Arrhythmogenic effects of tyrosine kinase inhibitors: a narrative review

IntroductionThe World Health Organization classification of chronic myeloproliferative disease encompasses eight entities of bone marrow neoplasms, among them Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1-positive chronic myeloid leukemia and polycythemia vera. Polycythemia vera requires, in the majority of cases (95%), the negativity of Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 rearrangement and the presence of the Janus kinase 2 mutation. We report a case of erythrocytosis as the primary manifestation of a chronic myeloid leukemia, with the presence of the Philadelphia chromosome and the Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion gene, and in the absence of any Janus kinase 2 mutation.Case presentationA 68-year-old Caucasian woman, with a history of cigarette consumption and obstructive sleep apnoea syndrome (undergoing continuous positive airway pressure treatment) had presented to our institution with fatigue and a hemoglobin level of 18.6g/L, with slight leukocytosis at 16G/L, and no other anomalies on her complete blood cell count. Examination of her arterial blood gases found only a slight hypoxemia; erythropoietin and ferritin levels were very low and could not explain a secondary erythrocytosis.Further analyses revealed the absence of any Janus kinase 2 mutation, thus excluding polycythemia vera. Taken together with a high vitamin B12 level, we conducted a Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 gene analysis and bone marrow cytogenetic analysis, both of which returned positive, leading to the diagnosis of chronic myeloid leukemia.ConclusionsTo date, this case is the first description of a Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1-positive chronic myeloid leukemia, presenting with erythrocytosis as the initial manifestation, and mimicking a Janus kinase 2 V617F-negative polycythemia vera. Her impressive response to imatinib therapy underscores the importance of not missing this diagnosis.

Simple SummaryThe tyrosine kinase inhibitor (TKI) imatinib was the first targeted therapy to show clinical efficacy against chronic myeloid leukemia (CML) through inhibition of the breakpoint cluster region–Abelson murine leukemia viral oncogene homolog (BCR-ABL), which is responsible for the disease. Two other generations of TKIs have succeeded imatinib, offering additional therapeutic solutions for a growing number of patients with imatinib-resistant CML. However, these clinical approaches although very effective, generate many unwanted side effects because of their daily administration. Attempts to stop TKI when the disease is no longer detectable at the molecular level, unfortunately result in relapses in more than half of cases. This highlights the presence of undetectable leukemia cells, recognized as leukemic stem cells (LSCs) that are TKI insensitive. It therefore appears necessary to identify new biochemical pathways in LSCs, the targeting of which would make re-sensitization to TKIs possible. The results presented here demonstrate that targeting the protein kinase Cδ (PKCδ) pathway represents a valid alternative for LSC elimination.Numerous combinations of signaling pathway blockades in association with tyrosine kinase inhibitor (TKI) treatment have been proposed for eradicating leukemic stem cells (LSCs) in chronic myeloid leukemia (CML), but none are currently clinically available. Because targeting protein kinase Cδ (PKCδ) was demonstrated to eliminate cancer stem cells (CSCs) in solid tumors, we evaluated the efficacy of PKCδ inhibition in combination with TKIs for CML cells. We observed that inhibition of PKCδ by a pharmacological inhibitor, by gene silencing, or by using K562 CML cells expressing dominant-negative (DN) or constitutively active (CA) PKCδ isoforms clearly points to PKCδ as a regulator of the expression of the stemness regulator BMI1. As a consequence, inhibition of PKCδ impaired clonogenicity and cell proliferation for leukemic cells. PKCδ targeting in K562 and LAMA-84 CML cell lines clearly enhanced the apoptotic response triggered by any TKI. A strong synergism was observed for apoptosis induction through an increase in caspase-9 and caspase-3 activation and significantly decreased expression of the Bcl-xL Bcl-2 family member. Inhibition of PKCδ did not modify BCR-ABL phosphorylation but acted downstream of the oncogene by downregulating BMI1 expression, decreasing clonogenicity. PKCδ inhibition interfered with the clonogenicity of primary CML CD34+ and BCR-ABL-transduced healthy CD34+ cells as efficiently as any TKI while it did not affect differentiation of healthy CD34+ cells. LTC-IC experiments pinpointed that PKCδ inhibition strongly decreased the progenitors/LSCs frequency. All together, these results demonstrate that targeting of PKCδ in combination with a conventional TKI could be a new therapeutic opportunity to affect for CML cells.

Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) tyrosine kinase inhibitors (TKIs) improve the outcome of patients with childhood Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) when they are incorporated into postremission induction chemotherapy. To date, no data are available on the impact of TKIs on minimal residual disease (MRD) at the end of induction therapy among patients who have a poor early response to 2 weeks of induction therapy that does not include TKIs. The authors analyzed the early response to TKIs during remission induction in children with Ph-positive ALL who were treated at St. Jude Children's Research Hospital. MRD was measured on days 15 and 42 of induction. TKIs were incorporated into induction therapy on day 22 in the post-TKI era. TKIs produced a marked drop in MRD levels: at the end of remission induction, 9 of 11 patients who received imatinib or dasatinib and conventional induction chemotherapy achieved MRD-negative status compared with only 2 of 16 patients who received chemotherapy alone (P < .001). The 5-year event-free survival rate (± standard deviation) was 68.6% ± 19.2% for the 11 patients who received TKIs versus 31.6% ± 9.9% for the 19 patients who did not (P = .022); notably, 2 of the former group underwent hematopoietic stem cell transplantation versus 15 of the latter group (P = .002). MRD levels and outcomes did not differ significantly among 498 patients with standard-risk/high-risk, Ph-negative ALL who were treated in the pre-TKI or post-TKI eras. TKIs administered in the early phases of therapy can dramatically reduce MRD and improve the outcome of childhood Ph-positive ALL.

Imatinib was the first representative of the class of Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog (BCR-ABL) tyrosine kinase inhibitors used for the treatment of chronic myeloid leukemia. Second-generation and third-generation drugs have been introduced in this therapy, affording increased patient survival. However, all BCR-ABL tyrosine kinase inhibitors have been shown to induce resistance, necessitating a search for new therapeutic options. The sunitinib, another tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and gastrointestinal stromal tumors is an isatin derivative. Isatin nucleus is highly versatile for the preparation of new substances, and several tyrosine kinase inhibitors examples have been obtained using it. This work aimed to design, synthesize, and biological evaluation of new compounds using the K562 cell line, which constitutively expresses the active BCR-ABL enzyme. Three new series of imatinib derivatives have been planned from the imatinib, and all have a phenylaminopyrimidine group as the main pharmacophore. Sunitinib was used as a structural prototype to planning the series 1 (8a–e) of hybrids between sunitinib and imatinib. Series 2 and 3 are 2-oxo-2-phenyacetamide and 2,2-difluoro-2-phenylacetamide derivatives, respectively. Isatins were used as the starting materials for all series. Compounds were synthesized using simple methodologies and were obtained in high purities. The compounds were tested against K562 cells, and four showed a reduction in cell viability, with EC50 values ranging from 0.37 to 2.02 μM, some of which are close to the imatinib standard (0.21 µM).

Primary central nervous system lymphoma (PCNSL) is an aggressive lymphoma that primarily affects the central nervous system. Current treatments, such as surgery, chemotherapy, and whole-brain radiotherapy, often fail to achieve satisfactory results. The prognosis for patients with refractory or relapsed (R/R) PCNSL is bleak. The optimal treatment for refractory or relapsed PCNSL is poorly defined due to a limited number of studies in this setting. Bruton's tyrosine kinase (BTK) inhibitors, as part of targeted therapy regimens, have undergone testing in several clinical trials against PCNSL and have shown promising results in the treatment of R/R PCNSL. In this meta-analysis, we aim to explore and critically appraise the evidence regarding the efficacy of BTK inhibitors in the treatment of refractory or relapsed PCNSL. A systematic search was conducted on multiple databases including PubMed, Embase, Cochrane library, Wanfang Data Knowledge Service Platform, and CNKI, covering the period up to November 2023. The inclusion criteria for studies were patients with R/R PCNSL who received BTK inhibitors, and reported data on overall response rate (ORR) and complete remission (CR). The pooled rates were calculated using a random-effects or fixed-effects model with a double arcsine transformation, and 95% CIs were determined for all outcomes. In total, 1 studies involving 185 patients were identified and included in the meta-analysis. The pooled complete remission (CR) rate of BTK inhibitors-based treatment for R/R PCNSL was found to be 50%. Subgroup analysis revealed that the CR rates for BTK inhibitor monotherapy, BTK inhibitor combined with chemotherapy, and BTK inhibitor combined with radiotherapy for R/R PCNSL were 7%, 68%, and 80%, respectively. The ORR for BTK inhibitors-based treatment for R/R PCNSL was 70%. Subgroup analysis showed that the ORR rates for BTK inhibitor monotherapy and BTK inhibitor combined with chemotherapy for R/R PCNSL were 55% and 83%, respectively. The most common adverse events (AEs) reported were hematologic AEs, including neutropenia, anemia, and thrombocytopenia. Severe nonhematologic AEs included rash, febrile neutropenia, increased levels of aspartate aminotransferase, and increased blood bilirubin. BTK inhibitors can be regarded as a safe and effective treatment option for R/R PCNSL, thereby providing a potential new avenue for R/R PCNSL treatment. However, it is important to note that further large-sample prospective randomized controlled trials are needed to validate these findings and establish their wider applicability.

The treatment for chronic myeloid leukemia has changed significantly over the past 15 years, and as of now, there are five BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase inhibitors that have gained approval for treatment of this disease. All five are very effective drugs, and the decision surrounding which to use in specific patients is based on numerous factors. Bosutinib is one of the newer tyrosine kinase inhibitors to gain approval, and has been studied in the first-line setting as well as after failure of other tyrosine kinase inhibitors. It is an SRC-ABL1 (steroid receptor co-activator-ABL1) inhibitor that works in the presence of most kinase domain mutations. The primary side effects of bosutinib are gastrointestinal upsets. In the appropriate clinical setting, bosutinib can be considered a valuable addition to the armamentarium of treatments available for chronic myeloid leukemia.

Tyrosine kinase inhibitors (TKIs) have transformed the treatment of a broad range of hematologic and solid malignancies. However, their expanding use has revealed a spectrum of cardiovascular (CV) toxicities, varying in frequency and severity across drug classes and individual agent. This review summarized the CV adverse effects associated with major classes of small-molecule TKIs including Bruton tyrosine kinase (BTK) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, BCR-ABL inhibitors, epidermal growth factor receptor (EGFR) inhibitors, BRAF/MEK inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors. It also highlights strategies for cardiac surveillance in accordance with the latest cardio-oncology guidelines. BTK inhibitors are associated with atrial fibrillation, hypertension, and bleeding, with hypertension representing a class effect. Newer agents show lower incidence rates of atrial fibrillation. VEGF TKIs are linked to hypertension, left ventricular (LV) dysfunction, and arterial thromboembolic events. BCR-ABL TKIs demonstrate more agent-specific toxicities, including pulmonary arterial hypertension with dasatinib, arterial thromboembolic events, and corrected QT interval (QTc) prolongation with nilotinib and ponatinib. Ponatinib shows dose-dependent toxicity. Imatinib and bosutinib have the most favorable CV safety profiles. Osimertinib, a third-generation EGFR inhibitor, is associated with LV dysfunction. BRAF and MEK inhibitors, especially when used in combination, are associated with hypertension, LV dysfunction, and QTc prolongation. Lorlatinib, an ALK inhibitor, exhibits a distinct cardiometabolic profile, including hyperlipidemia, hypertension, and weight gain. Understanding the class and agent-specific CV risks of TKIs is critical for monitoring and managing CV toxicities effectively. Individualized surveillance and early intervention, guided by the current guideline recommendations, are essential to minimizing CV complications, maintaining continuity of TKI therapies, and improving patient outcomes.

Exploiting the inherent promiscuity of drugs can enable recognition of important “off-target” effects that can be leveraged to repurpose drugs toward medical conditions not originally intended. Perhaps the classic example is the repurposing of imatinib, originally intended for breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL)-driven chronic myelogenous leukemia (CML), toward mast/stem cell growth factor receptor (KIT)-driven gastrointestinal stromal tumor (GIST) tumors (1). Compounds that have already demonstrated safety and utility in one disease can be rapidly redirected toward another disease entity, thereby quickening the pace of clinical trial development and proof of benefit from compounds. It is under this context that the report by Gao and colleagues (2) is important. This group took advantage of the recent US Food and Drug Administration (FDA) approval of ibrutinib, a small molecule tyrosine kinase inhibitor with activity against the Bruton tyrosine kinase and efficacy in mantle cell lymphoma (3). Previous studies had demonstrated that other tyrosine kinases,

Effect of Bruton's tyrosine kinase inhibitors on platelet aggregation in patients with acute myocardial infarction

In this review, we have highlighted a new class of drugs, Bruton's tyrosine kinase (BTK) inhibitors, and summarized the results of recent clinical trials in the treatment of multiple sclerosis. Multiple sclerosis (MS) is considered an autoimmune disease of the central nervous system, in which B-lymphocytes and myeloid cells, such as macrophages and microglia, play an important role in the pathogenesis. B-cells induce pathological processes by presenting autoantigens to T-lymphocytes, secreting pro-inflammatory cytokines, and forming ectopic lymphoid follicle-shaped clusters. Accordingly, the activation of microglia contributes to the development of chronic inflammation due to the production of chemokines, cytokines, reactive oxygen, and nitrogen species. BTK is an enzyme important in the activation and function of both B-lymphocytes and microglia. The demand for highly effective and well-tolerated drugs still remains at all stages of MS despite the availability of a number of effective drugs against the disease. Thus, in recent years BTK inhibitors have been the newest approach in the treatment of MS, since they affect the leading links of the pathogenesis of this disease and are able to pass through the blood-brain barrier. The study of new mechanisms of the development of MS continues in combination with the elaboration of new treatment methods, i.e., Bruton's tyrosine kinase inhibitors. The review provided the analysis of core studies evaluating the safety and efficacy of these drugs. In the future, positive results of these studies will be able to greatly expand the therapy for various forms of MS.

BackgroundChronic myeloid leukemia (CML) pathogenesis is mainly driven by the oncogenic breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) fusion protein. Since BCR-ABL displays abnormal constitutive tyrosine kinase activity, therapies using tyrosine kinase inhibitors (TKis) such as imatinib represent a major breakthrough for the outcome of CML patients. Nevertheless, the development of TKi resistance and the persistence of leukemia stem cells (LSCs) remain barriers to cure the disease, justifying the development of novel therapeutic approaches. Since the activity of histone deacetylase (HDAC) is deregulated in numerous cancers including CML, pan-HDAC inhibitors may represent promising therapeutic regimens for the treatment of CML cells in combination with TKi.ResultsWe assessed the anti-leukemic activity of a novel hydroxamate-based pan-HDAC inhibitor MAKV-8, which complied with the Lipinski’s “rule of five,” in various CML cells alone or in combination with imatinib. We validated the in vitro HDAC-inhibitory potential of MAKV-8 and demonstrated efficient binding to the ligand-binding pocket of HDAC isoenzymes. In cellulo, MAKV-8 significantly induced target protein acetylation, displayed cytostatic and cytotoxic properties, and triggered concomitant ER stress/protective autophagy leading to canonical caspase-dependent apoptosis. Considering the specific upregulation of selected HDACs in LSCs from CML patients, we investigated the differential toxicity of a co-treatment with MAKV-8 and imatinib in CML versus healthy cells. We also showed that beclin-1 knockdown prevented MAKV-8-imatinib combination-induced apoptosis. Moreover, MAKV-8 and imatinib co-treatment synergistically reduced BCR-ABL-related signaling pathways involved in CML cell growth and survival. Since our results showed that LSCs from CML patients overexpressed c-MYC, importantly MAKV-8-imatinib co-treatment reduced c-MYC levels and the LSC population. In vivo, tumor growth of xenografted K-562 cells in zebrafish was completely abrogated upon combined treatment with MAKV-8 and imatinib.ConclusionsCollectively, the present findings show that combinations HDAC inhibitor-imatinib are likely to overcome drug resistance in CML pathology.

Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and β-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy.

Nonadherence is common in patients with chronic myeloid leukemia (CML) and leads to treatment failure and poor outcomes. Side effects due to treatment are also common in patients with CML. However, no study has investigated the link between side effects and medication adherence for patients with CML in Taiwan. Therefore, the aim of our study was to explore the influence of side effects on medication adherence in Taiwanese patients with CML.CML in chronic-phase patients treated with breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 tyrosine kinase inhibitors were recruited. We designed a questionnaire to collect baseline patient information, medication adherence (measured using the 8-item Morisky Medication Adherence Scale), and side effects. Clinical outcomes were assessed by the 3-month early molecular response rate and the 12-month major molecular response rate. Statistical comparisons of different parameters between adherent and nonadherent groups were conducted.Fifty-eight patients were enrolled in this study, and 31% of them had poor adherence. The lack of information about treatment and medication was the major reason for poor medication adherence. Patients who were younger and unmarried were prone to poor adherence. The occurrence of side effects carried no statistically significant influence on adherence. Poor adherence resulted in a poor treatment response (lower 3-month early molecular response rate and lower 12-month major molecular response rate).Poor adherence is common in Taiwanese patients with CML. The main reason for a decrease in the adherence rate is the lack of comprehensive information about treatment and medication, particularly in young and single population. The next urgent step is to educate patients about their treatment and management of side effects to improve adherence and treatment outcome for patients with CML in Taiwan.

Tyrosine Kinase Inhibitors (TKIs) Targeting Syk and BTK Signaling Differentially Affect PI3K Signalosome Organization and Platelet Function

Chronic lymphocytic leukemia and small lymphocytic lymphoma remain the most prevalent adult leukemia in Western countries. Novel therapeutics have established long-term efficacy and have changed the landscape in patient management. In contrast, novel approaches pose opportunities for patients to be treated for finite durations. In this manuscript, we highlight long-term safety and efficacy data with Bruton's tyrosine kinase inhibitors and combination BCL2 + anti-CD20 therapies. We also offer key considerations for treatment selection and outline ongoing trials which may continue to expand therapeutic options and approaches. An electronic search of the PubMed database was performed to obtain key literature in chronic lymphocytic leukemia and small lymphocytic lymphoma published using the following search terms: chronic lymphocytic leukemia/small lymphocytic lymphoma, Richter syndrome, and histologic transformation. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. Chronic lymphocytic leukemia and small lymphocytic lymphoma are different manifestations of the same disease and are managed in much the same way. Bruton's tyrosine kinase inhibitors have demonstrated long and durable efficacy benefits in patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma and in the relapsed/refractory setting. Despite these benefits, long terms adverse events have posed challenges for patients and have led to treatment discontinuations. Additionally, the use of monotherapy Bruton's tyrosine kinase inhibitor's requires chronic use of the medications leading to added financial implications. BCL2 inhibition with venetoclax in combination with anti-CD20 monoclonal antibodies has offered a novel and finite treatment approach in frontline and relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Ongoing clinical trials are in investigating this modality further to enhance durable responses utilizing a combination Bruton's tyrosine kinase inhibitor's and BCL2 inhibitors. The treatment armamentarium of chronic lymphocytic leukemia/small lymphocytic lymphoma continues to evolve. Despite the long term, durable responses with Bruton's tyrosine kinase inhibitor's, it is likely that finite treatment durations could become the standard of care as a result of continued, long-term responses.