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Therapeutic drug monitoring (TDM) of imatinib (IM) in cancer therapy offers the potential to improve treatment efficacy while minimizing toxicity. There was a significant correlation between unbound concentration and clinical response and toxicity, compared with total plasma concentrations, and the quantification of unbound IM and its metabolite, N-desmethyl imatinib (NDI) are of interest for TDM. However, traditional unbound drug separation methods have shortcomings, especially are susceptible to non-specific binding (NSB) of drugs to the polymer-constructed components of filter membranes, which are difficult to avoid at present. Hence it is necessary to developed a reliable separation method for the analysis of the unbound fraction of IM and NDI in TDM. We developed and validated an hollow fiber solid phase microextraction (HF-SPME) method coupled with high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) that to measure unbound IM and NDI concentration in human plasma. It used the NSB phenomenon and solve the NSB problem. The preparation procedure only involves a common vortex and ultrasonication without dilution of samples and modification of membrane. A total of 50 chronic myeloid leukemia (CML) patients were enrolled in our study. The relationship between the unbound and total concentrations for IM and NDI, as well as the concentration ratios of NDI to IM in 50 clinical plasma samples were investigated. The extraction recovery is high to 95.5-106 % with validation parameters for the methodological results were all excellent. There were both a poor linear relationship between the unbound and total concentrations for IM (r 2 =0.504) and NDI (r 2 =0.201) in 50 clinical plasma samples. The unbound concentration ratios of NDI to IM varied widely in CML patients. The determination of unbound IM and NDI concentration is meaningful and necessary. The developed HF-SPME method is simple, accurate and precise that could be used to measure unbound IM and NDI concentration in clinical TDM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic myeloid leukemia (CML) treatment with Bcr-Abl tyrosine kinase inhibitors (TKIs) has significantly improved patient outcomes, yet challenges such as drug resistance and persistence of leukemic stem cells persist. This study explores the potential of naringenin, a natural flavonoid, to enhance the efficacy of Bcr-Abl TKIs in CML therapy. We showed that naringenin reduces viability of a panel of CML cell lines regardless of varying cellular origin and genetic mutations, and acts synergistically with dasatinib and ponatinib. Importantly, naringenin is effective in targeting blast crisis CML CD34 + cells by decreasing their colony formation, self-renewal and viability. Compared to CML, naringenin is significantly less effective against normal bone marrow (NBM) counterparts. In addition, naringenin significantly enhances the inhibitory effects of dasatinib in CML but not NBM CD34 + cells. Mechanism studies showed that naringenin's inhibitory effects were associated with the induction of oxidative stress and lipid damage, as evidenced by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Notably, naringenin upregulated genes related to mitochondrial biogenesis while downregulating antioxidant defense genes. Pretreatment with α-tocopherol, which inhibits lipid-mediated ROS production, completely abolished the ROS increase and restored cell viability, indicating that lysosomal lipid peroxidation plays a crucial role in naringenin's mechanism of action. In a CML xenograft mouse model, the combination of naringenin and dasatinib resulted in remarkably more tumor growth suppression compared to single drug alone. Importantly, this combination was well-tolerated, with no adverse effects on body weight observed. These findings suggest that naringenin, by inducing oxidative lipid damage, enhances the anti-leukemic effects of Bcr-Abl TKIs, offering a promising therapeutic strategy for CML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic Myeloid Leukemia (CML) is a malignant hematologic tumor caused by BCR-ABL fusion protein that binds with ATP to exert tyrosinase activity and persistently activates downstream phosphorylation pathways. The tyrosine kinase inhibitors (TKIs) represented by Imatinib are the key clinical therapy to the CML. While the mutations on the target lead to the serious drug resistance problems, especially the T315I mutation remains an unresolved challenge, and the cardiotoxicity has limited the clinical application of the third generation TKI Ponatinib despite its favorable efficacy against the T315I mutation. Even though, structural optimization of Ponatinib remains a potential strategy to overcome the resistance imposed by the mutation. Herein, we present a series of novel BCR-ABL/T315I tyrosine kinase inhibitors obtained by virtual screening using ZINC21710815, a BCR-ABL/T315I inhibitor reported earlier by our team, as a lead compound, and structural optimization of lead compounds against the T315I mutation, as well as screening of two novel compounds by activity evaluation and mechanistic studies, W4 and W8. W4 and W8 have better cell death-inducing effects and special selectivity against BaF3/T315I, which are worthy of further in-depth study to obtain more desirable anti-CML drugs as lead compounds., Competing Interests: Declaration of competing interest This research was supported by the National Natural Science Foundation of China (81403145) and the Natural Science Foundation of Gansu Province (20JR10RA602). Major science and technology project of Gansu Provine (Grant No. 23ZDFA013-4), the Key Project of the Natural Science Foundation of Gansu Province, China (Grant No. 21JR7RA439)., (Copyright © 2024. Published by Elsevier B.V.)

Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing., (© 2024. The Author(s).)

Background: Chronic myeloid leukemia (CML) is driven primarily by the constitutively active BCR-ABL fusion oncoprotein. Although the development of tyrosine kinase inhibitors has markedly improved the prognosis of CML patients, it remains a significant challenge to overcome drug-resistant mutations, such as the T315I mutation of BCR-ABL, and achieve treatment-free remission in the clinic., Purpose: The identification of new intervention targets beyond BCR-ABL could provide new perspectives for future research and therapeutic intervention. A network pharmacology analysis was conducted to identify the most promising natural product with anti-CML activity. Celastrol was selected for further analysis to gain insights into its mechanism of action (MoA), with the aim of identifying potential new intervention targets for BCR-ABL T315I-mutant CML., Methods: Transcriptomic and proteomic analyses were conducted to systematically investigate the molecular MoA of celastrol in K562 T315I cells. To identify the target proteins of celastrol, mass spectrometry-coupled cellular thermal shift assay (MS-CETSA) was carried out, followed by validations with genetic knockdown and overexpression, cell proliferation assay, comet assay, Western blotting, celastrol probe-based in situ labeling and pull-down assay, molecular docking, and biolayer interferometry., Results: Our multi-omics analyses revealed that celastrol primarily induces DNA damage accumulation and the unfolded protein response in K562 T315I cells. Among the twelve most potential celastrol targets, experimental evidence demonstrated that the direct interaction of celastrol with YY1 and HMCES increases the levels of DNA damage, leading to cell death., Conclusion: This study represents the first investigation utilizing a proteome-wide label-free target deconvolution approach, MS-CETSA, to identify the protein targets of celastrol. This study also develops a new systems pharmacology strategy. The findings provide new insights into the multifaceted mechanisms of celastrol and, more importantly, highlight the potential of targeting proteins in DNA damage and repair pathways, particularly YY1 and HMCES, to combat drug-resistant CML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

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., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Disease Overview: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of two cases/100 000. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults., Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22) (q34;q11.2), involving a fusion of the Abelson murine leukemia (ABL1) gene from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein., Frontline Therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first-line treatment of newly diagnosed CML in the chronic phase (CML-CP). Clinical trials with second and third-generation TKIs in frontline CML-CP therapy reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of their potent efficacy and the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy. All four TKIs are equivalent if the aim of therapy is to improve survival. In younger patients with high-risk disease and in whom the aim of therapy is to induce a treatment-free remission status, second-generation TKIs may be favored., Salvage Therapy: For CML post-failure on frontline therapy, second-line options include second and third-generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities and financial status, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least two TKIs and for all patients in advanced-phase disease. Older patients who have a cytogenetic relapse post-failure on all TKIs can maintain long-term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, and others)., (© 2024 Wiley Periodicals LLC.)

Twenty adults with newly diagnosed (ND) or relapsed/refractory (RR) Ph-positive acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia in lymphoid blast phase (CML-LBP), were treated with mini-hyperCVD, ponatinib, and blinatumomab. Complete molecular response was achieved in 78% of ND patients, while CR/CRi was achieved in 100% of RR and CML-LBP. The 3-year overall survival rate was 76% (95% CI, 47%-90%)., (© 2024 Wiley Periodicals LLC.)

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., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Abstract: Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20% to 30% of people still experienced therapy failure. Data from 1955 consecutive patients with chronic-phase CML diagnosed by the European LeukemiaNet recommendations from 1 center receiving initial imatinib or a second-generation (2G) TKI therapy were interrogated to develop a clinical prediction model for TKI-therapy failure. This model was subsequently validated in 3454 patients from 76 other centers. Using the predictive clinical covariates associated with TKI-therapy failure, we developed a model that stratified patients into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (P < .001). There was good discrimination and calibration in the external validation data set, and the performance was consistent with that of the training data set. Our model had the better prediction discrimination than the Sokal and European Treatment and Outcome Study long-term survival scores, with the greater time-dependent area under the receiver-operator characteristic curve values and a better ability to redefine the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G TKI-therapy failure in people with chronic-phase CML., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: In the ongoing battle against BCR-ABL+ leukemia, despite significant advances with tyrosine kinase inhibitors (TKIs), the persistent challenges of drug resistance and the enduring presence of leukemic stem cells (LSCs) remain formidable barriers to achieving a cure., Methods: In this study, we demonstrated that Disulfiram (DSF) induces ferroptosis to synergize with TKIs in inhibiting BCR-ABL+ cells, particularly targeting resistant cells and LSCs, using cell models, mouse models, and primary cells from patients. We elucidated the mechanism by which DSF promotes GPX4 degradation to induce ferroptosis through immunofluorescence, co-immunoprecipitation (CO-IP), RNA sequencing, lipid peroxidation assays, and rescue experiments., Results: Here, we present compelling evidence elucidating the sensitivity of DSF, an USA FDA-approved drug for alcohol dependence, towards BCR-ABL+ cells. Our findings underscore DSF's ability to selectively induce a potent cytotoxic effect on BCR-ABL+ cell lines and effectively inhibit primary BCR-ABL+ leukemia cells. Crucially, the combined treatment of DSF with TKIs selectively eradicates TKI-insensitive stem cells and resistant cells. Of particular note is DSF's capacity to disrupt GPX4 stability, elevate the labile iron pool, and intensify lipid peroxidation, ultimately leading to ferroptotic cell death. Our investigation shows that BCR-ABL expression induces alterations in cellular iron metabolism and increases GPX4 expression. Additionally, we demonstrate the indispensability of GPX4 for LSC development and the initiation/maintenance of BCR-ABL+ leukemia. Mechanical analysis further elucidates DSF's capacity to overcome resistance by reducing GPX4 levels through the disruption of its binding with HSPA8, thereby promoting STUB1-mediated GPX4 ubiquitination and subsequent proteasomal degradation. Furthermore, the combined treatment of DSF with TKIs effectively targets both BCR-ABL+ blast cells and drug-insensitive LSCs, conferring a significant survival advantage in mouse models., Conclusion: In summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment., (© 2024. The Author(s).)

Abstract: Deep molecular response (DMR) is a prerequite for treatment-free remission (TFR) in chronic myeloid leukemia in chronic phase (CML-CP). The JALSG (Japan Adult Leukemia Study Group) conducted a prospective randomized phase 3 CML212 study for de novo CML-CP to compare the cumulative achievement of molecular response 4.5 (MR4.5; international scale BCR::ABL1 ≤0.0032%) by 18 months between nilotinib and dasatinib treatment as a primary end point. A total of 454 patients were randomly assigned to the 300 mg nilotinib twice daily arm or to the 100 mg dasatinib daily arm (both n = 227). BCR::ABL1 messenger RNA levels were monitored every 3 months. Study treatment was stopped if the patients were judged as failure according to the European LekemiaNet 2009 criteria or showed intolerance. The cumulative achievement rates of MR4.5 by 18 months were 32.6% (95% confidence interval [CI], 26.5-39.1) in the nilotinib arm and 30.8% (95% CI, 24.9-37.3) in the dasatinib arm with no significant difference (P = .66). The cumulative achievement rates of early molecular response, complete cytogenetic response, and major molecular response by 12, 18, 24, and 36 months were almost the same between the 2 arms. There was no significant difference in progression-free survival (PFS) or overall survival (OS) between the 2 arms by log-rank tests (PFS, P = .58; OS, P = .64). These results suggest that nilotinib and dasatinib would be equally effective for patients with de novo CML-CP. This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry as #UMIN000007909., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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 (C 33 H 61 NO 5 S) 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.

The permeability glycoprotein, encoded by the ABCB1 gene, is widely implicated in multidrug resistance (MDR), as it has been shown to reduce the intracellular concentration of most small molecule therapeutics, including the majority of the breakpoint cluster region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used in the treatment of Philadelphia chromosome positive (Ph+) leukemias. With this in mind, we describe an integrated theoretical and experimental approach to shed light on substituent effects in the pendant anilino moiety of 4-anilinoquinazolines and 4-anilinoquinoline-3-carbonitrile-based kinase inhibitors and their influence on P-gp-mediated efflux. This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor 16a that exhibits a marked reduction in P-gp-mediated efflux ratio and potent activity in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived cell line (K562/Dox) overexpressing P-gp. Overall, we demonstrate that the P-gp-mediated efflux ratio can be minimized by computationally driven optimization of the molecular dipole and/or cp K a without recourse to intramolecular hydrogen bonds.

Platelets are essential blood components that maintain hemostasis, prevent excessive bleeding, and facilitate wound healing. Reduced platelet counts are implicated in various diseases, including leukemia, hepatitis, cancer, and Alzheimer's disease. Enhancing megakaryocytic differentiation is a promising strategy to increase platelet production. Compound K (CK), a major bioactive metabolite of ginsenosides from Panax ginseng , has demonstrated anti-cancer and neuroprotective properties. In this study, we investigated the effects of CK on megakaryocytic differentiation and apoptosis in chronic myeloid leukemia (CML) cell lines K562 and Meg-01. CK treatment significantly upregulated the mRNA expression of key megakaryocytic differentiation markers, including CD61, CD41, and CD42a, and promoted the formation of large, multinucleated cells in K562 cells. Additionally, flow cytometry analysis revealed that CK at 5 µM induced apoptosis, a critical process in thrombocytopoiesis, in both K562 and Meg-01 cells. RT 2 Profiler PCR array analysis further identified a marked increase in the expression of genes associated with the activation of the NLRP3 inflammasome in CK-treated K562 and Meg-01 cells. This study is the first to demonstrate that CK promotes megakaryocytic differentiation and apoptosis through the activation of the ERK/EGR1 and NLRP3 inflammasome pathways. These findings suggest that CK may enhance platelet production, indicating its potential as a therapeutic candidate for platelet-related disorders and other associated diseases.

Solitary fibrous tumours (SFTs) and chronic myeloid leukaemia (CML) are both uncommon neoplasms with distinct chromosomal aberrations and clinical presentations. Here, we present a case of a male in his late 50s with a history of intracranial SFT who presented 8 years after subtotal resection and adjuvant radiotherapy with splenic infarcts, a white blood cell of 83 000 cells/mL, and liver masses. He was treated with dasatinib for CML and temozolomide/bevacizumab for SFT. This case emphasises the benefits of broad differential diagnoses that include multiple concurrent disease processes when confronted with unusual presentations. It highlights the need for interdisciplinary efforts and personalised approaches when managing patients with multiple primary malignancies., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the early predictive value of halving time (HT) of BCR-ABL IS for deep molecular response (DMR) in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitor (TKI)., Methods: The continuous data of newly diagnosed CML patients with complete case data and first-line imatinib treatment admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2014 to June 2022 were retrospectively analyzed. Combined with the clinical characteristics of the patients and the efficacy analysis at each time point, a logistic regression model was used to explore the independent influencing factors of DMR, and combined HT of BCR-ABL IS with BCR-ABL IS level at 3 months to predict DMR of the patients., Results: Univariate and multivariate analyses showed that HT and 3-month BCR-ABL IS levels were independent influencing factors for MR4, MR4.5, and stable MR4.5 ( P < 0.05). ROC curve analysis determined that the best cut-off value of HT was 28 days. Compared with patients with HT>28 d, patients with HT≤28 d were more likely to obtain DMR at 2, 3, and 5 years, respectively (74.2% vs 27.3%, 71.2% vs 22.7%, and 63.6% vs 25.0%, all P < 0.001). The patients were divided into 4 groups according to BCR-ABL IS levels at 3 months and HT. Kaplan-Meier analysis showed that the patients in the BCR-ABL IS ≤10% and HT≤28 d group had a higher probability of obtaining cumulative MR4 and MR4.5 than those in the BCR-ABL IS ≤10% and HT>28 d group ( P < ＜0.05); Patients in the BCR-ABL IS >10% and HT≤28 d group had a higher probability of obtaining cumulative MR4 and MR4.5 than those in the BCR-ABL IS ＞10% and HT>28 d group ( P < 0.05)., Conclusion: In addition to BCR-ABL IS level, HT of BCR-ABL IS can be used as another important predictor of treatment efficacy in CML patients. The combination of BCR-ABL IS level and HT has a more accurate predictive value for long-term molecular response of CML patients after TKI treatment.

Objective: To evaluate the efficacy of serum myeloperoxidase and lactate dehydrogenase levels as tumour markers in chronic myeloid leukaemia patients after one-year treatment with tyrosine kinase inhibitors., Methods: The case-control study was conducted at the College of Medicine, Mustansiriyah University, Baghdad, Iraq, in collaboration with the National Centre of Haematology, Baghdad, from December 2019 to April 2020. The cases comprised chronic myeloid leukaemia patients aged ≥18 years who had completed one-year treatment with tyrosine kinase inhibitor. They were divided into two groups on the basis of major molecular response. Group 1 patients had major molecular response >0.1%, while group 2 patients had major molecular response <0.1%. Group 3 had healthy controls matched for age and gender. Serum myeloperoxidase and lactate dehydrogenase concentrations were measured using enzyme-linked immunosorbent assay. Data was analysed using SPSS 25., Results: Of the 88 subjects, 32(36.4%) were in group A with mean age 44.9±12.6 years, 26(29.5%) were in group B with mean age 48.23±10.6 years, and 30(34%) were in group C with mean age 43.1±9.3 years. There was a significant increase in myeloperoxidase and lactate dehydrogenase levels in patient groups compared group 3 controls (p<0.05). Between the patient groups 1 and 2, the difference was significant for myeloperoxidase (p<0.05), but not for lactate dehydrogenase (p>0.05)., Conclusions: There was higher oxidative stress in chronic myeloid leukaemia patients.

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., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

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., (© 2024 American Cancer Society.)

On October 29, 2021, FDA granted accelerated approval to asciminib (SCEMBLIX; Novartis), a tyrosine kinase inhibitor (TKI), for the treatment of adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more TKIs, and granted traditional approval to asciminib for adult patients with Ph+ CML in CP with the T315I mutation. The first indication was approved based on major molecular response (MMR) at 24 weeks in the ASCEMBL study, a randomized trial comparing asciminib with bosutinib in patients who had failed two or more TKIs. This indication was ultimately granted traditional approval on October 12, 2022, based on safety data and MMR rate at 96 weeks of 38% [95% confidence interval (CI), 30-46] in the asciminib arm versus 16% (95% CI, 8-26) in the bosutinib arm (P value: 0.001). The second indication was approved based on MMR rate by 96 weeks of 49% (95% CI, 34-64) in the single-arm CABL001X2101 study. The most common (≥20%) adverse reactions included upper respiratory tract infections, musculoskeletal pain, headache, fatigue, nausea, rash, and diarrhea. The most common (≥20%) laboratory abnormalities were thrombocytopenia, neutropenia, anemia, lymphopenia, hypertriglyceridemia, hyperuricemia, and increases in creatine kinase, alanine aminotransferase, aspartate aminotransferase, lipase, and amylase. This manuscript describes the basis for approval of these indications., (©2024 American Association for Cancer Research.)

Objective: A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells., Methods: HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer., Results: This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model., Conclusions: This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Competing Interests: Competing interests No potential conflict of interest was reported by the authors.

Background: While Chronic Myeloid Leukemia (CML) is a disease of older adults, there is a growing population of adolescent and young adults (AYAs) with CML. This study evaluated the clinical characteristics and outcomes of CML in AYAs., Patients and Methods: Data from medical records of adults with chronic phase CML diagnosed and treated at our center from 2011until 2021were retrospectively analyzed. Age between 18 and 29 years was used to define AYAs. Response to tyrosine kinase inhibitors (TKIs), progression to accelerated phase (AP) or blast crisis (BC), event-free survival (EFS) and overall survival (OS) were compared between AYAs and older adults., Results: Among 163 patients included, 41 (25.1%) were AYAs. AYAs were more likely to be males (P = .02), to present with symptoms (P = .004), had a higher median white blood cell count (P = .007), neutrophil count (P = .029), eosinophil count (P = 0.01), low-risk Sokal (P = .033) and Hasford (P = .005) groups. TKI-sensitivity as well as median times for achievement of complete cytogenetic and major molecular response were comparable between both groups. After a median follow-up of 76 (range: 11-235) months, there was no difference in OS (P = .528), or cumulative incidence of transformation to accelerated phase or blast crisis (P = .11). On the other hand, AYA had an inferior EFS (P = .034)., Conclusion: A quarter of the patients diagnosed with CML in our population were AYAs. Despite being characterized as "lower-risk," they presented with a greater disease burden, had a shorter EFS but comparable OS. Further studies are needed to better understand the disease biology of this group., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We evaluated the possibility of treatment-free remission (TFR) and durability of deep molecular response (DMR) with asciminib treatment by monitoring major BCR::ABL mRNA on the International Scale (BCR::ABL-IS) in 4 patients who needed to reduce or discontinue asciminib due to adverse event concerns, intolerance, or personal circumstances. IS increased in all 4 patients after discontinuation of asciminib, but 3 patients who resumed asciminib achieved DMR again. None of the patients achieved TFR with asciminib, but DMR could be achieved again by restarting asciminib after TFR failure. As this was a retrospective study in a small number of patients, no conclusions can be drawn regarding the possibility of TFR with asciminib. However, this study included patients with short treatment duration and DMR maintenance periods, so strict conditioning may be necessary. Safe dose reduction or TFR with asciminib may need to be considered in more cases., (© 2024. Japanese Society of Hematology.)

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., (© 2024. The Author(s).)

This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome-positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9-78.9) and 59.7% (95% CI, 51.4-67.7) attained or maintained major molecular response (MMR) and molecular response (MR) 4 , respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR 4 at 36 months were 87.2% (78.0-92.7) and 80.7% (69.4-88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8-92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML.ClinicalTrials.gov, NCT02228382., (© 2024. The Author(s).)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Conflict of Interest None declared., (Copyright © 2024 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Natural products (NP) have been an alternative therapy for several diseases for centuries, and they also serve as an essential source of bioactive molecules, enhancing our drug discovery capacity. Among these NP, some phytochemicals have shown multiple biological effects, including anticancer activity, with higher effectiveness and less toxicity than actual treatments, suggesting their possible use on resilient human malignancies such as leukemia. Imatinib mesylate (Im) is a selective tyrosine kinase inhibitor widely used as an anticancer drug, the gold standard to attend chronic myeloid leukemia (CML). Nevertheless, resistance to this drug in patients with CML renders it insufficient to eliminate cells with Philadelphia chromosome (BCR/ABL + ). Moreover, recent studies show that imatinib can induce genotoxic and chromosomic damage in some in vitro and in vivo models. These facts urge finding new therapeutic alternatives to increase the effectiveness of antileukemic treatment. Recent research has shown that the combined effects of phytochemicals with imatinib can improve the cytotoxicity or resensitized the resistant cells to this drug in diverse leukemia cell lines. Independent mechanisms of action among phytochemicals and imatinib include BCR/ABL regulation, downregulation of transcription factors, inhibition of anti-apoptotic and activation of pro-apoptotic proteins, apoptosis induction dependent- and independent of ROS-overproduction, membrane functions disruption, induction of cell cycle arrest, and cell death. This review summarizes and discusses the synergic effect of some phytochemicals combined with imatinib on leukemia cells and the mechanism of action proposed for these combinations, looking to contribute to developing new effective alternatives for leukemia treatment., Competing Interests: Declaration of competing interest The authors declare not competing interest exists in the writing and submission of this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Acute promyelocytic leukemia (APL) is the sub-type of Acute myeloid leukemia (AML) which is described by differentiation block at promyelocytic stage and t(15; 17) translocation with All trans retinoic acid (ATRA) and arsenic trioxide (ATO) as standard treatments. Chronic myeloid leukemia (CML) translocation t (19; 22) causes a rise in granulocytes and their immature precursors in the blood. Different mutations cause resistance to first-line tyrosine kinase therapies in CML. Beside drug resistance, leukemia stem cells (LSC) are critical resources for relapse and resistance in APL and CML. The drug toxicity and resistant profile associated with LSC and current therapeutics of APL and CML necessitate the development of new therapies. Imidazoles are heterocyclic nitrogen compounds with diverse cellular actions. The purpose of this research was to assess the anti-leukemic properties of four novel imidazole derivatives including L-4, L-7, R-35, and R-NIM04., Methods and Results: Pharmacological and biochemical approaches were used which showed that all four imidazole derivatives interfere with the NB4 cells proliferation, an APL cell line, while only L-7 exhibit anti-proliferative activity against K562 cells, a CML cell line. The anti-proliferative effect of imidazole derivatives was linked to apoptosis induction. Further real-time polymerase chain reaction (RT-PCR) analysis revealed downregulation of AXL-Receptor Tyrosine Kinase (AXL-RTK) and target genes of Wnt/beta-catenin pathway like c-Myc, Axin2 and EYA3. An additive effect was observed after combinatorial treatment of L-7 with standard drugs ATRA or Imatinib on the proliferation of NB4 and K562 cells respectively which was related to further downregulation of target genes of Wnt/beta catenin pathway., Conclusion: Imidazole derivatives significantly reduce proliferation of NB4 and K562 cells by inducing apoptosis, down regulating of AXL-RTK and Wnt/β-catenin target genes., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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.

Background: Double-hit lymphoma (DHL) with c-MYC gene translocation is highly aggressive and has a poor prognosis. In DHL cells, activation-induced cytidine deaminase (AID) promotes antibody class switch recombination (CSR), ultimately leading to c-MYC gene translocation caused by Myc/IgH DNA double-strand breaks. However, currently there is still no method to suppress the expression of AID., Methods: In this study, we compared the clinical significance of AID expression in DHL, Additionally, two human double-hit lymphoma cell lines were used to analyze the effect of imatinib mesylate on c-MYC in vitro, and the therapeutic effect was also evaluated in xenograft mouse models., Results: Imatinib mesylate downregulated the AID and c-MYC proteins in patients with chronic myelogenous leukemia associated with DHL. In addition, imatinib mesylate reduced AID and c-MYC expression in SU-DHL-4 and OCI-Ly18 DHL cells. Imatinib mesylate exerted significant inhibitory effects on the proliferation and metastasis of SU-DHL-4 and OCI-Ly18 cells. Finally, imatinib mesylate reduced not only tumor burden in DHL mouse models, but also AID and c-MYC expression in vivo., Conclusion: These findings reveal that imatinib mesylate effectively reduces the carcinogenic function of c-MYC in DHL, providing novel strategies for developing therapies targeting c-MYC-driven DHL., (© 2024. The Author(s).)

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. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226)., (Copyright © 2024 Massachusetts Medical Society.)

Unintended pregnancy for female patients with chronic myeloid leukemia (CML) raises the discussion of treatment choices due to the teratogenicity of tyrosine kinase inhibitor (TKI). We report 51 accidental pregnant CML chronic phase (CP) patients with TKI withdrawal immediately after pregnancy from December 2010 to February 2024 to observe the effect of short exposure to TKI on the fetus and the infant outcomes. 59 pregnancies resulted in 100% normal childbirth without birth abnormalities. The median TKI exposure duration was 4 (4-20) weeks in 58 pregnancies, and one pregnancy avoided TKI exposure due to treatment discontinuation of the patient with treatment-free remission (TFR). All newborns had normal birth weight except one premature infant with low birth weight less than the 10th percentile. Up to now, all the children are in good health. 13 (25.5%) and 30 (58.8%) patients had achieved major molecular response (MMR) and deep molecular response (DMR) at pregnancy, respectively. After TKI discontinuation, loss of MMR and complete hematologic response occurred in 6 (46.2%) and 2 (25.0%) patients at delivery, respectively. 38 patients resumed TKI treatment after delivery, and 13 patients without DMR loss sustained TFR after delivery. The median time to regain MMR and DMR were 3 (2-6) months and 6 (1-28) months, respectively. These results demonstrate that TKI discontinuation during pregnancy is feasible for CML-CP patients, and short TKI exposure of pregnant patients has little influence on children's growth and development., (© 2024. The Author(s).)

BCR-ABL1 compound mutations can lead to resistance to ABL1 inhibitors in chronic myeloid leukemia (CML), which could be targeted by combining the ATP-site inhibitor ponatinib and the allosteric inhibitor asciminib. Here, we report the clinical validation of this approach in a CML patient, providing a basis for combination therapy to overcome such resistance., Competing Interests: Declaration of interests B.J.D. serves on scientific advisory boards for Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, Novartis, Gilead Sciences (inactive), and Monojul (inactive); serves on scientific advisory boards and receives stock from Aptose Biosciences, Blueprint Medicines, EnLiven Therapeutics, Iterion Therapeutics, Third Coast Therapeutics, and GRAIL (inactive on scientific advisory board); is scientific founder of MolecularMD (inactive, acquired by ICON); serves on the board of directors and receives stock from Amgen and Vincera Pharma; serves on the board of directors for Burroughs Wellcome Fund and CureOne; serves on the joint steering committee for Beat AML LLS; is founder of VB Therapeutics; has a sponsored research agreement with EnLiven Therapeutics; receives clinical trial funding from Novartis, Bristol-Myers Squibb, and Pfizer., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Four afatinib derivatives were designed and modeled. These derivatives were compared to the known tyrosine-kinase inhibitors in treating Chronic Myeloid Leukemia, i.e., imatinib and ponatinib. The molecules were evaluated through computational methods, including docking studies, the non-covalent interaction index, Electron Localization and Fukui Functions, in silico ADMET analysis, QTAIM, and Heat Map analysis. The AFA(IV) candidate significantly increases the score value compared to afatinib. Furthermore, AFA(IV) was shown to be relatively similar to the ponatinib profile when evaluating a range of molecular descriptors. The addition of a methylpiperazine ring seems to be well distributed in the structure of afatinib when targeting the BCR-ABL enzyme, providing an important hydrogen bond interaction with the Asp381 residue of the DFG-switch of BCR-ABL active site residue and the AFA(IV) new chemical entities. Finally, in silico toxicity predictions show a favorable index, with some molecules presenting the loss of the irritant properties associated with afatinib in theoretical predictions.

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., (© 2024. The Author(s).)

Tyrosine kinase inhibitors (TKI) have improved the outcome and life expectancy of patients with chronic myeloid leukemia (CML). Patients are diagnosed with CML at younger ages, and patients treated for CML may become pregnant or choose to breastfeed. The information available to date on the safety of TKIs during pregnancy and lactation and the optimal management of these patients is largely anecdotal, based on personal or small-group experience, and heterogeneous. A panel of interested parties was convened by U.S. Food and Drug Administration to analyze the current data and discuss possible solutions. Possible solutions include prospective data collection, in clinical trials and in routine clinical practice, a more uniform and specific data collection, and greater coordination among involved entities. As patients with cancer are living longer, frequently receiving therapies for extended periods of time (or for life), data on appropriate management of patients through different reproductive phases of life are needed. It is thus time to change our approach for how to study treatment of cancer (including CML) during pregnancy or breastfeeding to develop evidence-based guidelines for safe and effective patient care., (©2024 American Association for Cancer Research.)

Cytarabine (Ara-C) is a commonly used chemotherapeutic drug for the treatment of leukemia, known for its significant tolerability. The down regulation of miR-203 in leukemia cells suggests its potential involvement in the pathogenesis of leukemia. In this study, we investigated the effects and possible mechanisms of miR-203 and Ara-C on proliferation and apoptosis of human leukemia K562 cells which were cultured with Ara-C and/or with transfection of miR-203 expression vectors. Our results showed that the combination of Ara-C and miR-203 synergistically inhibited the proliferation of K562 cells and the sensitivity of leukemia cells to Ara-C was increased by 2.5-fold with trasfection of miR-203. The proportion of apoptotic cells in the Ara-C and miR-203 combination group was higher than Ara-C or control plasmid group. Caspase-3 and caspase-9 activities were increased in Ara-C and miR-203 combination group. miR-203 down regulated the protein level of Bcr/abl in K562 cells compared with plasmid control. In conclusion, Ara-C in combination with miR-203 has a synergistic effect of proliferation inhibition and apoptosis induction in chronic myelogenous leukemia K562 cells, which may be associated with miR-203 down regulating Bcr/abl, thereby inhibiting cell proliferation and promoting cell apoptosis.

Lombardy represents the largest region of Italy by population, with almost 10 million residents, a dimension similar to a medium size country like Sweden or Belgium. The CML subcommittee of the Lombardy Hematology Network (REL-CML) conducted a study at the beginning of 2023. Prevalence was calculated by direct input from the 21 centers participating in REL-CML. Tyrosine Kinase Inhibitors (TKI) prescription records collected from the ARIA regional registry were used to estimate the number of CML patients followed in smaller centers not participating in REL-CML. A total of 2285 patients were registered, representing a prevalence of 0.23 ‰. These data were compared to a similar census conducted in 2005, at the beginning of the TKI era, where a prevalence of 0.029‰ was calculated. This indicates that an almost 10 times increase took place during this period of time. Imatinib represents the most frequently prescribed first-line TKI; its use in 2022 still represented 75% of total first line prescriptions. An increased concentration of the care of CML patients in specialized REL centers with a decreased dispersion of patients in small centers was also evident over this 18 year period of time. Nineteen % of patients discontinued treatment, highlighting persisting logistical and biological challenges; one some recommendations on CML management are included to this aim., (© 2024 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.)

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., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The therapeutic armamentarium of chronic myeloid leukemia (CML) has dramatically improved after small molecule tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 became available, with a life expectancy now close to that of the general population. Although highly effective, these drugs also have a toxicity profile that is often mild to moderate, but sometimes severe. Indeed, long-term treatment with TKIs can lead to chronic adverse events that can negatively affect patients' quality of life and can promote significant morbidity and mortality, particularly in the case of second- or third-generation TKIs. Treatment discontinuation has therefore become an emerging goal for CML patients and numerous studies have evaluated in off-TKI subjects what requirements are appropriate for an attempt at treatment-free remission (TFR). TFR eligibility is currently limited to a small population of subjects with both deep and sustained molecular responses to TKIs. For those attempting TFR, average success rates are promising, with 25%-30% of patients experiencing prolonged TFR. In case of failure to maintain sustained TFR, safety results to date are reassuring, with almost all patients responding successfully to resumption of TKIs, and advanced-phase disease progression representing a very rare event. The purpose of this review is to discuss guidelines for TKI discontinuation, clinical advances from clinical trials and real-life experiences, and describe areas of research, particularly regarding the biological factors capable of predicting the success of TFR., (© 2024 John Wiley & Sons Ltd.)

Background: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the BCR::ABL1 fusion gene arising from the Philadelphia chromosome (Ph) translocation t(9:22)(q34;q11), exhibits diverse clinical courses often influenced by additional chromosomal aberrations (ACAs). This report presents a case of CML har-boring a novel four-way Ph translocation involving the X chromosome, offering insights into the interplay between complex karyotypes and treatment response and emphasizing the need for further research into the role of ACAs in CML management., Methods: A 42-year-old man diagnosed with CML in the accelerated phase presented a novel four-way Ph translocation involving chromosomes X, 5, 9, and 22: 46,Y,t(X;5;9;22)(q26;q15;q34;q11.2). Despite achieving a major molecular response initially with imatinib and nilotinib, BCR::ABL1 levels (international scale) increased up to 24.0%, which prompted the use of second-line nilotinib., Results: Follow-up bone marrow (BM) studies revealed clonal evolution with trisomy 8 and an unclassified ABL1 mutation (E292V), potentially contributing to resistance. Though a transient major molecular response (MMR) occurred after a switch to third-line dasatinib, this change failed to achieve a deep molecular response, and BCR-ABL1 levels were elevated above the MMR., Conclusions: This case highlights the challenge of ACAs impacting CML treatment response and prognosis. Limited knowledge exists on complex Ph translocations involving the X chromosome, but this report contributes data for further research. Understanding ACA effects on therapeutic response and prognosis requires a detailed study of such complex chromosomal aberrations.