Outcomes of Dose Escalation of Imatinib in Chronic Myeloid Leukemia Patients: A Retrospective Analysis From an Indian University Teaching Hospital.

BACKGROUND: Chronic myeloid leukemia (CML) treatment in low- and middle-income countries faces significant financial and logistical constraints. In scenarios where second-line tyrosine kinase inhibitors (TKIs) are unavailable or unaffordable, dose escalation of imatinib provides an alternative. This study evaluates the efficacy, safety, and progression-free survival (PFS) outcomes of dose escalation of imatinib in CML patients who experienced suboptimal response or progression on standard doses. METHODS: A retrospective analysis of 123 CML patients treated at an Indian university teaching hospital from 2013 to 2016 was conducted. Patients who showed progression on a 400 mg dose of imatinib were escalated to 600 mg, and further to 800 mg if required. Demographic data, progression, and toxicity were analyzed. RESULTS: Out of 123 patients, 78 (63.4%) showed a complete hematologic response after dose escalation. The median PFS was 48 months, with a three-year PFS rate of 67%. Notable toxicities included Grade 3/4 neutropenia in 15% and gastrointestinal disturbances in 12%. Comparatively, studies suggest that switching to a second-line TKI in similar settings results in a higher PFS; however, our findings underscore that dose escalation of imatinib remains a viable alternative when financial constraints limit access to second-line therapies. CONCLUSION: In resource-constrained settings, dose escalation of imatinib can be an effective strategy for managing CML patients who progress on standard doses.

Pan-Canadian consensus recommendations for GIST management in high- and low-throughput centres across Canada.

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.

Phase II trial of imatinib mesylate in patients with PDGFRA/B-negative hypereosinophilic syndrome.

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.

Quantification of Histone H1 Subtypes Using Targeted Proteomics.

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.

Two different mutational types of familial gastrointestinal stromal tumors: Two case reports.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, and cases of GISTs tend to be of the disseminated type, with a global incidence of 10 to 15 cases/million each year. The rarer familial GISTs, which often represent a population, differ in screening, diagnosis, and treatment. Familial GISTs include primary familial GISTs with predominantly KIT/PDGFRA mutations and wild-type GISTs. However, whether the same genetic family has different phenotypes has not been reported. CASE SUMMARY: We report two cases of rare GISTs in the same family: A male patient with the V561D mutation in exon 12 of the PDGFRA gene, who has been taking the targeted drug imatinib since undergoing surgery, and a female patient diagnosed with wild-type GIST, who has been taking imatinib for 3 years since undergoing surgery. The favorable prognosis of these patients during the 7-year follow-up period validates the accuracy of our treatment strategy, and we have refined the entire process of diagnosis and treatment of familial GISTs in order to better manage this rare familial disease. CONCLUSION: Different mutation types of familial GISTs in the same family are very rare, thus it is very important to make the correct diagnosis and treatment strategies according to the results of molecular detection for the management of familial GISTs.

Impact of systemic steroids on the efficacy of first line imatinib treatment of patients with advanced gastrointestinal stromal tumors (GISTs).

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.

Imatinib is effective in some PDGFRA/B-negative hypereosinophilic syndromes: A step closer to unveiling underlying mechanisms.

Hypereosinophilic syndromes (HES) comprise different clonal, reactive, or idiopathic disorders characterized by elevated eosinophil levels and subsequent organ damage. Kim et al. in a multicentre, single-arm, prospective phase II study, treated 32 patients with PDGFRA/B-negative HES with imatinib at the dose of 100-400 mg daily. Respective overall and complete haematological response rates were 46.9% and 18.8%, and the median time to response was 1.5 months. The molecular basis of responses was identified by using whole-exome and whole-transcriptome sequencing in 11 patients. STAT5B::RARA, PAK2::PIGX, and FIP1L1::CHIC2 fusions were identified in responders, whereas RNF130::BRAF and WNK1::KDM5A were identified in non-responders. Imatinib could be a therapeutic option for some, possibly clonal, PDGFRA/B-negative HES. Commentary on: Kim et al. Phase II trial of imatinib mesylate in patients with PDGFRA/B-negative hypereosinophilic syndrome. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19828.

Imatinib Mesylate Causes Potential Cardiac Dysfunction in Patients With Chronic Myeloid Leukemia: the Results of a Case-control Study.

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.

Real World Outcomes with Treatment Free Remission in Chronic Myeloid Leukemia-Experience from a Tertiary Care Cancer Centre.

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.

Prognostic Significance of Regulatory T-Cells and PD-1 + CD8 T-Cells in Chronic Myeloid Leukemia Patients Treated with Generic Imatinib.

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.

Giant gastrointestinal stromal tumor resulting in intra-abdominal bleeding after failure of imatinib treatment, case report.

BACKGROUND: Gastrointestinal tumors (GIST) are mesenchymal soft tissue tumors that are commonly found in the stomach and are classified according to their site, size, and degree of mitosis. CASE PRESENTATION: A 40-year-old female patient presented to the emergency department complaining of abdominal pain; she was admitted, underwent multiple investigations, and was diagnosed with GIST; she was discharged and readmitted due to food intolerance; the patient was started on imatinib treatment but had a hemorrhagic shock while on therapy due to massive intraperitoneal hemorrhage that needed a lifesaving operation. DISCUSSION: Intraperitoneal bleeding is rare but should be taken into consideration in treating a patient with GIST, especially when the tumor has a risk for complications as enormous and even when proper treatment with chemotherapy agents such as imatinib is started. So, chemotherapy started for two weeks, but later, the patient developed symptoms and signs of intraabdominal bleeding and was diagnosed radiologically. However, due to patient instability, the decision was made to resection, which was done successfully. She was extubated and showed no signs of bleeding postoperatively. CONCLUSION: This case report sheds light on the rare presentation of a giant gastric GIST and the challenges associated with its management. The patient had a poor response to medical treatment with imatinib, which aimed to reduce the tumor size. Moreover, surgical management can be the best first line of management in giant GIST, as the larger the size of the GIST, the more complications can occur.

[Halving Time of BCR-ABL Transcripts as a Precise Predictor for Deep Molecular Response in Patients with Chronic Myeloid Leukemia Treated with TKI].

OBJECTIVE: To investigate the early predictive value of halving time (HT) of BCR-ABLIS 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-ABLIS with BCR-ABLIS level at 3 months to predict DMR of the patients. RESULTS: Univariate and multivariate analyses showed that HT and 3-month BCR-ABLIS 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-ABLIS levels at 3 months and HT. Kaplan-Meier analysis showed that the patients in the BCR-ABLIS≤10% and HT≤28 d group had a higher probability of obtaining cumulative MR4 and MR4.5 than those in the BCR-ABLIS≤10% and HT>28 d group (P < ＜0.05); Patients in the BCR-ABLIS>10% and HT≤28 d group had a higher probability of obtaining cumulative MR4 and MR4.5 than those in the BCR-ABLIS＞10% and HT>28 d group ( P < 0.05). CONCLUSION: In addition to BCR-ABLIS level, HT of BCR-ABLIS can be used as another important predictor of treatment efficacy in CML patients. The combination of BCR-ABLIS level and HT has a more accurate predictive value for long-term molecular response of CML patients after TKI treatment.

Imatinib decreases germ cell survival and germline stem cell proliferation in rodent testis ex vivo and in vitro.

BACKGROUND: 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. OBJECTIVES: To analyze whether imatinib or dasatinib exposure ex vivo and in vitro is harmful to adult male rodent germ cells and mGSCs. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Stretching the structural envelope of imatinib to reduce ß-amyloid production by modulating both ß- and γ-secretase cleavages of APP.

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 Aß 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 Aß 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.

Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.

OPINION STATEMENT: Gastrointestinal stromal tumor (GIST) is characterized by well-defined oncogenes. Despite the significant improvement in treatment outcomes with adjuvant imatinib therapy for patients, drug resistance remains a major challenge for GIST therapy. This review focuses on the mechanisms contributing to drug resistance phenotype in GIST, such as primary imatinib-resistant mutants, secondary mutations, non-covalent binding of TKI to its target, tumor heterogeneity, re-activation of pro-survival/proliferation pathways through non-KIT/PDGFRA kinases, and loss of therapeutic targets in wild-type GIST. Corresponding suggestions are proposed to overcome drug-resistance phenotype of GIST. This review also summarizes the suitability of currently approved TKIs on different KIT/PDGFRA mutations and updates related clinical trials. Recent potent drugs and emerging strategies against advanced GISTs in clinical trials are presented. Additionally, metabolic intervention offers a new avenue for clinical management in GIST. A landscape of metabolism in GIST and metabolic changes under imatinib treatment are summarized based on currently published data. The OXPHOS pathway is a promising therapeutic target in combination with TKI against sensitive KIT/PDGFRA mutants. Comprehensive understanding of the above resistance mechanisms, experimental drugs/strategies and metabolic changes is critical to implement the proper therapy strategy and improve the clinical therapy outcomes for GIST.

Increased plasma imatinib exposure and toxicity in chronically treated GIST patients with SARS-CoV-2 infection: a case series.

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 LC-MS/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.

Effect of recombinant CYP3A4 variants and interaction on imatinib metabolism in vitro.

The aim of this study was to investigate the catalytic activity of 26 Cytochrome P450 3A4 (CYP3A4) variants and drug interactions on imatinib metabolism in recombinant insect microsomes. This study was designed with an appropriate incubation system and carried out in the constant temperature water. By using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to measure the quantities of its metabolite N-desmethyl imatinib, to elucidate the impacts of the CYP3A4 genetic polymorphism and drug interactions on the metabolism of imatinib. Consequently, as compared to CYP3A4.1, the intrinsic clearance (CLint) values of the variations were dramatically changed, rising from 2.34 % to 120.57 %. CYP3A4.14 showed an increase in CLint in comparison to CYP3A4.1, and the remaining 24 variants demonstrated decreases in catalytic activity for the metabolism of imatinib. In addition, the metabolism of imatinib was decreased to varied degrees by ketoconazole, itraconazole, and fluconazole in CYP3A4.1 and CYP3A4.18. Moreover, most of CYP3A4 variants showed similar trend of enzyme activity under different substrates of imatinib and cabozantinib, except 6 variants (CYP3A4.3,.4,.10,.15,.29 and.31). The first study of the effects of 26 CYP3A4 variants on imatinib metabolism will contribute to the clinical evaluation of imatinib and help personalize therapy in clinical settings.

A randomized study of 6 versus 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse.

BACKGROUND: The administration of adjuvant imatinib during 3 years is indicated after resection of primary localized GIST at high risk of recurrence, but many patients relapse afterwards. METHODS: IMADGIST (NCT02260505) was a multicenter, open-label, randomized phase III study evaluating the maintenance of imatinib for 3 more years (6-year arm) compared with interruption (3-year arm) from the day of randomization, conducted in the French Sarcoma Group. The primary endpoint was intent-to-treat disease-free survival. Secondary endpoints included overall survival, time to imatinib resistance, response after imatinib reintroduction at relapse, and safety. RESULTS: From 24 December 2014 to 4 April 2023, 136 patients aged ≥18 years, Eastern Cooperative Oncology Group performance status ≤2, with a localized gastrointestinal stromal tumor with an R0 or R1 surgery, and a risk of tumor recurrence ≥35% according to National Comprehensive Cancer Network (NCCN) risk classification were randomized in 14 centers. Sixty-five patients were randomized to the 3-year arm versus 71 to the 6-year arm. There were 68 males and females. Primary sites were gastric and small bowel in 60 (44%) and 64 (47%) patients, respectively. Respectively, 52 (38%) and 71 (52%) patients had a risk of relapse of 35%-70% and >70%. With a median follow-up of 55 months (interquartile range 46-59 months) after randomization, disease-free survival was significantly superior in the 6-year arm [hazard ratio: 0.40 (0.20-0.69), P = 0.0008]. Time to imatinib resistance, survival, adverse events, and quality of life were not different in the two arms. CONCLUSIONS: Three additional years of adjuvant imatinib reduces the risk of relapse in patients who have received 3 years of adjuvant imatinib with an acceptable tolerance.