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We report the first case of imatinib use in an adolescent with diabetes and suggest that it impacts the natural course of disease. A 14-year-old male patient presented in diabetic ketoacidosis (DKA) and was diagnosed with presumed autoantibody-negative type 1 diabetes (T1D) as well as myeloid neoplasm with platelet-derived growth factor receptor beta (PDGFRB) rearrangement. After starting exogenous insulin and imatinib, he experienced a 1.7-point reduction in glycated hemoglobin (HbA1c) and a 71% reduction in insulin requirement with sustained partial diabetes remission. Our case suggests imatinib as a potential therapeutic agent for pediatric T1D.

BACKGROUND: Mesenchymal neoplasms of the uterus encompass a diverse group of tumors, with varying characteristics and origins, collectively accounting for 8% of uterine malignancies. The most common variants include uterine leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, adenosarcoma, and undifferentiated sarcoma. Clinical presentation is often nonspecific and can lead to delayed diagnosis. Uterine sarcomas are generally aggressive, resulting in poorer prognosis compared to carcinomas. Recent advances in molecular techniques, such as next-generation sequencing (NGS), have led to the identification of new subtypes of uterine sarcomas, including COL1A1::PDGFB fusion-associated fibrosarcoma, which has a specific chromosomal translocation t(17;22)(q22;q13). Imatinib, a tyrosine kinase inhibitor (TKI), is an effective treatment for dermatofibrosarcoma protuberans (DFSP), marked by this translocation. CASE: We present the case of a 42-year-old woman diagnosed with COL1A1::PDGFB fusion-associated uterine fibrosarcoma. The patient underwent total hysterectomy and excision of the tumor, initially misdiagnosed as a low-grade leiomyosarcoma. Subsequent histological examination, immunohistochemistry, and fluorescence in situ hybridization (FISH) confirmed the diagnosis. After 10 months, disease recurrence was detected, and Imatinib therapy was initiated at a dose of 400 mg daily. An allergic reaction led to a temporary discontinuation, but upon resumption with appropriate medication, a positive radiological response was observed. The patient achieved a complete remission after 2 years and is still on Imatinib treatment. CONCLUSIONS: COL1A1::PDGFB fusion-associated uterine fibrosarcoma is an extremely rare mesenchymal neoplasm. In a case we present herein, we treated a patient with imatinib as first-line medical therapy. The patient is currently in complete remission after 37 months from treatment start. To the best of our knowledge, this represents a unique observation. We also provide a detailed literature review of the published cases so far. Prospective case series are needed to further understand the natural history of these tumors and optimize treatment strategies.

Background: Chronic Myeloid Leukemia (CML), accounting for 15–20% of adult leukemia cases, is marked by the Philadelphia chromosome, resulting from the t(9;22)(q34;q11) translocation. This leads to uncontrolled cell proliferation and survival. Imatinib therapy lowers BCR-ABL levels, influencing telomere-associated proteins and increasing telomerase accessibility, indirectly boosting its activity. This study investigates the effects of MST-312 and imatinib, both individually and combined, on a CML cell line. Methods: The K562 cells were subjected to different doses of MST-312 and imatinib, including four combination concentrations. Cell viability and metabolic activity were measured using trypan blue and MTT assays at 24-, 36-, and 48-h post-treatment. Flow cytometry (AnnexinV/PI) assessed cell apoptosis after 36 h of treatment with MST-312 and imatinib, both individually and in combination. The expression levels of Bax, Bcl-2, hTERT, P21, P53, and c-Myc were determined via qRT-PCR. Results: Both MST-312 and imatinib independently reduced cell viability in a dose- and time-dependent manner. Their combination further decreased cell viability compared to monotherapy. Treatment of K562 cells with MST-312 and imatinib for 36 h increased Bax expression and the Bax/Bcl-2 ratio while decreasing Bcl-2 expression. Combined treatment significantly reduced hTERT ansd P21 gene expression compared to imatinib alone. Conclusions: The combination of MST-312 and imatinib shows potential as a CML therapy. However, further research and clinical trials are necessary to validate these findings and determine their clinical relevance. [ABSTRACT FROM AUTHOR]

We propose a novel framework that addresses the deficiencies of Randomized clinical trial data subgroup analysis while it transforms ObservAtional Data to be used as if they were randomized, thus paving the road for precision medicine. Our approach counters the effects of unobserved confounding in observational data through a two-step process that adjusts predicted outcomes under treatment. These adjusted predictions train decision trees, optimizing treatment assignments for patient subgroups based on their characteristics, enabling intuitive treatment recommendations. Implementing this framework on gastrointestinal stromal tumors (GIST) data, including genetic sub-cohorts, showed that our tree recommendations outperformed current guidelines in an external cohort. Furthermore, we extended the application of this framework to RCT data from patients with extremity sarcomas. Despite initial trial indications of universal treatment necessity, our framework identified a subset of patients who may not require treatment. Once again, we successfully validated our recommendations in an external cohort. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by excessive proliferation of myeloid cells. The COVID-19 pandemic has raised concerns regarding the impact of SARS-CoV-2 on patients with malignancies, particularly those with CML. This study aimed to investigate the effects of SARS-CoV-2 proteins on CML cell viability and the protective role of vitamin K2 (VK2) in conjunction with imatinib. Experiments conducted on K562 CML cells demonstrated that the SARS-CoV-2 envelope protein induces cytotoxicity and activates caspase 3/7, which are key markers of apoptosis. VK2 mitigated these cytotoxic effects and decreased cytokine production while inhibiting colony formation. Furthermore, the combination of VK2 with imatinib significantly reduced cellular proliferation, diminished mitochondrial membrane potential, and markedly suppressed colony formation. These findings suggest that VK2 protects CML cells from SARS-CoV-2-induced cytotoxicity and enhances the therapeutic efficacy of imatinib, presenting a potential strategy to improve CML treatment during the COVID-19 pandemic. [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]

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study, we synthesized and tested radically altered IMT isomers (IMTi's) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory factors released during severe coronavirus disease-19 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are known to influence drug exposure, but data on the effect of mild infection are few. Here we describe for the first time an increase in plasma imatinib and norimatinib concentrations observed in a series of 5 patients treated with imatinib for gastrointestinal stromal tumor (GIST) after mild COVID-19. Methods: The patients were undergoing routine therapeutic drug monitoring (TDM) and pharmacogenetic (PGx) analyses of polymorphisms in genes involved in imatinib metabolism and transport (CYP3A4, CYP3A5, ABCB1, and ABCG2) when SARS-CoV-2 infection occurred. Imatinib and its active metabolite norimatinib concentrations were determined at Ctrough using a validated LCMS/MS method. PGx analyses were performed by KASP genotyping assays on a Real-Time PCR system. All patients received imatinib 400 mg/day. Case 1 was prospectively monitored. Cases 2-5 were identified retrospectively Results: On average, imatinib Ctrough increased significantly by 70% during COVID-19, whereas norimatinib showed a 44% increase compared with pre-COVID-19 levels. Elevated plasma imatinib concentrations persisted up to 6 months after infection remission. In 3 cases, this increase reflected the occurrence or worsening of imatinib side effects. Conclusion: This case-series highlights the clinical impact of SARS-CoV-2 infection on the management of patients with GIST treated with imatinib. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Conclusions Imatinib and dasatinib are tyrosine kinase inhibitors (TKIs) increasingly used to treat several diseases in both children and adults at fertile age. We have previously shown that imatinib has adverse effects on developing testis, and imatinib‐treated male patients have been reported to have reduced sperm counts. However, the cellular level effects of imatinib and dasatinib on adult male germ cells and germline stem cells (mGSCs) have not been thoroughly investigated.To analyze whether imatinib or dasatinib exposure ex vivo and in vitro is harmful to adult male rodent germ cells and mGSCs.Seminiferous tubule segments of adult male mouse or rat were cultured in the presence or the absence of imatinib or dasatinib. Stage‐specific effects were monitored by 3H‐thymidine incorporation assay (DNA synthesis), immunohistochemistry (cleaved Caspase‐3; apoptosis), immunofluorescence (KI67, GFRα1, STRA8, c‐KIT, LIN28A; proliferation and spermatogonial differentiation) and flow cytometry (Hoechst). Mouse mGSCs were exposed to imatinib and dasatinib to study proliferation, apoptosis, and differentiation.Imatinib decreased stage‐specific DNA synthesis, and induced apoptosis in cultured rat seminiferous tubule segments. Imatinib also had an adverse effect on mGSC proliferation both in vitro and ex vivo, but did not induce cell death in cultured mGSCs. Imatinib did not impinge on induction of spermatogonial differentiation but suppressed c‐KIT expression in nascent differentiating spermatogonia, providing a plausible mechanism for its pro‐apoptotic function in spermatogenic cells. Clinically relevant doses of dasatinib did not induce apoptosis in seminiferous tubules but decreased mGSC colony growth in vitro.Imatinib exposure ex vivo and in vitro impinges on male rodent germ cell proliferation and survival. The plausible mechanism in spermatogenic cells is the inhibition of SCF/c‐KIT signaling, and reduced expression of c‐KIT. Dasatinib did not show significant adverse effects with clinical doses ex vivo but inhibited mGSC colony growth in vitro. [ABSTRACT FROM AUTHOR]

Summary The role of imatinib in PDGFRA/B‐negative hypereosinophilic syndromes (HES) is controversial because of the heterogeneity of HES and the scarcity of prospective studies. We conducted a phase II clinical trial to evaluate the efficacy of imatinib in PDGFRA/B‐negative HES. Thirty‐two patients were treated with imatinib (100–400 mg daily), and the molecular basis of their response was identified using whole‐exome sequencing (WES) and whole‐transcriptome sequencing (WTS). The haematological response rate was 46.9%, with a complete haematological response (CHR) rate of 18.8%. The median time to response was 1.5 months. Among the six patients who achieved CHR, five maintained it until the 24th cycle of imatinib and one lost response after 20 months. The median progression‐free survival was 4.3 months. WES and WTS were conducted for 11 patients. The number of non‐silent mutations did not differ between responders and non‐responders. Nine differentially expressed genes, including SNORD15A, were downregulated in responders. STAT5B::RARA, PAK2::PIGX, and FIP1L1::CHIC2 fusions were identified in patients with sustained responses, and RNF130::BRAF and WNK1::KDM5A fusions were identified in non‐responders. Imatinib, along with an appropriate biomarker, could be a promising option for PDGFRA/B‐negative HES. [ABSTRACT FROM AUTHOR]

Background: Effective management of adverse events is required to maintain sufficient imatinib dosing when treating patients with gastrointestinal stromal tumors (GISTs). Skin rash is a common adverse event of imatinib, which can be effectively controlled by systemic steroid treatment without imatinib dose modification or interruption. However, the impact of the use of systemic steroids on the efficacy of imatinib treatment remains unclear. Methods: Between October 2014 and February 2022, 277 consecutive patients from a prospective registry of GIST patients were included as the study population. Patients who started systemic steroids due to grade ≥ 3 skin rash or grade 2 skin rash with grade 2 pruritis were classified as the steroid group, whereas patients who did not develop a skin rash or those who did not require steroids for a mild skin rash were classified as the control group. Efficacy outcomes were compared between the two groups. Results: Among the 277 patients, 30 (10.8%) were treated with systemic steroids for skin rash. There was no significant difference in progression free survival (PFS) or overall survival (OS) between the steroid and control groups (3-year PFS, 67.7% vs. 65.1%, p = 0.53; 3-year OS, 91% vs. 89.9%, p = 0.67, respectively). The use of systemic steroids was not an independent factor associated with PFS (hazard ratio 0.73, 95% confidence interval 0.36–1.49, p = 0.39) and OS (hazard ratio 0.37, 95% confidence interval 0.12–1.18, p = 0.09). In the steroid group, patients who successfully maintained the imatinib dosage showed a trend toward more favorable survival outcomes than those who did not (3-year PFS, 73.3% vs. 44.4%, p = 0.34; 3-year OS, 95.8% vs. 75.0%, p = 0.15, respectively). Conclusions: The use of systemic steroids for the control of imatinib induced severe skin rash did not adversely affect the efficacy outcomes of imatinib in patients with advanced GIST. [ABSTRACT FROM AUTHOR]

Background and Objective: When utilizing population pharmacokinetic (popPK) models for a priori dosage individualization, selecting the best model is crucial to obtain adequate doses. We developed and evaluated several model-selection and ensembling methods, using external evaluation on the basis of therapeutic drug monitoring (TDM) samples to identify the best (set of) models per patient for a priori dosage individualization. Methods: PK data and models describing both hospitalized patients (n = 134) receiving continuous vancomycin (26 models) and patients (n = 92) receiving imatinib in an outpatient setting (12 models) are included. Target attainment of four model-selection methods was compared with standard dosing: the best model based on external validation, uninformed model ensembling, model ensembling using a weighting scheme on the basis of covariate-stratified external evaluation, and model selection using covariates in decision trees that were subsequently ensembled. Results: Overall, the use of PK models improved the proportion of patients exposed to concentrations within the therapeutic window for both cohorts. Relative improvement of proportion on target for best model, unweighted, weighted, and decision trees were − 7.0%, 2.3%, 11.4%, and 37.0% (vancomycin method-development); 23.2%, 7.9%, 15.6%, and, 77.2% (vancomycin validation); 40.7%, 50.0%, 59.5%, and 59.5% (imatinib method-development); and 19.0%, 28.5%, 38.0%, and 23.8% (imatinib validation), respectively. Conclusions: The best (set of) models per patient for a priori dosage individualization can be identified using a relatively small set of TDM samples as external evaluation. Adequately performing popPK models were identified while also excluding poor-performing models. Dose recommendations resulted in more patients within the therapeutic range for both vancomycin and imatinib. Prospective validation is necessary before clinical implementation. [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]

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]

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]

Introduction: BCR-ABL fusion gene is targeted in the treatment of chronic myeloid leukemia and is essentia l in its follow-up. MicroRNAs are small RNA molecules with oncogenic and tumor suppressor properties. The aim of this study is to elucidate the r oles of BCR-ABL1-related miRNAs in TKI resistance in CML. Materials and Methods: This study was carried out on peripheral bloods collected from 25 imatinib-sensitive and 25 imatinib-resistant CML patients, and 50 healthy controls. miR-23a, miR-138, miR-181, miR-152-3p and miR-101 expression levels were determined by qRTPCR. Results: Our results showed that miR-23a, miR-101, miR-152 and miR-181 were downregulated in CML patients while miR-138 was downregulated in imatinib resistant group compared to sensitive group. Conclusion: To the best of our knowledge, our study is the first study comparing miRNA expression le vels in imatinib-sensitive and resistant CML cases. miR-138 may have a potential to be an indicator of imatinib resistance. This may provide evidence for potential therapeutic targets as well as novel prognostic biomarkers of imatinib resistanc 1e in CML. [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]

The impact of T-regulatory cells (Tregs), PD-1 + CD8 T-cells, and their dynamics during treatment with imatinib mesylate remains poorly understood in patients with chronic myeloid leukemia (CML). We conducted a prospective study on newly diagnosed, treatment-naïve adult (> 18 years old) patients with CML in the chronic phase (CP) and age- and sex-matched controls. Peripheral blood samples were collected at diagnosis and after three months of imatinib therapy to assess Tregs and PD-1 + CD8 T-cell levels using flow cytometry. The study comprised 57 patients with a median age of 39 years, including 27 males (47%). At baseline, the mean percentage of Tregs was significantly higher in CML patients (3.6 ± 0.32%) compared to controls (1.58 ± 0.21%) (p < 0.0001) but decreased significantly after three months of imatinib treatment (1.73 ± 0.35%) (p < 0.0001). Baseline Treg% exhibited positive correlations with Sokal (r = 0.29), Hasford (r = 0.33), EUTOS (r = 0.28), and ELTS (r = 0.31) risk scores (p < 0.05), as well as with the BCR-ABL transcript levels at three months (p = 0.03). Furthermore, the mean baseline percentage of PD-1 + CD8 T-cells was significantly elevated in CML patients (7.66 ± 0.36%) compared to controls (2.65 ± 0.32%) (p < 0.0001) and also decreased after treatment (3.44 ± 0.37%) (p < 0.0001). The baseline percentage of PD-1 + T-cells demonstrated positive correlations with Sokal (r = 0.26), Hasford (r = 0.27), and ELTS (r = 0.41) risk scores (p < 0.05). Our findings reveal a significantly higher proportion of Tregs and PD-1 + CD8 T-cells in patients with CML-CP compared to healthy controls, notably diminished following imatinib treatment. These observations suggest the potential for immunotherapy as a promising approach to managing immune exhaustion in CML patients. [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]

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]

Imatinib may be a useful targeted agent for patients with advanced gastric adenocarcinoma who have KIT mutations. [ABSTRACT FROM AUTHOR]

Background: The optimal duration of preoperative imatinib (IM) remains controversial. This study aimed to evaluate the safety, therapeutic effectiveness, and optimal duration of preoperative IM in patients with locally advanced gastric gastrointestinal stromal tumors (GIST). Methods: The clinicopathologic data of 41 patients with locally advanced gastric GIST who received preoperative IM and underwent surgical resection from January 2014 and December 2021 were retrospectively analyzed. Results: After a median of 7.0 (IQR: 4.5–10) months of preoperative IM treatment, 30 patients experienced adverse events (AEs), 80% of which were grade 1/2 AEs. The mean tumor size decreased from 12.71 ± 5.34 cm to 8.26 ± 4.00 cm, with a reduction rate of 35%. Setting 8 months as the cut‐off value according to the results of ROC analysis. The proportion of laparoscopic surgery was higher in patients with short‐term (≤8 months) versus long‐term (>8 months) preoperative IM. Compared with the subtotal/total gastrectomy group, patients in the local gastrectomy group exhibited less intraoperative blood loss, shorter length of postoperative hospital stay, and fewer postoperative complications. The 3‐year recurrence‐free survival (RFS) and overall survival (OS) rates were 82.9% and 97.6%, and the expected 5‐year RFS and OS rates were 75.6% and 90.2% respectively. RFS was better in the short‐term than in the long‐term preoperative IM treatment group, and it was also better in pre‐ plus postoperative IM treatment group than that in the preoperative IM alone group. Both univariate and multivariate COX analysis showed that a higher mitotic index and long‐term preoperative IM treatment were associated with worse RFS, while postoperative IM treatment could significantly improve RFS. Conclusions: The study suggests that in patients with locally advanced gastric GIST, preoperative short‐term (≤8 months) use of IM is associated with higher RFS than long‐term use. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract, usually arising in the stomach or in the small bowel. Most GISTs are diagnosed early due to the presence of symptoms (e.g., abdominal discomfort/pain, anemia, etc.); at times, diagnosis could be incidental (e.g., ultrasound or endoscopic examinations performed for other reasons, surgical intervention for a different disease, etc.). Diagnosis occurs when the tumor is already metastatic in 10-20% of cases. The most common metastatic sites are liver, peritoneum, and loco-regional lymph nodes. Here, we present the case of a male patient with an atypical presentation of disease: as a matter of fact, during his oncological history, he developed metastases in unlikely sites, such as penis, scrotum, myocardium, and soft tissues. [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]

Purpose: Imatinib adherence and persistence are key components of the successful treatment of Chronic Myeloid Leukemia (CML). In Belgium, there is no study assessing these behaviors at a national level. Our study aimed to provide the first nationwide measure and to identify associated pharmacy-based predictors (age, gender, comorbidities). We also assessed mortality and transplantation incidence according to adherence status. Methods: Based on medico-administrative database linkage, we identified a retrospective Belgian cohort of 1194 patients diagnosed with CML between 2004 and 2016 and treated with imatinib. Adherence was measured over 24 months, considering the proportion of days covered (PDC). Persistence was measured as the time until discontinuation (gap of ≥ 90 days). Multivariable Poisson regression models with robust standard error were conducted to identify predictors associated with adherence (≥ 90% PDC). To identify factors associated with persistence, a multivariable Cox regression was performed. Results: At six months, 60.3% of patients were adherent, declining to 41.5% at 12 months, and to 30.1% at two-year follow-up (n=998). Adherence was greater at a younger age (eg 31– 40 years vs ≥ 75 years, adjusted prevalence ratio (aPR) 1.73; 95% confidence interval (CI): 1.09– 2.77) and among patients with no comorbidity (0 vs ≥ 2 comorbidities (aPR 1.56; 95% CI: 1.11– 2.19). The median persistence was 334.5 days (Q1:200–Q3:505.5); persistence at 24 months was 83.6% (n=998). Only age was associated with higher risk of discontinuation, with adjusted hazard ratio (aHR) of 6.05 for patients ≥ 75 years (95% CI: 5.52– 6.58). Transplants and deaths mainly occurred in patients defined as non-adherent at 24 months. Conclusion: This Belgian nationwide representative study revealed a critical low level of imatinib adherence, which decreased over time even though persistence was high at six months. We pinpointed pharmacy-based predictors that were easily identifiable by health care stakeholders in order to undertake interventions to improve adherence. Plain Language Summary: The introduction of imatinib, a new oral anticancer medication, has transformed chronic myeloid leukemia (CML) from a fatal disease to a chronic disease. However, the success of imatinib partly depends on how long a patient continues to take it (persistence) and the extent to which they take imatinib as prescribed (adherence). Over a 24-month follow-up period, this study aimed to provide an assessment of imatinib adherence and persistence for the first time and to identify associated risk factors. Using pharmacy dispensing data, our study revealed that whilst very few CML patients discontinued imatinib, a considerable proportion struggled to adhere to imatinib recommendations, with a decreasing rate of adherence and persistence over time. We have identified some demographic and clinical characteristics associated with higher risk of poor adherence and early discontinuation. The current study's findings will help healthcare professionals to screen adherence behaviors prospectively and design specific interventions to maintain long-term optimal adherence to imatinib. [ABSTRACT FROM AUTHOR]

Gynecomastia refers to the abnormal enlargement of the male breast caused by the proliferation of the glandular component of the breast, typically due to sexual hormone disturbance. Multiple medications have been linked to the development of gynecomastia with varying incidences. This adverse event has also been associated with TKIs such as imatinib, dasatinib, and rarely nilotinib. However, it is poorly described and regarded as a rare event. Herein, we present the first case of a CML patient who developed gynecomastia after switching from imatinib to flumatinib. The patient is an 82-year-old male. He was diagnosed with CML and initially treated with imatinib. However, the treatment response milestone after three months of imatinib was not achieved. Hence, flumatinib was used to replace imatinib. Unexpectedly, two weeks later, he developed gynecomastia. Gynecomastia usually causes distress to patients, and there are currently no clear mechanisms or management strategies for this condition. Inspired by this case and through a review of the literature, we propose possible mechanisms and management strategies for this rare adverse event associated with TKIs, along with future perspectives. This may assist others in dealing with this issue and stimulate research on it. [ABSTRACT FROM AUTHOR]

Introduction: Imatinib, a tyrosine kinase inhibitor, is the first-line therapy for patients with KIT mutation in gastrointestinal stromal tumor (GIST). Nausea, vomiting, diarrhea, dyspepsia and abdominal pain are common gastrointestinal adverse reactions of imatinib, but imatinib-induced ulcerative colitis (UC) is rarely reported. Case report: We presented a case of UC induced by imatinib in a 56-year-old male patient who experienced this adverse event after 5 years of imatinib 400 mg/d treatment following GIST resection. Management and outcome: The patient's diarrhea and bloody stools showed significant improvement following the discontinuation of imatinib therapy and administration of antidiarrheal medications. Then, imatinib was restarted at a daily dosage of 400 mg. Discussion: UC is a rare adverse event associated with imatinib. Physicians should consider the possibility of UC induced by imatinib when patients present with diarrhea and bloody stool after receiving imatinib treatment. This case offered objective evidence of UC induced by imatinib. [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]

Background: Acquired multidrug resistance is often blamed for the failure of chemotherapy in patients with malignant tumors, including chronic myeloid leukemia (CML). In this study, the authors investigated the role of circular RNA 0080145 (circ_0080145) in imatinib (IM) resistance of CML. Materials and Methods: Quantitative real-time polymerase chain reaction was applied to measure the expression of circ_0080145, microRNA-326 (miR-326), and PTPRF interacting protein alpha 1 (PPFIA1) mRNA. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to determine the half maximal inhibitory concentration (IC50) of IM and cell proliferation. Flow cytometry analysis was utilized to assess cell apoptosis. The levels of glucose uptake and lactate production were examined using specific kits. Protein levels were detected through Western blot assay. The targeting relationship between miR-326 and circ_0080145 or PPFIA1 was verified by dual-luciferase reporter assay. The murine xenograft model was constructed to investigate the effect of circ_0080145 in vivo. Results: circ_0080145 was upregulated in IM-resistant CML patients and cells. circ_0080145 silencing suppressed IM resistance, cell growth, and glycolysis and induced apoptosis in IM-resistant CML cells in vitro. Moreover, circ_0080145 knockdown blocked tumor growth and IM resistance in vivo. miR-326 was a target of circ_0080145, and miR-326 inhibition restored the effects of circ_0080145 silencing on cell progression and IM resistance. In addition, PPFIA1 was a target gene of miR-326. The suppressive roles in IM resistance, cell growth and glycolysis, and the promotional role in apoptosis mediated by miR-326 were abolished by PPFIA1 overexpression in IM-resistant CML cells. Conclusion: circ_0080145 contributes to IM resistance via modulating miR-326/PPFIA1 axis, which might provide a novel avenue for CML therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The FGF/FGFR-mediated pathway coordinates the activity of VEGF/VEGFR signaling in IM-resistant GISTs. Mechanistically, FGF2 triggers the activation of the FGFR pathway, turns on the activation of VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. This was observed in IM-resistant GIST T-1R cells acquired IM resistance due to "RTK switch" (KIT loss/FGFR activation) and led to the impressive synergy scores between FGFR and VEGFR inhibitors, thereby providing a rationale to re-evaluate the effectiveness of combined anti-FGFR and VEGFR therapeutic strategies for GIST-acquired IM resistance via KIT-independent mechanisms. We showed previously that the autocrine activation of the FGFR-mediated pathway in GIST lacking secondary KIT mutations was a result of the inhibition of KIT signaling. We show here that the FGF2/FGFR pathway regulates VEGF-A/VEGFR signaling in IM-resistant GIST cells. Indeed, recombinant FGF2 increased the production of VEGF-A by IM-naive and resistant GIST cells. VEGF-A production was also increased in KIT-inhibited GIST, whereas the neutralization of FGF2 by anti-FGF2 mAb attenuated VEGFR signaling. Of note, BGJ 398, pan FGFR inhibitor, effectively and time-dependently inhibited VEGFR signaling in IM-resistant GIST T-1R cells, thereby revealing the regulatory role of the FGFR pathway in VEGFR signaling for this particular GIST cell line. This also resulted in significant synergy between BGJ 398 and VEGFR inhibitors (i.e., sunitinib and regorafenib) by enhancing their pro-apoptotic and anti-proliferative activities. The high potency of the combined use of VEGFR and FGFR inhibitors in IM-resistant GISTs was revealed by the impressive synergy scores observed for regorafenib or sunitinib and BGJ 398. Moreover, FGFR1/2 and VEGFR1/2 were co-localized in IM-resistant GIST T-1R cells, and the direct interaction between the aforementioned RTKs was confirmed by co-immunoprecipitation. In contrast, IM-resistant GIST 430 cells expressed lower basal levels of FGF2 and VEGF-A. Despite the increased expression VEGFR1 and FGFR1/2 in GIST 430 cells, these RTKs were not co-localized and co-immunoprecipitated. Moreover, no synergy between FGFR and VEGFR inhibitors was observed for the IM-resistant GIST 430 cell line. Collectively, the dual targeting of FGFR and VEGFR pathways in IM-resistant GISTs is not limited to the synergistic anti-angiogenic treatment effects. The dual inhibition of FGFR and VEGFR pathways in IM-resistant GISTs potentiates the proapoptotic and anti-proliferative activities of the corresponding RTKi. Mechanistically, the FGF2-induced activation of the FGFR pathway turns on VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. Thus, our data uncovers the novel mechanism of the cross-talk between the aforementioned RTKs in IM-resistant GISTs lacking secondary KIT mutations and suggests that the dual blockade of FGFR and VEGFR signaling might be an effective treatment strategy for patients with GIST-acquired IM resistance via KIT-independent mechanisms. [ABSTRACT FROM AUTHOR]

The authors present the case of a 39-year-old male with an initial diagnosis of de novo acute myeloid leukemia who, despite complete remission without measurable residual disease after conventional induction chemotherapy, presented with persistent splenomegaly and eosinophilia. As reactive eosinophilia was excluded and CBFB::MYH11 and RUNX1::RUNX1T1 gene fusions were not identified in additional molecular studies, we decided to test for other causes of clonal eosinophilia. Cytogenetic and molecular testing identified FIP1L1::PDGFRA gene fusion and prompted the introduction of imatinib. The initial diagnosis of de novo acute myeloid leukemia was changed to myeloid/lymphoid neoplasm with eosinophilia and FIP1L1::PDGFRA in the blast phase as myeloid blast count in the bone marrow at the diagnosis was >20%. The patient has maintained a complete molecular response with imatinib at a dose of 100 mg for more than two years. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The Imatinib drug is used to treat blood cancer by inhibiting the BCRABL tyrosine kinase enzyme, which prevents the proliferation of cancer cells. Materials & Methods: In order to predict the binding affinity of 555 compounds of imatinib derivatives as ABL-BCR tyrosine kinase inhibitors, quantitative structure-activity relationship (QSAR) modeling was performed using the Monte Carlo method. The data were randomly divided into four series, including training, invisible training, calibration, and validation sets, as well as they were randomly repeated three times. Results: The results of three random divisions indicated reliable models for predicting the set of external tests with correlation coefficient (R2) and cross-validation correlation coefficient (Q2) in the range of 0.8575-0.8775 and 0.7620-0.7793. Consequently, the obtained models help identify hybrid descriptors for increasing or decreasing binding affinity (Ki) as BCR-ABL tyrosine kinase inhibitors. The mechanical interpretation of the model is given in the form of a report of descriptors that decrease and increase pKi, as well as examples of these descriptors. Conclusion: The results reveal that the designed models can be considerably effective in estimating the biological effect of imatinib derivatives proposed by researchers and medicinal chemists. Therefore, it is possible to predict its possible biological effects by spending less time and money before conducting in vitro or in vivo experiments. [ABSTRACT FROM AUTHOR]

Background/Aim: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses and a multifactorial etiology. While imatinib has demonstrated efficacy in the treatment of immune-related diseases, its potential effects in IBD treatment remain underexplored. Materials and Methods: This study aimed to investigate the therapeutic effects of imatinib in colitis treatment. A dextran sulfate sodium (DSS)-induced colitis model was used to mimic IBD in mice. Imatinib was administered orally to mice simultaneously with DSS treatment. The effects of imatinib on DSS-induced colitis were evaluated by analyzing colitis-related pathology, including the disease activity index (DAI), histological lesions, inflammatory markers, and tight junction integrity. Additionally, western blot analysis and quantitative real-time polymerase chain reaction were used to assess inflammatory markers, tight-junction proteins, and cell death. Results: In the DSS-induced colitis model, imatinib treatment exerted protective effects by attenuating weight loss, restoring colon length, reducing spleen weight, and improving the DAI score and histological lesions. Additionally, imatinib reduced the level of proinflammatory cytokines, including TNF- α, IL-6, and IL-1β. Furthermore, imatinib treatment restored tight-junction integrity and decreased the expression of apoptosis marker proteins. Conclusion: Overall, imatinib treatment significantly alleviated the symptoms of DSS-induced colitis by influencing the expression of proinflammatory cytokines, tight junction proteins, and apoptotic markers in mice. These findings highlight imatinib as a potential therapeutic candidate for IBD. [ABSTRACT FROM AUTHOR]

Xiaodong Wang, Chunhui Shou, Kankai Zhu, Weili Yang, Jiren Yu Gastroenterology Department, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Jiren Yu, Gastroenterology Department, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China, Email yujr0909@zju.edu.cnAbstract: A new lump in patients with a history of gastrointestinal stromal tumor (GIST) may indicate resistance to medication and recurrence. It is important to monitor for recurrence or metastasis after surgery for GIST, especially in cases of high-risk GIST, as it determines the subsequent treatment. However, it is difficult to differentiate between GIST and DF by imaging. Tissue biopsy and final diagnosis through pathological analysis are usually required. Here, we report 2 cases of primary diagnosis with high-risk GIST and suspected tumor recurrence during Imatinib treatment. The mass was not located where the previous GIST lesion had been. After the complete excision of the mass through laparoscopic surgery, the pathological findings revealed that it was not a recurrence of GIST, but a desmoid-type fibromatosis.Keywords: lumpectomy, pathological diagnosis, GIST, imatinib

Abstract Background Effective management of adverse events is required to maintain sufficient imatinib dosing when treating patients with gastrointestinal stromal tumors (GISTs). Skin rash is a common adverse event of imatinib, which can be effectively controlled by systemic steroid treatment without imatinib dose modification or interruption. However, the impact of the use of systemic steroids on the efficacy of imatinib treatment remains unclear. Methods Between October 2014 and February 2022, 277 consecutive patients from a prospective registry of GIST patients were included as the study population. Patients who started systemic steroids due to grade ≥ 3 skin rash or grade 2 skin rash with grade 2 pruritis were classified as the steroid group, whereas patients who did not develop a skin rash or those who did not require steroids for a mild skin rash were classified as the control group. Efficacy outcomes were compared between the two groups. Results Among the 277 patients, 30 (10.8%) were treated with systemic steroids for skin rash. There was no significant difference in progression free survival (PFS) or overall survival (OS) between the steroid and control groups (3-year PFS, 67.7% vs. 65.1%, p = 0.53; 3-year OS, 91% vs. 89.9%, p = 0.67, respectively). The use of systemic steroids was not an independent factor associated with PFS (hazard ratio 0.73, 95% confidence interval 0.36–1.49, p = 0.39) and OS (hazard ratio 0.37, 95% confidence interval 0.12–1.18, p = 0.09). In the steroid group, patients who successfully maintained the imatinib dosage showed a trend toward more favorable survival outcomes than those who did not (3-year PFS, 73.3% vs. 44.4%, p = 0.34; 3-year OS, 95.8% vs. 75.0%, p = 0.15, respectively). Conclusions The use of systemic steroids for the control of imatinib induced severe skin rash did not adversely affect the efficacy outcomes of imatinib in patients with advanced GIST.

Introduction: Sickle cell disease (SCD) is a common hemoglobinopathy worldwide that causes painful crises and hospitalization of patients. These attacks decrease survival and cause chronic end-organ damage in these patients. Hypothesis: For this reason, finding new treatment approaches could be helpful. Method: In this study, Imatinib was applied as a mast cell inhibitor to reduce pain crises in these patients. Seven patients resistant to hydroxyurea and folic acid treatment and who had at least four painful crises per year with hospitalization were enrolled in this study with treatment with Imatinib (100 mg, twice daily). Subsequently, the number and duration of hospitalizations, analgesic requirement, the severity of chronic pain, and changes in the hematological parameters of these patients were evaluated before and after the treatment. Results: The data showed that the total number of hospitalizations and the entire duration of hospitalizations were reduced 16 times after treatment with Imatinib, without apparent changes in hematological parameters. Also, the demand for pethidine, tramadol, and nonsteroidal anti-inflammatory drugs (NSAIDs) was reduced in all patients. The average reduction in chronic pain was over 70%. Conclusion: This study demonstrates that treatment with Imatinib in patients with SCD or sickle cell anemia (SCA) may be a suitable therapeutic option for reducing painful crises.

Abstract Introduction Medication‐related osteonecrosis of the temporal bone is rare and has been reported to be associated with the use of anti‐resorptive and biologic agents. Here, we present the first case of tyrosine‐kinase inhibitor‐related external auditory canal (EAC) osteonecrosis as well as two cases related to anti‐resorptive therapies. Methods A retrospective case series. Results Case one: an 84‐year‐old female presented with chronic otitis externa and osteonecrosis of EACs bilaterally. She had a history of osteoporosis treated with denosumab and risedronic acid. She successfully underwent left EAC reconstruction using an inferiorly‐based pedicle periosteal flap while the right ear canal was managed conservatively. Case two: a 69‐year‐old male presented with osteonecrosis of the right EAC. He had a history of osteoporosis treated with alendronic acid and zoledronic acid. His osteonecrosis is conservatively managed with local debridement and antibiotic application. Case three: a 60‐year‐old male presented with osteonecrosis of the right inferior EAC. He had a history of chronic myelogenous leukemia treated with a tyrosine‐kinase inhibitor, imatinib. After failing conservative therapy, he underwent right ear canal reconstruction using a periosteal vascular pedicle flap without complication and experienced complete resolution to his symptoms. Conclusion Anti‐resorptive agents and/or tyrosine kinase inhibitors may lead to dysregulation of bone remodeling and result in rare cases of temporal bone osteonecrosis. When a local debridement and antibiotic therapy fail, definitive surgical excision of necrotic bone with subsequent reconstruction of the EAC may offer patients a possible resolution in symptoms.

Low‐dose antiangiogenic therapies have demonstrated the ability to enhance normalization of tumor vessels, consequently improving hypoxia levels, drug delivery, and promoting anticancer immune responses. Mast cells have been identified as contributors to resistance against antiangiogenic therapy and facilitators of abnormal neoangiogenesis. In this study, we demonstrate that by simultaneously targeting intratumoral mast cells with Imatinib and administering low‐dose anti‐VEGFR2 therapy, antitumor efficacy can be enhanced in preclinical models. Thus, combinatory treatment overcomes therapy resistance, while concurrently promoting tumor vessel normalization. Notably, histomorphometric analysis of tumor sections revealed that vessel perfusion could be improved through mast cell inhibition and, despite a significantly reduced microvessel density, the combination treatment did not result in elevated tumor hypoxia levels compared to anti‐VEGFR2 therapy alone. Short‐term Imatinib application effectively increased antitumor efficacy, and by prolonging the application of Imatinib tumor vessel normalization was additionally improved. The combination of mast cell depletion and antiangiogenic treatments has not been investigated in detail and promises to help overcoming therapy resistance. Further studies will be required to explore their impact on other treatment approaches, and subsequently to validate these findings in a clinical setting. [ABSTRACT FROM AUTHOR]

Purpose: This work aimed to evaluate the impact of a guaranteed access program to imatinib on the survival of patients with Chronic Myeloid Leukemia. Methods: We carried out a retrospective, observational, and analytical study of the database of patients diagnosed with Chronic Myeloid Leukemia of the Instituto Nacional de Cancerología and the Hospital General de México Dr. Eduardo to assess overall survival based on guaranteed access or not to imatinib. Results: With an average follow-up of 99 months, all patients' estimated 20-year overall survival was 72% (95% CI, 76–67). A significant difference was found in the 20-year survival probability in favor of patients with guaranteed access 76% (95% CI, 81–71) vs. 61% (95% CI, 69–52) (p < 0.001), in addition to those in which they had better attachment 81.2% (95% CI, 85–76) vs. 44.9% (95% CI, 52–37) (p < 0.001). Conclusion: CML is the most frequent chronic leukemia in Mexico. It mainly affects the economically active population (mean age 40), and the prognosis in our country has improved, emulating developed countries; however, the results depend on access to treatment and proper monitoring. [ABSTRACT FROM AUTHOR]

Background: Despite the promising of introduction of tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) remains a significant cause of annual mortality. Red blood cell distribution width (RDW), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) are parameters derived from a complete blood count (CBC) commonly used to diagnose anemia, autoimmune diseases, and inflammation. These parameters have been reported to have a strong association with various diseases, including hematologic malignancies. Objectives: The study aims to identify whether RDW, NLR, and PLR can act as predictors of survival in newly diagnosed and treated CML patients. Materials and Methods: The study involved 60 Iraqi patients (37 males, 23 females, aged 17–69 years) with CML at chronic phase, who were referred to the National Center of Hematology/Mustansiriyah University, Baghdad, from February 2022 to December 2022. Twenty were newly diagnosed (T0), and 40 were under TKI treatment (T+), with 20 on imatinib and 20 on nilotinib. Additionally, a control group of 20 age- and gender-matched healthy subjects was included. CBC assessed red blood cell (RBC) indices across all groups. Results: There was no significant difference in the age of CML patients at the onset of disease between males (34.5 ± 11.7 years) and females (34 ± 11.9 years). Likewise, there was no significant difference in the treatment of CML patients with imatinib or nilotinib between males (48% and 52%) and females (53.3% and 47.7%), respectively. Most RBC indices for patients and controls were within normal ranges without significant differences. However, RDW% in T0 was markedly elevated (20.4%), with about 80% showing anisocytosis, surpassing both T+ and controls, and exceeding the upper limit of normal. The total and differential white blood cell (WBC) counts were significantly higher in T0 compared to T+, exceeding their normal ranges. Additionally, the NLR was significantly higher in T0 (8.13) compared with T+ and controls (1.80 and 1.87, respectively). Platelet count, mean platelet volume, and platelet distribution width (PDW%) differed significantly among the three groups but remained within the normal range. However, PLR in T0 (31 ± 24) was significantly lower than those in T+ and controls (130 ± 43 and 102 ± 27, respectively). Conclusion: It can be concluded that the monitoring of some parameters in peripheral blood in CBC test (as a simple and inexpensive test) such as RDW%, NLR%, and PLR% during the therapy course of CML patients may act as predictive markers to evaluate the prognosis of disease in CML patients and the degree of response to certain TKI treatment.

Abstract Background Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME. Methods CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T. Results The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α. Conclusions These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.

Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), increase the survival of chronic myeloid leukemia (CML) patients but do not eradicate the disease as leukemia stem cells (LSCs) with primitive and quiescent signatures persist after TKI monotherapy, driving disease relapse. Using single-cell publicly available transcriptomic data, we investigated potentially tractable vulnerabilities in this persistent CML LSC population. GAS2 is significantly upregulated when comparing LSCs from CML patients in remission to normal hematopoietic stem cells (HSCs). A topoisomerase IIβ inhibitor, XK469, was proposed to be repurposed as a candidate small-molecule inhibitor of GAS2, and its effect was investigated in cell line models in combination with IM in vitro. Alone, XK469 could induce cell cycle arrest/differentiation in CML cells and reduce cell viability. In combination with IM, XK469 significantly increased CML cell apoptosis and reduced CML cell clonogenic capacity. These results suggest that GAS2 is a targetable vulnerability in CML LSCs and that using XK469 in combination with TKI potentiates the sensitivity of CML cells to IM.

Imatinib, a small molecule kinase inhibitor, is used as a cancer growth blocker. However, one of its most serious side effects is congestive cardiac failure. Reducing drug toxicity may be achieved through the use of drug delivery systems. Biocompatible metal-organic framework (MOF) materials, namely FeMIL-100 and FeMIL-101-NH2, were employed as potential imatinib carriers. They efficiently delivered the drug as an anticancer agent while minimizing cardiotoxicity. Notably, the release of imatinib from FeMIL-100 was rapid in acidic conditions and slower in pH-neutral environments, allowing targeted delivery to cancer cells. The carrier's pH-dependent stability governed the drug release mechanism. Two release models—Korsmeyer–Peppas and Weibull—were fitted to the experimental data and discussed in terms of drug release from a rigid microporous matrix. Cytotoxicity tests were conducted on two cell lines: HL60 (a model cell line for acute myeloid leukemia) and H9c2 (a cell line for cardiomyocytes). Overall, the metal-organic framework (MOF) carriers mitigated imatinib's adverse effects without compromising its effectiveness. [ABSTRACT FROM AUTHOR]

Purpose: Model-based methods can predict pediatric exposure and support initial dose selection. The aim of this study was to evaluate the performance of allometric scaling of population pharmacokinetic (popPK) versus physiologically based pharmacokinetic (PBPK) models in predicting the exposure of tyrosine kinase inhibitors (TKIs) for pediatric patients (≥ 2 years), based on adult data. The drugs imatinib, sunitinib and pazopanib were selected as case studies due to their complex PK profiles including high inter-patient variability, active metabolites, time-varying clearances and non-linear absorption. Methods: Pediatric concentration measurements and adult popPK models were derived from the literature. Adult PBPK models were generated in PK-Sim® using available physicochemical properties, calibrated to adult data when needed. PBPK and popPK models for the pediatric populations were translated from the models for adults and were used to simulate concentration-time profiles that were compared to the observed values. Results: Ten pediatric datasets were collected from the literature. While both types of models captured the concentration-time profiles of imatinib, its active metabolite, sunitinib and pazopanib, the PBPK models underestimated sunitinib metabolite concentrations. In contrast, allometrically scaled popPK simulations accurately predicted all concentration-time profiles. Trough concentration (Ctrough) predictions from the popPK model fell within a 2-fold range for all compounds, while 3 out of 5 PBPK predictions exceeded this range for the imatinib and sunitinib metabolite concentrations. Conclusion: Based on the identified case studies it appears that allometric scaling of popPK models is better suited to predict exposure of TKIs in pediatric patients ≥ 2 years. This advantage may be attributed to the stable enzyme expression patterns from 2 years old onwards, which can be easily related to adult levels through allometric scaling. In some instances, both methods performed comparably. Understanding where discrepancies between the model methods arise, can further inform model development and ultimately support pediatric dose selection. [ABSTRACT FROM AUTHOR]

Imatinib is an oral molecular targeted therapy that acts as a tyrosine kinase inhibitor. Silkworms present a promising experimental model for elucidating the pharmacokinetic and toxicity profiles of various compounds. This study aimed to establish an experimental paradigm for investigating the pharmacokinetics of imatinib in silkworms. A comparative analysis of imatinib pharmacokinetic parameters across silkworms, humans, mice, and rats revealed similarities in time to maximum concentration (Tmax) and apparent clearance values between silkworms and humans. However, differences in elimination half-life (t1/2) and apparent volume of distribution between silkworms and humans remained within 5- and 4-fold ranges, respectively. Importantly, mice demonstrated pharmacokinetic parameters closer to those of humans than rats during imatinib studies. Additionally, silkworms and mice exhibit similar Tmax and t1/2 values. This study highlights the potential of silkworms as valuable tools for investigating imatinib metabolism in pharmacokinetic studies. Furthermore, it underscores the applicability of silkworms in elucidating the pharmacokinetic parameters of various molecular-targeted drugs, thus facilitating advancements in drug development and evaluation. [ABSTRACT FROM AUTHOR]