Chronic Myelogenous Leukemia Patients Research Articles

Effect of Csn-B Combined with Imatinib on Apoptosis of Chronic Myeloid Leukemia Cells through Nur77/Pim-1/Drp1 Pathway

To investigate the anti- chronic myelogenous leukemia (CML) activity of Nur77-specific agonist Csn-B combined with imatinib by promoting Nur77 expression, and explore the potential role of its signaling pathway. Firstly, CCK-8 and Transwell assay were used to detect the inhibitory effects of Csn-B, imatinib, and their combination on the proliferation and migration of K562 cells. Furthermore, the apoptosis rate of K562 cells treated with Csn-B, imatinib, and their combination was detected by flow cytometry. The expression levels of Nur77, Pim-1, Drp1, p-Drp1 S616, Bcl-2 and Bax in K562 cells were detected by Western blot. Finally, the expression levels of reactive oxygen species (ROS) in K562 cells treated with Csn-B, imatinib and their combination were detected by immunofluorescence assay. The level of Nur77 in CML patients decreased significantly compared with normal population in dataset of GSE43754 (P < 0.001). Csn-B combined with imatinib could significantly inhibit the proliferation and migration of K562 cells (both P < 0.001), and induce apoptosis (P < 0.001). Csn-B promoted Nur77 expression in K562 cells, and synergistically enhanced imatinib sensitivity when combined with imatinib. Csn-B combined with imatinib could significantly enhanced ROS levels in K562 cells and mitochondria compared with single-drug treatment (both P < 0.001). Csn-B combined with imatinib can enhance ROS expression and induce apoptosis of K562 cells through Nur77/Pim-1/Drp1 pathway.

Analysis of the pharmacoeconomic effectiveness of the tyrosine kinase inhibitors therapy in patients with chronic myeloid leukemia in a Single Hematology Center in Plovdiv, Bulgaria

Summary: Chronic myelogenous leukemia (CML) is a pluripotent hemopoietic stem cell malignancy characterized by the presence of a BCR-ABL1 fusion gene derived from a balanced translocation between the long arms of chromosomes 9 and 22 [t(9;22) (q34; q11)] known as the Philadelphia (Ph) chromosome. CML is an acquired hematopoietic stem cell disease common to myelo- and lymphopoiesis, characterized by uncontrolled proliferation of granulopoiesis (Shuvaev et al. 2015; Yordanov and Varbanova 2019). Relevance and goals: Second-generation tyrosine kinase inhibitors (TKIs) (nilotinib, dasatinib, and bosutinib) have an advantage over imatinib (first-generation) in the frequency and speed of achieving cytogenetic and molecular responses in the treatment of chronic myelogenous leukemia (CML), but they cause severe adverse effects and are much more expensive than imatinib, especially if we compare them to the prices of the registered generic products of Imatinib and Dasatinib. “Novartis Tasigna® trial shows superior results to Glivec® in patients with early-stage chronic myeloid leukemia”, reported on 10/20/2021 by Pierre Perrin-Montlouis. In the first direct comparison of these two oral therapies back in 2009 (Тasigna (nilotinib) 2009), as first-line treatment for CML, the results of Tasigna showed statistically significant improvement over Glivec in every measure of efficacy, including major molecular response (MMR), complete cytogenetic response (CCyR) and prevention of progression to accelerated or blast phase, with responses achieved faster in the Tasigna group than in the Glivec group. Furthermore, in the last ten years, CML patients who have achieved a stable deep molecular response for at least 2 years have been included in clinical trials for the management of treatment-free remission (TFR) (Kim et al. 2013; Saußele et al. 2016). On the other hand, the ever-increasing costs of diagnosis, treatment and monitoring of the response of CML to the various therapeutic strategies require conducting pharmacoeconomic analyses of the cost-effectiveness and cost-utility types in order to evaluate which are the cost-effective strategies with a view to introducing them into therapeutic practice. The present study aims to analyze the pharmacoeconomic efficiency of the TKI inhibitors used by the patients with CML-CP in the first and second lines, treated in the hematology clinic at UMHAT “St. George”, MU- Plovdiv during the period 2018–2022. Methods: An economic analysis of the medicinal use of TKIs for a 5-year period (2018–2022) was performed at the national level according to data from the National Health Insurance Fund and the availability, accessibility, and usability of original and generic TKIs in Bulgaria were evaluated. The direct medical costs for the therapy of all patients were calculated, including the costs of the TKI therapy, laboratory tests, and monitoring of the molecular response for the entire treatment period from the appointment of the TKI therapy until the end of 2022. A comparative analysis was conducted to assess the cost-effectiveness of the different therapeutic strategies with TKIs on the first and second lines of treatment of patients with CML-CP in the hematology clinic at UMHAT “St. George” Medical University, Plovdiv, using the decision analysis method and conducting one-way and probalistic sensitivity analyses. Results: The sensitivity analyzes of all pharmacoeconomic models showed the robustness and reliability of the obtained results. The threshold limits of medical costs and the frequency of achieving a deep molecular response determining the choice of first- and second-generation tyrosine kinase inhibitors as first- and second-line therapy for patients with chronic myeloid leukemia in the chronic phase have been determined. Prescribing doctors prefer the original MPs to generic analogues, which is also assumed by the current regulations, according to which even for expensive MPs dispensing by protocols, the prescription is by trade and not by international non-proprietary names (INN), which is why the use of the much cheaper generic MPs is negligibly low compared to original MPs. A personalized approach to the patient’s therapy and monitoring the patient’s molecular response to it, as well as stopping therapy in 25–30% of patients suitable to stop it safely when in TFR phase with a probability of more than 50% of not having a relapse will save additional costs that, by improving the cost-effectiveness of therapy for patients with CML, will be directed towards the treatment of new patients with this or other diseases. Conclusion: These pharmacoeconomic models can be applied to improve diagnostic and therapeutic standards in clinical practice and for the efficient use of the very limited resources for health care in countries like Bulgaria. The conducted cost-effectiveness analyses confirmed that the hematologists at the University Center in Plovdiv adhere to the recommendations of Leukemia Net and the Bulgarian Medical Society of Hematology and achieve not only good therapeutic but also pharmacoeconomic efficiency in the treatment of CML-СР patients in first- and second- line therapy.

ASP210: a potent oligonucleotide-based inhibitor effective against TKI-resistant CML cells.

Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy due to acquired resistance. Safe and effective treatment modalities targeting leukemic clones that escape TKI therapy could hence be game changers in the professional management of these patients. Here, we aimed to investigate the efficacy of a novel therapeutic oligonucleotide of unconventional design, called ASP210, to reduce BCR-ABL1 mRNA levels in TKI-resistant CML cells, with the assumption of inducing their apoptosis. Imatinib- and dasatinib-resistant sublines of BCR-ABL1-positive MOLM-7 and CML-T1 cells were established and exposed to 0.25 and 2.5 µM ASP210 for 10 days. RT-qPCR showed a remarkable reduction of the target mRNA level by >99% after a single application. Cell viability was monitored daily by trypan blue staining. In response to the lack of driver oncoprotein BCR-ABL1, TKI-resistant CML cells underwent apoptosis regardless of the presence of the clinically relevant T315I mutation by day 5 after redosing with ASP210. The effect was selective for cancer cells, indicating a favorable safety profile for this therapeutic modality. Furthermore, the spontaneous uptake and high intracellular concentrations of ASP210 suggest its potential to be effective at relatively low doses. The present findings suggest that ASP210 is a promising therapeutic avenue for patients with CML who fail to respond to TKI therapy.NEW & NOTEWORTHY Effective treatment modalities targeting leukemic clones that escape tyrosine kinase inhibitor (TKI) therapy could be game changers in the professional management of patients displaying primary resistance, intolerance, or acquired resistance to TKIs. Although delivering authentic innovations today is more complex than ever, we developed a highly potent and safe oligonucleotide-based modality against BCR-ABL1 mRNA named ASP210 that effectively induces cell death in BCR-ABL1-positive TKI-resistant cells while sparing BCR-ABL1-negative healthy cells.

Subarachnoid haemorrhage in a newly diagnosed Chronic Myelogenous Leukemia patient: A diagnostic challenge

Subarachnoid haemorrhage in a newly diagnosed Chronic Myelogenous Leukemia patient: A diagnostic challenge

Unveiling IL6R and MYC as Targeting Biomarkers in Imatinib-Resistant Chronic Myeloid Leukemia through Advanced Non-Invasive Apoptosis Detection Sensor Version 2 Detection.

The management of chronic myelogenous leukemia (CML) has seen significant progress with the introduction of tyrosine kinase inhibitors (TKIs), particularly Imatinib. However, a notable proportion of CML patients develop resistance to Imatinib, often due to the persistence of leukemia stem cells and resistance mechanisms independent of BCR::ABL1 This study investigates the roles of IL6R, IL7R, and MYC in Imatinib resistance by employing CRISPR/Cas9 for gene editing and the Non-Invasive Apoptosis Detection Sensor version 2 (NIADS v2) for apoptosis assessment. The results indicate that Imatinib-resistant K562 cells (K562-IR) predominantly express IL6R, IL7R, and MYC, with IL6R and MYC playing crucial roles in cell survival and sensitivity to Imatinib. Conversely, IL7R does not significantly impact cytotoxicity, either alone or in combination with Imatinib. Further genetic editing experiments confirm the protective functions of IL6R and MYC in K562-IR cells, suggesting their potential as therapeutic targets for overcoming Imatinib resistance in CML. This study contributes to understanding the mechanisms of Imatinib resistance in CML, proposing IL6R and MYC as pivotal targets for therapeutic strategies. Moreover, the utilization of NIADS v2 enhances our capability to analyze apoptosis and drug responses, contributing to a deeper understanding of CML pathogenesis and treatment options.

Immunological and Molecular Investigation of BCR-ABL1 in Samples of Iraqi Chronic Myeloid Leukemia Patients

Background: Chronic myelogenous leukemia (CML) is a blood malignancy that affects hematopoietic stem cells. Also, it is commonly identified by the Philadelphia chromosome. This chromosome produces a protein with strong tyrosine kinase activity and functions as a tumorigenic factor. Objective: This study aimed to investigate the Immunological and Molecular of BCR-ABL1 gene expression and ABL1 protein in patients admitted to the Oncology and Hematology Center of the Kirkuk Governorate, Iraq. Materials and Methods: A study was conducted in Kirkuk Governorate, Iraq, from the beginning of November 2022 to May 2023 on Chronic Myeloid Leukemia patients in the Oncology and Hematology Center, which was hospital-based and cross-sectional. The study comprised fifty-three patients with Chronic Myeloid Leukemia. They were diagnosed using a complete blood count (CBC), a molecular test BCR-ABL1, and an immunological test ABL1 protein. The research did not include patients with missing data and those without consent. Fifty-three peripheral blood samples from 53 CML patients at chronic stages of CML were taken, and using automated Gene Xpert BCR-ABL1 Ultra assay, BCR-ABL1 transcript quantification was conducted on them. Results: The research included fifty-three patients in total (27 males, 28 females), with a mean age of 47.3 12.8 years. The average of BCR\_ABL1 by RT\_ qPCR 3.22 0.09 and the mean of ABL1 by Enzyme-linked Immune sorbent assay (ELISA) reigned is 981 891. Conclusion: Values of the quantitative real-time reverse transcription polymerase chain reaction (RT\_ qPCR) by Gene Xpert Ultra level range between 38.62 and 0.00 with a mean of 3.22 0.09. The RT\_ qPCR level showed that 22% of the patients were in good condition, 11% of them had a strong response to treatment, and other 11% showed a complete cytogenetic response (CCyR), which is also a good outcome; however, 78% of the patients either not taking their medication, or there is true resistance. These two methods used different techniques; the former is a nuclear-derived method that detects the presence of specific genetic materials of any pathogen; in the current research, BCR-ABL1 is the target. The latter is a test that detects and measures antibodies, antigens, proteins, and glycoproteins in biological samples, so ABL1 is the target.

The Mozart effect in chronic myeloid leukaemia.

Clinical research has not been able to establish whether the differences between first- and second-generation BCR-ABL 1 kinase inhibitors are clinically relevant with regard to outcome. In the study by Alcazer etal., a relevant difference seems to emerge-paradoxically in the absence of the drugs-as demonstrated by differences in the relapse kinetics after cessation of therapy. Commentary on: Alcazer etal. Kinetics of molecular recurrence after tyrosine kinase inhibitor cessation in chronic phase chronic myelogenous leukaemia patients. Br J Haematol 2024;204:1536-1539.

Inhibition of LATS kinases reduces tumorigenicity and increases the sensitivity of human chronic myelogenous leukemia cells to imatinib

Chronic myelogenous leukemia (CML) is a clonal hematologic malignancy of the myeloid lineage caused by the oncogenic BCR/ABL fusion protein that promotes CML cell proliferation and protects them against drug-induced apoptosis. In this study, we determine LATS1 and LATS2 expression in CML cells derived from patients who are resistant to imatinib (IM) treatment. Significant upregulation of LATS1 and LATS2 was found in these CML patients compared to healthy donors. To further explore whether the expression of LATS1/2 contributes to the IM-resistant phenotype, IM-resistant CML cell lines generated by culturing CML-derived erythroblastic K562 cells in increasing concentrations of IM were used as in vitro models. Up-regulation of LATS1 and LATS2 was observed in IM-resistant K562 cells. Reduction of LATS using either Lats-IN-1 (TRULI), a specific LATS inhibitor, or shRNA targeting LATS1/2 significantly reduced clonogenicity, increased apoptosis and induced differentiation of K562 cells to late-stage erythroid cells. Furthermore, depletion of LATS1 and LATS2 also increased the sensitivity of K562 cells to IM. Taken together, our results suggest that LATS could be one of the key factors contributing to the rapid proliferation, reduced apoptosis, and IM resistance of CML cells. Targeting LATS could be a promising treatment to enhance the therapeutic effect of a conventional BCR/ABL tyrosine kinase inhibitor such as IM.

Correlation analysis of bone marrow microvessel density and miRNA expression on drug resistance in patients with chronic myelogenous leukemia after tyrosine kinase inhibitor treatment

ABSTRACT Objective: This study analyzed the relationship between bone marrow microvessel density (MVD) and the expression of four miRNAs with chronic myelogenous leukemia (CML) resistance after tyrosine kinase inhibitor (TKI) treatment. Methods: 234 CML patients were divided into resistance and non-resistance groups in terms of the results of the 5-year follow-up. Patients were divided into the Optimum response group and the Warning/Failure group based on TKI response. MVD was determined by immunohistochemistry, and the expression levels of four miRNAs (miR-106a, miR-155, miR-146a, and miR-340) in bone marrow biopsy specimens were examined by qPCR. We evaluated the association of MVD with four miRNAs and them predictive value for CML resistance after TKI treatment. Results: The MVD and the levels of miR-106a, miR-155, and miR-146a were significantly higher while the miR-340 level was lower in the resistance group than the non-resistance group. Besides, MVD had a significant correlation with the levels of miR-340 and miR-155. According to the results of survival analysis, MVD as well as miR-340 and miR-155 levels were observably correlated with 5-year survival of patients without TKI resistance. The results of the ROC curve indicated that the MVD, miR-106a, miR-340, and miR-155 had good predictive accuracy for CML resistance after TKI treatment. As for the results of multivariate analysis, disease stage, risk level (high risk), high MVD, low miR-340 expression, and high miR-155 expression were all independent risk factors for CML resistance. Conclusion: MVD and the expression of miR-340 and miR-155 are closely associated with CML resistance after TKI treatment.

Precision Isolation of Circulating Leukemia Cells in Chronic Myelogenous Leukemia Patients Using a Novel Microfluidic Device and Its Clinical Applications

Chronic Myelogenous Leukemia (CML) is a prevalent hematologic malignancy characterized by the malignant transformation of myeloid cells and their proliferation in the peripheral blood. The management of CML poses significant challenges, particularly in detecting and eradicating minimal residual disease, which is crucial for preventing relapse and improving survival outcomes. Traditional minimal residual disease detection methods, such as bone marrow aspiration, are invasive and have limitations which include the potential for sampling errors and false negatives. This study introduces a novel label-free microfluidic chip designed for the segregation and recovery of circulating leukemia cells, offering a non-invasive liquid biopsy approach with potential applications in precision medicine. Over July 2021 to October 2023, we recruited 56 CML patients across various disease stages and collected blood samples for analysis using our microfluidic device. The device demonstrated high efficacy in isolating circulating leukemia cells, with an optimal capture efficiency of 78% at a sample flow rate of 3 mL/h. Our results indicate that the microfluidic device can efficiently segregate and quantify circulating leukemia cells, providing a detailed understanding of CML progression and treatment response. The significant reduction in circulating leukemia cell counts in patients in complete remission highlights the device’s potential in monitoring treatment efficacy. Furthermore, the device’s sensitivity in detecting minimal residual disease could offer a more reliable prognostic tool for therapeutic decision-making in CML management.

Co-Diagnosis of Sickle Cell and Chronic Myelogenous Leukemia: Exploratory Analysis from a Nationally Representative Database

Background: Chronic myelogenous leukemia (CML) developing in patients with sickle cell disease (SCD) has been reported infrequently in case studies to date (1). Prevalent thought relates its infrequency to the shortened life expectancy in the SCD population. However, with advancements in medical care, longevity of these patients has been increasing. Resultingly, risk factors for CML related to their disease and its treatments may accumulate, including chronic inflammation, heightened cell turnover, iron overload, immunomodulation from frequent transfusions, blood and marrow transplantation, and hydroxyurea use (2,3). Most specifically, the elevated and continuous inflammatory cell stimulation due to vaso-occlusion may enhance changes in granulocytic cell differentiation, increasing the risk for CML (3). By leveraging a nationwide database, we aim to describe characteristics associated with the development of CML in SCD patients. Methods: Hospitalizations for SCD and CML were identified using ICD-10 coding from the 2020 National Inpatient Sample (NIS). Those hospitalizations with a co-diagnosis of SCD and CML were included in this study, and further evaluated for demographics, comorbidities, transfusion status, length of stay, mortality, and charges during admission. The NIS is the largest all-payer inpatient database in the US and approximates a 20% stratified sample of inpatient discharges from &amp;gt;5000 hospitals across 48 states (98% of U.S. population). Sampling weights were applied to generate nationally representative estimates. Results: In the 2020 NIS sample upon weighting, there were 60 hospitalizations with a co-diagnosis of SCD and CML. The vast majority of these patients presented with active CML (92%) and in sickle cell crisis (83%). Overall, half of the sample comprised those patients who were between the ages of 29.5-49 years old, with a median age of 40.5. Fifty percent (n=30) of the hospitalizations were female; 92% (n=55) were African American; 58% were hospitalized in the Southern region; 25% in the West, and 17% in the Northeastern United States. The majority of hospitalizations (92%) occurred in teaching hospitals and 83% were in large-bed size hospitals. Common comorbidities were similar to that expected in the general SCD population, including history of transient ischemic attack (42%), history of pulmonary embolism/venous thromboembolism (42%), chronic kidney disease (33%), anemia (33%), and pulmonary hypertension (33%). Seventeen percent of patients had a transfusion during the hospitalization (n=15). The mean length of stay among these hospitalizations was 4.25 days. There were no deaths during these hospitalizations. Mean charges during hospitalization were $53,973. Conclusion: Previously observed in rare case studies, here we present an exploratory analysis from a national inpatient database demonstrating a population of 60 adult patients with SCD and a co-diagnosis of CML. Specifically, we observe concomitant development of CML in the SCD patient population correlated with a younger age (median age 40.5) than expected compared to traditional CML patients (median age 64). There is some evidence to suggest that chronic inflammation associated with sickle cell with extended life expectancies and treatment burden may be associated with myeloid cancers. These studies will need to be followed up with prospective analyses to investigate a potential increased risk of CML in the SCD population. Literature Cited: 1. Chen L et al., Chronic myelogenous leukemia in sickle cell anemia. Arch Pathol Lab Med. 2005;129(3):423-424. doi:10.5858/2005-129-423-CMLISC 2. Brunson A et al., Increased risk of leukemia among sickle cell disease patients in California. Blood. 2017;130(13):1597-1599. doi:10.1182/blood-2017-05-78323. 3. Stankovic et al., Chronic myeloid leukaemia and sickle cell disease: could imatinib prevent vaso-occlusive crisis?. Br J Haematol. 2011;155(2):271-272. doi:10.1111/j.1365-2141.2011.08670.x

A Deeply Quiescent Subset of CML LSC depend on FAO yet Avoid Deleterious ROS by Suppressing Mitochondrial Complex I.

Disease relapse and therapy resistance remain serious impediments to treating cancer. Leukemia stem cells (LSC) are therapy resistant and the cause of relapse. A state of deep quiescence appears to enable cancer stem cells (CSC) to acquire new somatic mutations essential for disease progression and therapy resistance. Both normal hematopoietic stem cells (HSC) and LSC share many common features, thereby complicating the safe elimination of LSC. A recent study demonstrated that long lived normal oocytes exist without mitochondrial complex I (MC-1), expressing it in a developmentally regulated fashion, thereby mitigating their vulnerability to ROS. Quiescent CSC rely on mitochondrial FAO, without complex I expression, thereby avoiding the generation of damaging ROS, similar to long lived normal human stem cells. A deeper understanding of the biology of therapy resistance is important for the development of optimal strategies to attain complete leukemia cures. Here, using scRNA-sequencing and ATAC-seq on primary chronic myelogenous leukemia (CML) patient samples, combined with bioinformatics analyses, we further examine the heterogeneity of a previously characterized in vitro imatinib-selected CD34-CD38- CML LSC population. We utilized a series of functional analyses, including single-cell metabolomic and Seahorse analyses, to validate the existence of the deepest quiescent leukemia initiators (LI) subset. Current study revealed heterogeneity of therapy resistant LSC in CML patients and their existence of two functionally distinct states. The most deeply quiescent LI suppress the expression of MC-1, yet are highly dependent on fatty acid oxidation (FAO) for their metabolic requirements and ATAC-seq demonstrated increased chromatin accessibility in this population, all consistent with an extremely primitive, quiescent stemness transcriptional signature. Importantly, the specific CREB binding protein (CBP)/β-catenin antagonist ICG-001 initiates the differentiation of LSC, including LI, decreases chromatin accessibility with differentiation and increasing expression of MC-1, CD34, CD38 and BCR-ABL1, thereby resensitizing them to imatinib. We investigated the biological aspects related to LSC heterogeneity in CML patients and demonstrated the ability of specific small molecule CBP/β-catenin antagonists to safely eliminate deeply quiescent therapy resistant CSC. These observations may represent an attractive generalizable therapeutic strategy that could help develop better protocols to eradicate the quiescent LSC population.

Tyrosine kinase inhibitors induced thyroid dysfunction: myth or reality?

Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disorder. It is associated with acquired genetic changes in the hematopoietic stem cells in the form of BCR-ABL fusion gene also known as Philadelphia chromosome. We prospectively studied thyroid function at baseline and at 6 months of imatinib treatment in 26 newly diagnosed BCR-ABL positive CML patients. The thyroid-stimulating hormone (TSH) levels increased significantly from baseline (3.20 ± 0.978 mIU/L vs. 3.724 ± 1.726 mIU/L, p < 0.05) after 6 months of treatment, 88.4% of the patients remained euthyroid. Only 2 patients had subclinical hypothyroidism, 1 had hypothyroidism after 6 months of tyrosine kinase inhibitors (TKI) therapy. Imatinib did not have any significant effect on thyroid function in CML patients in this study.

High sensitivity c-reactive protein and circulating biomarkers of endothelial dysfunction in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of patients with chronic myelogenous leukemia (CML); however, they may cause cardiovascular (CV) toxicities. In this cross-sectional study, we explored whether high-sensitivity C-reactive protein (hsCRP) and novel markers of vascular dysfunction were associated with exposure to specific TKIs, in 262 CML patients. Hs-CRP level was not associated with CML disease activity or treatment with a specific TKI. Body mass index (OR: 1.15, 95% CI: 1.108–1.246; p < 0.001) and CML duration (OR: 1.004, 95% CI: 1.001–1.008; p = 0.024) were independently associated with higher hs-CRP. In exploratory analyses, novel endothelial-centric markers (e.g. ET-1 and VCAM-1) were differential across the various TKIs, particularly amongst nilotinib- and ponatinib-treated patients. While Levels of hs-CRP do not appear to be correlated with specific TKIs, circulating markers of vascular dysfunction were altered in patients treated with specific TKIs and should be explored as potential markers of TKI-associated CV risk.

A Concise Review on Analytical Methods for Determination of Nilotinib

Abstract: Nilotinib hydrochloride is a tyrosine kinase inhibitor licensed to treat chronic myelogenous leukemia in patients with the Philadelphia Chromosome (Ph+). Researchers at Novartis Pharmaceuticals discovered novel inhibitors that are effective against imatinib-resistant BCR-ABL mutations. As a consequence, Nilotinib was discovered. Several analytical approaches were employed to address the quantitative as well as qualitative assessment of Nilotinib from diverse biological and pharmaceutical matrices during the development of Nilotinib. The literature search was conducted by evaluating publications reporting on nilotinib analytical methodologies from 2006 to 2022. This review briefly summarizes the drug profile, viz. stereochemistry, mechanism of action, resistance, pharmacokinetics, pharmacodynamics, side effects, and several analytical techniques used to assess Nilotinib in dosage form, bulk, and biological fluids. The determination of Nilotinib using analytical methods is important for therapeutic drug monitoring, optimizing dosage, ensuring safety and efficacy, and conducting comparative studies. A variety of techniques are gathered and examined, including spectroscopy, electrophoresis, voltammetry, Raman spectroscopy, differential scanning calorimetry, X-ray diffraction, chromatography, and hybrid techniques. They are also useful for studying the pharmacokinetics of the drug. These methods play a crucial role in the effective and personalized treatment of patients with chronic myeloid leukemia and other conditions where Nilotinib is used.

Anti-Cancer Role of Dendrosomal Nano Solanine in Chronic Myelogenous Leukemia Cell Line through Attenuation of PI3K/AKT/mTOR Signaling Pathway and Inhibition of hTERT Expression.

Solanine was primarily known as a toxic compound. Nonetheless, recently the apoptotic role of solanine through suppression of PI3K/AKT/mTOR signaling pathway has been shown against many malignancies except chronic myelogenous leukemia (CML). Sustaining the aforementioned pro-survival pathway, BCR-ABL fused oncoprotein in CML activates NF-kB and c- MYC for apparent immortalizing factor hTERT. Since solanine is a poor water-soluble molecule, herein, a nanocarrier was employed to intensify its pernicious effect on cancerous cells. The current research aimed at evaluating the effect of dendrosomal nano solanine (DNS) on leukemic and HUVEC cells. DNS characterization was determined by NMR, DLS and TEM. The viability, apoptosis and cell cycle of DNS and imatinib-treated cells were determined. A quantitative real-time PCR was employed to measure the expression of PI3K, AKT, mTOR, S6K, NF-kB, c-MYC and hTERT mRNAs. The Protein levels were evaluated by western blot. Investigating the anticancer property of free and dendrosomal nano solanine (DNS) and the feasible interplaying between DNS and imatinib on leukemic cells, we figured out the potential inhibitory role of DNS and DNS+IM on cancerous cells in comparison with chemotherapy drugs. Moreover, results revealed that the encapsulated form of solanine was much more preventive on the expression of PI3KCA, mTOR, NF-kB, c-MYC and hTERT accompanied by the dephosphorelating AKT protein. The results advocate the hypothesis that DNS, rather than solanine, probably due to impressive penetration, can restrain the principal pro-survival signaling pathway in erythroleukemia K562 and the HL60 cell lines and subsequently declined mRNA level of hTERT which causes drug resistance during long-term treatment. Additionally, combinational treatment of DNS and IM could also bestow an additive anti-leukemic effect. As further clinical studies are necessary to validate DNS efficacy on CML patients, DNS could have the potency to be considered as a new therapeutic agent even in combination with IM.

Application and clinical significance of intercellular proximity labeling technique in chronic myelogenous leukemia

Objective: This study aimed to explore the application of interaction-dependent fucosyl-biotinylation (FucoID), a chemical biology-based proximity labeling technique, in capturing tumor antigen-specific T cells and its clinical value in chronic myelogenous leukemia (CML) . Methods: Flow cytometry and fluorescence microscopy were employed to evaluate the experimental parameters for FucoID in CML. Peripheral blood samples were obtained from 14 newly diagnosed CML patients in the chronic phase. These samples underwent flow cytometry-based sorting and were subsequently labeled with FucoID to facilitate the isolation of tumor cells and T cells, followed by the immunophenotypic identification of tumor antigen-specific T cells. Finally, the diagnostic and therapeutic potential of FucoID in CML was assessed. Results: Initially, the experimental parameters for FucoID in CML were established. The proportion of CD3(+) T cells in patients was (8.96±6.47) %, exhibiting a marked decrease compared with that in healthy individuals at (38.89±22.62) %. The proportion of tumor-specific antigen-reactive T cells was (3.34±4.49) %, which demonstrated interpatient variability. In addition, the proportion of tumor-specific antigen-active T cells in CD4(+) T cells was (3.95±1.72) %, which was generally lower than the proportion in CD8(+) T cells at (5.68±2.18) %. Compared with those in tumor-specific antigen-nonreactive T cells, CCR7(-)CD45RA(-) effector memory T cells and CCR7(-)CD45RA(+) effector T cells were highly enriched in tumor-specific antigen-reactive T cells. Moreover, the intensity of tumor immune reactivity in patients exhibited a significant correlation with white blood cell count (WBC) and hemoglobin (HGB) levels in peripheral blood, while no such correlation was observed with other clinical baseline characteristics. Conclusion: The combination of FucoID and flow cytometry enables the rapid identification and isolation of tumor antigen-specific T cells in CML. The successful application of this method in CML and the implications of our findings suggest its potential clinical value in the field of hematologic malignancies.

Rash with different types of BCR-ABL inhibitors in chronic myelogenous leukemia: a systematic review and meta-analysis.

Objective: A meta-analysis was conducted to systematically review the risks of all-gradeaswell ashigh-grade rash in chronic myelogenous leukemia (CML) patients using different types of BCR-ABL inhibitors. Methods: Literature publishedbetween 2000 and April 2022 were searched using PubMed, Cochrane Library, Embase and ClinicalTrials.gov. Results: A total of12 studies were included for meta-analysis. The results showed that the incidence of all-gradeor high-grade rash associated withnew-generationBCR-ABLinhibitorshad no significant difference compared with astandard dose of imatinib. Subgroup analysis suggested that, compared with imatinib, the incidence of all grades of rash was higher in thenilotinib, bosutinib andponatinib groups. Conclusion: For CML patients treated with nilotinib, bosutinib and ponatinib, the occurrence of skin toxicity should not be ignored.

Beyond Busulfan: Building a Better Conditioner for Bone Marrow Transplantation

Beyond Busulfan: Building a Better Conditioner for Bone Marrow Transplantation

Impact of initiating oral anticancer agents for leukemia on adherence to medications for multiple chronic conditions.

Increased use of oral anticancer agents (OAAs) has empowered adults with chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML) to manage their therapy, but this shift may complicate medication use, particularly among adults with multiple chronic conditions (MCC). This retrospective cohort study used 2013-2018 commercial and Medicare claims data to assess medication use in adults with CML or CLL. To be included, patients must have been at least 18 years old, diagnosed with and had 2+ claims for an OAA indicated for either CML or CLL, continuously enrolled 12 months before and after OAA initiation, and treated for (2+ fills) at least two select chronic conditions. Proportion of days covered (PDC) determined medication adherence and was compared for 12 months before and after OAA initiation by Wilcoxon signed-rank tests, McNemar's tests, and difference-in-differences models. Among CLL patients, mean OAA adherence in the first year of therapy was 79.8% (SD: 21.1) and 74.7% (SD: 24.9) for commercial and Medicare patients, respectively; mean adherence for CML patients was 84.5% (SD: 15.8) and 80.1% (SD: 20.1) for commercial and Medicare patients, respectively. Adherence and the proportion adherent (PDC ≥ 80%) to comorbid therapies was generally unchanged following OAA initiation. Consistently unremarkable changes in MCC adherence were observed in 12-month difference-in-differences models, but significant decline was observed in MCC adherence after 6 months of OAA use. OAA initiation among adults with CML or CLL was not associated with significant, initial changes to adherence to medications for chronic diseases.