Tyrosine Kinase Inhibitors Research Articles

Úloha imunoterapie pri liečbe hepatocelulárneho karcinómu

Hepatocellular carcinoma (HCC) represents the most common primary liver malignancy, accounting for approximately 75–80% of all liver cancer cases. The global incidence of hepatocellular carcinoma is increasing due to rising rates of underlying diseases, creating a significant cancer burden and a significant clinical challenge due to its often late presentation and limited effective treatment options. Immune checkpoint inhibitors have revolutionized the treatment approach in various malignancies. In the treatment of advanced hepatocellular carcinoma, immunotherapy has proven to be more effective than tyrosine kinase inhibitors, which have been a treatment option for a decade. Clinical trials such as the HIMALAYA and IMbrave150 have demonstrated significant survival benefits, showing superior efficacy compared to sorafenib. Despite these promising results, not all HCC patients respond to immunotherapy equally. There is a need to search for reliable prognostic and predictive biomarkers that can help predict which patients are most likely to benefit from immunotherapy, thereby personalizing treatment and improving outcomes. The purpose of this article is to provide a summary of clinical trials on immunotherapy for various stages of hepatocellular carcinoma.

Outcomes of pregnancy in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

Young female patients with chronic myeloid leukemia (CML) often face challenges becoming pregnant due to the teratogenicity of tyrosine kinase inhibitors (TKIs). The authors conducted a nationwide survey of female patients with CML who experienced pregnancy between 2002 and 2020. Information for 70 pregnancies in 49 patients was obtained. There were three types of pregnancies: CML onset during pregnancy (n=9), unplanned pregnancy mostly during treatment with a TKI (n=25), and planned pregnancy during treatment-free remission (TFR) or treatment with interferon-alpha (IFN-α) (n=36). The median duration from CML diagnosis to pregnancy in patients with planned pregnancy was significantly longer than that in patients with unplanned pregnancy (10.6 years vs. 4.1 years, p<.001). In 48 pregnancies that resulted in childbirth, TFR and treatment with IFN-α were chosen in 26 and 17 pregnancies, respectively. Sustained major or deeper molecular response was observed in 18 of 26 pregnancies with TFR. The patients who fulfilled the requirements for TKI therapy discontinuation by European LeukemiaNet recommendations achieved a TFR rate of 77% in pregnancy. Treatment with IFN-α might be effective for patients who are in complete cytogenetic response or deeper response (response rate, 76%). Pregnancy by TFR or treatment with IFN-α could be a safe and feasible way for patients with CML. However, a substantial duration of treatment with a TKI before conception may be needed for planned pregnancy. Planning and evaluation for pregnancy should be considered at the time of CML onset for female patients with childbearing potential.

Co-delivery of Interferon Regulatory Factor 5 (IRF5) siRNA and dasatinib by a disulfide bond bearing polymeric carrier for enhanced anti-inflammatory effects

Co-delivery of chemical drugs and nucleic acids has attracted a great interest recently for treatment of inflammatory diseases. Dasatinib (DB), a tyrosine kinase inhibitor with anti-cancer effects, and Interferon Regulatory Factor 5 (IRF5) siRNA have shown anti-inflammatory effects. In the present study, a novel redox-responsive polymeric micelle was designed for co-delivery of DB and IRF5 siRNA-expressing plasmid (psiRF5) to enhance anti-inflammatory effects on macrophages. psiRF5 was condensed efficiently to redox-responsive micelles of DB-conjugated chitosan (CN) composed of disulfide bond, from different molecular weights of CN to form CN-SS-DB/psiRF5 micelles. The micelles with optimum N/P ratios had particle sizes of 287.8 and 245.4 nm and positive zeta potentials. The disulfide bond bearing micelles showed a redox-responsive drug release, protected the plasmid from being dissociated or degraded in exposure with heparin, serum and DNase I, and significantly enhanced the transfection efficiency and IRF5-gene silencing compared to naked psiRF5. The optimum micelles exhibited a dramatic reduction in IRF5 expression and revealed a notably higher anti-inflammatory effect than either DB or psiRF5, as indicated by more IL-10 and less IL-6 and TNF-α production by LPS-stimulated RAW264.7 macrophages incubated with the co-delivery system. The resultant nanocarriers might be promising for more effective treatment of inflammatory diseases.

The efficacy and safety of ZR2 versus R-CHOP-like for elderly patients with newly diagnosed diffuse large B cell lymphoma: a single-center prospective study in China.

Bruton's tyrosine kinase inhibitors have been demonstrated preliminary efficacy in diffuse large B-cell lymphoma (DLBCL). To compare the safety and efficacy of zanubrutinib plus rituximab and lenalidomide (ZR2) and R-CHOP-like for elderly patients with newly diagnosed DLBCL, we conducted this single-center prospective study. Patients were treated with 6 cycles of ZR2 or R-CHOP-like regimen for the first-line treatment. The primary endpoint was complete response ratio (CRR). The secondary outcome measures were progression-free survival (PFS), overall survival (OS), and adverse events. Between June 15, 2020, and March 11, 2023, 30 patients with ZR2 and 60 patients with R-CHOP-like were enrolled. There were no significant differences observed in CRR (P = 0.878), PFS (P = 0.555) and OS (P = 0.769) between ZR2 and R-CHOP-like group. While, patients in ZR2 group had the following features: significantly older (P = 0.002), more unfit (P < 0.001) and higher prognosis risk scores (P = 0.025). The incidence of grade ≥ 3 anemia (P = 0.008) and pneumonia (P = 0.001) was significantly lower in ZR2 group. Patients with germinal center B-cell-like subtype (GCB), large masses or TP53 mutations had a satisfactory remission rate in ZR2 group (57.1%, 77.8% and 60.0%, respectively). ZR2 and R-CHOP-like regimen had similar efficacy and survival. While, the safety profile for ZR2 was superior. GCB subtype, large masses and TP53 mutations may benefit from ZR2 regimen as well. Patients with EBV-positive and CARD11 mutations may need additional treatment rather than ZR2. Patients with gastrointestinal DLBCL have to be monitored closely by abdominal enhanced CT every cycle. Overall, ZR2 chemo-free regimen might be more appropriate for elderly DLBCL patients.

Spatially resolved subcellular protein-protein interactomics in drug-perturbed lung-cancer cultures and tissues.

Protein-protein interactions (PPIs) regulate signalling pathways and cell phenotypes, and the visualization of spatially resolved dynamics of PPIs would thus shed light on the activation and crosstalk of signalling networks. Here we report a method that leverages a sequential proximity ligation assay for the multiplexed profiling of PPIs with up to 47 proteins involved in multisignalling crosstalk pathways. We applied the method, followed by conventional immunofluorescence, to cell cultures and tissues of non-small-cell lung cancers with a mutated epidermal growth-factor receptor to determine the co-localization of PPIs in subcellular volumes and to reconstruct changes in the subcellular distributions of PPIs in response to perturbations by the tyrosine kinase inhibitor osimertinib. We also show that a graph convolutional network encoding spatially resolved PPIs can accurately predict the cell-treatment status of single cells. Multiplexed proximity ligation assays aided by graph-based deep learning can provide insights into the subcellular organization of PPIs towards the design of drugs for targeting the protein interactome.

Osteonecrosis of the jaw in patients with clear cell renal cell carcinoma treated with targeted agents: a case series and large-scale pharmacovigilance analysis

ObjectiveTo optimize the use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for cancer patients, we characterized and evaluated ONJ related to TKIs and ICIs by analyzing a public database and reviewing the relevant literature. TKIs and ICIs are limited to drugs that treat renal cancer recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Kidney Cancer.MethodsWe described a case series of patients experiencing ONJ while on TKIs or ICIs. We also analyzed spontaneous reports submitted to the FAERS in an observational and retrospective manner between January 2004 and December 2022. Selecting ONJ’ adverse events to TKIs and ICIs. Associations between TKIs, ICIs and ONJ were assessed using reporting odds ratios (ROR), drug interaction signals based on the Ω shrinkage measure.Results29 patients with ONJ events while on TKIs and ICIs were included in our case series. 240 were related to ONJ AEs. Specifically, 32.1% ICSRs were linked to sunitinib, 16.7% to lenvatinib, 12.9% to pazopanib, 12.5% to nivolumab, 10.0% to axitinib, 5.4% to sorafenib, 5.0% to pembrolizumab, 4.2% to cabozantinib, and 1.3% to ipilimumab. More ICSRs were generally seen in male and reported in Europe. The median age was 63 years. Renal cancer and lung cancer was the most common indication for TKIs and ICIs, respectively. Excluding missing data, the prevalence of mortality was highest for sunitinib-related ONJ ICSRs (18.5%), followed by sorafenib-related ONJ ICSRs (15.4%). With the criteria of ROR, sunitinib and lenvatinib were significantly associated with ONJ AEs. With the criteria of Ω, nivolumab + cabozantinib was significantly associated with ONJ AEs.ConclusionTKIs and ICIs have been reported to have significant ONJ side effects. Patients and physicians need to recognize and monitor these potentially fatal adverse events.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Evolving Patient-Centred Therapies for Metastatic NSCLC

The metastatic non-small cell lung cancer (mNSCLC) treatment landscape has vastly expanded over the past two decades as a result of advancements in biomarker testing. However, unmet needs remain both in terms of treatment options for some patient groups, and patient support throughout the treatment journey. In this symposium, Jarushka Naidoo, Consultant Medical Oncologist, Beaumont RCSI Cancer Centre, Dublin, Ireland; Terri Conneran, KRAS Kickers, Charlotte, North Carolina, USA; Luis Paz-Ares, Chair of the Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; and Alexander Drilon, Chief of Early Drug Development and Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, USA, focused on patient-centric approaches to mNSCLC treatment, starting with a patient and patient advocacy group perspective on what patients want from their care team during their treatment journey. The panel also discussed both immuno-oncology (I-O) monotherapy and combination therapy, including dual I-O therapies for patients with programmed death-ligand 1 (PD-L1) tumour expression &lt;1%, as well as the treatment landscape for KRASG12C-mutated mNSCLC, and ongoing trials of KRAS-targeted agents. In addition, the latest data on tyrosine kinase inhibitors (TKI) for patients with alterations in ROS1 and NTRK genes were discussed, focusing on next-generation TKIs. Finally, the panel discussed patient cases, taking into account specific considerations and how to best approach treatment decisions.

Serum creatine kinase elevation following tyrosine kinase inhibitor treatment in cancer patients: Symptoms, mechanism, and clinical management.

Molecular targeted tyrosine kinase inhibitors (TKIs) have produced unprecedented treatment response in cancer therapy for patients harboring specific oncogenic mutations. While the TKIs are mostly well tolerated, they were reported to increase serum levels of creatine kinase (CK) and cause muscle metabolism-related toxicity. CK is an essential enzyme involved in cellular energy metabolism and muscle function. Elevated serum CK levels can arise from both physiological and pathological factors, as well as triggered by specific drug classes. The incidence of serum CK elevation induced by a few approved TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib combination [Food and Drug Administration, United States]; aumolertinib, and sunvozertinib [only approved by National Medical Products Administration, China]) were over 35%. CK elevation-related symptoms include myopathy, myositis, inclusion body myositis (IBM), cardiotoxicity, rhabdomyolysis, rash, and acneiform dermatitis. High-level or severe symptomatic CK elevation may necessitate dose reduction and indirectly dampen TKI efficacy. This review presents an updated summary about the prevalence rate and recent research about mechanisms leading to TKI-induced serum CK elevation in cancer patients. The utility of monitoring serum CK levels for predicting TKI-induced adverse effects and their management will also be discussed.

Clinical characteristics and prognostic factors of epidermal growth factor receptor-mutated non-small cell lung cancer transformed into small-cell lung cancer after treatment

Objective: To analyze the clinical characteristics and prognostic factors of non-small cell lung cancer (NSCLC) patients with sensitive epidermal growth factor receptor (EGFR) mutations who developed small cell lung cancer (SCLC) transformation after treatment with EGFR tyrosine kinase inhibitors (TKI). Methods: We conducted a retrospective collection of clinical data for 21 patients with advanced EGFR mutant NSCLC who developed SCLC transformation after EGFR-TKI treatment at Beijing Chest Hospital, Capital Medical University from January 2015 to December 2021. The clinical characteristics were summarized and the prognosis analysis was conducted. Patients were followed up until February 2024. The efficacy was evaluated using Solid Tumor Response Evaluation Criteria, and survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the differences in survival time (OS) between limited stage and extensive stage in transformed SCLC patients. Cox proportional hazards model was used to analyze the influencing factors of survival after SCLC transformation. Results: Among the 21 patients, there were 5 males and 16 females, with an age range of 33-74 years old [(58.9±2.6) years old]. All 21 patients were adenocarcinoma with sensitive EGFR mutations. There were 18 cases (85.7%) with EGFR gene 19del mutation, including 1 case of 19del+anaplastic lymphoma kinase (ALK) mutation, and 3 cases of L858R mutation. Among the transformed SCLC, there were 11 cases of pure SCLC and 10 cases of mixed SCLC (coexisting of adenocarcinoma and small cell carcinoma components). The median time from diagnosis of NSCLC to SCLC transformation was 12.0 months (95%CI: 7.6-16.3 months). Among the 21 cases of SCLC transformation, there were 13 cases with the extensive stage and 8 cases with the limited stage. Among them, 16 patients received systemic chemotherapy based on etoposide, of which 13 cases could be evaluated for efficacy, 11 cases could be calculated for PFS. Five cases had partial remission, 5 cases were stable, 3 cases had disease progression, and 3 cases cloud not be evaluated. The median progression free survival time (PFS) was 4.8 months (95%CI: 2.8-6.8 months). The median survival time (OS) after SCLC transformation in 21 patients was 10.6 months (95%CI: 7.0-14.2 months), with a median OS of 8.8 months (95%CI: 6.3-11.4 months) for patients with the extensive stage and 27.5 months (95%CI: 9.6-34.4 months) for patients with the limited stage, with statistically significant differences (P=0.002). Cox proportional hazards model analysis showed that the limited stage after SCLC transformation was a protective factor for OS (HR=0.32, 95%CI: 0.12-0.73, P=0.010). The median OS of 21 patients from the diagnosis of lung cancer was 24.9 months (95%CI: 13.0-36.7 months). Conclusions: NSCLC patients with SCLC transformation are all adenocarcinomas, and the proportion of EGFR19del mutations is relatively high. After SCLC transformation, the standard chemotherapy regimen for SCLC is generally used for treatment. The OS after SCLC transformation is related to the stage, and the prognosis is better in the limited stage.

Philadelphia chromosome-positive or Philadelphia chromosome-like B-cell precursor acute lymphoblastic leukemia with multilineage involvement in pediatric patients: a report of two cases and literature review.

Based on driver mutations and gene expression profiles, the International Consensus Classification currently divided the entity 'Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL)' into two subtypes: lymphoid-only and multilineage involvement (Ph+ ALL-L and -M, respectively). The similar biological characteristics of Ph-like ALL and Ph+ ALL drove us to assume that Ph-like ALL-M subtypes exist. This report presents two pediatric ALL cases (one Ph+ and one Ph-like) with minimal residual disease negativity established by multicolor flow cytometry but persistent transcript detection by quantitative PCR (qPCR) even after second-line treatment with tyrosine kinase inhibitors combined with blinatumomab immunotherapy. Using droplet digital PCR, BCR::ABL1 or TPM3::PDGFRB transcripts were identified in CD19+ cells as well as in non-CD19+ cells, suggesting the presence of a Ph+ or Ph-like ALL-M subtype originating from hematopoietic stem cells. This report provides information for better characterization, diagnosis, and treatment of these ALL subtypes.

The Effects of Nebivolol-Gefitinib-Loratadine Against Lung Cancer Cell Lines.

Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines. A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay. The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells). The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment.

Combined targeting of GPX4 and BCR-ABL tyrosine kinase selectively compromises BCR-ABL+ leukemia stem cells

BackgroundIn the ongoing battle against BCR-ABL+ leukemia, despite significant advances with tyrosine kinase inhibitors (TKIs), the persistent challenges of drug resistance and the enduring presence of leukemic stem cells (LSCs) remain formidable barriers to achieving a cure.MethodsIn this study, we demonstrated that Disulfiram (DSF) induces ferroptosis to synergize with TKIs in inhibiting BCR-ABL+ cells, particularly targeting resistant cells and LSCs, using cell models, mouse models, and primary cells from patients. We elucidated the mechanism by which DSF promotes GPX4 degradation to induce ferroptosis through immunofluorescence, co-immunoprecipitation (CO-IP), RNA sequencing, lipid peroxidation assays, and rescue experiments.ResultsHere, we present compelling evidence elucidating the sensitivity of DSF, an USA FDA-approved drug for alcohol dependence, towards BCR-ABL+ cells. Our findings underscore DSF’s ability to selectively induce a potent cytotoxic effect on BCR-ABL+ cell lines and effectively inhibit primary BCR-ABL+ leukemia cells. Crucially, the combined treatment of DSF with TKIs selectively eradicates TKI-insensitive stem cells and resistant cells. Of particular note is DSF’s capacity to disrupt GPX4 stability, elevate the labile iron pool, and intensify lipid peroxidation, ultimately leading to ferroptotic cell death. Our investigation shows that BCR-ABL expression induces alterations in cellular iron metabolism and increases GPX4 expression. Additionally, we demonstrate the indispensability of GPX4 for LSC development and the initiation/maintenance of BCR-ABL+ leukemia. Mechanical analysis further elucidates DSF’s capacity to overcome resistance by reducing GPX4 levels through the disruption of its binding with HSPA8, thereby promoting STUB1-mediated GPX4 ubiquitination and subsequent proteasomal degradation. Furthermore, the combined treatment of DSF with TKIs effectively targets both BCR-ABL+ blast cells and drug-insensitive LSCs, conferring a significant survival advantage in mouse models.ConclusionIn summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment.

Stereotactic Radiosurgery Dose Reduction for Melanoma Brain Metastases Patients on Immunotherapy or Target Therapy: A Single-Center Experience.

Better local control but higher rates of adverse radiation events (ARE) have been reported when combining American Society for Radiation Oncology (ASTRO)-guideline-suggested dose (SD) stereotactic radiosurgery (SRS) with immunotherapy or targeted therapy for melanoma brain metastases. The objective of this study is to explore the efficacy and safety of lower prescription doses compared with ASTRO guidelines for single-fraction SRS for patients with melanoma metastases who are concurrently receiving immunotherapy or targeted therapy. We conducted a retrospective, single-center study on 194 patients who underwent SRS between 2009 and 2022. After propensity score matching, 71 patients with 292 metastases were included in the ASTRO-SD (20-24 Gy for <2 cm, 18 Gy for ≥2 to <3 cm) group and 33 patients with 292 metastases in the reduced dose (RD, <20 Gy for <2 cm, <18 Gy for ≥2 to <3 cm) group. The median diameter (5.4 vs 5.2 mm, P = .6), prescription volume (0.2 vs 0.2 cm3, P = .2), and radiographic follow-up (11 vs 12 months, P = .2) were similar in the 2 groups. The cumulative incidence of progressing metastases was significantly higher in the SD compared with the RD group (P = .018). Higher prescription volumes and ASTRO-suggested radiation doses were associated with local progression in multivariable analysis. Radiographic AREs were significantly more common in the SD compared with the RD group (8.6% vs 3.1%, P = .005). BRAF and other tyrosine kinase inhibitors' concurrent use, higher prescription volumes, and ASTRO-suggested radiation doses were associated with an increased risk of radiographic ARE. This study provides evidence that RD SRS could offer reduced toxicity rates, while maintaining high local control as compared with the current guideline-SDs for the treatment of melanoma brain metastases.

Positioning Imatinib for Pulmonary Arterial Hypertension (PIPAH) study

Abstract Introduction Pulmonary arterial hypertension (PAH) is characterised by pre-capillary pulmonary vascular remodelling. Imatinib, a tyrosine kinase inhibitor, was the first treatment investigated in PAH patients with the primary aim of targeting vascular remodelling. A Phase 3 study showed that imatinib 400mg daily reduces pulmonary vascular resistance and increases exercise capacity but only 43% of patients continued the drug for 6 months. Concerns about safety prevented regulatory approval. Purpose To identify a safe and tolerated dose of oral Imatinib and evaluate efficacy in the dose range 100-400mg daily. Methods Oral Imatinib was added to the background therapy of 17 patients with PAH; prior intracranial haemorrhage was excluded by cross sectional imaging and none were receiving an anticoagulant. The first patient started on 100mg daily. The next 12 patients were recruited serially at a minimum of 4 week intervals and started on 200mg, 300mg or 400mg, according to a Bayesian adaptive design (Continuous Reassessment Method, CRM). Patients 14-17 were recruited as an extension cohort to better understand the safety and tolerability of the 100mg and 200mg doses. The primary endpoint was safety and tolerability at 4 weeks. Imatinib was continued for up to 24 weeks. Thirteen patients had implanted devices that provided remote daily measurements of cardiopulmonary haemodynamics and heart rate and rhythm and physical activity. Non-invasive measures of systemic blood pressure, weight and oxygen saturations were made remotely. We compared the time-haemodynamic response relationship with that produced by licensed treatments in a similar patient cohort. Results The recommended starting dose from the CRM was 200mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (P&amp;lt;0.01), increased cardiac output (P=0.08) and reduced total pulmonary resistance (TPR, P&amp;lt;0.001, Figure). There was a clear dose-TPR response relationship (r2=0.52, p&amp;lt;0.01). A reduction in TPR was evident within the first week and plateaued at 4-5 weeks. Withdrawal of Imatinib led to an increase to baseline in TPR over 4-5 weeks. This contrasts with a sharp fall in TPR with licensed therapy and rapid increase on treatment withdrawal. There was a small reduction in systemic vascular resistance (P&amp;lt;0.05) with Imatinib that reached plateau before TPR. Conclusions Oral Imatinib 200mg daily is well tolerated and effective as an add-on treatment in PAH. The time course of the initial haemodynamic response and the gradual return to baseline on withdrawal distinguishes Imatinib from licensed treatments and is supportive of a mechanism of action beyond reliance on vasodilation. Remote monitoring enables the safe evaluation of the withdrawal of an investigational drug in patients established on best medical therapy.Figure 1.

Cardiovascular events in CML patients treated with nilotinib: validation of the HFA-ICOS baseline risk score

Abstract Background The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, a potent 2nd generation TKI, showed higher rates of major molecular response than imatinib, however was associated with higher rates of cardiovascular (CV) toxicity. Objectives To describe the CV events associated with nilotinib in a real-world CML population and assess the predictive value of the HFA-ICOS baseline risk score in clinical practice. Methods The HFA-ICOS baseline risk was calculated (low, medium, high /very high) for patients with CML treated with nilotinib between 2006 and 2021. The incidence of all CV events, ischaemic events and Major CV Adverse Events (MACE) were reviewed and compared among the different risk groups. Results A total of two hundred and twenty-nine eligible patients were included in the analysis. The incidence of CV events, ischaemic events, and MACE, while on nilotinib, were 20.9% (95% CI: 15.7% to 26.2%), 12.7% (95% CI: 8.4% to 16.9%), and 12.2% (95% CI: 7.9% to 16.5%) respectively, following a median duration of treatment with nilotinib of 34.4 months for the entire cohort. Patients with a higher HFA-ICOS baseline risk score had higher rates of all CV events (low: 11.2%, medium: 28.2% [HR: 2.8, 95% CI: 1.2 to 6.2], high/very high: 32.4% [HR: 3.5, 95% CI: 1.8 to 6.8]), ischaemic events (low: 5.2%, medium: 17.9% [HR: 3.7, 95% CI: 1.2 to 10.9] , high/very high: 21.6% [HR: 3.7, 95% CI: 1.4 to 9.7]) and MACE (low: 7.8% , medium: 10.3% [HR:1.2, 95% CI: 0.38 to 4.1], high/very high: 20.2% [HR: 2.2, 95% CI: 0.9 to 5.3]). The predictive tool presented an 89% NPV, and an area under the ROC curve: 0.65 for all CV events, an NPV of 95% and AUC 0.68 for ischaemic events and NPV 92% and AUC 0.62 for MACE. Conclusions The HFA-ICOS risk stratification tool has been shown to be an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk categories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients, as it also underscores the potential for further improvement in the overall discriminatory ability of the model.

First-line Treatment Selection for Advanced Hepatocellular Carcinoma

The treatment landscape of advanced/unresectable hepatocellular carcinoma (uHCC) has rapidly evolved since 2018. Over recent years, various systemic therapies and treatment approaches have been explored. Systemic therapy has primarily relied on tyrosine kinase inhibitors (TKIs); however, immune checkpoint inhibitors (ICIs) have more recently entered the realm of the treatment armamentarium.

Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover

Non-small cell lung cancer (NSCLC) is a prevalent and fatal malignancy with a significant global impact. Recent advancements have introduced targeted therapies like tyrosine kinase inhibitors (TKIs) such as osimertinib, which have improved patient outcomes, particularly in those with EGFR mutations. Despite these advancements, acquired resistance to TKIs remains a significant challenge. Hence, one of the current research priorities is understanding the resistance mechanisms and identifying new therapeutic targets to improve therapeutic efficacy. Herein, we identified high expression of c-Met in osimertinib-resistant NSCLC cells, and depletion of c-Met significantly inhibited the proliferation of osimertinib-resistant cells and prolonged survival in mice, suggesting c-Met as an attractive therapeutic target. To identify effective anti-tumor agents targeting c-Met, we screened a compound library containing 641 natural products and found that only xanthohumol exhibited potent inhibitory effects against osimertinib-resistant NSCLC cells. Moreover, combination treatment with xanthohumol and osimertinib sensitized osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. Mechanistically, xanthohumol disrupted the interaction between USP9X and Ets-1, and inhibited the phosphorylation of Ets-1 at Thr38, promoting its degradation, thereby targeting the Ets-1/c-Met signaling axis and inducing intrinsic apoptosis in osimertinib-resistant NSCLC cells. Overall, the research highlights the critical role of targeting c-Met to address osimertinib resistance in NSCLC. By demonstrating the efficacy of xanthohumol in overcoming resistance and enhancing therapeutic outcomes, this study provides valuable insights and potential new strategies for improving the clinical management of NSCLC.

Angiotensin receptor-neprilysin inhibitor (Sacubitril/Valsartan) in cancer therapy-related cardiac dysfunction: real-world experience from a nurse-led cardio-oncology clinic

Abstract Introduction Cancer therapy-related cardiac dysfunction (CTRCD) is a common toxicity amongst patients receiving anti-cancer treatment1. Angiotensin receptor-neprilysin inhibitor (ARNI) Sacubitril/Valsartan is recommended to reduce Heart Failure (HF) admissions and cardiovascular mortality2. However, patients with active cancer were excluded from the key trials of ARNI. This study aims to provide a real-world experience of ARNI prescription and management from the perspective of a nurse-led Cardio-Oncology clinic. Methods This is a single centre, retrospective, observational cohort study performed at a Cardio-Oncology specialist centre between the period of 2021 to 2024. Adult cancer patients receiving anti-cancer therapy were included if they had symptomatic HF or asymptomatic CTRCD, were initiated on ARNI and followed up in the nurse-led Cardio-Oncology clinic. Results Twenty-nine patients were started on ARNI (see Figure 1). The mean age of the patients was 66+11 years and 17 (59%) were male. Cardiovascular risk factors were common: hypertension (45%), hyperlipidaemia (35%), diabetes mellitus (21%), and smoking (17%). Haematological and breast malignancies were most common (31% and 21% respectively), followed by gynaecological malignancies (14%). Twenty-one (72%) were treated with cytotoxic chemotherapy including 10 (35%) received anthracyclines. Five (17%) patients received human epidermal growth factor receptor 2 (HER2) targeted therapies, 3 (10%) were on tyrosine kinase inhibitors, and 2 (7%) received immunotherapy. Twenty-five (86%) patients presented with symptomatic HF while 4 (14%) had asymptomatic CTRCD. The median N-terminal-pro B-type natriuretic peptide (NTproBNP) level was elevated at 1325(806-4330)ng/L. Thirteen (45%) patients tolerated the maximum dose of 200mg twice daily, while 16 (56%) could only tolerate middle and lowest dosages. ARNI dose up titration to the maximum tolerated dose took 26 (15-79) days. Twenty-eight (97%) patients were on beta blockers, 26 (90%) received SGLT2 inhibitors, 25 (86%) on mineralocorticoid receptor antagonists, and 10 (35%) patients required diuretics. The most common side effect was symptomatic hypotension in 11 (38%) patients. Two (7%) had hyperkalemia, 1 (3%) acute kidney injury following initiation, and 1 (3%) had dizziness without significant hypotension. Nine (31%) required dose reduction allowing ARNI to be continued, while 3 (10%) patients had to permanently discontinue ARNI. There were no cardiovascular deaths, cancer deaths or HF admissions. Conclusion The Cardio-Oncology nurse-led clinic permits rapid up-titration of ARNI to target dosages in patients with CTRCD, resulting in significant improvements in cardiac function. The nurse lead clinic education, support and side effect management allowed uninterrupted continuation of cancer treatment. Whether this approach translates into be better cardiac and cancer outcomes requires further study.

Cardiovascular and non-cardiovascular adverse events in patients with hematologic malignacies treated with BTK inhibitors: a real-world analysis

Abstract Background Bruton tyrosine kinase (BTK) inhibitors play an important role in targeted treatment of B-cell lymphoproliferative disorders. However, adverse events may limit the proper course of treatment in many patients. Purpose To compare the risk of cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia (CLL) or small cell lymphocytic lymphoma (SLL) treated with first-generation BTK inhibitor ibrutinib versus second-generation acalabrutinib, using real-world data from electronic medical records. Methods We used data from a large collaborative multinational network ( TriNetX), that emcompasses more than 100 healthcare organizations worldwide. We queried the databank for patients aged ≥ 18 years with chronic lymphocytic leukemia or small-cell lymphomas treated with ibrutinib or acalabrutinib in the past 10 years before the analysis. We used propensity score matching to balance the cohorts. The 3-year cumulative incidences and hazard ratios for the following outcomes were calculated: atrial flutter or fibrillation, other arrhythmias, heart failure, ischemic stroke or peripheral embolism, acute coronary syndrome, bleeding, and sepsis. Results We compared 2,107 patients in each group. The 3-year incidences of atrial fibrillation or flutter in the acalabrutinib and ibrutinib groups were 7.11% and 14.78% respectively, with a lower ratio in patients treated with acalabrutinib than those treated with ibrutinib (hazard ratio, HR 0.68, 95% CI 0.55-0.84). New-onset hypertension occurred during the 3-year follow-up in 16.29% patients in the acalabrutinib group versus 27.8% patients in the ibrutinib group (HR 0,81, 95% CI 0.66-0.98). The incidence of sepsis was 6.49% in patients treated with acalabrutinib versus 11.37% in those treated with ibrutinib group (HR 0.77, 95% CI 0.60-0.98). Concerning the other adverse events, there were no significant differences between the two groups. Conclusions In this large real-world analysis, patients with CLL or SLL treated with acalabrutinib had a better cardiovascular and non-cardiovascular safety profile than those treated with ibrutinib, with lower incidence of atrial flutter or fibrillation, new-onset arterial hypertension, and sepsis.Figure 1.Cardiovascular outcomesFigure 2.Non-cardiovascular outcomes