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The absorption and bioavailability of most tyrosine kinase inhibitors are affected by gastrointestinal pH as they are weak basic lipophilic drugs. Hence, concomitant use of acid reducing agents (ARAs) is frequently restricted. Particularly comedication of crystalline dasatinib (Sprycel) and proton‐pump inhibitors (PPIs) should be avoided. Drug–drug interaction (DDI) studies with PPIs report approximately 40%‐80% bioavailability reduction of dasatinib. Limitations in the design of these studies do not allow for assessing the near maximum DDI as timing of PPI dosing was either not reported or 22 h prior to dasatinib intake. We conducted a DDI study of crystalline dasatinib and omeprazole in healthy, fasted participants, investigating the impact of PPI comedication on dasatinib plasma exposure at a time point when the near maximum DDI effect is expected. Participants were administered omeprazole (day 2‐5) to reach steady state. On day 6, a single dose of crystalline dasatinib was given. Crystalline dasatinib dosing alone on day 1 served as control (single dose). The dosing interval between omeprazole administration and crystalline dasatinib was 10 h (median [range: 9‐10 h]). Dasatinib Cmax and AUC0‐24 were reduced by 96% and 89% by omeprazole comedication. Cmax was 224.6 ± 104.7 ng/mL (mean ± SD) and 8.0 ± 4.5 ng/mL (P < .0001) and AUC0‐24 was 797.6 ± 274.5 and 90.6 ± 38.1 h·ng/mL (P < .0001) without and with omeprazole. T1/2 was 5.7 ± 1.5 h (mean ± SD) with crystalline dasatinib dosing alone and could not be reliably calculated with comedication. To ensure optimal patient outcome, it is vital to investigate bioavailability of pH‐sensitive drugs at the maximal DDI effect of ARAs to understand the worst‐case influence for efficient clinical management. [ABSTRACT FROM AUTHOR]

Simple Summary: Myeloproliferative neoplasms (MPNs) are exceedingly rare in children, adolescents, and young adults. The current literature focuses mainly on older patients, so the purpose of the review is to present the genetic landscape of pediatric patients. Modern genetic diagnostics makes it possible to identify genetic markers involved in the pathomechanisms of these uncommon clonal marrow disorders. Excluding driver gene mutations (JAK2, MPL, CALR), over 20 other mutations have been described as of significance to MPNs. The aim of the review is to improve and present knowledge of MPNs and genetic targets for diagnosis and therapy in children, adolescents, and young adults. Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages. These clonal marrow disorders are extremely rare in pediatric patients. MPN is reported to occur 100 times more frequently in adults, and thus research is primarily focused on this patient group. At present, modern diagnostic techniques, primarily genetic, facilitate the identification of the biology of these diseases. The key genes are JAK2, MPL, and CALR, namely, driver mutations, which are present in approximately 90% of patients with suspected MPN. Moreover, there are more than 20 other mutations that affect the development of these hematological malignancies, as evidenced by a review of the literature. The pathogenic mechanism of MPNs is characterized by the dysregulation of the JAK/STAT signaling pathway (JAK2, MPL, CALR), DNA methylation (TET2, DNMT3A, IDH1/2), chromatin structure (ASXL1, EZH2), and splicing (SF3B1, U2AF2, SRSF2). Although rare, myeloproliferative neoplasms can involve young patients and pose unique challenges for clinicians in diagnosis and therapy. The paper aims to review the biological markers of MPNs in pediatric populations—a particular group of patients that has been poorly studied due to the low frequency of MPN diagnosis. [ABSTRACT FROM AUTHOR]

Abdalla Fadul,1 Elmustafa Abdalla,1 Anas Mohamed,1 Bashir Ali,1 Nusiba Elamin,1 Ahmed Abdelghafar Alsayed,1 Abdulrahman F Al-Mashdali,2 Kalpana Singh,3 Shehab F Mohamed2 1Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar; 2Department of Hematology, Hamad Medical Corporation, Doha, Qatar; 3Department of medical biostatistics, Hamad Medical Corporation, Doha, QatarCorrespondence: Abdalla Fadul, Department of Internal Medicine, Hamad Medical Corporation, Al-Rayyan Road, PO Box 3050, Doha, Qatar, Tel +97477999443, Fax +97444397857, Email aabdu69044@gmail.comBackground: Elevated vitamin B12 (B12) levels are linked to an increased risk of cancers, including hematological malignancies. This study focuses on the relationship between elevated B12 and myeloproliferative neoplasms (MPNs): Polycythemia Vera (PV), Primary Myelofibrosis (MF), Essential Thrombocytosis (ET), and Chronic Myeloid Leukemia (CML). Elevated B12 in MPNs is believed to arise from increased transcobalamin I (TCI) secretion by proliferating leukocytes, leading to higher serum levels. B12 may serve as a diagnostic and prognostic biomarker for these conditions. However, its sensitivity, specificity, and cutoff levels are unclear.Aim: To assess the prevalence of high B12 levels in MPN patients, determine the median levels, identify a diagnostic cutoff, and evaluate the sensitivity and specificity of B12 as a marker.Methods: Data were retrieved from the National Center for Cancer Care and Research in Doha, Qatar, for MPN patients from January 2016 to December 2022.Results: A total of 467 patients were included: 232 with CML, 98 with PV, 88 with ET, and 50 with MF. The majority were male (66%) and of Asian origin (56%), with a median age of 48.7 years. CBC results showed median hemoglobin of 9.2 g/dL, WBC count of 73 x 10^3/uL, and platelet count of 531 x 10^3/uL. Elevated B12 levels were found in 95 patients (20%): 71% CML, 14% PV, 10% MF, and 5% ET. Extreme elevations were seen in 59 patients. The mean B12 level decreased from 747.3 ± 686.5 pg/mL before treatment to 397.9 ± 343.7 pg/mL after one year (p=0.01). Median levels were 458 pg/mL (718) before treatment and 301 pg/mL (229) after. In the extreme high B12 group, the mean was 1722 pg/mL before and 677 pg/mL after treatment.Conclusion: Elevated B12 levels are associated with disease activity in CML. However, their role as a reliable marker for disease monitoring remains uncertain, and further studies are needed to confirm their utility for CML progression.Keywords: Vitamin B12, myeloproliferative neoplasms, MPNs, chronic myeloid leukemia, CML, polycythemia vera, PV, essential thrombocythemia, ET, myelofibrosis, MF

Considering the general view that unconventional immune effectors play a major role in antitumor immunity, we recently postulated that the distinct new innate CD8 T-cell pool (co-expressing the transcription factor Eomesodermin and innate markers such as KIR/NKG2A) may counteract tumor cells, and thereby be potential target for cancer therapy. Here, to test this assumption, we used successfully targeted anti-leukemic therapy discontinuation (TFR) in chronic myeloid leukemia (CML). Numerical and functional status of innate CD8 T-cells, iNKT cells and γδ T-cells, in comparison with NK cells, was compared longitudinally between non-relapsed patients (i.e., with > 12 months TFR) and relapsed patients (i.e., who experienced molecular recurrence during the first 12 months after TKI cessation) in a prospective pilot cohort (n=32), starting from treatment discontinuation (D0). Perforin, a key cytotoxic immune player, was expressed in a significantly higher proportion of both innate CD8 T-cell and NK-cell subsets in non-relapsed patients, compared with relapsed patients at D0. In parallel, we assessed the expression of PD-1, an exhaustion marker used as target in cancer therapy. For all T-cell subsets, surface-expression level of PD-1 decreased in non-relapsed patients compared with relapsed patients at D0. This was particularly the case when considering iNKT cells for which surface-expression level of PD-1 even decreased relative to healthy control subjects. Lastly, we found a negative correlation between the proportion of innate CD8 T-cells expressing PD-1 and those expressing perforin in non-relapsed patients at D0. The fact that this was not the case in conventional CD8 T-cells is compatible with a reprogrammed effector profile preferentially targeting innate CD8 T-cells in non-relapsed patients. All in all, our results highlight NK cells and innate CD8 T-cells harboring cytotoxic content, as well as global downregulation of PD-1-expression on effector T-cells, as potential predictive functional signatures for successful TFR in CML. Considering innate CD8 T-cells, further investigations are needed to determine whether their possible contributory role in cancer surveillance in CML could be extended to other cancers, and also whether their targeting by immune cheek-point inhibitors could enhance their anti-tumoral functions. [ABSTRACT FROM AUTHOR]

Quantitation of BCR-ABL1 with the quantitative reverse transcriptase polymerase chain reaction (RT-PCR) is very important in monitoring chronic myeloid leukemia (CML), which relies on an RNA reference material. A genomic RNA reference material (RM) containing the BCR-ABL1 P210 fusion mutation was developed, and an absolute quantitative method based on one-step reverse transcription digital PCR (RT-dPCR) was established for characterizing the RM. The proposed dPCR method demonstrates high accuracy and excellent analytical sensitivity, as shown by the linear relationship (0.94 < slope < 1.04, R2≧0.99) between the measured and nominal values of b2a2, b3a2, and ABL1-ref within the dynamic range (104–101 copies/reaction). Homogeneity and stability assessment based on dPCR indicated that the RM was homogeneous and stable for 24 months at −80 °C. The RM was used to evaluate inter-laboratory reproducibility in eight different laboratories, demonstrating that participating laboratories could consistently produce copy concentrations of b3a2 and ABL1-ref, as well as the BCR-ABL1/ABL1 ratio (CV < 2.0%). This work suggests that the RM can be employed in establishing metrological traceability for detecting mutations in the BCR-ABL1 fusion gene, as well as in quality control for testing laboratories. [ABSTRACT FROM AUTHOR]

• Progesterone reduces the viability of the human chronic myeloid leukemia cell line (K562). • Progesterone increases expression of membrane progesterone receptors (mPRα, mPRβ) on the human chronic myeloid leukemia cell line (K562). Progesterone (P4) has an important effect (activatory or inhibitory) on cell proliferation. Although there is evidence of the impact of progesterone on sex-linked cancers, it can affect other cancer cells expressing P4 receptors (PRs). We evaluated the expression of membrane P4 receptors (mPRs) and the viability in progesterone-treated K562 cells to inspect the possible effects route of progesterone on this (CML) cancer cell line. K562 cells were exposed to various concentrations of progesterone or no exposure for 48 and 72 h. The percentage of viability and cells that expressed mPRα and mPRβ were evaluated by MTT test and flow cytometry respectively. Progesterone significantly increased the expression of mPRα and especially mPRβ on the surface of K562 cells and significantly decreased their viability (p ≤ 0.05). Progesterone can reduce viability in K562 cells. Our findings showed that progesterone affects its receptor expression on K562 cells. Thus it may influence the performance of K562 cells in addition to its direct effects on these cells (via binding to its receptors). [ABSTRACT FROM AUTHOR]

Introduction: Chronic myeloid leukemia is characterized by the dysregulated growth of granulocytes, driven by the Philadelphia chromosome translocation. The prevalence of CML is higher in men, with a median age of 57 years and a five-year survival rate of 85%. Tyrosine kinase inhibitors such as Imatinib have revolutionized CML treatment. However, resistance or intolerance to first-line Imatinib requires second-generation TKIs like Nilotinib and Dasatinib. This study aims to evaluate the response of patients treated with these TKIs at a hematology clinic. Methods: This retrospective study analyzed 100 randomly selected CML patients treated between 2020 and 2022. Data were collected on patient demographics, disease progression, treatment regimens, and response rates. Patients who started on Imatinib and later switched to second-line TKIs due to resistance or side effects were followed to assess treatment efficacy. Results: The cohort had a median age of 43 years, with 52% males and 48% females. Most patients (95%) initiated treatment with Imatinib, with 6% experiencing mild side effects and 4% severe side effects leading to treatment changes. In patients resistant to Imatinib, second-generation TKIs showed favorable responses: Dasatinib was effective in patients with advanced disease, while Nilotinib was useful for those intolerant to Imatinib. One patient resistant to both was successfully treated with Bosutinib, a third-generation TKI. Conclusion: Our findings highlight the efficacy of secondgeneration TKIs for managing Imatinib-resistant CML. Dasatinib and Nilotinib effectively managed disease progression, though side effects were a concern. The use of third-generation TKIs like Bosutinib provides additional therapeutic options for refractory cases. [ABSTRACT FROM AUTHOR]

Leukemia represents a diverse group of hematopoietic neoplasms that can be classified into different subtypes based on the molecular aberration in the affected cell population. Identification of these molecular classification is required to identify specific targeted therapeutic approaches for each leukemic subtype. In general, targeted therapy approaches achieve good responses in some leukemia subgroups, however, resistance against these targeted therapies is common. In this review, we summarize molecular drug resistance biomarkers in targeted therapies in BCR::ABL1-driven chronic myeloid leukemia (CML) and JAK2-driven myeloproliferative neoplasms (MPNs). While acquisition of secondary mutations in the BCR::ABL1 kinase domain is the a common mechanism associated with TKI resistance in CML, in JAK2-driven MPNs secondary mutations in JAK2 are rare. Due to high prevalence and lack of specific therapy approaches in MPNs compared to CML, identification of crucial pathways leading to inhibitor persistence in MPN model is utterly important. In this review, we focus on different alternative signaling pathways activated in both, BCR::ABL1-mediated CML and JAK2-mediated MPNs, by combining data from in vitro and in vivo-studies that could be used as potential biomarkers of drug resistance. In a nutshell, some common similarities, especially activation of PDGFR, Ras, PI3K/Akt signaling pathways, have been demonstrated in both leukemias. In addition, induction of the nucleoprotein YBX1 was shown to be involved in TKI-resistant JAK2-mediated MPN, as well as TKI-resistant CML highlighting deubiquitinating enzymes as potential biomarkers of TKI resistance. Taken together, whole exome sequencing of cell-based or patients-derived samples are highly beneficial to define specific resistance markers. Additionally, this might be helpful for the development of novel diagnostic tools, e.g., liquid biopsy, and novel therapeutic agents, which could be used to overcome TKI resistance in molecularly distinct leukemia subtypes. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) prevalence is currently increasing due to the great efficacy of tyrosine kinase inhibitor (TKI) therapy. Discontinuation of treatment in the long-term, owing to avoid off-target side effects or treatment-free remission (TFR), has become an additional treatment goal in CML patients who achieved a deep molecular response (DMR). Second-generation TKIs (2 G-TKIs) have a significantly higher rate of DMR than imatinib. Hence, especially in young patients with a strategy of TFR, 2 G-TKIs are becoming the most frequently used TKIs and may increase TFR attempts in the future. In this review, the main findings extrapolated from clinical trials and real-life evidence regarding 2 G-TKIs discontinuation were discussed, through broad research on Medline, Embase, and archives from EHA and ASH congresses. Overall, TFR rate after 2 G-TKIs is ranging from 40% to 60% for selected patients with sustained DMR and it can be considered a safe procedure, that have become, nowadays, a daily practice. However, many crucial aspects regarding treatment choices, timings, as well as predictive factors, patient communication, and optimal strategies need to be better clarified to improve successful TFR rate. [ABSTRACT FROM AUTHOR]

Considering the general view that unconventional immune effectors play a major role in antitumor immunity, we recently postulated that the distinct new innate CD8 T-cell pool (co-expressing the transcription factor Eomesodermin and innate markers such as KIR/NKG2A) may counteract tumor cells, and thereby be potential target for cancer therapy. Here, to test this assumption, we used successfully targeted anti-leukemic therapy discontinuation (TFR) in chronic myeloid leukemia (CML). Numerical and functional status of innate CD8 T-cells, iNKT cells and γδ T-cells, in comparison with NK cells, was compared longitudinally between non-relapsed patients (i.e., with > 12 months TFR) and relapsed patients (i.e., who experienced molecular recurrence during the first 12 months after TKI cessation) in a prospective pilot cohort (n=32), starting from treatment discontinuation (D0). Perforin, a key cytotoxic immune player, was expressed in a significantly higher proportion of both innate CD8 T-cell and NK-cell subsets in non-relapsed patients, compared with relapsed patients at D0. In parallel, we assessed the expression of PD-1, an exhaustion marker used as target in cancer therapy. For all T-cell subsets, surface-expression level of PD-1 decreased in non-relapsed patients compared with relapsed patients at D0. This was particularly the case when considering iNKT cells for which surface-expression level of PD-1 even decreased relative to healthy control subjects. Lastly, we found a negative correlation between the proportion of innate CD8 T-cells expressing PD-1 and those expressing perforin in non-relapsed patients at D0. The fact that this was not the case in conventional CD8 T-cells is compatible with a reprogrammed effector profile preferentially targeting innate CD8 T-cells in non-relapsed patients. All in all, our results highlight NK cells and innate CD8 T-cells harboring cytotoxic content, as well as global downregulation of PD-1-expression on effector T-cells, as potential predictive functional signatures for successful TFR in CML. Considering innate CD8 T-cells, further investigations are needed to determine whether their possible contributory role in cancer surveillance in CML could be extended to other cancers, and also whether their targeting by immune cheek-point inhibitors could enhance their anti-tumoral functions.

Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8+PD-1+ cells in patients losing TFR. The level of CD8+PD-1+ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8+PD-1+ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8+PD-1+ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is induced by the expression of the fused tyrosine kinase BCR-ABL, which is caused by a chromosomal translocation. BCR-ABL inhibitors have been used to treat CML; however, the acquisition of resistance by CML cells during treatment is a serious issue. We herein demonstrated that BCR-ABL induced the expression of the RNA helicase DDX5 in K562 cells derived from CML patients in a manner that was dependent on its kinase activity, which resulted in cell proliferation and survival. The knockout of DDX5 decreased the expression of BIRC5 (survivin) and activated caspase 3, leading to apoptosis in K562 cells. Similar results were obtained in cells treated with FL118, an inhibitor of DDX5 and a derivative compound of camptothecin (CPT). Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors (TKIs) have significantly lowered mortality of chronic myeloid leukemia (CML) patients adjusting life expectancy to that of the standard population. However, CML and its treatment with TKIs causes a high disease burden. Physical exercise (PE) could be a non-pharmacological approach to reducing these and improving quality of life. Purpose: The aim of this study was to determine the individual disease burden as well as PE preferences of CML patients and to deduce thereof specific PE recommendations. Methods: This multicenter survey was conducted in cooperation with the LeukaNET/Leukemia-patient network including CML patients aged =18 years (German Registry of Clinical Trials, DRKS00023698). The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1-30 (mild), 31-70 (moderate), or 71-100 (severe). Information about patients' PE needs and preferences depending on their motivation was recorded. Results: A total of 212 questionnaires were analyzed (52% female, median age 54 years). The prevalence of moderate-to-severe symptoms was 49% for fatigue, 40% for musculoskeletal pain, and 37% for concentration problems. Other commonly reported symptoms included skin reactions (42%) and weight gain (24%). The proportion of overweight/obese patients was 52%. Half of all respondents requested more information regarding PE. Patients with CML preferred individual training (82%), located outdoors (71%), at home (47%), or in an indoor swimming pool (31%). Regarding the training frequency, sportsinactive patients preferred a frequency of 1-2 training sessions per week, whereas sports-active patients preferred 3-4 sessions per week (p <0.001). Sports-inactive patients preferred a training time of 15-45 minutes, while sports-active patients preferred 30-60 minutes (p = 0.002). Subsequently, PE recommendations were developed for patients with CML. Combined resistance and endurance training (moderate intensity twice per week for 30 minutes) was recommended for beginners. Obese patients should prioritize joint-relieving sports. To reduce the risk of skin reactions, direct sunlight and possibly water sports should be avoided, and UV protection should be used. Conclusion: Counseling and motivation of CML patients to be physically active should be part of the standard of care as well as support for implementation. [ABSTRACT FROM AUTHOR]

In most cases, COVID-19 is characterized by a mild clinical course. However, there are groups of patients at high risk of mortality and morbidity of COVID-19, including groups comprising older age (> 65 years), diabetes, hypertension, obesity, cancer, and hematological malignancies. Hematological patients are at high risk due to disease-related immune disorders and treatment-related factors. This review aims to summarize studies on COVID-19 in patients with the most common hematological neoplasms. We describe the fatality rate of COVID-19, the risk of severe disease, the efficacy and side effects of vaccines against COVID-19, and vaccine-drug interactions in chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), diffuse large B cell lymphoma (DLBCL) as well as chronic myeloid leukemia (CML). We focus mainly on the use of mRNA vaccines, not other types of vaccines. Hematological patients are a priority group for vaccination against COVID-19, but serological response varies according to the type of hematological malignancy, with better responses in myeloid malignancies and poorer responses in CLL and lymphoma patients. Extended studies are needed to answer questions about a limited response to vaccines and the use of booster doses in CLL and patients treated with anti-CD38 therapy, BTKi therapy, anti-CD20 antibody or ruxolitinib therapy, as well as patients with non-Hodgkin lymphoma (NHL). [ABSTRACT FROM AUTHOR]

Although the involvement of glycan structures in diseases has long been recognized, their detailed and high-throughput investigation has only recently been made possible due to technological advancements. For this reason, glycosylation is a generally understudied phenomenon, however it could provide critical information on the pathobiology of many disorders by virtue of its widespread abundance and critical role in protein function. Here, we focus on myeloid malignancies, conditions for which the survival rates are often poor and curative therapeutic options are generally limited. We review the current literature on (1) N-glycosylation of major hematopoietic growth receptors found mutated in myeloid malignancies, (2) chemoresistance through intracellular glycan-related processes, and (3) mechanisms by which altered N-glycosylation contributes to interactions between myeloid blasts and bone marrow stromal cells leading to niche hijacking. For each topic, we describe the related pathobiology and its (potential) clinical implications. The combination of glycoproteomic and genomic information is expected to result in a deeper molecular understanding of the pathobiology of these diseases, which could subsequently be used for improving prognostication and therapeutic strategies.

Leukemia represents a diverse group of hematopoietic neoplasms that can be classified into different subtypes based on the molecular aberration in the affected cell population. Identification of these molecular classification is required to identify specific targeted therapeutic approaches for each leukemic subtype. In general, targeted therapy approaches achieve good responses in some leukemia subgroups, however, resistance against these targeted therapies is common. In this review, we summarize molecular drug resistance biomarkers in targeted therapies in BCR::ABL1-driven chronic myeloid leukemia (CML) and JAK2-driven myeloproliferative neoplasms (MPNs). While acquisition of secondary mutations in the BCR::ABL1 kinase domain is the a common mechanism associated with TKI resistance in CML, in JAK2-driven MPNs secondary mutations in JAK2 are rare. Due to high prevalence and lack of specific therapy approaches in MPNs compared to CML, identification of crucial pathways leading to inhibitor persistence in MPN model is utterly important. In this review, we focus on different alternative signaling pathways activated in both, BCR::ABL1-mediated CML and JAK2-mediated MPNs, by combining data from in vitro and in vivo-studies that could be used as potential biomarkers of drug resistance. In a nutshell, some common similarities, especially activation of PDGFR, Ras, PI3K/Akt signaling pathways, have been demonstrated in both leukemias. In addition, induction of the nucleoprotein YBX1 was shown to be involved in TKI-resistant JAK2-mediated MPN, as well as TKI-resistant CML highlighting deubiquitinating enzymes as potential biomarkers of TKI resistance. Taken together, whole exome sequencing of cell-based or patients-derived samples are highly beneficial to define specific resistance markers. Additionally, this might be helpful for the development of novel diagnostic tools, e.g., liquid biopsy, and novel therapeutic agents, which could be used to overcome TKI resistance in molecularly distinct leukemia subtypes.

The BCR-ABL fusion gene, formed by the fusion of the breakpoint cluster region protein (BCR) and the Abl Oncogene 1, Receptor Tyrosine Kinase (ABL) genes, encodes the BCR-ABL oncoprotein, which plays a crucial role in leukemogenesis. Current therapies have limited efficacy in patients with chronic myeloid leukemia (CML) because of drug resistance or disease relapse. Identification of novel strategies to treat CML is essential. This study aims to explore the efficiency of novel CRISPR-associated protein 9 (Cas9)/dual-single guide RNA (sgRNA)-mediated disruption of the BCR-ABL fusion gene by targeting BCR and cABL introns. A co-expression vector for Cas9 green fluorescent protein (GFP)/dual-BA-sgRNA targeting BCR and cABL introns is constructed to produce lentivirus to affect BCR-ABL expression in CML cells. The effects of dual-sgRNA virus-mediated disruption of BCR-ABL are analyzed via the use of a genomic sequence and at the protein expression level. Cell proliferation, cell clonogenic ability, and cell apoptosis are assessed after dual sgRNA virus infection, and phosphorylated BCR-ABL and its downstream signaling molecules are detected. These effects are further confirmed in a CML mouse model via tail vein injection of Cas9-GFP/dual-BA-sgRNA virus-infected cells and in primary cells isolated from patients with CML. Cas9-GFP/dual-BA-sgRNA efficiently disrupts BCR-ABL at the genomic sequence and gene expression levels in leukemia cells, leading to blockade of the BCR-ABL tyrosine kinase signaling pathway and disruption of its downstream molecules, followed by cell proliferation inhibition and cell apoptosis induction. This method prolongs the lifespan of CML model mice. Furthermore, the effect is confirmed in primary cells derived from patients with CML.

Advancements and the use of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of Chronic Myeloid Leukemia (CML), achieving unprecedented success rates and expanding their applications to various neoplasms. However, the use of TKIs is not without its drawbacks. Skin, gastrointestinal, and central nervous systems are particularly susceptible to adverse effects, including a higher incidence of autoimmune responses in treated individuals. In this report, we present a unique case of bullous pemphigoid, a rare autoimmune disease, which has not been previously associated with TKI therapy as an adverse effect, particularly appearing after discontinuing Imatinib® treatment.

OBJECTIVE: The use of tyrosine kinase inhibitors (TKIs) and other targeted therapeutics plays a pivotal role in treatment management for individuals diagnosed with chronic myeloid leukemia (CML). However, some patients may experience fewer favorable outcomes and treatment resistance. Our work aims to use whole transcriptome sequencing to evaluate the variations in gene expression patterns among individuals with CML based on their response to TKI therapy. PATIENTS AND METHODS: Ten blood samples were obtained from two groups of patients diagnosed with CML: those at the initial diagnosis stage and those at the recurrence stage. RNA extraction was performed on all samples and used for next-generation sequencing. The data analysis was performed using the DESeq2 R program. RESULTS: In total, 499 genes were identified as having statistically significant differences in expression levels between the two groups. Of these, 122 genes exhibited upregulation, and 377 genes exhibited downregulation. We observed a notable dysregulation in the expression levels of NTRK2 (with a fold change more significant than +5). A significant proportion of the genes that were expressed demonstrated involvement in several biological processes, including the cell cycle, PI3K-AKT signaling system, cellular senescence, oxidative phosphorylation, microRNA in cancer, FOXO signaling pathway, P53 signaling pathway, and other related pathways. CONCLUSIONS: The results demonstrate a correlation between signaling pathways and the development of treatment resistance in patients with CML. These pathways exhibited enhanced efficacy in transmitting signals downstream of the TKI target, BCR-ABL. Several target genes require additional validation in a more extensive cohort study to verify their correlation with TKI resistance. The present research highlights that many BCR-ABL-independent pathways may be correlated with resistance, thus enhancing the prospective therapy options for patients with CML. [ABSTRACT FROM AUTHOR]

Cutaneous adverse events are commonly reported in adult patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs); however, little is known about the cutaneous reactions in children receiving TKIs for CML. As pediatric patients may require lifelong TKI therapy, it is essential to understand the wide range of potential cutaneous toxicities. We examined all case studies, cohort studies, and clinical trials in PubMed/MEDLINE and Embase that reported cutaneous reactions to first‐, second‐, and third‐generation TKIs in children 18 years or younger with CML. This review article focuses on the TKI drug types and doses, patient demographic characteristics, features of skin reactions, and clinical outcomes. [ABSTRACT FROM AUTHOR]

BackgroundTyrosine kinase inhibitors (TKIs) have significantly lowered mortality of chronic myeloid leukemia (CML) patients adjusting life expectancy to that of the standard population. However, CML and its treatment with TKIs causes a high disease burden. Physical exercise (PE) could be a non-pharmacological approach to reducing these and improving quality of life.PurposeThe aim of this study was to determine the individual disease burden as well as PE preferences of CML patients and to deduce thereof specific PE recommendations.MethodsThis multicenter survey was conducted in cooperation with the LeukaNET/Leukemia-patient network including CML patients aged ≥18 years (German Registry of Clinical Trials, DRKS00023698). The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1–30 (mild), 31–70 (moderate), or 71–100 (severe). Information about patients’ PE needs and preferences depending on their motivation was recorded.ResultsA total of 212 questionnaires were analyzed (52% female, median age 54 years). The prevalence of moderate-to-severe symptoms was 49% for fatigue, 40% for musculoskeletal pain, and 37% for concentration problems. Other commonly reported symptoms included skin reactions (42%) and weight gain (24%). The proportion of overweight/obese patients was 52%. Half of all respondents requested more information regarding PE. Patients with CML preferred individual training (82%), located outdoors (71%), at home (47%), or in an indoor swimming pool (31%). Regarding the training frequency, sports-inactive patients preferred a frequency of 1–2 training sessions per week, whereas sports-active patients preferred 3–4 sessions per week (p

The discovery of imatinib, a specific inhibitor of Abl kinase, revolutionized the therapeutic approach to chronic myeloid leukemia (CML); however, its efficacy can be impeded by the emergence of novel mutations within the kinase domain, particularly AblT315I, that lead to the development of drug resistance. It therefore remains necessary to identify specific inhibitors that can effectively target imatinib-resistant CML harboring the AblT315I mutation. A natural product library sourced from the ZINC database was screened against the experimental structure of AblT315I kinase to identify compounds that selectively target the mutated kinase. The top-scoring compound was empirically tested for inhibition of AblT315I kinase using a luminescence-based kit and for impact on cellular proliferation using the BaF3-BCR-ABL-T315I stable cell line. Computational docking and molecular dynamic simulations identified the compound SISB-A1, N-[1-(4-bromophenyl)-3-methyl-1H-pyrazol-5-yl]-2-[(2-oxo-4-phenyl-2H-chromen-7-yl)oxy] acetamide, to effectively bind the catalytic domain of the mutant AblT315I kinase. Moreover, SISB-A1 exhibited greater preference than imatinib for amino acid residues of the mutant kinase's active site, including isoleucine 315. MMPBSA-based Gibbs binding free energy estimation predicted SISB-A1 to have a free energy of −51.5 versus −65.0 kcal/mol for the conventional AblT315I inhibitor ponatinib. Cell proliferation assays showed SISB-A1 to have a GI50 of 164.0 nM against the ABL-T315I stable cell line, whereas imatinib had a GI50 of 5035 nM. The IC50 value obtained for SISB-A1 against the AblT315I kinase was 197.9 nM. The results indicate SISB-A1 to have a notable ability to bind the catalytic domain of the AblT315I mutant kinase and effectively suppress its activity, thereby surpassing the associated resistance to imatinib. Continued advancement of this lead compound has the potential to yield innovative therapeutics for imatinib-resistant CML. [ABSTRACT FROM AUTHOR]

Advancements and the use of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of Chronic Myeloid Leukemia (CML), achieving unprecedented success rates and expanding their applications to various neoplasms. However, the use of TKIs is not without its drawbacks. Skin, gastrointestinal, and central nervous systems are particularly susceptible to adverse effects, including a higher incidence of autoimmune responses in treated individuals. In this report, we present a unique case of bullous pemphigoid, a rare autoimmune disease, which has not been previously associated with TKI therapy as an adverse effect, particularly appearing after discontinuing Imatinib® treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nilotinib is a potent, second-generation inhibitor of BCR-ABL1 tyrosine kinase and has been approved as frontline and salvage therapy for patients with chronic-phase chronic myeloid leukemia (CP-CML). METHODS: In this single-institution, phase 2 study, 122 patients with newly diagnosed CP-CML received nilotinib 400 mg twice daily. The median follow-up on study was 78.3 months (interquartile range, 58.4-96.5 months). RESULTS: Fifty-six percent of patients remained on therapy at the last follow-up. Both the complete cytogenetic response rate and the major molecular response (MR) rate were 91%. Seventy-five percent and 59% of patients achieved a ≥4.5-log reduction in BCR-ABL1 transcripts (MR4.5) and a sustained MR4.5 beyond 2 years, respectively. The estimated event-free survival and overall survival rates at 5 years were 89% and 93%, respectively, and the corresponding rates at 10 years were 85% and 88%, respectively. Treatment discontinuation due to toxicity occurred in 19% of patients, mostly because of cardiovascular events (10%) and biochemical abnormalities (6%). The top 3 nonhematologic toxicities were rash (55%), elevated bilirubin (57%), and elevated aminotransferases (48%). Hematologic toxicity was transient and mild. Ischemic cardiovascular adverse events occurred in 8% of patients. Four patients (3%) progressed to accelerated or blast phase while on therapy, and 7 patients (6%) died on study. CONCLUSIONS: The current data confirm the long-term efficacy of nilotinib 400 mg twice daily in patients with CP-CML. A majority of patients can achieve sustained MR4.5.

Abstract Background Frailty is a marker of poor prognosis in older adults with hematologic malignancies and contributes to the severe vulnerability of the aging population to adverse health outcomes. This study aimed to determine the association between frailty and outcomes in hospitalized patients with chronic myeloid leukemia (CML). Methods The International Classification of Diseases (ICD-10) identified data on hospitalized patients 20 years or older admitted with CML between 2016 and 2018 in the US National Inpatient Sample (NIS) database. The cohort was further divided into groups of patients with or without frailty. Logistic regression analysis was performed to determine associations between study variables and clinical outcomes. A stratified analysis of the association between frailty and in-hospital mortality by age group was also performed. Results A total of 13,849 hospitalized patients with CML were included, 49.6% of whom had frailty. The mean age of the patients was 65.1 years, and 7,619 (56.2%) of them were male. Frailty was associated with nearly 4 times the risk of in-hospital mortality, 3 times the risk of unfavorable discharge, 3 times the risk of prolonged LOS,, and significantly more in total hospital costs. In addition, frailty was associated with a significantly increased risk of in-hospital mortality in all age subgroups ( 60 years) compared with no frailty. Conclusions Frailty strongly predicts poor clinical outcomes in US patients with CML.

The effective and sensitive monitoring of Minimal Residual Disease or Measurable Residual Disease (MRD) is a very important aspect in the management of patients affected by hematologic malignancies. The recent availability of new technologies has opened to the improvement of MRD monitoring. It is particularly relevant in patients affected by Chronic Myeloid Leukemia (CML). MRD monitoring is key in the management of CML patients thanks to the efficacy of TKIs therapy. Moreover, the policies of TKIs discontinuation aimed at treatment free remission are strongly based on the good selection of patients eligible for stopping TKIs therapy. The recently described application of digital PCR in CML patients monitoring seems to improve the accuracy and precision in the identification of optimal responders. The present review reports an overview on the application of digital PCR in the monitoring of MRD in CML and its impact on TKIs discontinuation trials and, consequently, on TFR success.

Imatinib has been the first and most successful tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML), but many patients develop resistance to it after a satisfactory response. Glutathione (GSH) metabolism is thought to be one of the factors causing the emergence of imatinib resistance. Since hsa-miR-203a-5p was found to downregulate Bcr-Abl1 oncogene and also a link between this oncogene and GSH metabolism is reported, the present study aimed to investigate whether hsa-miR-203a-5p could overcome imatinib resistance by targeting GSH metabolism in imatinib-resistant CML cells. After the development of imatinib-resistant K562 (IR-K562) cells by gradually exposing K562 (C) cells to increasing doses of imatinib, resistant cells were transfected with hsa-miR-203a-5p (R+203). Thereafter, cell lysates from various K562 cell sets (imatinib-sensitive, imatinib-resistant, and miR-transfected imatinib-resistant K562 cells) were used for GC-MS-based metabolic profiling. L-alanine, 5-oxoproline (also known as pyroglutamic acid), L-glutamic acid, glycine, and phosphoric acid (Pi)—five metabolites from our data, matched with the enumerated 28 metabolites of the MetaboAnalyst 5.0 for the GSH metabolism. All of these metabolites were present in higher concentrations in IR-K562 cells, but intriguingly, they were all reduced in R+203 and equated to imatinib-sensitive K562 cells (C). Concludingly, the identified metabolites associated with GSH metabolism could be used as diagnostic markers.

Objective: To determine the association between major leukemias and age and assess differences with respect to gender, cytogenetics and hematological parameters among patients presenting at a tertiary care hospital. Study Design: Cross sectional study. Place and Duration of Study: Medical Oncology Department, Jinnah Postgraduate Medical Center, Karachi, Pakistan from Oct 2019 to Mar 2020. Methodology: Two hundred and three patients of either gender >14 years presenting with confirmed diagnosis of acute or chronic leukemia based on bone marrow biopsy and immunophenotyping were enrolled in the study. Data regarding socio-demographics, duration of disease, family history, co-morbids and hematological parameters were collected. Results: The mean age of the study sample was estimated as 35.46±15.14 years ranging from 14-85 years. Out of 203 patients, 69(34%) of the patients had Acute Myeloid Leukemia, 55(27.1%) had Acute Lymphoblastic Leukemia, 61(30%) had Chronic Myeloid Leukemia and 18(8.9%) had Chronic Lymphocytic Leukemia. AML and ALL are the most frequent leukemias in the age group 19-50 years while CML and CLL more frequently presented in the age group 31-50 years. No case of CLL has been reported in age less than 31 years. Overall, statistically significant difference was observed between age and types of leukemia (p<0.05). Significant association was found between age and leukemia types among males (p<0.05), normal cytogenetics, hyperdiploidy and t (9;22) (p<0.05) and hematological parameters (p<0.05. Conclusion: In conclusion, statistically significant association was observed between age and types of leukemia. Further more significant association was also found between age and leukemia types among males; cytogenetics; and hematological parameters. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular events are one of the main long-term complications in patients with chronic myeloid leukemia (CML) receiving treatment with tyrosine kinase inhibitors (TKIs). The proper choice of TKI and the adequate management of risk factors may reduce cardiovascular comorbidity in this population. Methods: This study evaluated the cardiovascular risk of a cohort of patients with CML at diagnosis and after follow-up in a specialized cardiovascular risk consultation. In order to do this, we performed data analysis from 35 patients who received TKIs and were referred to the aforementioned consultation between 2015 and 2018 at our center. Cardiovascular risk factors were analyzed separately, as well as integrated into the cardiovascular SCORE, both at diagnosis and at the last visit to the specialized consultation. Results: At the time of diagnosis, 60% had some type of risk factor, 20% had a high or very high risk SCORE, 40% had an intermediate risk, and 40% belonged to the low risk category. During follow-up, the main cardiovascular adverse event observed was hypertension (diagnosed in 8 patients, 23%). 66% of patients quit smoking, achieving control of blood pressure in 95%, diabetes in 50%, weight in 76%, and dyslipidemia in 92%. 5.7% of patients suffered a thrombotic event and a significant percentage of patients showed a reduction in their SCORE. Conclusion: Our study shows the benefit of controlling cardiovascular risk factors through follow-up in a specialized consultation for patients with CML treated with TKI. [ABSTRACT FROM AUTHOR]

Simple Summary: Reverse transcriptases (RT) play a crucial role in BCR::ABL1 fusion transcript monitoring of chronic myeloid leukemia (CML). RT enzyme and reaction conditions may contribute to impairment of stoichiometry in cDNA synthesis potentially biasing in qRT-PCR data. We have comparatively investigated the performance of the MLV-RT and SuperScript IV with random-hexamer vs. target-specific priming by means of the Acrometrix™ BCR::ABL1 reference panel and 37 clinical specimens. Our experiments identified priming type and RT type as major factors for diagnostic data variation. Variation was mainly due to different efficacies of RT enzymes to process low- (<50) and high-copy targets. The impairment of the high-performing SuperScript IV in processing low- (BCR::ABL1) and high-copy-number (GUSB or ABL1) RNA targets equally was not reflected by the diagnostically relevant Log (BCR::ABL1/GUSB%) values. For improving BCR::ABL1 assay sensitivity with a faithful representation of diagnostic targets, increased RNA/cDNA amounts and distinct RT/priming combinations are highly recommended. Reverse transcriptases (RT) are essential tools in BCR::ABL1 fusion transcript monitoring in chronic myeloid leukemia (CML). The RT type and cDNA priming method may impair the stoichiometry of cDNA synthesis, thereby potentially introducing a bias in BCR::ABL1 qRT-PCR data. Using the Acrometrix™ BCR::ABL1 reference panel and 37 clinical specimens, we have comparatively investigated the performance of the RTs MLV and SuperScript IV with random hexamer vs. target-specific priming. Quantitative RT-PCR results identified the priming type and RT type as major factors for diagnostic data variation, mainly due to the different efficacies of processing BCR::ABL1 low-copy-numbers (<50) compared to GUSB or ABL1 high-copy targets. The impairment of SuperScript IV in processing low- and high-copy-number RNA targets equally was not reflected by the diagnostically relevant Log (BCR::ABL1/GUSB%) values. Therefore, the correct representation of housekeeping and BCR::ABL1 target genes should have priority when aiming at as high a number of housekeeping gene copies as possible. Our data suggest that for improving BCR::ABL1 assay sensitivity, increased RNA/cDNA amounts and the use of distinct RT/priming combinations are advantageous. However, for inter-laboratory harmonization, the proper conversion factor according to the CML international standard (IS) has to be reevaluated each time the grade of RT is changed. [ABSTRACT FROM AUTHOR]

Acute leukemia is the most common malignancy in childhood, while chronic myeloid leukemia is rare, accounting for only 2% to 3% of all leukemia in childhood and 9% in adolescents, with an annual incidence of 1 and 2.2 cases per million in the two groups. The goal in Pediatrics is remission and cure with tyrosine kinase inhibitors (TKIs) and monitoring closely for long-term effects of TKI use. [ABSTRACT FROM AUTHOR]

Simple Summary: Tyrosine kinase inhibitors (TKI), such as imatinib, nilotinib, and dasatinib, are the first-line treatment of choice for patients with chronic myeloid leukemia (CML). However, patients may develop serious cardiovascular events (CVE) with their use. Cardiotoxicity is an important issue given the associated mortality of CVE and the long-term nature of TKI treatment. This study aimed to investigate the association of the presence of somatic myeloid mutations (including those with a reported role in clonal hematopoiesis) at diagnosis and the development of CVE for 102 patients on TKI treatment. The presence of a somatic myeloid mutation was a significant risk factor for CVE on any TKI and shortened the CV event-free survival for patients receiving first-line imatinib treatment. Our work shows that the low risk of CVE, traditionally associated with first-line imatinib, was increased by the presence of myeloid mutations as well as older age. Our findings may help inform first-line TKI choice. For chronic myeloid leukemia (CML) patients with a known risk of cardiovascular events (CVE), imatinib is often recommended for first-line tyrosine kinase inhibitor (TKI) treatment rather than a second-generation TKI (2G-TKI) such as nilotinib or dasatinib. To date, very few studies have evaluated the genetic predisposition associated with CVE development on TKI treatment. In this retrospective study of 102 CML patients, 26 CVEs were reported during an average follow-up of over 10 years. Next-generation sequencing identified pathogenic/likely pathogenic mutations in genes associated with myeloid malignancies in 24.5% of the diagnostic samples analyzed. Patients with a recorded CVE had more myeloid mutations (0.48 vs. 0.14, p = 0.019) and were older (65.1 vs. 55.7 years, p = 0.016). Age ≥ 60 years and receiving a 2G-TKI in first-line were CVE risk factors. The presence of a pathogenic somatic myeloid mutation was an independent risk factor for CVE on any TKI (HR 2.79, p = 0.01), and significantly shortened the CV event-free survival of patients who received first-line imatinib (by 70 months, p = 0.011). Indeed, 62% of patients on imatinib with mutations had a CVE vs. the 19% on imatinib with a mutation and no CVE. In conclusion, myeloid mutations detectable at diagnosis increase CVE risk, particularly for patients on imatinib, and might be considered for first-line TKI choice. [ABSTRACT FROM AUTHOR]

The prognosis of chronic myeloid leukemia (CML) on tyrosine kinase inhibitor (TKI) treatment is based on the quantification of BCR::ABL1 fusion gene transcript copy number, harmonized by an international scale (IS) based on TaqMan-based real-time quantitative PCR (qRT-PCR). In Ethiopia, as in most low- and middle-income countries (LMICs), access to standard diagnostic, follow-up, and prognostic tools is very limited, and it has been challenging to strictly follow international guidelines. This seriously compromises clinical outcome, despite the availability of TKIs through the Glivec International Patient Assistance Program (GIPAP). Multiplex PCR (mpx-PCR), conventionally regarded as a "screening tool," offers a potential solution to this problem. A total of 219 samples from confirmed CML patients were assayed. In reference to qRT-PCR, the AUC of ROC curve for mpx-PCR was 0.983 (95% CI: 0.957 to 0.997). At the optimum cut-off value, equivalent to BCR::ABL1 (IS) transcript copy number of 0.6%, the specificity and sensitivity were 93% and 95%, respectively, with 94% accuracy. Albeit the sensitivity and accuracy of mpx-PCR decrease below the optimum cutoff of 0.6% (IS), the specificity at 0.1% (IS) was 100%, making it an attractive means to rule-out relapse and drug non-adherence at later stages of treatment, which is particularly an issue in a low income setting. We conclude that the relative simplicity and low cost of mpx-PCR and prognostic relevant cutoff values (0.1–0.6% IS) should allow its use in peripheral clinics and thus maximize the positive impact of TKIs made available through GIPAP in most LMICs. [ABSTRACT FROM AUTHOR]

Introduction: The ligand-activated transcription factors, nuclear hormone receptors (NHRs), remain unexplored in hematological malignancies except for retinoic acid receptor alpha (RARA). Methods: Here we profiled the expression of various NHRs and their coregulators in Chronic myeloid leukemia (CML) cell lines and identified a significant differential expression pattern between inherently imatinib mesylate (IM)-sensitive and resistant cell lines. Results: Retinoid-X-receptor alpha (RXRA) was downregulated in CML cell lines inherently resistant to IM and in primary CML CD34+ cells. Pre-treatment with clinically relevant RXRA ligands improved sensitivity to IM in-vitro in both CML cell lines and primary CML cells. This combination effectively reduced the viability and colony-forming capacity of CML CD34+ cells in-vitro. In-vivo, this combination reduced leukemic burden and prolonged survival. Overexpression (OE) of RXRA inhibited proliferation and improved sensitivity to IM in-vitro. In-vivo, RXRA OE cells showed reduced engraftment of cells in the bone marrow, improved sensitivity to IM, and prolonged survival. Both RXRA OE and ligand treatment markedly reduced BCR::ABL1 downstream kinase activation, activating apoptotic cascades and improving sensitivity to IM. Importantly, RXRA OE also led to the disruption of the oxidative capacity of these cells. Conclusion: Combining IM with clinically available RXRA ligands could form an alternative treatment strategy in CML patients with suboptimal response to IM. [ABSTRACT FROM AUTHOR]

This study aimed to design and synthesize active hybrids of β‐elemene and nitric oxide (NO) donor pharmacophore as potential agents for treating leukemia. Derivatives reported herein exerted better inhibitory effects against human chronic myeloid leukemia K562 cells compared to β‐elemene (IC50 > 100 μM). The most potent compound 18f showed an IC50 value of 0.53 μM against K562 cells, as well as a high NO release level in vitro. In the K562 xenograft tumor mice model, compound 18f effectively inhibited the growth of the tumor, with a significant inhibition rate of 73.18%. After treatment with compound 18f, the body weight of mice did not decrease, indicating that it possessed good safety profile. All these proved that compound 18f was an excellent potential agent against leukemia. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular events are one of the main long-term complications in patients with chronic myeloid leukemia (CML) receiving treatment with tyrosine kinase inhibitors (TKIs). The proper choice of TKI and the adequate management of risk factors may reduce cardiovascular comorbidity in this population.Methods: This study evaluated the cardiovascular risk of a cohort of patients with CML at diagnosis and after follow-up in a specialized cardiovascular risk consultation. In order to do this, we performed data analysis from 35 patients who received TKIs and were referred to the aforementioned consultation between 2015 and 2018 at our center. Cardiovascular risk factors were analyzed separately, as well as integrated into the cardiovascular SCORE, both at diagnosis and at the last visit to the specialized consultation.Results: At the time of diagnosis, 60% had some type of risk factor, 20% had a high or very high risk SCORE, 40% had an intermediate risk, and 40% belonged to the low risk category. During follow-up, the main cardiovascular adverse event observed was hypertension (diagnosed in 8 patients, 23%). 66% of patients quit smoking, achieving control of blood pressure in 95%, diabetes in 50%, weight in 76%, and dyslipidemia in 92%. 5.7% of patients suffered a thrombotic event and a significant percentage of patients showed a reduction in their SCORE.Conclusion: Our study shows the benefit of controlling cardiovascular risk factors through follow-up in a specialized consultation for patients with CML treated with TKI.

Background: Frailty is a marker of poor prognosis in older adults with hematologic malignancies and contributes to the severe vulnerability of the aging population to adverse health outcomes. This study aimed to determine the association between frailty and outcomes in hospitalized patients with chronic myeloid leukemia (CML). Methods: The International Classification of Diseases (ICD-10) identified data on hospitalized patients 20 years or older admitted with CML between 2016 and 2018 in the US National Inpatient Sample (NIS) database. The cohort was further divided into groups of patients with or without frailty. Logistic regression analysis was performed to determine associations between study variables and clinical outcomes. A stratified analysis of the association between frailty and in-hospital mortality by age group was also performed. Results: A total of 13,849 hospitalized patients with CML were included, 49.6% of whom had frailty. The mean age of the patients was 65.1 years, and 7,619 (56.2%) of them were male. Frailty was associated with nearly 4 times the risk of in-hospital mortality, 3 times the risk of unfavorable discharge, 3 times the risk of prolonged LOS,, and significantly more in total hospital costs. In addition, frailty was associated with a significantly increased risk of in-hospital mortality in all age subgroups (< 40 years, 40–59 years, and > 60 years) compared with no frailty. Conclusions: Frailty strongly predicts poor clinical outcomes in US patients with CML. [ABSTRACT FROM AUTHOR]

Simple Summary: There is still a lack of reliable molecular predictors to achieve major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) in the therapeutic management of newly diagnosed chronic myeloid leukemia (CML). Employing a proprietary fluorogenic flow cytometry assay, we recently identified separase proteolytic activity as a potential marker of molecular response and BCR::ABL1 positivity of CD34+ cells in TKI-treated CML patients. Here, we analyzed the expression and predictive value of ESPL1/Separase, PTTG1/Securin and PTTG1IP/Securin interacting protein transcript levels in white blood cells of CML patients (n = 97) at the time of diagnosis by means of qRT-PCR. We establish a novel distance (cut-off) score based on ESPL1, PTTG1 and PTTG1IP gene expression levels that can serve as predictors of TKI non-response in about 10% of analyzed non-responding patients and may have potential benefit for the risk stratification of CML patients. The achievement of major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) is a milestone in the therapeutic management of patients with newly diagnosed chronic myeloid leukemia (CML). We analyzed the predictive value of gene expression levels of ESPL1/Separase, PTTG1/Securin and PTTG1IP/Securin interacting protein for MMR achievement within 12 months. Relative expression levels (normalized to GUSB) of ESPL1, PTTG1 and PTTG1IP in white blood cells of patients (responders n = 46, non-responders n = 51) at the time of diagnosis were comparatively analyzed by qRT-PCR. 3D scatter plot analysis combined with a distance analysis performed with respect to a commonly calculated centroid center resulted in a trend to larger distances for non-responders compared to the responder cohort (p = 0.0187). Logistic regression and analysis of maximum likelihood estimates revealed a positive correlation of distance (cut-off) with non-achieving MMR within 12 months (p = 0.0388, odds ratio 1.479, 95%CI: 1.020 to 2.143). Thus, 10% of the tested non-responders (cut-off ≥ 5.9) could have been predicted already at the time of diagnosis. Future scoring of ESPL1, PTTG1 and PTTG1IP transcript levels may be a helpful tool in risk stratification of CML patients before initiation of TKI first = line treatment. [ABSTRACT FROM AUTHOR]

Modern clinical therapy of chronic myeloid leukemia (CML) with TKIs is highly efficacious in most CML patients, while it is not remedial and generally confined due to intolerance or resistance. CML is currently considered a severe disease. Interestingly, stem cell transplantation in the past decade was an attractive clinical therapeutic option in CML patients, but it is not successful due to independently more death rates in older patients. So, the targeting of BCR::ABL oncoprotein is extensively used to enhance the reduction in a higher percentage of CML patients by tyrosine kinase inhibitors (TKIs). However, resistance or intolerance responses to these inhibitors are responsible for future deterioration and further development of disease. At this point, the clinical treatment of CML is a major challenge, and the lack of molecular responses to TKIs are not succeeded with chemotherapy alone. So, the considerable efficacious clinical necessities remain unmet. Therefore, continuous efforts are needed to explore new potential treatment strategies with an increasing understanding of CML biology. Therefore, this review deals with the investigation of TKI treatment with interferon, chemotherapy (Hydroxyurea, Homoharringtonine, Omacetaxine, Cytarabine), and several other new TKIs under beneficial clinical trials. Additionally, the approaches towards TKIs-resistant or intolerant CML cells where the respective signaling pathway gets up-regulated are also targeted with its inhibitor. This review presents evidence that new TKIs under clinical and pre-clinical trials may improve the chemotherapy of CML. [ABSTRACT FROM AUTHOR]

Background & Objective: Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by an aberrant BCR-ABL fusion protein. Imatinib mesylate (IM) is a tyrosine kinase inhibitor that induces clinical remissions in chronic-phase CML patients. The T315I mutation at the gatekeeper residues of BCR-ABL confers resistance to both IM and second-generation TKIs, including dasatinib and nilotinib. Our objective was to determine the prevalence of T315I mutation between two groups of CML patients before and during Imatinib treatment in North-East of Iran. Materials & Methods: This study was conducted on 100 newly diagnosed cases of CML (before commencing IM treatment) and 25 IM-resistant CML patients. PCRRFLP, ASO-PCR, and direct sequencing were performed to detect T315I mutations. Results: The median age of newly-diagnosed and IM-resistant patients was 48±14 and 50±12.3 years, respectively. Males/Females ratio was 1 and 1.08 for newly diagnosed and IM-resistant patients, respectively. There was no significant difference regarding the age and sex between the two groups. During the study, T315I mutational analysis was performed for all 125 patients. The prevalence of T315I mutation was 0% and 4% for newly-diagnosed and IM-resistant patients, respectively. T315I mutation was not detected before IM administration, although it was detected in 1(4%) among resistant patients who were at least 6-months on IM treatment. Conclusion: These observations suggest that T315I mutation may be categorized as secondary resistance and induce clonal expansion due to BCR/ABL instability. Hence, BCR-ABL mutations [ABSTRACT FROM AUTHOR]

Background: Imatinib has changed the treatment of chronic myeloid leukemia (CML) drastically since 15 years. It is usually well tolerated, but severe persistent marrow aplasia is an unusual complication of imatinib while using it in CML. The aim of this study is to describe our experience confronting this rare side effect and review the available data worldwide. Patients and Methods: It was a retrospective analysis conducted at a center from February 2002 to February 2015. This study was endorsed by our Institutional Review Board (IRB) and written consent was taken from all patients. Patients diagnosed as Philadelphia (Ph) chromosome‑positive CML either in chronic phase (CP), accelerated phase (AP), or blastic crisis (BC) were included. There were a total of 1,576 patients with CML treated with imatinib during this period. Karyotyping and quantitative reverse transcriptase polymerase chain reaction (RT‑qPCR) were done at the time of pancytopenia for all patients. Results: In total, 11 (males = 5, females = 6) patients met our inclusion criteria from 1,576 patients of CML. The median age was 58 years (range 32–76). Out of 11 patients 8, 2, and 1 patients were in CP, AP, and BC phases, respectively. The median time of administration of imatinib was 3.3 months(range 1.5–6). The average time of marrow recovery was 10.4 months(range 5–15). Two patients expired (one from septicemia and the other from intracranial hemorrhage). BCR‑ABL transcripts level by RT‑PCR revealed the existence of the disease in all patients. Conclusion: Imatinib is a very well‑tolerated tyrosine kinase inhibitor (TKI), but is associated with persistent myelosuppression when used in older age, advanced phase of the disease, and treated previously. After confirming persistent marrow aplasia, the treatment is mainly supportive. It is striking that the disease is still persistent, which is confirmed by RT‑PCR. There is no consensus regarding recalling imatinib at lower doses or the use of second‑generation TKI (nilotinib, dasatinib) in these patients. [ABSTRACT FROM AUTHOR]

The effective and sensitive monitoring of Minimal Residual Disease or Measurable Residual Disease (MRD) is a very important aspect in the management of patients affected by hematologic malignancies. The recent availability of new technologies has opened to the improvement of MRD monitoring. It is particularly relevant in patients affected by Chronic Myeloid Leukemia (CML). MRD monitoring is key in the management of CML patients thanks to the efficacy of TKIs therapy. Moreover, the policies of TKIs discontinuation aimed at treatment free remission are strongly based on the good selection of patients eligible for stopping TKIs therapy. The recently described application of digital PCR in CML patients monitoring seems to improve the accuracy and precision in the identification of optimal responders. The present review reports an overview on the application of digital PCR in the monitoring of MRD in CML and its impact on TKIs discontinuation trials and, consequently, on TFR success. [ABSTRACT FROM AUTHOR]

Introduction: The ligand-activated transcription factors, nuclear hormone receptors (NHRs), remain unexplored in hematological malignancies except for retinoic acid receptor alpha (RARA).Methods: Here we profiled the expression of various NHRs and their coregulators in Chronic myeloid leukemia (CML) cell lines and identified a significant differential expression pattern between inherently imatinib mesylate (IM)-sensitive and resistant cell lines.Results: Retinoid-X-receptor alpha (RXRA) was downregulated in CML cell lines inherently resistant to IM and in primary CML CD34+ cells. Pre-treatment with clinically relevant RXRA ligands improved sensitivity to IM in-vitro in both CML cell lines and primary CML cells. This combination effectively reduced the viability and colony-forming capacity of CML CD34+ cells in-vitro. In-vivo, this combination reduced leukemic burden and prolonged survival. Overexpression (OE) of RXRA inhibited proliferation and improved sensitivity to IM in-vitro. In-vivo, RXRA OE cells showed reduced engraftment of cells in the bone marrow, improved sensitivity to IM, and prolonged survival. Both RXRA OE and ligand treatment markedly reduced BCR::ABL1 downstream kinase activation, activating apoptotic cascades and improving sensitivity to IM. Importantly, RXRA OE also led to the disruption of the oxidative capacity of these cells.Conclusion: Combining IM with clinically available RXRA ligands could form an alternative treatment strategy in CML patients with suboptimal response to IM.

Simple Summary: TKI have vastly improved long-term outcomes for patients with CML, although it is still hard for a proportion of patients to obtain ideal molecular responses. Advances in NGS technology have enabled the incorporation of somatic mutation profiles in classification and prognostication. With an increased focus on achieving deep molecular responses, we try to explore the risk conferred by additional genomic lesions other than BCR∷ABL through NGS technology. We also figure out how clinical characteristics, distinct TKI options and risk scores influence the achieving of molecular responses. This research has the potential to lay the foundation for improved risk classification according to clinical and genomic risk and to enable more precise early identification of TKI. A proportion of patients with somatic variants show resistance or intolerance to TKI therapy, indicating additional mutations other than BCR∷ABL1 may lead to TKI treatment failure or disease progression. We retrospectively evaluated 151 CML patients receiving TKI therapy and performed next-generation sequencing (NGS) analysis of 22 CML patients at diagnosis to explore the mutation spectrum other than BCR∷ABL1 affecting the achievement of molecular responses. The most frequently mutated gene was ASXL1 (40.9%). NOTCH3 and RELN mutations were only carried by subjects failing to achieve a major molecular response (MMR) at 12 months. The distribution frequency of ASXL1 mutations was higher in the group that did not achieve MR4.0 at 36 months (p = 0.023). The achievement of MR4.5 at 12 months was adversely impacted by the presence of >2 gene mutations (p = 0.024). In the analysis of clinical characteristics, hemoglobin concentration (HB) and MMR were independent factors for deep molecular response (DMR), and initial 2GTKI therapy was better than 1GTKI in the achievement of molecular response. For the scoring system, we found the ELTS score was the best for predicting the efficacy of TKI therapy and the Socal score was the best for predicting mutations other than BCR∷ABL. [ABSTRACT FROM AUTHOR]

The T315I-inclusive compound mutation, the multiple mutations including the T315I mutation on the same BCR::ABL1 gene, confers resistance to diverse tyrosine kinase inhibitors (TKIs). Development of the F311I/T315I compound mutation has been reported in chronic myeloid leukemia patients who sequentially showed clinical resistance to imatinib and dasatinib. The establishment of a human leukemia model with the T315I-inclusive compound mutation remains an experimental challenge. Here, we introduced the F311I/T315I compound mutation into the intrinsic BCR::ABL1 gene of a human TKI-sensitive Philadelphia chromosome-positive leukemia cell line via homologous recombination using the CRISPR/Cas9 system and obtained three types of sublines: the F311I mutation alone, the T315I mutation alone, and the F311I/T315I compound mutation. The F311I subline was sensitive to dasatinib but moderately resistant to imatinib and nilotinib, while the T315I subline and the F311I/T315I subline were highly resistant to these TKIs. Notably, the T315I subline and the F311I/T315I subline were sensitive to therapeutic concentrations of ponatinib, although more resistant than the F311I subline. Moreover, the T315 subline and the F311I/T315 subline were sensitive to asciminib at therapeutic concentration, as was the F311I subline. This is the first human leukemia model in which the impact of the T315I-inclusive compound mutation on TKI sensitivity was directly confirmed., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This work was supported by the JSPS KAKENHI grant number JP23K24298. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nguyen et al.)

Background/aim: According to American Cancer Society's recent estimates, about 5,330 men and 3,950 women are diagnosed each year with chronic myeloid leukemia (CML). Roughly, 750 men and 530 women are predicted to die as a result of CML, establishing a dire need for advancements in CML treatment. Tyrosine kinase inhibitors (TKIs) imatinib and dasatinib have profound effects for prognosis and delaying survival from CML. The role of inecalcitol in the treatment and prevention of various cancers including leukemia has been established. The aim of this study was to analyze the putative synergistic treatment effects of inecalcitol in combination with imatinib or dasatinib on various cell lines including AR-230, LAMA-84-s, KCL-22, and U-937., Materials and Methods: Cells grown in plates were treated alone or with varying combinations of inecalcitol, imatinib, and dasatinib and incubated for 48 h at 37°C. Cell death was determined using MTT assay., Results: KCL-22 and U-937 were resistant to both combination treatments, whereas AR-230 exhibited a maximal antiproliferative effect (24%) with the combined treatment of imatinib (0.325 μM) and inecalcitol (15.8 μM) (p<0.001). With dasatinib (0.456 nM) and inecalcitol (15.8 μM), AR-230 exhibited a 34% antiproliferative effect (p<0.001). In drastic contrast, LAMA84-s exhibited a 45% antiproliferative effect (with the combined treatment of imatinib (0.325 μM) and inecalcitol (15.8 μM) (p<0.006). Notably, with dasatinib (0.456 nM) and inecalcitol (15.8 μM), LAMA84-s exhibited approximately 78% cell killing (p<0.007)., Conclusion: The study suggests that the synergistic effects of inecalcitol with imatinib on cell killing are more drastic in some cells than others. These varying effects may be due to differences in cell metabolism., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Abayomi O Bamgboje,1 Muheez A Durosinmi,2 Tuoyo O Mene-Afejuku,3 Micheal O Fagbayimu,4 Olusola Fajobi,5 Michael O Balogun6 1Department of Internal Medicine, SCL Healthcare St Vincent’s/Holy Rosary Hospital, Miles city, Montana, 59101, USA; 2Department of Hematology and Immunology Obafemi Awolowo University Teaching Hospitals Complex Ile-Ife, Osun state, Nigeria; 3Department of Cardiology Tower Health System, Reading Hospital, West Reading, Pennsylvania, USA; 4Department of Surgery Obafemi Awolowo University Teaching Hospitals Complex Ile-Ife, Osun State, Nigeria; 5Department of Community Medicine Awolowo University Teaching Hospitals Complex Ile-Ife, Osun State, Nigeria; 6Department of Internal Medicine Cardiology Unit Obafemi Awolowo University Teaching Hospitals Complex Ile-Ife, Osun State, NigeriaCorrespondence: Abayomi O Bamgboje, Department of Internal Medicine, 1233 North 30th Street, Billings, MT, 59101, USA, Tel +1 9293189246, Email yomibamgboje@yahoo.comPurpose: Chronic myeloid leukemia (CML) is one of the common hematological malignancies in Nigeria. Cardiac abnormalities are associated with CML irrespective of treatment with tyrosine kinase inhibitors such as imatinib, which is available gratis in Nigeria.Objective: To assess the prevalence and patterns of cardiac dysfunction among patients with CML irrespective of treatment with imatinib using transthoracic echocardiography, and 12-lead surface electrocardiography.Patients and Methods: CML patients without Imatinib, CML patients with imatinib, and apparently healthy (age- and sex-matched) controls were 70 each in the study. Various echocardiographic parameters were measured and data obtained were analyzed, and the level of significance was taken as p < 0.05.Results: Of 70 CML patients with imatinib, 54.3% were men and 45.7% were women, while the CML group without imatinib had 62.9% men and 37.1% women, non-CML control had 54.3% men and 45.7% women. The average hematocrit was significantly lower in the CML group without Imatinib compared with the other groups (p< 0.001). And, 12.9% and 17.1% of CML groups with and without imatinib had LVH, respectively, and none of the non-CML controls had LVH (P< 0.041). Impaired left ventricular relaxation in 25.71% and 28.57% of CML patients with and without imatinib respectively but only 8.57% of the non-CML control had impaired left ventricular relaxation (p=0.236). Mitral valve regurgitation was the most frequent valvular abnormality across the groups. Pulmonary hypertension in 17.4% and 20% of CML patients with and without imatinib, respectively, but none of the non-CML controls had pulmonary hypertension (p< 0.001). Pericardial effusion in 32.86% and 45.71% of CML patients with and without imatinib, respectively, but none of the non-CML controls had pericardial effusion (p< 0.001). There was no significant difference in the QTC interval across the three groups.Conclusion: Cardiac abnormalities are present in CML patients with or without Imatinib treatment, with significant prevalence than what is seen in the non-CML control group.Keywords: chronic myeloid leukemia, CML, tyrosine kinase inhibitor-imatinib, cardiac dysfunction

Abstract Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm driven by BCR-ABL1 oncoprotein, which plays a pivotal role in CML pathology, diagnosis, and treatment as confirmed by the success of tyrosine kinase inhibitor (TKI) therapy. Despite advances in the development of more potent tyrosine kinase inhibitors, some mechanisms particularly in terms of CML leukemic stem cell (CML LSC) lead to intrinsic or acquired therapy resistance, relapse, and disease progression. In fact, the maintenance CML LSCs in patients who are resistance to TKI therapy indicates the role of CML LSCs in resistance to therapy through survival mechanisms that are not completely dependent on BCR-ABL activity. Targeting therapeutic approaches aim to eradicate CML LSCs through characterization and targeting genetic alteration and molecular pathways involving in CML LSC survival in a favorable leukemic microenvironment and resistance to apoptosis, with the hope of providing a functional cure. In other words, it is possible to develop the combination therapy of TKs with drugs targeting genes or molecules more specifically, which is required for survival mechanisms of CML LSCs, while sparing normal HSCs for clinical benefits along with TKIs.