeda, Janssen, GSK Educational grants: Celgene, Roche

Provider Perceptions of Shine and Ibrutinib, Bendamustine, and Rituximab in the First-Line Setting

Background: According to the National Cancer Care Network guidelines, chemoimmunotherapy with bendamustine + rituximab (BR) is considered standard first-line (1L) therapy for mantle cell lymphoma (MCL), followed by autologous hematopoietic cell transplant (ASCT) consolidation. Most MCL patients who are refractory to BR therapy and/or ineligible for ASCT will relapse. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, recently received accelerated approval as a second line (2L) chemotherapy for MCL to help prevent relapse in ASCT- ineligible patients. Expanding upon the success of the ibrutinib' approval in the 2L, the SHINE trial (NCT01776840) sought to determine the efficacy of ibrutinib in combination with BR in the 1L setting as a therapy for older, ASCT-ineligible patients with stage II-IV MCL. At the American Society of Clinical Oncology (ASCO) 2022 annual conference, it was reported that the SHINE trial had satisfied the primary endpoint of improved progression-free survival. We surveyed providers' perceptions of the SHINE trial and the likelihood that they would adopt ibrutinib + BR (IBR) therapy in the 1L setting. Methods: At two live events held in June and July of 2022, U.S.-based oncologists who treat MCL (n=89) were invited to hear discussions on select abstracts presented at ASCO 2022, including an abstract on the SHINE trial. The demographic profile of our participant population was collected via a pre-event survey. Participants' perceptions and reactions regarding the SHINE trial were collected in real-time using an electronic keypad. Not all participants who attended answered every survey question. Descriptive statistics were used to assess participants' perceptions and reactions. Results: Within a typical 3-month period, 35 (39%) participants reported that they are referred < 1 new patient with MCL, while 34 (37%) participants reported that they are referred ≥ 1 new patient with MCL. Seventy-three (82%) participants self-identified as community providers. Participants possessed an average of 22 years of clinical experience. During clinical hours, the median amount of time participants reported they focus on direct patient care was 90% (20%-100%). Sixty-three (71%) of participants stated that they prefer standard BR therapy as a 1L therapy for patients diagnosed with MCL. Sixty-four (72%) of the participants reported atrial fibrillation, and 54 (61%) reported bleeding 54 (61%) as the most concerning issues when considering IBR therapy. Sixty-nine (78%) participants agreed that if FDA approved, IBR would be likely adopted as their primary, 1L MCL regimen. Conclusions: Overall, our participants' perceptions of the SHINE trial data were positive. Following the presentation of the SHINE trial and data for the IBR regimen in MCL, participants were most concerned with the atrial fibrillation and bleeding adverse events, respectively. Despite these safety concerns, nearly 4 in 5 (78%) participants consider it likely that they would prescribe the IBR regimen based on the SHINE study results and assuming FDA approval, as a 1L therapy for patients diagnosed with MCL. Second generation BTK inhibitors have demonstrably improved safety and efficacy profiles, and many of our participants expressed a desire to see further studies of second generation BTK inhibitors added to the BR therapy backbone as a potential future regimen of interest.

Durable Responses from Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study

Introduction: R-CHOP remains the standard of care for DLBCL but fails in a proportion of patients (pts.) either through refractory lymphoma or relapse after achieving an initial remission. In the phase III PHOENIX study (NCT01855750), the addition of the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (I) to R-CHOP (R-CHOP-I) did not improve the outcome for non-germinal centre like DLBCL. However, R-CHOP-I treated pts. who were aged less than 60 years had a significantly improved progression free survival (PFS) and overall survival (OS) compared to those receiving R-CHOP alone. In pts. aged over 60 years, the addition of I increased toxicity and compromised the delivery of R-CHOP. Acalabrutinib (A) is a second generation BTKi, with enhanced kinase selectivity and potential for better efficacy and tolerability over first-generation inhibitors. Therefore, we combined A with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy. Methods: Eligible pts. were treatment naive with histologically confirmed DLBCL. All received 6 cycles of R-CHOP on a standard 21-day schedule, with the addition of A in cycles 2-6. A continuation phase of A only, for 2 cycles of 28 days was administered after R-CHOP-A. The primary objective of the phase Ib was to establish a recommended phase II dose (RP2D) of A in combination with R-CHOP (modified 6+6 design) with 24 months follow-up. Phase II assessed the overall response rate (ORR) of the combination and ascertained additional safety information. Secondary endpoints included metabolic complete response rates (mCR), PFS and OS and their relation to the cell of origin (COO), pharmacokinetics and pharmacodynamics. COO was determined by HTG EdgeSeq transcriptome analysis. Recruitment of pts. over the age of 65 was suspended as an urgent safety measure (USM) following the abstract release of data from PHOENIX (Nov 2018). ACCEPT reopened to all ages after a comprehensive safety review by the Independent Data Monitoring Committee (Sep 2019). The trial was endorsed by CRUK (CRUKDE/16/006) and coordinated by Southampton Clinical Trials Unit. Results: From May 2017 to Jan 2020, 38 pts. were enrolled (safety population: pts. in receipt of any component of therapy). The median age was 64 years (range 24-80, 39% >65 years old); 76% stage III/IV; 71% abnormal LDH; 29% B symptoms; 34% bulk; 24% high IPI; 32% high-intermediate IPI. Seven of the enrolled pts. were found to be ineligible (insufficient material for translational work, 2pts.; taking a proton pump inhibitor during therapy, 2 pts.; follicular histology, 1pt.; abnormal LFTs at baseline, 1pt.; age >65 at time of USM, 1 pt). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The RP2D was chosen as 100mg bd acalabrutinib. The most common ≥grade3 adverse events were neutropenia (34% of pts.), febrile neutropenia (16%) and diarrhoea (11%). The most frequently reported serious adverse event was febrile neutropenia (13% of pts.). Age did not compromise the delivery of full dose R-CHOP in combination with A. One of 7 eligible pts. in the first cohort (A 100mg od) progressed on therapy and subsequently died, 1 pt. not achieving mCR received additional radiotherapy. Twenty-four eligible patients received the RP2D in either dose escalation or expansion. Four pts. withdrew early from treatment (1 pt subject withdrawal, 2 pts. investigator withdrawal and 1pt. due to toxicity) and are included in the efficacy analysis. The RP2D ORR was 96% (95% CI 79-100) with 79% (95% CI 58-93) of pts. achieving a mCR (4 pts. partial response (PR), 1pts. stable disease (SD)). One pt. with MYC/BCL2/BCL6 rearrangements and 1 pt. with MYC/BCL6 rearrangement achieved a mCR; neither have progressed. mCR was achieved in 9 of 12 ABC pts. (83%), 9/9 GCB pts and 1/2 unclassified pts. (PR 2, 0, 1 pts. respectively, 1/1 fail). At the RP2D with a median follow-up of 30 months, the 24 months EFS was 90% (95% CI 66-97), PFS was 95% (95% CI 68-99) and OS was 96% (95% CI 73-99) - 1 pt. progressed at 11 months and 1 double expressor patient with SD received subsequent chemotherapy prior to progression then died of PD. R-CHOP did not affect the pharmacokinetics of A. Additional translational data will be presented. Conclusions: Acalabrutinib is well tolerated in combination with R-CHOP chemotherapy and may be associated with improved efficacy. This is being explored in the randomised REMoDL-A (NCT04546620) and ESCALADE (NCT04529772) trials.

Cost-Effectiveness Analyses of First Line Ibrutinib Versus Acalabrutinib Versus Zanubrutinib Followed By Second Line Venetoclax Plus Rituximab in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients

Background. Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKI) has significantly improved progression-free (PFS) and overall survival (OS) outcomes when compared with chemoimmunotherapy in the front line setting of CLL. Following the approval of the first generation of BTKI (ibrutinib, IBR) in 2016 as first line (1L) treatment of CLL, second generation BTKIs with more favorable safety profiles were approved/recommended in 2020 (acalabrutinib, ACA) and 2021 (zanubrutinib, ZAN). We performed a network meta-analysis (NMA) of these three BTKIs in terms of PFS in support of cost-effectiveness analyses from US payer perspective. Methods. We conducted a NMA of 5 trials (Woyach 2018, Burger 2015, Sharman 2020, Tam 2021, Goede 2014) on the PFS hazard ratios (HR) of the 3 BTKIs and any other CLL interventions that connected in the network. We specified a 5-state Markov model to capture the disease and clinical pathway for CLL patients over a 10 years' time horizon: progression free (PF) on 1L treatment [PF1]; progression before initiating second line (2L) treatment [P1]; PF on 2L treatment [PF2]; progression after 2L treatment [P2]; and death. Patients started PF on 1L treatment with a BTKI and moved to other states based on extracted transition probabilities from lognormal parametric distributions fitted to Kaplan-Meier PFS curves of phase III trials of IBR, ACA and ZAN. Venetoclax plus rituximab (VR) was considered the 2L treatment with PF2, P2 and death in 2L extracted from Seymour 2018. The transition probabilities of PF on 1L treatment and progression after 1L were adjusted based on the NMA results. OS and time to next treatment (TTNT) after first progression were considered the same for the three BTKIs. Costs of regimens (wholesale acquisition cost), adverse event (AE) management, and disease progression were incorporated into the appropriate health states. Utilities of PF1 (0.799), P1 (0.66), PF2 (0.55) and P2 (0.42) were obtained from literature. Annual discount rate of 3.0% was applied. Life years (LY), quality adjusted LY (QALY), and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated. Probabilistic sensitivity analyses (PSA; 10,000 iterations) were performed to obtain cost-effectiveness acceptability curves (CEAC). Results. Compared with IBR, ACA (HR=0.54; 95%CI=0.41-0.72) but not ZAN (HR=1.03; 95%CI=0.80-1.34) was associated with a statistically significant lower HR of progression or death. At 10 years, 77% of ACA patients were in PF1 and 9% in PF2, compared to 49% and 28% of ZAN patients, and 50% and 27% of IBR patients. As shown in the table, in base case analyses, total costs of IBR treatment were higher by $104,331 over ACA and by $350,340 over ZAN; with ACA being higher by $246,009 over ZAN. Survival was estimated to be 6.83 LYs for IBR, 7.02 LYs for ACA (+0.19) and 6.82 LYs for ZAN (-0.01). QALYs were estimated to be 5.00 for IBR, 5.46 for ACA (+0.46) and 5.09 for ZAN (+0.09). This yielded negative (cost saving) ICER of $-549,110/LYg and ICUR of $-226,806/QALYg for ACA over IBR. The statistically non-significant survival benefit, the 0.01 LY lost but 0.09 QALY gained, and the lower cost of ZAN over IBR yielded an ICER of $35,034,000/LYg and a negative (cost saving) ICUR of $3,892,666/QALYg. Compared to ZAN, treatment with ACA was associated with incremental costs of $246,009, 0.20 LY and 0.37 QALY differentials, yielding ICER of $1,230,045/LYg yet ICUR of $664,889/QALYg. All estimates were confirmed with negligible differences in PSAs. In a scenario analysis for the PF1 state only, QALY gains were 5.25 for ACA, 4.40 for ZAN and 4.34 for IBR. Considering cost differentials of $-69,138 for ACA and $-352,297 for ZAN relative to IBR, the corresponding ICURs were $-75,975/QALYg and $-5,871,617/QALYg, resp. Conclusion. Clinically over the course of 1L treatment with a BTKI followed by 2L treatment with VR, ACA in 1L is associated with greater reductions in the risk of progression or death compared to IBR and ZAN over 10 years. This benefit comes at lower cost than IBR, which resulted in cost-saving ICUR and ICER estimates; but at higher cost than ZAN, which resulted in an ICUR of ~$665,000 per QALY gained. Proportionately, QALY results came out more favorably than LY results. This rather unusual result is attributable to the better safety profiles and lower AE costs of ACA and ZAN, coupled with lower pricing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

In silico Evaluation of BTK Inhibitors Mechanisms That Could Induce Atrial Fibrillation and Hypertension in the Treatment of Chronic Lymphocytic Leukemia

Introduction: Ibrutinib (IBRU) and acalabrutinib (ACALA) are first and second generation Bruton Tyrosine Kinase inhibitors (BTKi), respectively, approved for the treatment of chronic lymphocytic leukemia (CLL). Beside the main target, BTKis may inhibit other tyrosine kinases leading to unfavorable off-target effects. The introduction of second generation BTKis was based on their potential of greater selectivity and affinity for BTK inhibition and therefore fewer off-target side effects. Despite many survival benefits, IBRU is associated with adverse events probably due to the off-target inhibition; of concerns are the cardiovascular events. The second-generation BTKi ACALA is more selective to BTK and with less off-target inhibition. A randomized phase III trial comparing ACALA and IBRU in CLL patients demonstrated non-inferior progression free survival with ACALA, along with fewer cardiovascular events, such as atrial fibrillation (AF) and hypertension (HT). Here we present a systems biology- and artificial intelligence-based in silico study to infer the likely pharmacological mechanisms that underlie AF and HT induced by these drugs. Methods: Therapeutic Performance Mapping System (TPMS) technology (Anaxomics Biotech, Spain) was used to create mechanistic models of ACALA and IBRU at the protein interactome level. First, published evidence was reviewed and compiled to molecularly characterize CLL, AF, HT and the target profile of these drugs. Then, supervised machine learning algorithms were applied to computationally infer AF and HT mechanisms. Model-derived measures were used to rank the targets more likely to trigger AF and HT. Finally, the potential mechanisms of action of inhibiting these targets were identified. Although the models are protein-based, the interactome in which they are build include gene and RNA regulation data; for standardization purposes, gene names are used for genes/proteins mentioned in this abstract. Results: The results show that BTK inhibition is not the only factor contributing to AF and HT induction, as they could be mediated by other off-targets impacting pathophysiological processes (Tables 1 and 2). Regarding AF, potential off-target mechanism of action is the inhibition of TEC and ERBB4, which can downregulate PIK3CA and NOS3 involved in atrial fibrosis and downregulate ZFHX3 and the sodium channels SCN1B and SCN5A having an impact in electrophysiology regulation. While no ACALA-specific AF off-targets were identified, IBRU data showed specific off-targets potentially involved in AF mechanisms such as structural remodeling and atrial fibrosis (HCK, FGR, LYN, FYN, YES1 and FLT3), electrophysiology regulation (LYN and SRC), and autonomic nervous system remodeling (CSK). Regarding HT, potential off-target mechanism of action is the inhibition of RIPK2 and ERBB4, which can trigger HT through the following common pathways: modulation of pro- and anti-inflammatory cytokines (IL6, IL10 and TNFA), induction of oxidative stress (NOS3), and endothelial dysfunction (MME, ROCK1, ROCK2, VEGFA and VEGFD). No ACALA-specific HT off-targets or mechanisms were detected, while seven IBRU-specific off-targets were involved in inflammation related to HT (LCK, JAK3 and FLT3) and oxidative stress and endothelial dysfunction (ERBB2, BLK, SRC and CSK). Conclusions: BTKi selectivity is key for CLL disease control and BTK inhibition is not the only factor for AF and HT. This analysis supports that BTKi-induced AF and HT are off-target effects that can partly be mediated by TEC and ERBB4, and RIPK2 and ERBB4 inhibition, respectively. However, other IBRU-specific off-targets and mechanisms could also explain its association with the higher incidence of AF and HT. Although potential literature bias and inhibition potency should be considered in prospective studies, our findings are a starting point to understand ACALA and IBRU differences regarding AF and HT incidence in CLL patients. Study and medical writing support were funded by AstraZeneca. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment Patterns and Outcomes after Ibrutinib Discontinuation Among Elderly Medicare Beneficiaries with Chronic Lymphocytic Leukemia: An Observational Study

Background: Most prior studies of ibrutinib discontinuation in chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) rely on data from clinical trials and/or selected medical centers, which are often limited to younger and/or commercially insured patients and may not be generalizable to routine clinical practice. Also, limited data are available on the next line of treatment initiated after ibrutinib discontinuation in the real-world setting. The objective of this study was to examine ibrutinib discontinuation patterns, overall survival (OS) and factors associated with these patterns among elderly Medicare beneficiaries in the U.S. Methods: This retrospective cohort study used 2013-2019 100% Medicare claims data to identify beneficiaries who newly initiated ibrutinib from 1/1/2014 to 12/31/2018. Study eligibility criteria included: continuous Medicare Part A, B, and D coverage in 12-months before and at least 4-months after the index date (first ibrutinib prescription claim date), CLL/SLL diagnosis in the 12-month pre-index period and at any time over follow-up, ≥66 years on index date, absence of ≥2 diagnoses for another FDA-approved indication for ibrutinib, and absence of ibrutinib prescription in the 12-month pre-index period. Outcomes included ibrutinib discontinuation (defined as the presence of a consecutive 60-day gap in ibrutinib treatment), time to ibrutinib discontinuation, type of CLL/SLL treatment initiated after ibrutinib discontinuation, and OS. Cox regression models were used to examine factors associated with ibrutinib discontinuation. Results: Our final sample included a total of 11,870 Medicare patients newly initiating ibrutinib treatment. Nearly two-thirds (65.2%) of our cohort discontinued ibrutinib use over a median follow up of 25.2 months (IQR: 14.4-39.6) from initiation. Among those who discontinued ibrutinib, 51.1% discontinued within 6 months and 69.2% within 12 months. Among discontinuers, approximately 39% initiated another CLL/SLL treatment after ibrutinib discontinuation over a median follow up of 14.4 months (IQR: 4.8-27.6) post-ibrutinib discontinuation. Of the patients who initiated another CLL/SLL treatment after ibrutinib discontinuation, 21.3%, 18.9%, 10.8%, and 10.0% received venetoclax, rituximab, bendamustine and idelalisib, respectively, either as monotherapy or combination therapy. About 25% of patients who discontinued ibrutinib restarted treatment with ibrutinib at some point during follow-up. In multivariable analysis, patients aged ≥80 years (Hazard ratio [HR]: 1.51; 95% CI: 1.41-1.63); lack of low-income subsidy (LIS) to cover all or part of prescription out-of-pocket costs (HR: 1.08; 95% CI: 1.01-1.16); initiation of ibrutinib as part of combination therapy (HR: 1.16, 95% CI: 1.08-1.25); evidence of prior history of CLL treatment (HR: 1.14, 95% CI 1.08-1.20); atrial fibrillation (HR: 1.27, 95% CI 1.19-1.35); conduction disorders (HR: 1.11, 95% CI 1.03-1.20); heart failure (HR:1.09, 95% CI: 1.01-1.17) and; any hospitalization in the 12-month pre-index period were associated with discontinuation (HR:1.10, 95% CI:1.04-1.16). Lastly, median OS in the entire sample was 4.4 years after ibrutinib initiation. The 3-year survival rate was 72.2% for non-discontinuers but only 56.8% for discontinuers. Among patients who discontinued ≤12 months after initiation, less than half (47.4%) were still alive after 3 years. Conclusions: In this large real-world analysis utilizing 100% Medicare files, the majority (65.2%) of elderly individuals initiating ibrutinib for CLL/SLL discontinued therapy over a median follow up of 25.2 months. Discontinuation was most likely in those with advanced age and baseline comorbidities. Overall, our findings demonstrate a high unmet need with ibrutinib, the widely used first generation Bruton-tyrosine kinase inhibitor (BTKI), in the elderly U.S. population with CLL/SLL. With the development of second and later generations of BTKIs, it will be important to confirm they offer lower discontinuation rates and improved real-world outcomes.

Abstract 1400: AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK

Abstract Introduction: Bruton's tyrosine kinase (BTK) has been recently recognized as a validated drug target for the treatment of B-cell malignances. The emergence of clinical resistance to the first-generation covalent BTK inhibitors is, however, becoming a serious concern. Patients are reported to develop resistance during the treatment due to substitution of cysteine residue at position 481 with serine (C481S mutation) in BTK, which prevents the covalent binding of the first-generation irreversible BTK inhibitors, resulting in the loss of inhibitory activities. Therefore, there is a high unmet medical need for new therapeutic approaches to overcome the BTK C481S-mediated resistance. Material and methods: Compounds were tested in biochemical assays using recombinant human wildtype (WT) and C481S mutant BTKs. Cellular activity of AS-1763 was evaluated in human diffuse large B cell lymphoma (DLBCL) cell lines, OCI-Ly10 and its BTK[C481S] knock-in cells. The in vivo antitumor activity of AS-1763 was assessed in two tumor xenograft mouse models bearing WT or BTK [C481S] knock-in OCI-Ly10 cells. Results: We have discovered AS-1763 as an orally available, highly potent, selective and reversible BTK inhibitor. AS-1763 showed potent inhibitory activities for WT BTK (an activated form, BTK[A]) and the C481S mutant with sub-nanomolar IC50s (IC50 = 0.85 and 0.99 nM for BTK[A] and BTK[C481S], respectively). In cellular assays, AS-1763 exhibited strong antiproliferative activities for WT and BTK [C481S] knock-in OCI-Ly10 cells. AS-1763 demonstrated significant tumor growth inhibition and tumor regression in WT as well as BTK[C481S] knock-in OCI-Ly10 xenograft model. Conclusions: The preclinical data support the clinical development of AS-1763 in patients with B-cell malignancies both having WT and C481S mutation in BTK. The first-in-human Phase 1 clinical trial of AS-1763 in healthy volunteers (EudraCT 2020-005599-37) is currently ongoing, and the Phase 1b study in patients is expected to begin in 2022. Citation Format: Wataru Kawahata, Tokiko Asami, Takao Kiyoi, Takayuki Irie, Shigeki Kashimoto, Hatsuo Furuichi, Masaaki Sawa. AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1400.

Current approach to Waldenström Macroglobulinemia

Waldenström Macroglobulinemia (WM) is a unique, low grade, IgM lymphoplasmacytic lymphoma with a heterogeneous clinical course. A paucity of high-grade evidence from large phase 3 trials remains a major issue in the field despite a rapidly expanding therapeutic armamentarium against WM. Prior knowledge of the patients’ MYD88L265P and CXCR4 mutation status aids in treatment decision making if Bruton's tyrosine kinase (BTK) inhibitor therapy is being considered. Head-to head comparative data to inform optimal approach are lacking, and a particularly vexing issue for the clinicians is choosing between fixed-duration bendamustine-rituximab (BR) therapy and an indefinite BTK inhibitor-based regimen, given that both approaches are well tolerated and effective, particularly for the patient population harboring MYD88L265P mutation. For the patients with MYD88WT genotype, chemo-immunotherapy such as BR is preferred, although zanubrutinib, a potent second generation BTK inhibitor, with its reduced off target effects and greater BTK occupancy compared to its predecessor, ibrutinib, has also recently shown activity in MYD88WT WM. This review summarizes the current literature pertaining to the diagnosis, prognosis, and the treatment of WM.