Treatment Of Chronic Myeloid Leukemia Research Articles

Exploring the Impact of Protein Chain Selection in Binding Energy Calculations with DFT.

Calculation of binding free energies between a protein and a ligand are highly desired for computer-aided drug design. Here we approximate the binding energies of ABL1, an enzyme which is the target for drugs used in the treatment of chronic myeloid leukaemia, with minimal models and density functional theory (DFT). Starting from the crystal structures of protein-drug complexes, we estimated the binding free energies having used all available individual molecules (protein chains) within each structure, not only a single one as commonly used, in order to see if the choice of the protein chain is important in such calculations. Differences were observed between chains in the same file. Energy decomposition analysis (EDA) revealed that the most important factors for binding were exchange, repulsion and electrostatics. The desolvation term varied dramatically between the inhibitors (between 4.2 and 92.3 kcal/mol). All functionals showed similar patterns in the EDA and in discriminating between the ligands. Non-covalent interactions (NCI) analysis was used to further explain the differences between protein chains and functionals. Overall, it is shown that small minimal models of a drug binding site can be useful to infer on the suitability of an initial crystal structure for further analysis such as EDA.

The treatment and diagnostic plan for chronic myeloid leukemia in Libyan oncology centers

Background: CML is one of the best understood diseases from the aspect of its cytogenetic abnormalities and the molecular mechanisms involved. CML was the first human disease in which a specific abnormality of the karyotype, the Philadelphia (Ph) chromosome, could be linked to a malignant disease. Later on, it was shown that the Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22, which produces the BCR-ABL fusion oncogene. Accordingly, in this study; we are going to determine whether the team workers in Libyan oncology centers actually following these steps of guidelines as it has been used internationally or there are some differences and special circumstances prevent them to apply the guidelines. Objectives: The present study aimed to explore the methods and plans used for diagnosis and treatment of CML patients in Libyan oncology centres and to confirm the most effective methods in diagnosis and treatment of CML by using a statistical analysing of some special data related to a well investigated cases by making a comparison between those plans. Methods: 173 and 153 CML patient files who has registered in Sabratha oncology institute and Misurata oncology institute -which are both considered as the main oncology centers in Libya- during the last sixteen years were investigated. Then, ten CML case files have randomly chosen from total CML patient files (51) and (78) cases from both oncology institutes which represents (35% and 45%) of all cases respectively (Male and Female, five from each institute). All results of laboratory investigations (CBC, biochemistry profiles, blood film, bone marrow, cytogenetic and molecular analysis) have been recorded and statistically analyzed to know the hematological, cytogenetic and molecular responses during the treatment period. CML patients chosen were at varying disease stages (chronic, accelerated, and blastic phases). The drugs used for treatment included 500 mg of Hydroxyurea, 400 mg, 600 mg and 800 mg of Glivec, and 600 mg of Tasigna in rare cases. Results and conclusion: The study has indicated the existence of a clear deficiency gap represented in a widespread lack of many capabilities such as the lack of some devices, equipments, operating materials and qualified experts. Moreover, the study has confirmed that the treatment plan has modified depending on the results of the complete blood count (CBC) only during all periods of the treatment without achieving other important investigation used for treatment follow up such as bone marrow aspiration, blood film examination, cytogenetic examination and molecular diagnostic. This study-as the first study dealing with this important topic- clarified many shortcomings of the diagnostic and treatment plan followed in both oncology institutes. As a recommendation, it is necessary to apply all international standard steps of the diagnosis and treatment in particular.

Critical review of clinical data and expert-based recommendations for the use of bosutinib in the treatment of chronic myeloid leukemia.

Chronic myeloid leukemia (CML), characterized by the presence of the BCR::ABL1 fusion gene, has undergone a transformative shift with the introduction of tyrosine kinase inhibitors (TKIs). The current availability of six different TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib) in clinical practice makes it important to know their efficacy and toxicity profile for treatment optimization. This review examines the latest insights regarding the use of bosutinib in CML treatment. Clinical trials have demonstrated the effectiveness of bosutinib, positioning it as a first-line treatment that can induce sustained molecular responses. Importantly, it can also be effective in patients who have experienced treatment failure or intolerance with prior TKIs, revealing the potential of bosutinib also in second- and later-line settings. Even in the advanced phase of CML, bosutinib has demonstrated its capacity to achieve molecular responses, expanding its usefulness. Real-world evidence studies echo these findings, emphasizing bosutinib's effectiveness in achieving deep molecular responses, maintaining remissions, and serving as an alternative for patients intolerant or resistant to other TKIs as a second-line therapy. Notably, one of the greatest strengths of bosutinib is its favorable safety profile, in particular the low incidence of vascular complications with its use, which is undoubtedly a comparative advantage over other TKIs. In summary, the latest research highlights the versatility of bosutinib in CML treatment and underscores its pivotal role in optimizing patient management in challenging cases. Continuing research and investigation will further establish bosutinib's place in the evolving landscape of CML therapy, offering an alternative for CML patients across different treatment stages.

Application of artificial intelligence in chronic myeloid leukemia (CML) disease prediction and management: a scoping review

BackgroundNavigating the complexity of chronic myeloid leukemia (CML) diagnosis and management poses significant challenges, including the need for accurate prediction of disease progression and response to treatment. Artificial intelligence (AI) presents a transformative approach that enables the development of sophisticated predictive models and personalized treatment strategies that enhance early detection and improve therapeutic interventions for better patient outcomes.MethodsAn extensive search was conducted to retrieve relevant articles from PubMed, Scopus, and Web of Science databases up to April 24, 2023. Data were collected using a standardized extraction form, and the results are presented in tables and graphs, showing frequencies and percentages. The authors adhered to the PRISMA-ScR checklist to ensure transparent reporting of the study.ResultsOf the 176 articles initially identified, 12 were selected for our study after removing duplicates and applying the inclusion and exclusion criteria. AI’s primary applications of AI in managing CML included tumor diagnosis/classification (n = 9, 75%), prediction/prognosis (n = 2, 17%), and treatment (n = 1, 8%). For tumor diagnosis, AI is categorized into blood smear image-based (n = 5), clinical parameter-based (n = 2), and gene profiling-based (n = 2) approaches. The most commonly employed AI models include Support Vector Machine (SVM) (n = 5), eXtreme Gradient Boosting (XGBoost) (n = 4), and various neural network methods, such as Artificial Neural Network (ANN) (n = 3). Furthermore, Hybrid Convolutional Neural Network with Interactive Autodidactic School (HCNN-IAS) achieved 100% accuracy and sensitivity in organizing leukemia data types, whereas MayGAN attained 99.8% accuracy and high performance in diagnosing CML from blood smear images.ConclusionsAI offers groundbreaking insights and tools for enhancing prediction, prognosis, and personalized treatment in chronic myeloid leukemia. Integrated AI systems empower healthcare practitioners with advanced analytics, optimizing patient care and improving clinical outcomes in CML management.

Global Trial Representation and Availability of Tyrosine Kinase Inhibitors for Treatment of Chronic Myeloid Leukemia.

Background: Evaluating clinical trial representation for countries with different socio-demographic index (SDI) and tyrosine kinase inhibitor (TKI) availability for chronic myeloid leukemia (CML). Methods: CML incidence rates (IRs) and disability-adjusted life years (DALYs) (1999-2019) from the Institute of Health Metrics and Evaluation were analyzed. Trials investigating TKI use in CML were obtained from ClinicalTrials.gov. Site data for eligible trials (N = 30) and DALYs were analyzed. TKI approvals, DALYs, and IRs were summarized by SDI. Results: North America (NA) had significant decreases in annual percent change (APC) in DALYs and incidence rates from 1999 to 2004. IRs were highest in Europe and Central Asia (ECA) and NA, while DALYs were highest in South Asia (SAsia) and Sub-Saharan Africa (SSA). Countries in the high-SDI quintile were likely to have lower DALYs than lower-SDI quintiles. Differences in regional DALYs vs. sites in TKI trials were significant for SAsia, SSA, and ECA. High-SDI countries were included in all 30 trials, and TKI approvals were prominent in high-SDI (142) vs. low-SDI (14) countries. Conclusions: The inclusion of disproportionately affected countries during the design of and recruitment into clinical trials should occur, as should TKI availability. The lack of representation demonstrates healthcare disparities.

A lower initial dose of bosutinib for patients with chronic myeloid leukemia patients resistant and/or intolerant to prior therapy: a single-arm, multicenter, phase 2 trial (BOGI trial)

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.

Asciminib monotherapy as frontline treatment of chronic-phase chronic myeloid leukemia: results from the ASCEND study

AbstractAsciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965.

Insights into existing and futuristic treatment approach for chronic myeloid leukaemia.

Oncogenes play a crucial part in human cancer development, and when particular drugs obstruct the proteins produced by these oncogenes, the tumoural process can be ceased. For instance, in chronic myeloid leukaemia (CML), all pathological traits are associated with a single oncogene, BCR-ABL1. CML is a triphasic cancerous disorder of haematopoietic stem cells, marked by a balanced translocation between chromosomes 9 and 22, leading to the genesis of a Philadelphia chromosome encompassing the BCR-ABL1 fusion gene. This fusion oncogene further produces a constitutive active tyrosine kinase protein, enhancing the downstream signalling pathways and constitutes cancer. The treatment for CML has been entirely altered from chemotherapy and immunotherapy to targeted therapy with the emergence of tyrosine kinase inhibitors (TKIs) which inhibit BCR-ABL1 kinase activity. However, the inhibitory mechanism of TKIs is constrained by BCR-ABL1 dependent and independent resistance mechanisms, prompting the exploration of novel therapeutics through extensive clinical trials to develop next-generation drugs with enhanced potency. The persistent challenges posed by CML have motivated researchers to seek innovative strategies for its eradication, such as the application of the genome editing tool CRISPR/Cas9. This review provides insights into existing CML diagnoses, treatment modalities, resistance mechanisms, drugs under trial phases and new potential therapeutic drugs. Furthermore, the review looks ahead to a visionary perspective wherein the CRISPR/Cas9 approach holds the potential to evolve into a prospective curative measure for CML.

Pharmaceutical inhibition of BCL6 ameliorates resistance to imatinib in chronic myeloid leukemia

The tyrosine kinase inhibitors (TKIs) have improved overall survival of CML (chronic myeloid leukemia) patients and allow them to experience normal life expectancy. However, relapse and drug resistance remain the main challenges in the clinical treatment of CML. The B-cell lymphoma 6 (BCL6) is essential to regulation of multiple function such as immune response and lymphomagenesis in lymph node germinal cells. Recent studies have shown that BCL6 is required for the maintenance of leukemia stem cells in CML, but the expression of Bcl-6 in response to Imatinib and the underlying mechanism are still unclear. Here, we found that BCL6 is expressed at high levels in primary CML bone marrow samples and CML TKI-resistance cell lines. CML cells with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, BI-3812. Treatment of CML cells with BCL6 inhibitor and TKIs suggested enhanced anti-leukemia activity. In summary, our findings suggest BCL6 as a therapeutic target for the treatment of CML.

Asciminib: the next-generation bullet for first-line treatment of chronic myeloid leukemia

The standard of care for chronic myeloid leukemia (CML) involves tyrosine kinase inhibitors (TKIs), which suppress tyrosine kinase activity of BCR::ABL1. Hochhaus etal. reported that asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, showed superior efficacy and favorable safety compared with TKIs in the phase 3 ASC4FIRST trial in patients with newly diagnosed chronic-phase CML.1.

Morphology, Morphometry, and Immunohistochemical Profile of Megakaryocytes and Bone Marrow Microenvironment in Disease Progression and Therapy Resistance in Chronic Myeloid Leukemia.

Background Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML) since the beginning of the century. However, resistance to therapy and the progression of disease tend to occur in certain patients. The bone marrow microenvironment may play a role in the disease outcome. Megakaryocytes have multiple roles in the regulation and maintenance of the hematopoietic stem cell microenvironment. In the current study, we evaluated the association of megakaryocyte morphology, morphometry, and microenvironment with disease progression and therapy resistance in CML. Methodology Megakaryocyte morphology and morphometry were analyzed and compared between the different phases (chronic and advanced) at diagnosis in 150 cases of BCR-ABL-positive CML. All CML-CP patients (n = 119) were followed up on tyrosine kinase inhibitor therapy for a minimum of 15 months and classified based on their treatment outcome as a response, resistance to therapy, or progression of disease based on standard criteria. Immunohistochemistry on a bone marrow trephine biopsy was done for vascular endothelial growth factor (VEGF), FOXP3, CD150, CD48, CD44, osteopontin, CXCL12, N-cadherin, PDL-1, and IL-7, and their expression on megakaryocytes and their association with treatment outcome was evaluated. Results The morphology and morphometry of megakaryocytes showed a heterogeneous population in CML. Morphology and morphometric parameters, when compared between the chronic and advanced phases of disease at diagnosis, did not show any statistical difference. Megakaryocytes were variably positive for VEGF, FOXP3, CD150, CD48, osteopontin, N-cadherin, CXCL12, CD44, PDL-1, and IL-7. However, only CD44-positive megakaryocytes were statistically associated with the treatment outcome. The patients with a higher expression of CD44 megakaryocytes progressed to the advanced phase of the disease during therapy compared to those who responded. Conclusion Megakaryocyte morphology and morphometry were heterogeneous in CML; however, they did not show any significant difference with either the phase of the disease or with treatment outcomes. Among the various immunohistochemical markers of the microenvironment, only CD44-positivity on megakaryocytes was associated with poor treatment outcomes.

Gallic Acid Enhances the Efficacy of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia through Inhibition of Mitochondrial Respiration and Modulation of Oncogenic Signaling Pathways.

While BCR::ABL1 tyrosine kinase inhibitors have transformed the treatment paradigm for chronic myeloid leukemia (CML), disease progression and treatment resistance due to BCR::ABL1-dependent and BCR::ABL1-independent mechanisms remain a therapeutic challenge. Natural compounds derived from plants have significantly contributed to cancer pharmacotherapy. This study investigated the efficacy of an active component of Leea indica, a local medicinal plant, in CML. Using high-performance liquid chromatography-electrospray ionization-mass spectrometry, a chemical constituent from L. indica extract was isolated and identified as gallic acid. Commercially obtained gallic acid was used as a chemical standard. Gallic acid from L. indica inhibited proliferation and induced apoptosis in CML cell lines, as did the chemical standard. Furthermore, gallic acid induced apoptosis and decreased the colony formation of primary CML CD34+ cells. The combination of isolated gallic acid or its chemical standard with BCR::ABL1 tyrosine kinase inhibitors resulted in a significantly greater inhibition of colony formation and cell growth compared to a single drug alone. Mechanistically, CML cells treated with gallic acid exhibited the disruption of multiple oncogenic pathways including ERK/MAPK, FLT3 and JAK/STAT, as well as impaired mitochondrial respiration. Rescue studies showed that gallic acid is significantly less effective in inducing apoptosis in mitochondrial respiration-deficient ρ0 cells compared to wildtype cells, suggesting that the action of gallic acid is largely through the inhibition of mitochondrial respiration. Our findings highlight the therapeutic potential of L. indica in CML and suggest that gallic acid may be a promising lead chemical constituent for further development for CML treatment.

[Artículo traducido] Asciminib para el tratamiento de la leucemia mieloide crónica en tercera línea: análisis coste-efectividad basado en el enfoque de remisión libre de tratamiento

IntroductionThe first targeted therapy in oncology, imatinib, revolutionized chronic myeloid leukemia (CML) treatment and spurred research in targeted therapies for various cancers. CML results from a chromosomal translocation, forming the BCR-ABL1 fusion gene. Asciminib has been recently approved for 3rd-line refractory or intolerant patients. Treatment-free remission (TFR) is attainable with sustained deep molecular response (DMR) and this approach could be incorporated into pharmacoeconomic models. AimsTo establish a cost-effectiveness model comparing asciminib to approved third-generation tyrosine kinase inhibitors (TKIs) (bosutinib and ponatinib) with a focus on achieving TFR. Additionally, the budgetary impact of incorporating asciminib as a therapeutic alternative is assessed. MethodsThis model is based on a Markov chain with seven states. The condition for achieving TFR is to remain for 5 years in DMR state. Efficacy of the model was measured in QALYs, and the costs included in the base case analysis are based in Spain. A probabilistic (PSA) and deterministic analysis (DSA) were carried out to assess the variability of the model. There were achieved two independent models comparing asciminib vs. bosutinib and asciminib vs. ponatinib. ResultsAsciminib, when compared with ponatinib, is a cost-saving alternative, as efficacy is similar between alternatives, and asciminib has a lower cost of 30,275 €. Asciminib showed 4.33 more QALYs and a higher cost (203,591 €) than bosutinib, resulting in an ICER of €47,010.49 per QALY. PSA shows that the parameters with higher influence in the variability of the model were the probability of transitioning to BP and probabilities of achieving MMR and DMR. A one-way analysis reports that the drug cost has a higher influence on both models, and the discount rate significantly affects the asciminib vs. bosutinib model. ConclusionAsciminib broadens therapeutic choices for patient’s refractory or intolerant to two prior lines of treatment in a cost-effective manner. The costs of drugs significantly impact the overall cost of the disease, emphasizing the importance of the selected discount rates for each drug. Given the relatively low incidence of CML, the introduction of asciminib has a limited budgetary impact, warranting individualized decisions based on patient`s clinical characteristics.

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case-Control Study.

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients' blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

Perspectives on Drug Development for the Treatment of Chronic Myeloid Leukemia in Pregnant Patients and Patients Who Are Breastfeeding.

Tyrosine kinase inhibitors (TKI) have improved the outcome and life expectancy of patients with chronic myeloid leukemia (CML). Patients are diagnosed with CML at younger ages, and patients treated for CML may become pregnant or choose to breastfeed. The information available to date on the safety of TKIs during pregnancy and lactation and the optimal management of these patients is largely anecdotal, based on personal or small-group experience, and heterogeneous. A panel of interested parties was convened by U.S. Food and Drug Administration to analyze the current data and discuss possible solutions. Possible solutions include prospective data collection, in clinical trials and in routine clinical practice, a more uniform and specific data collection, and greater coordination among involved entities. As patients with cancer are living longer, frequently receiving therapies for extended periods of time (or for life), data on appropriate management of patients through different reproductive phases of life are needed. It is thus time to change our approach for how to study treatment of cancer (including CML) during pregnancy or breastfeeding to develop evidence-based guidelines for safe and effective patient care.

A Quality by Design (QbD) driven gradient high performance liquid chromatography method development for the simultaneous estimation of dasatinib and nilotinib in lipid nanocarriers

Tyrosine kinase inhibitors (TKIs) are effective as a targeted treatment for chronic myeloid leukemia (CML), which can selectively suppress BCR-ABL1 kinase activity. CML therapy with TKIs combination has been supported by in-vitro, in-vivo, and patient-based data where the nilotinib-dasatinib co-administration has exerted superior anticancer efficacy with greater cellular uptake, less resistance to chemotherapy, and no additive adverse events encountered. Therefore, it is essential to develop a suitable analytical method for the simultaneous estimation of these drugs in the developed novel lipid nanocarriers like liposomes. Design of Experiment (DoE) has been implemented as a tool of QbD to systematically investigate the relation between the HPLC method attributes and analytical responses, i.e., chromatographic detection, quantification, and peak properties for dasatinib and nilotinib. An Ishikawa diagram is constructed to delineate possible influencing variables to the analytical performances. Afterward, 4 factors 2 level full factorial design (FFD) was employed to model and identify the main effects and interaction effects between the factors selected after the initial risk assessment. The suggested design space for optimized chromatographic conditions by QbD analysis is linear within the selected range of drug concentrations, accurate and precise, sensitive, and robust according to the ICH guidelines. The optimal method is comprised of a 1 mL/min flow rate of mobile phase (ACN and 20 mM KH2PO4 of pH 7.00) in gradient mode at 25 °C column temperature for 20 μL sample injection volume and detection wavelength fixed at 297 nm. Most importantly, this novel HPLC method is simple and selective enough to evaluate dasatinib and nilotinib content in the lipid nanocarriers.

Comparative efficacy and safety of first-line tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and network meta-analysis.

Tyrosine kinase inhibitors (TKIs) have become the preferred drugs for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). This study aims to compare the safety and efficacy of different TKIs as first-line treatments for CML using network meta-analysis (NMA), providing a basis for the precise clinical use of TKIs. A systematic search was conducted on PubMed, Cochrane Library, Embase, China National knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Databases (VIP), SinoMed and ClinicalTrials.gov to include RCTs that compared the different TKIs as first line treatment for CML. The search timeline was from inception to 21 July 2023. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the frequentist NMA methods, the efficacy and safety of different TKIs were compared, including the rates of major molecular response (MMR), complete cytogenetic response (CCyR), all grade adverse events, grade 3 or higher hematologic adverse events and liver toxicity. A total of 25 RCTs involving 6,823 patients with CML and 6 types of TKIs were included. In terms of efficacy, second-generation TKIs such as dasatinib, nilotinib, and radotinib showed certain advantages in improving patients' MMR and CCyR compared to imatinib. Additionally, imatinib 800 mg provided better MMRs and CCyRs than imatinib 400 mg. As far as safety was concerned, there was no significant difference in the incidence of all grade adverse events among the different TKIs. All TKIs can cause serious grade 3-4 hematologic adverse events, including anemia, thrombocytopenia, and neutropenia. Dasatinib more likely caused anemia, bosutinib thrombocytopenia, and imatinib neutropenia, whereas nilotinib and flumatinib might have better safety profiles in terms of severe hematologic adverse events. For liver toxicity, radotinib 400 mg and imatinib 800 mg, respectively, had the highest likelihood of ranking first in incidence rates of all grade ALT and AST elevation. In CML, second-generation TKIs are more clinically effective than imatinib even if this last drug has a relatively better safety profile. Thus, as each second-generation TKI has a distinct clinical efficacy and safety, and is associated with different economic factors, its choice should be dictated by the specific patient clinical conditions (patient's specific disease characteristics, comorbid conditions, potential drug interactions, as well as their adherence). Nevertheless, due to the limited number of original research, additional high-quality studies are needed to achieve any firm conclusion on which second-generation TKI is the best choice for that peculiar patient.

Exploring treatment decision-making in chronic myeloid leukemia in chronic phase.

The introduction of tyrosine kinase inhibitors (TKIs) has transformed the treatment of chronic myeloid leukemia (CML). Each approved TKI has its own risk-benefit profile, and patients have choices across lines of therapy. Identifying the initial and subsequent treatment that will lead to the best possible outcome for individual patients is challenging. In this review, we summarize data for each approved TKI across lines of therapy in patients with CML in chronic phase, highlighting elements of each agent's safety and efficacy profile that may impact patient selection, and provide insights into individualized treatment sequencing decision-making aimed at optimizing patient outcomes.

S1P Signaling Genes as Prominent Drivers of BCR-ABL1-Independent Imatinib Resistance and Six Herbal Compounds as Potential Drugs for Chronic Myeloid Leukemia.

Imatinib (IM), a breakthrough in chronic myeloid leukemia (CML) treatment, is accompanied by discontinuation challenges owing to drug intolerance. Although BCR-ABL1 mutation is a key cause of CML resistance, understanding mechanisms independent of BCR-ABL1 is also important. This study investigated the sphingosine-1-phosphate (S1P) signaling-associated genes (SphK1 and S1PRs) and their role in BCR-ABL1-independent resistant CML, an area currently lacking investigation. Through comprehensive transcriptomic analysis of IM-sensitive and IM-resistant CML groups, we identified the differentially expressed genes and found a notable upregulation of SphK1, S1PR2, and S1PR5 in IM-resistant CML. Functional annotation revealed their roles in critical cellular processes such as proliferation and GPCR activity. Their network analysis uncovered significant clusters, emphasizing the interconnectedness of the S1P signaling genes. Further, we identified interactors such as BIRC3, TRAF6, and SRC genes, with potential implications for IM resistance. Additionally, receiver operator characteristic curve analysis suggested these genes' potential as biomarkers for predicting IM resistance. Network pharmacology analysis identified six herbal compounds-ampelopsin, ellagic acid, colchicine, epigallocatechin-3-gallate, cucurbitacin B, and evodin-as potential drug candidates targeting the S1P signaling genes. In summary, this study contributes to efforts to better understand the molecular mechanisms underlying BCR-ABL1-independent CML resistance. Moreover, the S1P signaling genes are promising therapeutic targets and plausible new innovation avenues to combat IM resistance in cancer clinical care in the future.

Management of Chronic Myeloid Leukemia that is Intolerant or Resistant to Front-Line Treatment

With advances in treatment for chronic myeloid leukemia (CML), the natural history of chronic phase (CP) CML has changed, with most individuals expected to live a normal life expectancy. The goal of therapy for most is to achieve a long-term deep molecular response (DMR) with the potential for medication discontinuation and treatment-free remission (TFR).1 Currently, six oral therapies have been approved for CP-CML in Canada: (1) imatinib, a first-generation tyrosine kinase inhibitor (TKI); (2) dasatinib, (3) nilotinib, and (4) bosutinib, the second-generation TKIs (2G-TKIs); (5) ponantinib, a third-generation TKI; and (6) asciminib, specifically targeting the ABL Myristoyl pocket (STAMP) inhibitor. Classically, treatment for CP-CML has consisted of front-line imatinib and switching to a 2G-TKI upon treatment resistance or intolerance. Increasingly, patients are being prescribed an upfront 2G-TKI with the goal of achieving quicker and deeper molecular remissions and a TFR.2 Challenges arise in CML when treatment with either two TKIs (imatinib + 2G-TKI) or one 2G-TKI fails, given the lack of evidence to inform clinical decision-making at this juncture. This paper aims to define TKI failure and help guide the selection of second-line treatment after failure of front-line therapy.