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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]

Fast, accurate damage assessment of numerous buildings for large areas is vital for saving lives, enhancing decision‐making, and expediting recovery, thereby increasing urban resilience. The traditional methods, relying on expert mobilization, are slow and unsafe. Recent advances in machine learning (ML) have improved assessments; however, quantum‐enhanced ML (QML), a rapidly advancing field, offers greater advantages over classical ML (CML) for large‐scale data, enhancing the speed and accuracy of damage assessments. This study explores the viability of leveraging QML to evaluate the safety of reinforced concrete buildings after earthquakes, focusing on classification accuracy only. A QML algorithm is trained using simulation datasets and tested on real‐world damaged datasets, with its performance compared to various CML algorithms. The classification results demonstrate the potential of QML to revolutionize seismic damage assessments, offering a promising direction for future research and practical applications. [ABSTRACT FROM AUTHOR]

Pityriasis rosea is an acute, self‐limited exanthem that typically occurs in adolescence and young adulthood, classically featuring ovoid erythematous and scaly lesions on the trunk and proximal extremities. While its cause is not definitively known, the classic form of pityriasis rosea may result from the reactivation of latent human herpesvirus (HHV) infections (HHV‐6 and HHV‐7). Interestingly, drug eruptions that clinically and/or histopathologically resemble pityriasis rosea have also been reported. These pityriasis rosea‐like drug eruptions tend to occur at an older age and have a shorter duration than the classic type. As there are different management paradigms, the distinction between classic pityriasis rosea and the mimicking drug eruption is important to recognize. Herein, we report a case of a pityriasis rosea‐like drug eruption that occurred in association with imatinib mesylate treatment for chronic myeloid leukemia. We also review the clinicopathologic features of reported cases of pityriasis rosea‐like drug eruption, including those due to imatinib. While the clinical morphology of the cutaneous drug‐related eruption mimics the lesions seen in classic pityriasis rosea, the presence of unique histopathologic findings, including necrotic keratinocytes, interface dermatitis, and eosinophils, may aid in distinction. [ABSTRACT FROM AUTHOR]

Precise and reliable predictive parameters to accurately identify chronic myeloid leukemia (CML) patients who can successfully discontinue their tyrosine kinase inhibitor (TKI) treatment are lacking. One promising parameter is depth of molecular response measured by BCR::ABL1 digital PCR (dPCR). The aim of this study was to validate a previously described prediction cutoff of 0.0023%IS and to assess the value of dPCR for treatment‐free remission (TFR) prediction in relation to other clinical parameters. A droplet‐based dPCR assay assessed BCR::ABL1 %IS prior to TKI discontinuation. The primary endpoint was molecular recurrence (MolR) by 36 months. A total of 186 patients from Canada, Germany, and the Netherlands were included. In patients with a first TKI discontinuation attempt (n = 163), a BCR::ABL1 dPCR < and ≥0.0023%IS had a MolR probability of 33% and 70%, respectively. Patients treated less than 6 years with a BCR::ABL1 dPCR <0.0023%IS had a MolR probability of 31%. After correction for treatment duration, both high dPCR value and the use of imatinib (vs. second‐generation TKI) were significantly associated with a higher risk of MolR (HR of 3.66, 95%CI 2.06–6.51, p <.001; and 2.85, 95%CI 1.25–6.46, p =.013, respectively). BCR::ABL1 dPCR was not associated with TFR outcome after second TKI discontinuation, however, with the limitation of a small number of patients analyzed (n = 23). In conclusion, BCR::ABL1 digital PCR based on the cutoff of 0.0023%IS is a valuable predictive tool to identify CML patients with a high probability of TFR success after first TKI discontinuation, including patients treated for less than 6 years. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is a major cause of chronic myeloid leukemia (CML) relapse, therapeutic failure, and a poor prognosis. However, Agaricus blazei Murill (AbM) is a mushroom that might have anticancer and other medicinal properties. Therefore, this study aimed to determine the effects of combining the acidic RNA protein complex FA‐2‐b‐β extracted from AbM with imatinib (IM) on MDR in the K562/ADR leukemia cell line in vitro and in xenograft mouse models. The combination of FA‐2‐b‐β and IM significantly inhibited cell proliferation and promoted apoptosis in K562/ADR cells compared with either alone. Western blotting (WB) revealed that the combination significantly reduced p‐PI3K, p‐AKT, and p‐mTOR protein expression. The combination also inhibited tumor growth in mice with K562/ADR xenografts. These findings suggested that FA‐2‐b‐β enhances the effects of IM on K562/ADR cell proliferation and apoptosis, potentially by inhibiting the PI3K/AKT/mTOR pathway and downregulating P‐glycoprotein (P‐gp) expression. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion Asciminib, a novel allosteric BCR::ABL1 inhibitor, targets the ABL1 myristoyl pocket to potentially reduce toxicity and enhance efficacy. It is approved for Philadelphia chromosome‐positive chronic‐phase chronic myeloid leukemia (CML‐CP) in patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs) or those with the T315I mutation.This retrospective analysis evaluated patients with CML treated with asciminib under a managed‐access program across eight Israeli centers from July 2019 to August 2022. We assessed treatment responses, toxicities, event‐free survival (EFS), and overall survival (OS) using Kaplan–Meier methods.The study included 30 patients who had received a median of three prior TKIs, with 73% starting asciminib due to intolerance. After a median follow‐up of 7.1 months, 85% of those without prior complete cytogenetic response (CCyR) achieved CCyR, and 60% previously not in major molecular response (MMR) attained MMR. Resistance was rare (10%), with no cardiovascular events reported despite high baseline comorbidity (73%). Median EFS was 47 months; median OS was not reached.Asciminib demonstrates significant efficacy and tolerability in heavily pretreated patients with CML‐CP, with no new cardiovascular events observed. Further long‐term studies are necessary to explore its full cardiovascular impact. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm in which all the patients has the translocation (9;22) that generates de BCR::ABL1 tyrosine kinase. Despite this disease possessing a good biomarker (BCR::ABL1 transcripts level) for diagnosis and prognosis, many studies has been performed to investigate other molecules, such as the long noncoding RNAs (lncRNAs) and mRNAs, as potential biomarkers with the aim of predicting a change in BCR::ABL1 levels and as an associated biomarker. A RNAseq was performed comparing 6 CML patients with high BCR::ABL1 expression with 6 healthy control individuals, comprising the investigation cohort to investigate these molecules. To validate the results obtained by RNAseq, samples of 87 CML patients and 42 healthy controls were used in the validation cohort by RT-qPCR assays. The results showed lower expression of HOTAIR and PTGS2 in CML patients. The HOTAIR expression is inversely associated with BCR::ABL1 expression in imatinib-treated CML patients, and to PTGS2 showing that CML patients with high BCR::ABL1 expression showed reduced PTGS2 expression. [ABSTRACT FROM AUTHOR]

Background: Treatment-free remission (TFR) is a new long-term goal for treating selected patients with chronic myeloid leukemia in the chronic phase (CML-CP). Still, the appropriate group in which TFR can be attempted and the factors influencing it have not yet been identified. This meta-analysis aimed to explore TFR in CML-CP patients who achieved a deep molecular response (DMR) before Tyrosine kinase inhibitors (TKIs) discontinuation and to explore possible factors influencing TFR and the safety of discontinuation. Methods: We performed a systematic review and single-arm meta-analysis with a systematic search of published literature up to September 2023 in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The assessment was performed using the MINORS scale. Random-effects models were used to calculate outcome metrics, including overall mean TFR rates at 12 and 24 months and subgroup differences. Data synthesis and analysis were done by Stata17.0 software. Results: A total of 19 single-arm trials involving 2336 patients were included in this meta-analysis, with an overall mean TFR rate of 59% [95CI:0.56–0.63] at 12 months and 55% [95CI:0.52–0.59] at 24 months, and no CML-related deteriorations or deaths reported during the TFR period. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (P = 0.003), and molecular response depth MR5.0 (P = 0.020). Conclusion: Our study demonstrated that prior interferon therapy and attainment of a molecular response depth of MR5.0 or greater were associated with higher TFR rates, with patients who attained MR5.0 or greater achieving a TFR rate of up to 62% in the second year after TKI discontinuation. Considering the high heterogeneity of the included trials, the above influences still require further validation and more detailed subgroup analysis in future discontinuation trials. Systematic review registration:https://www.crd.york.ac.uk/prospero/ (Registration No. CRD42023471334). [ABSTRACT FROM AUTHOR]

Background: Leukocytosis and thrombocytosis often follow splenectomy in blunt trauma patients, complicating the postoperative identification of infection. While the platelet count to white blood cell ratio provides diagnostic assistance to discern between expected laboratory alterations and infection, diagnoses such as leukemia are often overlooked. Case presentation: A 53-year-old Hispanic male presented with abdominal pain, nausea, tachycardia, and focal peritonitis 4 days after being assaulted and struck multiple times in the abdomen. Initial white blood cell count was 38.4 × 109/L, platelet count was 691 × 109/L, and lipase was 55 U/L. Computed tomography abdomen/pelvis demonstrated a hematoma encasing the distal pancreas and abutting the stomach and colon. Emergent laparotomy revealed a nearly transected pancreas and devascularized colon, necessitating a distal pancreatectomy, splenectomy, and colonic resection with primary anastomosis. Postoperatively, he had a persistently elevated leukocytosis, thrombocytosis, segmented neutrophils, eosinophilia, and basophilia (peak at 70, 2293, 64, 1.1, and 1.2 × 109/L, respectively). Despite sepsis workup, including repeat computed tomography, no source was identified. Hematology/oncology was consulted for concern for hematologic etiology, with genetic testing and bone marrow biopsy performed. The diagnosis of breakpoint cluster–Abelson gene-positive chronic myeloid leukemia was made based on genetic tests, including polymerase chain reaction and fluorescence in situ hybridization analysis, which confirmed the presence of the Philadelphia chromosome. Bone marrow biopsy suggested a chronic phase. The patient was treated with hydroxyurea and transitioned to imatinib. Conclusions: Thrombocytosis following splenectomy is a common complication and a plate count to white blood cell count ratio < 20 indicates infectious etiology. A significantly elevated white blood cell count (> 50 × 109/L) and thrombocytosis (> 2000 × 109/L) may suggest something more ominous, including chronic myeloid leukemia , particularly when elevated granulocyte counts are present. Chronic myeloid leukemia workup includes peripheral smear, bone marrow aspiration, and determination of Philadelphia chromosome. Post-splenectomy vaccines are still indicated within 14 days; however, the timing of immunization with cancer treatment must be considered. Tyrosine kinase inhibitors are the first-line therapy and benefits of pretreatment with hydroxyurea for cytoreduction remain under investigation. Additionally, tyrosine kinase inhibitors have been associated with gastrointestinal perforation and impaired wound healing, necessitating heightened attention in patients with a new bowel anastomosis. [ABSTRACT FROM AUTHOR]

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin's aglycon—1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments. [ABSTRACT FROM AUTHOR]

Patients with chronic myeloid leukemia (CML) respond to tyrosine kinase inhibitors (TKIs); however, CML leukemic stem cells (LSCs) exhibit BCR::ABL kinase-independent growth and are insensitive to TKIs, leading to disease relapse. To prevent this, new therapies targeting CML-LSCs are needed. Rates of mitochondria-mediated oxidative phosphorylation (OXPHOS) in CD34+CML cells within the primitive CML cell population are higher than those in normal undifferentiated hematopoietic cells; therefore, the inhibition of OXPHOS in CML-LSCs may be a potential cure for CML. NK-128 (C33H61NO5S) is a structurally simplified analog of JCI-20679, the design of which was based on annonaceous acetogenins. NK-128 exhibits antitumor activity against glioblastoma and human colon cancer cells by inhibiting OXPHOS and activating AMP-activated protein kinase (AMPK). Here, we demonstrate that NK-128 effectively suppresses the growth of CML cell lines and that the combination of imatinib and NK-128 is more potent than either alone in a CML xenograft mouse model. We also found that NK-128 inhibits colony formation by CD34+ CML cells isolated from the bone marrow of untreated CML patients. Taken together, these findings suggest that targeting OXPHOS is a beneficial approach to eliminating CML-LSCs, and may improve the treatment of CML. [ABSTRACT FROM AUTHOR]

HIV-1 infection cannot be cured due to long-lived viral reservoirs formed by latently infected CD4+ T cells. "Shock and Kill" strategy has been considered to eliminate the viral reservoir and achieve a functional cure but the stimulation of cytotoxic immunity is necessary. Ponatinib is a tyrosine kinase inhibitor (TKI) clinically used against chronic myeloid leukemia (CML) that has demonstrated to be effective against HIV-1 infection in vitro. Several TKIs may induce a potent cytotoxic response against cancer cells that makes possible to discontinue treatment in people with CML who present long-term deep molecular response. In this longitudinal study, we analyzed the capacity of ponatinib to induce an antiviral response against HIV-1 infection in peripheral blood mononuclear cells (PBMCs) obtained from people with CML previously treated with imatinib for a median of 10 years who changed to ponatinib for 12 months to boost the anticancer response before discontinuing any TKI as part of the clinical trial NCT04043676. Participants were followed-up for an additional 12 months in the absence of treatment. PBMCs were obtained at different time points and then infected in vitro with HIV-1. The rate of infection was determined by quantifying the intracellular levels of p24-gag in CD4+ T cells. The levels of p24-gag+ CD4+ T-cells were lower when these cells were obtained during and after treatment with ponatinib in comparison with those obtained during treatment with imatinib. Cytotoxicity of PBMCs against HIV-infected target cells was significantly higher during treatment with ponatinib than during treatment with imatinib, and it was maintained at least 12 months after discontinuation. There was a significant negative correlation between the lower levels of p24-gag+ CD4+ T-cells and the higher cytotoxicity induced by PBMCs when cells were obtained during and after treatment with ponatinib. This cytotoxic immunity was mostly based on higher levels of Natural Killer and Tγd cells seemingly boosted by ponatinib. In conclusion, transient treatment with immunomodulators like ponatinib along with ART could be explored to boost the antiviral activity of cytotoxic cells and contribute to the elimination of HIV-1 reservoir. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia (CML) can manifest ocular complications stemming from hematologic irregularities or direct infiltration of neoplastic cells. This article details the case of a patient with newly diagnosed CML exhibiting elevated platelet counts (PLT) who developed panuveitis accompanied by retinal vascular occlusion. Case presentation: A 52-year-old woman experienced a notable decline in vision in her left eye over a 2-week period. Classical anterior uveitis, vitreous cavity opacity, optic nerve edema, and retinal vascular obstruction were observed. The right eye exhibited papilledema and retinal vein tortuosity. Despite admission, the condition of both eyes deteriorated, accompanied by a continuous increase in PLT. She was diagnosed with CML based on bone marrow biopsy and chromosomal examination. Following platelet apheresis therapy and chemotherapy, the condition of her right eye significantly improved, but the left eye's condition remained irreversible. Conclusions: This is a rare case of newly diagnosed CML presenting with diverse ocular manifestations in both eyes. The disparate outcomes in eyes with varying lesion stages underscore the importance of prompt diagnosis. [ABSTRACT FROM AUTHOR]

Histone H1 is involved in the regulation of chromatin structure. Human somatic cells express up to seven subtypes. The variability in the proportions of somatic H1s (H1 complement) is one piece of evidence supporting their functional specificity. Alterations in the protein levels of different H1 subtypes have been observed in cancer, suggesting their potential as biomarkers and that they might play a role in disease development. We have developed a mass spectrometry-based (MS) parallel reaction monitoring (PRM) assay suitable for the quantification of H1 subtypes. Our PRM method is based on the quantification of unique peptides for each subtype, providing high specificity. Evaluation of the PRM performance on three human cell lines, HeLa, K562, and T47D, showed high reproducibility and sensitivity. Quantification values agreed with the electrophoretic and Western blot data, indicating the accuracy of the method. We used PRM to quantify the H1 complement in peripheral blood samples of healthy individuals and chronic myeloid leukemia (CML) patients. In CML, the first line of therapy is a tyrosine kinase inhibitor, imatinib. Our preliminary data revealed differences in the H1 complement in CML patients between imatinib responders and non-responders. These results support further research to determine if the H1 content or subtype composition could help predict imatinib response. [ABSTRACT FROM AUTHOR]

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1–2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3–4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies. [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]

The oral cavity is a frequent site for head and neck cancers, which rank as the sixth most common cancer globally, with a 5-year survival rate slightly over 50%. Current treatments are limited, and resistance to therapy remains a significant clinical obstacle. IsCT1, a membrane-active peptide derived from the venom of the scorpion Opisthacanthus madagascariensis, has shown antitumor effects in various cancer cell lines, including breast cancer and chronic myeloid leukemia. However, its hemolytic action limits its potential therapeutic use. This study aims to assess the antitumor and antiproliferative activities of synthetic peptides derived from IsCT1 (IsCT-P, AC-AFPK-IsCT1, AFPK-IsCT1, AC-KKK-IsCT1, and KKK-IsCT1) in the context of oral squamous cell carcinoma. We evaluated the cytotoxic effects of these peptides on tongue squamous cell carcinoma cells and normal cells, as well as their impact on cell cycle phases, the expression of proliferation markers, modulators of cell death pathways, and mitochondrial potential. Our results indicate that the IsCT1 derivatives IsCT-P and AC-AFPK-IsCT1 possess cytotoxic properties towards squamous cell carcinoma cells, reducing mitochondrial membrane potential and the proliferative index. The treatment of cancer cells with AC-AFPK-IsCT1 led to a positive modulation of pro-apoptotic markers p53 and caspases 3 and 8, a decrease in PCNA and Cyclin D1 expression, and cell cycle arrest in the S phase. Notably, contrary to the parental IsCT1 peptide, AC-AFPK-IsCT1 did not exhibit hemolytic activity or cytotoxicity towards normal cells. Therefore, AC-AFPK-IsCT1 might be a viable therapeutic option for head and neck cancer treatment. [ABSTRACT FROM AUTHOR]

Summary Third‐generation tyrosine kinase inhibitors (TKIs) have much potential for the treatment of BCR::ABL1‐positive leukaemia, particularly that harbouring the ABL1 T315I mutation. Olverembatinib (HQP1351), a novel third‐generation TKI, has favourable efficacy and safety profiles in chronic myeloid leukaemia. Here, we present the clinical findings from 31 BCR::ABL1‐positive acute lymphoblastic leukaemia (ALL) patients who received olverembatinib. Among the 14 patients with overt relapsed/refractory (R/R) disease (including 10 with the T315I mutation), 71.4% achieved an overall response. Of the other 17 patients with minimal residual disease (MRD)‐positive ALL (including 14 with the T315I mutation), 60.0% and 47.1% achieved MRD flow negativity and complete molecular remission, respectively. With a median follow‐up time of 16.3 months, the median event‐free survival and overall survival were 3.9 and 8.3 months respectively, in overt R/R patients, and 11.5 and 18.4 months in MRD‐positive patients. Allogeneic haematopoietic stem cell transplantation further improved outcomes among responders. The safety profile was generally manageable. This study suggests that olverembatinib‐based therapy is another promising option for BCR::ABL1‐positive ALL in addition to ponatinib, especially for patients with MRD‐positive disease and a single T315I mutation. [ABSTRACT FROM AUTHOR]

Background: Ponatinib is a third‐generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome–positive leukemias. Herein, we report the long‐term follow‐up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Methods: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6‐month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Results: Fifty‐one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21–75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2–25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second‐line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6‐month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24‐month event‐free survival rate was 97%. After a median follow‐up of 128 months, the 10‐year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Conclusion: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio‐/vaso‐occlusive and other severe toxicities. Treatment with ponatinib in the frontline setting of chronic myeloid leukemia in chronic phase was associated with high molecular response rates, with 12‐month cumulative rates of major molecular response and MR4 of 82% and 72%, respectively. However, it was associated with an increased incidence of toxicity, in particular serious grade 2‐3 cardiovascular adverse events in 16% of the patients. [ABSTRACT FROM AUTHOR]

This study aimed to report the collective clinical characteristics of oral side effects associated with imatinib therapy according to age, sex, and clinical condition. A bibliographic review was performed using the PubMed, Web of Science, Scopus, Cochrane Library, and Embase databases. Forty-five cases of oral side effects due to imatinib therapy were identified in the literature. With the addition of five new cases seen at the authors' institution, a total of 50 cases were analysed. Of the five new cases, four with gastrointestinal stromal tumours developed oral lichenoid lesions (OLLs), and one with chronic myeloid leukaemia (CML) developed oral hyperpigmentation (OHP). Of the total 50 patients, 26 were male and 24 were female, and age ranged from 29 to 86 years. Most patients were ≥50 years old (80%); only three patients were jaw was the least common, with just five cases (10%). Among the patients with OHP, the predominant clinical condition was CML (22 cases, 91.7%). In conclusion, the possibility of oral side effects needs to be considered during the examination of patients receiving imatinib therapy. [ABSTRACT FROM AUTHOR]

The advent of tyrosine kinase inhibitors (TKIs) has changed the natural history of chronic myeloid leukemia (CML), and the transformation from the chronic phase to the blast phase (BP) is currently an uncommon situation. However, it is one of the major remaining challenges in the management of this disease, as it is associated with dismal outcomes. We report the case of a 63-year-old woman with a history of CML with poor response to imatinib who progressed to myeloid BP-CML, driven by the acquisition of t(8;21)(q22;q22)/RUNX1::RUNX1T1. The patient received intensive chemotherapy and dasatinib, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, she suffered an early relapse after allo-HSCT with the acquisition of the T315I mutation in ABL1. Ponatinib and azacitidine were started as salvage treatment, allowing for the achievement of complete remission with deep molecular response after five cycles. Advances in the knowledge of disease biology and clonal evolution are crucial for optimal treatment selection, which ultimately translates into better patient outcomes. [ABSTRACT FROM AUTHOR]

Unlike second-generation tyrosine kinase inhibitors, effects of imatinib on the cardiovascular (CV) system are debatable. The current case–control study aimed to evaluate the CV effects of imatinib in patients with chronic myeloid leukemia (CML) using non-invasive 2D-echocardiography testing. Patients with CML ≥ 13 years attending the adult haematology clinic of a tertiary care hospital in north India were prospectively enrolled over 1.5 years. The study population (n = 110) consisted of 35 newly diagnosed patients (treatment-naïve group) and 75 patients under imatinib therapy ≥ 1 year (treated group). All the eligible patients were subjected to 2D-echocardiography to calculate pulmonary artery systolic pressure (PASP), left ventricular ejection fraction (LVEF) and deceleration time (DT). These parameters were compared between the two groups. P-value < 0.05 was considered statistically significant. The median age of study population was 40 years (range, 13–73) and M:F ratio was 1.14:1. Both the groups had similar demographics at the diagnosis including CV risk factors. The median PASP of the treated group was 2 mm Hg higher than the treatment-naïve group (25 vs 23 mm Hg, p-value = 0.919). The median LVEF of the treated group was 3.2% lower than the treatment-naïve group (58.5% vs 61.72%, p-value = 0.577). The median DT of the treated group was 7 ms shorter than treatment-naïve group (211 vs 204 ms, p-value = 0.411). Imatinib causes potential cardiac dysfunction in patients with CML. Large scale prospective follow-up trials in the same cohort of patients are needed to validate the findings of our study. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukaemia (CML) is caused by balanced translocation t(9::22)(q34;q11) resulting in formation of pathogenic BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of CML. Ongoing treatment with TKI leads to side effects and has financial impact. Teratogenic potential of TKI and growth disturbance also represent an important challenge. Thus, TKI discontinuation in form of treatment free remission (TFR) has emerged as a new and important therapeutic goal. In this retrospective study, we reviewed CML patients who were kept on TFR. Inclusion criteria was patient age ≥ 18 years diagnosed with CML in chronic phase who met the criteria for TFR and opted for same and who were in DMR but stopped TKI for any reason. We analysed the data for baseline characteristics, molecular relapse (MR), survival without molecular relapse (SWMR), TFR duration and factors affecting MR. We included 38 patients in this analysis. Thirty five (92%) patients were treated with imatinib at diagnosis. Median duration of TKI treatment was 135 months. 37 patients (97.5%) achieved DMR on TKI and median time from TKI initiation to DMR was 96 months. Median duration of DMR prior to TKI discontinuation was 41 months. TKI was discontinued after counselling for TFR in 26 patients (68%) while it was discontinued due to intolerance in 10 patients (29%). At median molecular follow up of 25 months, nine patients (23.7%) had molecular relapse. Median SWMR was not reached and 2 year estimated SWMR was 65.2% (95%CI,47.2- 83.2). Of all relapses, 5/9 (55.5%) occurred in the first six months of TFR. On univariate analysis, duration of TKI and duration of DMR were predictive of molecular relapse. On multivariate analysis, none of these factors were found to be significant. This retrospective study suggests that for CML CP patients achieving deep molecular response, discontinuing TKI therapy in real-world settings may be feasible while potentially achieving comparable outcomes. [ABSTRACT FROM AUTHOR]

Diagnosing Chronic Myeloid Leukemia (CML) during pregnancy presents challenges for both haematologists and obstetricians. Limited data exists regarding the management of pregnancy-associated CML in low- and middle-income countries (LMICs). This study aimed to assess pregnancy, foetal, and long-term disease outcomes in female patients newly diagnosed with CML in the chronic phase (CML-CP) during pregnancy. A retrospective analysis was conducted on female CML-CP patients presenting between January 2002 and December 2022 at our institution. Inclusion criteria encompassed patients newly diagnosed with CML-CP during pregnancy. Data pertaining to pregnancy outcomes, foetal development, and disease progression were analysed through a comprehensive review of medical records. Among the female CML patients, thirteen were diagnosed with CML-CP during pregnancy. The median patient age was 24 years (range: 20–35). Diagnoses occurred in the first trimester for six patients, the second trimester for three, and the third trimester for four. Outcomes included five elective terminations (38.5%), five pre-term deliveries (38.5%), and three full-term deliveries (23.1%). Management included observation in 6 (46.3%), hydroxyurea in 3 (23.1%), imatinib in 3 (23.1%) and Interferon-α (IFN-α) in 1 (7.7%) patients. Noteworthy obstetric complications encompassed threatened abortion with intrauterine foetal death (IUFD) (1 patient), intrauterine growth retardation (IUGR) (3 patients), oligohydramnios (2 patients), antepartum haemorrhage (1 patient), placental abruption (1 patient), and postpartum haemorrhage (3 patients). At a median follow-up duration of 10.7 years, 11 patients were at a major molecular remission (including 2 patients with deep molecular remission) and two patients progressed to the accelerated phase. The diagnosis and management of CML during pregnancy is a complex and challenging task that requires collaboration between haematologists and obstetricians. Effective management of newly diagnosed CML-CP during pregnancy is contingent on the trimester of presentation. Further research and collaboration are warranted to develop standardised guidelines for managing pregnancy-associated CML, particularly in LMICs. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms by which cancer cells switch between different adaptive states and evade therapeutic interventions is essential for clinical management. In this study, the in vivo cellular dynamics of a new chronic myeloid leukaemia cell line displaying altered phenotype and resistance to tyrosine kinase inhibitors were investigated in correlation with their parental cells for invasiveness/metastasis, angiogenic potential and population kinetics. We showed that the cells exhibiting drug resistance and plastic phenotype possess an increased capacity for invasion compared to their parental cells, that exposure to imatinib mesylate has the potential to enhance cellular motility and that in a leukaemic cell population, even a minority of plastic cells exhibit improved migratory ability. Furthermore, we show that these plastic cells have angiogenic and extravasation potential. The present study provides significant insights into the cellular dynamics displayed by a TKI‐resistant, phenotypically plastic CML cell line, using a zebrafish (Danio rerio) xenograft model. [ABSTRACT FROM AUTHOR]

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

Summary Superfine and regular grinding methods were used to mill mulberry leaves (ML), and the chemical composition and physical characteristics of the powders were investigated. Compared to regular grinding, superfine grinding reduced particle size from 121.44 μm to 18.69 μm. Compared to coarse mulberry leaf (CML), the fine mulberry leaf (FML) powder had a greater water solubility index, soluble dietary fibre content and 1‐deoxynojirimycin (DNJ) content. Both types of ML powders were substituted for flour at various percentages (3%, 6%, 9% and 12%), and their effects on the biscuits' textural qualities and sensory assessment were examined. The adhesiveness, cohesiveness and springiness of biscuit doughs were all reduced by ML powder addition, while their hardness was raised. The inclusion of ML powders increased the hardness of the biscuits significantly, whereas only the addition of FML powders decreased their fracturability. Additionally, the DNJ contents in FML biscuits were significantly higher than that in CML biscuits. The sensory assessment revealed that biscuits containing 9% FML powder received the best rating. [ABSTRACT FROM AUTHOR]

Background: BCR-ABL is a constitutively active tyrosine kinase that stimulates multiple downstream signaling pathways to promote the survival and proliferation of chronic myeloid leukemia (CML) cells. The clinical application of specific BCR-ABL tyrosine kinase inhibitors (TKIs) has led to significantly improved prognosis and overall survival in CML patients compared to previous treatment regimens. However, direct targeting of BCR-ABL does not eradicate CML cells expressing T315I-mutated BCR-ABL. Our previous study revealed that inhibiting CREB binding protein (CBP) is efficacious in activating β-catenin/p300 signaling, promoting cell differentiation and inducing p53/p21-dependent senescence regardless of BCR-ABL mutation status. We hypothesize that the specific inhibition of CBP may represent a novel strategy to promote β-catenin/p300-mediated differentiation and suppress cancer cell proliferation for treating CML patients. Methods: The anticancer efficacy of PBA2, a novel CBP inhibitor, in CML cells expressing wild-type or T315I-mutated BCR-ABL was investigated in vitro and in vivo. Cell differentiation was determined by the nitroblue tetrazolium (NBT) reduction assay. The extent of cellular senescence was assessed by senescence-associated β-galactosidase (SA-β-Gal) activity. Cytotoxicity was measured by MTS assay. RNA interference was performed to evaluate the cell proliferation effects of CBP knockdown. The interaction of β-catenin and CBP/p300 was examined by co-immunoprecipitation assay. Results: PBA2 exhibited significantly higher anticancer effects than imatinib in CML cells harboring either wild-type or T315I-mutated BCR-ABL both in vitro and in vivo. Mechanistically, PBA2 reduced CBP expression and promoted β-catenin-p300 interaction to induce cell differentiation and senescence. Conclusion: Our data supported the rational treatment of CML by inhibiting the β-catenin/CBP pathway regardless of BCR-ABL mutation status. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) typically occurs in late adulthood. Pediatric CML is a rare form of leukemia. In all age groups, the characteristic genetic driver of the disease is the BCR::ABL1 fusion gene. However, additional genomic events contribute to leukemic transformation, which is not yet well-characterized in pediatric CML. We investigated the mutational landscape of pediatric CML to determine whether predisposing germline variants may play a role in early-age disease development. Whole exome sequencing and targeted sequencing were performed in pediatric and adult CML samples to identify age-related germline and somatic variants in addition to the BCR::ABL1 translocation. Germline variants were detected in about 60% of pediatric patients with CML, with predominantly hematopoietic genes affected, most frequently ASXL1, NOTCH1, KDM6B, and TET2. The number of germline variants was significantly lower in adult patients with CML. If only confirmed pathogenic variants were regarded as cancer-predisposing variants, the occurrence was ~ 10% of pediatric CML, which is comparable to other hematological malignancies and most childhood cancer entities in general. We hypothesize that the interaction with the strong oncogene BCR::ABL1 may also favor the development of leukemia by weaker variants in the same genes. In pediatric patients, the germline variants of genes associated with clonal hematopoiesis may increase the likelihood that an incidental BCR::ABL1 translocation triggers the early manifestation of CML. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions In people with chronic‐phase chronic myeloid leukemia (CML) receiving imatinib and achieving major molecular response (MMR), dose reduction may decrease adverse events but may be associated with a loss of molecular response. Whether digital droplet polymerase chain reaction (ddPCR) can identify persons in whom dose reduction might be unsuccessful is unknown.Data from 716 consecutive subjects who achieved MMR after initial imatinib therapy (400 mg/day) were obtained. A total of 486 subjects remained on full‐dose imatinib, whereas 230 subjects had their dose reduced to 300 or 200 mg/day. The outcomes of these cohorts were compared via landmark and propensity score matching analyses.Imatinib dose reduction showed no significant effect on the subsequent achievement of deeper molecular responses (4‐ and 4.5‐log reductions in BCR::ABL1 transcripts; MR4 and MR4.5), maintenance of MMR, or attainment of therapy‐free remission when compared with subjects without dose reduction. In subjects achieving MR4, however, the probability of maintaining MR4 (p = .002) was lower in the reduced‐dose group. In multivariable analyses, failure to achieve MR4.5 as determined by ddPCR at the time of dose reduction was significantly associated with briefer MMR failure‐free survival (FFS; hazard ratio [HR], 10.3; 95% confidence interval [CI], 1.3–82.9; p = .03) and MR4 FFS (HR, 6.8; 95% CI, 2.6–18.0; p < .001).Imatinib dose reduction after achieving MMR does not adversely affect response deepening or MMR maintenance in chronic‐phase CML but compromises MR4 maintenance. The results of ddPCR may identify people who benefit from imatinib dose reduction. [ABSTRACT FROM AUTHOR]

Introduction: Up to 30% of CML patients will require a therapeutic change during follow-up due to intolerance and/or resistance to first-line tyrosine kinase inhibitor (TKI) approach. In this context, bosutinib (BOS) has not only demonstrated its efficacy, but also presents a favorable safety profile, without comorbid conditions representing an absolute contraindication to its use. Methods: To gain further into BOS treatment in real life, we conducted a retrospective analysis on the outcome of CML patients receiving BOS in 18 hematological centers, all belonging to the “REL” (Lombard Hematology Network). Results: Of 546 regularly followed CML cases, a total of 132 patients were reported as being treated with BOS, most frequently (62.9%) in second line. Interestingly, most patients (63.6%) switched to BOS due to intolerance to the previous TKI, while resistance to the last treatment was reported in the remaining 36.4% of patients. Despite a permanent discontinuation rate of 18.9%, over 80% of patients achieved at least a major molecular response and seven cases were able to attempt treatment-free remission. Conclusion: Although in this survey BOS represented the preferred option especially in patients intolerant rather than resistant to previous TKIs, we confirmed that BOS represents a safe and effective therapeutic option beyond the first line in the real-life setting. [ABSTRACT FROM AUTHOR]

Background: In the era of tyrosine kinase inhibitor (TKI) treatment, the progression of chronic myeloid leukemia (CML) remains a significant clinical challenge, and genetic biomarkers for the early identification of CML patients at risk for progression are limited. This study explored whether essential circular RNAs (circRNAs) can be used as biomarkers for diagnosing and monitoring CML disease progression and assessing CML prognosis. Methods: Peripheral blood (PB) samples were collected from 173 CML patients (138 patients with chronic phase CML [CML-CP] and 35 patients with accelerated phase/blast phase CML [CML-AP/BP]) and 63 healthy controls (HCs). High-throughput RNA sequencing (RNA-Seq) was used to screen dysregulated candidate circRNAs for a circRNA signature associated with CML disease progression. Quantitative real-time PCR (qRT-PCR) was used for preliminary verification and screening of candidate dysregulated genes, as well as subsequent exploration of clinical applications. Receiver operating characteristic (ROC) curve analysis, Spearman's rho correlation test, and the Kaplan-Meier method were used for statistical analysis. Results: The aberrant expression of hsa_circ_0006010 and hsa_circ_0002903 during CML progression could serve as valuable biomarkers for differentiating CML-AP/BP patients from CMP-CP patients or HCs. In addition, the expression levels of hsa_circ_0006010 and hsa_circ_0002903 were significantly associated with the clinical features of CML patients but were not directly related to the four scoring systems. Furthermore, survival analysis revealed that high hsa_circ_0006010 expression and low hsa_circ_0002903 expression indicated poor progression-free survival (PFS) in CML patients. Finally, PB hsa_circ_0006010 and hsa_circ_0002903 expression at diagnosis may also serve as disease progression surveillance markers for CML patients but were not correlated with PB BCR-ABL1/ABL1IS. Conclusions: Our study demonstrated that PB levels of hsa_circ_0006010 and hsa_circ_0002903 may serve as novel diagnostic, surveillance, and prognostic biomarkers for CML disease progression and may contribute to assisting in the diagnosis of CML patients at risk for progression and accurate management of advanced CML patients. [ABSTRACT FROM AUTHOR]

This document discusses the use of chromosomal genomic array testing (CGAT) in adults with newly-diagnosed acute lymphoblastic leukemia (ALL). The study found that CGAT can identify genetic abnormalities that can help determine prognosis and guide treatment decisions. Specifically, the study found that deletions in the IKZF1 gene, which is associated with a poorer prognosis in pediatric ALL, may not have the same negative prognostic significance in adults treated with chemotherapy. The study also identified other genetic abnormalities, such as deletions in the ETV6 and ZCCHC7 genes, which were associated with shorter overall survival. The document suggests that routine CGAT should be used in the initial workup of adults with ALL, but further research is needed to confirm these findings. [Extracted from the article]

BACKGROUND RESULTS CONCLUSION Nε‐carboxymethyllysine (CML), Nε‐carboxyethyllysine (CEL) and α‐aminoadipic acid (AAA) are important foodborne hazards and their intake can cause a variety of diseases in humans. It is extremely important to investigate the formation mechanism of CML, CEL and AAA, as well as their association with each other when aiming to control their production.A multi‐response kinetic model was developed within the glucose‐lysine Maillard reaction model system. The concentrations of glucose, lysine, glyoxal (GO), methylglyoxal (MGO), CML, CEL and AAA were quantified at different temperature (100–160 °C) and at different intervals (0–60 min). The experimental data were fitted to the proposed model to calculate kinetic parameters for the corresponding steps. The results indicated that the production of CML was primarily relied on the direct oxidative cleavage of the Amadori product, rather than the reaction between GO and Lys, whereas CEL and AAA were generated through the reaction of MGO with Lys. Significantly, the reaction between α‐dicarbonyl compounds and Lys preferentially generated CML and CEL, resulting in the lower concentrations of AAA compared to CML and CEL.The multi‐response kinetic model developed in the present study can be applied well to the Maillard reaction. The relationship between the formation mechanisms of CML, CEL and AAA is also explained. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN. [ABSTRACT FROM AUTHOR]

BACKGROUND Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs). METHODS In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels =0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum. RESULTS A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%). CONCLUSIONS: In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP‐CML patients.A retrospective analysis was conducted on 332 CP‐CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the “Campus CML” project.Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second‐generation TKIs (2G‐TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G‐TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra‐hematologic toxicity (9.5%), with no significant difference between IM and 2G‐TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G‐TKIs.IM was in our Centers the preferred frontline therapy for older CP‐CML patients, with increasing utilization after the introduction of generic formulations. However, 2G‐TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population. [ABSTRACT FROM AUTHOR]

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

Background: In Nigeria, since 2002, Imatinib mesylate (glivec®) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria. Method: This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002–2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1–1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant. Results: The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal (r = 0.733, p = 0.011) and EUTOS (r = 0.102, p = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively. Conclusion: This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria. [ABSTRACT FROM AUTHOR]

Summary: Chronic myeloid leukaemia (CML) management is complicated by treatment‐emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management. [ABSTRACT FROM AUTHOR]

Summary: Diagnosing chronic myeloid leukaemia (CML) during pregnancy is rare. Tyrosine kinase inhibitors (TKIs) have traditionally been contraindicated owing to their teratogenicity. Management decisions should consider the risks to mother and foetus of uncontrolled disease and teratogenic medications. Further cases are required to build upon the paucity of current literature. We report 22 cases of CML diagnosed during pregnancy from 2002 to date. Twenty‐one pregnancies resulted in healthy babies and one patient miscarried. Some patients remained untreated throughout pregnancy but the majority received one or both of interferon‐α and leucapheresis. One patient was started on imatinib at Week 26, and one on hydroxycarbamide in the third trimester. We report haematological parameters during pregnancy to provide clinicians with realistic expectations of management. There were no fetal abnormalities related to treatment during pregnancy. Seventeen patients achieved at least major molecular response on first‐line TKI. A diagnosis of CML during pregnancy can be managed without significant consequences for mother or child. Leucapheresis and interferon‐α are generally safe throughout pregnancy. Despite having been avoided previously, there is growing evidence that certain TKIs may be used in particular circumstances during the later stages of pregnancy. Future work should aim to further elucidate this safety profile. [ABSTRACT FROM AUTHOR]

Background and Objective: Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200-mg b.i.d. dosage in patients harboring T315I, using model-informed drug development. Methods: Data were collected from 199 patients in the phase I (NCT02081378; 10−200 mg b.i.d. or 10−400 mg q.d.) and 154 patients in the phase III (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure–response (efficacy/safety) analyses. Results: PopPK showed comparable exposure (area under the curve, AUC0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure–response analyses predicted similar major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens. Conclusions: Similarity between 40 mg b.i.d. and 80 mg q.d. regimens was investigated, demonstrating similar and substantial efficacy with well-tolerated safety in patients without T315I mutation. The 200-mg b.i.d. dose was deemed safe and effective for patients with T315I mutation. [ABSTRACT FROM AUTHOR]

Background: In the last two decades, tyrosine kinase inhibitors (TKIs) and advances in molecular diagnostics have revolutionized management and long-term clinical outcomes in chronic myeloid leukemia (CML). Real-world data from different countries allow for the identification of country-specific issues in the clinical management and development of specific plans for improvement. Here, we aimed to analyze the trend in overall survival in Bulgarian CML patients since 2000. Methods: We retrieved publicly available Bulgarian CML data from several sources such as the Bulgarian National Cancer Registry, Bulgarian National Statistical Institute, and National Health Insurance Fund since 2000. We used the retrieved data of a total of 1513 Bulgarian CML patients to describe the trends in overall survival (OS), conditional overall survival, life expectancy, and life years lost over five time periods. We also described the trends in healthcare expenditures for TKIs and CML patients' coverage with TKIs since 2014. Results: In both uni- and multivariate models, we found a constant increase in OS over the three 5-year periods until 2014. The period 2015–2019 was not associated with an additional increase in OS. Identical dynamics in the improvement in life expectancy (LE) and in life years lost (LYLs) was observed. Additionally, conditional 5-year survival did not improve during 2015–2019 in comparison to 2010–2014. Population-level data did not show consistent changes in the documented number of deaths due to CML since 2013. The period after 2013 is marked by a constant increase in the annual expenditures for TKIs, reaching to about 2.0 EUR/capita. The number of patients who received at least one TKI also increased during that period. Conclusions: After the initial significant improvement in the clinical outcomes for Bulgarian CML patients until 2014, subsequent periods did not bring further benefit in spite of the improved coverage with second- and third-line TKIs. Multiple factors may contribute to these suboptimal outcomes. Therefore, one can propose several additional measures at the country level, which could lead to additional improvement in the OS of Bulgarian CML patients. [ABSTRACT FROM AUTHOR]

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

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by bone marrow expansion and the proliferation of one or more myeloid cell lineages, predominantly driven by the expression of the constitutively active fusion product tyrosine kinase BCR:ABL1. Rarely, CML patients directly develop a blast crisis (BC), mostly of myeloid origin. CML at blast crisis with a T-cell phenotype at diagnosis, without any prior history of CML, is extremely rare. Herein, we describe one rare CML case, in a young man showing an unusual and early T-lymphoid blastic crisis at diagnosis, as the first onset of a previously unknown CML. The multidisciplinary collaboration between laboratorians and clinicians for the diagnosis and management of this atypical case was crucial in outlining both a targeted pharmacological treatment and a successful hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Olverembatinib (HQP1351) is a BCR‐ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug‐resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open‐label, 2‐part, fixed‐sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time‐concentration curve (AUC)0‐last, and AUC0‐inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers. [ABSTRACT FROM AUTHOR]

Imatinib is the tyrosine kinase inhibitor used as the gold standard for the treatment of Chronic Myeloid Leukemia. However, about 30% of patients do not respond well to this therapy. Variants in drug administration, distribution, metabolism and excretion (ADME) genes play an important role in drug resistance especially in admixed populations. We investigated 129 patients diagnosed with Chronic Myeloid Leukemia treated with imatinib as first choice therapy. The participants of the study are highly admixed, populations that exhibit genetic diversity and complexity due to the contributions of multiple ancestral groups. Thus, the aim of this work was to investigate the association of 30 SNVs in genes related to response to treatment with Imatinibe in CML. Our results indicated that for the rs2290573 of the ULK3 gene, patients with the recessive AA genotype are three times more likely to develop resistance over time (secondary resistance) (p = 0.019, OR = 3.19, IC 95%= 1.21–8.36). Finally, we performed interaction analysis between the investigated variants and found several associations between SNVs and secondary resistance. We concluded that the variant rs2290573 of the ULK3 gene may be relevant for predicting treatment response of CML with imatinib, as well as possible treatment resistance. The use of predictive biomarkers is an important tool for therapeutic choice of patients, improving their quality of life and treatment efficacy. [ABSTRACT FROM AUTHOR]

Background: To evaluate the outcomes of first‐line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML‐CP) in real‐world clinical practice. Methods: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. Results: Nilotinib‐treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib‐treated patients. However, there was no significant difference in 5‐year overall survival (OS) or progression‐free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib‐treated patients had a higher failure‐free survival (FFS) and event‐free survival (EFS) than imatinib‐treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). Conclusions: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort. [ABSTRACT FROM AUTHOR]

This paper studies a novel time‐varying coefficient integer‐valued time series model driven by observation. The model is suitable for modeling negative integer‐valued time series based on the Poisson difference distribution and extended binomial thinning operator. Main methods used to estimate the parameters are the conditional least squares (CLS) and conditional maximum likelihood (CML) methods. This paper also discusses the consistency and asymptotic normality of the estimation results. Likelihood ratio tests are employed to examine the existence of covariate and observation. Numerical simulations are conducted to verify the accuracy and stability of the model. Finally, a real data application is presented to demonstrate the usefulness and adaptability of this newly proposed model. [ABSTRACT FROM AUTHOR]

Overexpression of matrix metalloproteinase‐2 (MMP‐2) possesses a correlation with leukemia especially chronic myeloid leukemia (CML). However, no such MMP‐2 inhibitor has come out in the market to date for treating leukemia. In this study, synthesis, biological evaluation, and molecular modeling studies of a set of biphenylsulfonamide derivatives as promising MMP‐2 inhibitors were performed, focusing on their potential applications as antileukemic therapeutics. Compounds DH‐18 and DH‐19 exerted the most effective MMP‐2 inhibition (IC50 of 139.45 nM and 115.16 nM, respectively) with potent antileukemic efficacy against the CML cell line K562 (IC50 of 0.338 µM and 0.398 µM, respectively). The lead molecules DH‐18 and DH‐19 reduced the MMP‐2 expression by 21.3% and 17.8%, respectively with effective apoptotic induction (45.4% and 39.8%, respectively) in the K562 cell line. Moreover, both these compounds significantly arrested different phases of the cell cycle. Again, both these molecules depicted promising antiangiogenic efficacy in the ACHN cell line. Nevertheless, the molecular docking and molecular dynamics (MD) simulation studies revealed that DH‐18 formed strong bidentate chelation with the catalytic Zn2+ ion through the hydroxamate zinc binding group (ZBG). Apart from that, the MD simulation study also disclosed stable binding interactions of DH‐18 and MMP‐2 along with crucial interactions with active site amino acid residues namely His120, Glu121, His124, His130, Pro140, and Tyr142. In a nutshell, this study highlighted the importance of biphenylsulfonamide‐based novel and promising MMP‐2 inhibitors to open up a new avenue for potential therapy against CML. [ABSTRACT FROM AUTHOR]