OBJECTIVE: We studied the short- and long-term effects of imatinib in hospitalised COVID-19 patients.
METHODS: Participants were randomised to receive standard of care (SoC) or SoC with imatinib. Imatinib dosage was 400mg daily until discharge (max 14 days). Primary outcomes were mortality at 30 days and 1 year. Secondary outcomes included recovery, quality of life and long COVID symptoms at 1 year. We also performed a systematic review and meta-analysis of randomised trials studying imatinib for 30-day mortality in hospitalised COVID-19 patients.
RESULTS: We randomised 156 patients (73 in SoC and 83 in imatinib). Among patients on imatinib, 7.2% had died at 30 days and 13.3% at 1 year and in SoC 4.1% and 8.2% (adjusted HR 1.35, 95% CI 0.47-3.90). At 1-year, self-reported recovery occurred in 79.0% in imatinib and in 88.5% in SoC (RR 0.91, 0.78-1.06). We found no convincing difference in quality of life or symptoms. Fatigue (24%) and sleep issues (20%) frequently bothered patients at one year. In the meta-analysis, imatinib was associated with a mortality risk ratio of 0.73 (0.32-1.63; low certainty evidence).
CONCLUSIONS: The evidence raises doubts regarding benefit of imatinib in reducing mortality, improving recovery and preventing long COVID symptoms in hospitalised COVID-19 patients.

BACKGROUND: For gastric GISTs, neoadjuvant imatinib is most often reserved for tumors near the gastroesophageal junction, multi-visceral involvement, or limited metastatic disease. Whether localized gastric GISTs benefit from neoadjuvant therapy (NAT) remains unknown. We sought to examine factors associated with NAT utilization for localized gastric GISTs and evaluate implications on survival.
METHODS: The National Cancer Database identified patients with localized gastric GISTs treated with NAT (2010-2020), excluding tumors extending beyond the gastric wall, located in the cardia, or with metastatic disease. Multivariable logistic regression assessed characteristics of NAT use. After 1:1 propensity score matching, Kaplan-Meier methods and multivariable Cox regression assessed overall survival (OS).
RESULTS: Of 7,203 patients, 762 (10.6%) received NAT followed by resection. On multivariable analysis, increasing tumor size was associated with NAT use (<2.0cm vs 2.0-5.0cm OR:2.03, 95%CI 1.19-3.47, p=0.010; vs >5cm OR:16.87, 95%CI 10.02-28.40, p<0.001). After propensity score matching, 1,506 patients remained. Median OS for NAT was 46.0 months vs 43.0 months for resection (p=0.059) which was independently predictive of improved survival (HR:0.89; 95%CI 0.80-0.99, p=0.041). Subgroup analysis by tumor size showed no survival differences for tumors <2.0cm or 2.0-5.0cm. Median OS was higher for tumors >5.0cm treated with NAT (NAT:45.4 months [IQR 29.5-65.9]. vs upfront resection:42.3 months [26.9-62.8]) and associated with improved survival on multivariable analysis (HR:0.88; 95%CI 0.78-0.99, p=0.040).
CONCLUSIONS: Although patients who received NAT had improved survival, this was primarily due to tumors >5.0cm. Expanding NAT selection criteria to include localized gastric GISTs >5.0cm may improve outcomes and warrants investigation through clinical trials.

Imatinib is a tyrosine kinase inhibitor (TKI) and is a commonly used medication for treatment of chronic myelogenous leukemia (CML). Aplastic anemia is a very uncommon complication of Gleevec, and only a few cases are reported in the literature. We present a case of a 63-year-old Asian female who was initiated on imatinib for treatment of CML with good response in cell counts. Four months after Gleevec initiation, the patient was admitted to the hospital with extreme fatigue and noted to have severe pancytopenia. Patient received multiple blood transfusions. Finally, the patient underwent bone marrow biopsy, which showed concern for aplastic anemia with marked hypocellular bone marrow. Gleevec was held, blood counts were monitored, and supportive care was given. Patient had slow recovery of her blood counts. There remains scarcity of data on this topic and no criteria exist to predict the myelosuppression with TKI therapy. Our case report aims to reemphasize the need for increased research on myelosuppression with TKI therapy.

The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the importance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In the OPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improve the molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitutional exomes and RNAseq data of these patients. We performed an association analysis between the constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks of treatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5\'/3\' (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.

This study evaluated the probable relevance of a non-covalent conjugate of imatinib with TP10 in the context of a neuroprotective effect in Parkinson\'s disease. Through the inhibition of c-Abl, which is a non-receptor tyrosine kinase and an indicator of oxidative stress, imatinib has shown promise in preclinical animal models of this disease. The poor distribution of imatinib within the brain tissue triggered experiments in which a conjugate was obtained by mixing the drug with TP10, which is known for exhibiting high translocation activity across the cell membrane. The conjugate was tested on the HT-22 cell line with respect to its impact on MPP+-induced oxidative stress, apoptosis, necrosis, cytotoxicity, and mortality. Additionally, it was checked whether the conjugate activated the ABCB1 protein. The experiments indicated that imatinib+PEG4+TP10 reduced the post-MPP+ oxidative stress, apoptosis, and mortality, and these effects were more prominent than those obtained after the exposition of the HT-22 cells to imatinib alone. Its cytotoxicity was similar to that of imatinib itself. In contrast to imatinib, the conjugate did not activate the ABCB1 protein. These favorable qualities of imatinib+PEG4+TP10 make it a potential candidate for further in vivo research, which would confirm its neuroprotective action in PD-affected brains.

Chemotherapy resistance is a major obstacle in cancer therapy, and identifying novel druggable targets to reverse this phenomenon is essential. The exosome-mediated transmittance of drug resistance has been shown in various cancer models including ovarian and prostate cancer models. In this study, we aimed to investigate the role of exosomal miRNA transfer in chronic myeloid leukemia drug resistance. For this purpose, firstly exosomes were isolated from imatinib sensitive (K562S) and resistant (K562R) chronic myeloid leukemia (CML) cells and named as Sexo and Rexo, respectively. Then, miRNA microarray was used to compare miRNA profiles of K562S, K562R, Sexo, Rexo, and Rexo-treated K562S cells. According to our results, miR-125b-5p and miR-99a-5p exhibited increased expression in resistant cells, their exosomes, and Rexo-treated sensitive cells compared to their sensitive counterparts. On the other hand, miR-210-3p and miR-193b-3p were determined to be the two miRNAs which exhibited decreased expression profile in resistant cells and their exosomes compared to their sensitive counterparts. Gene targets, signaling pathways, and enrichment analysis were performed for these miRNAs by TargetScan, KEGG, and DAVID. Potential interactions between gene candidates at the protein level were analyzed via STRING and Cytoscape software. Our findings revealed CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, and GIT2 as novel gene targets that may play roles in exosomal imatinib resistance transfer as well as mTOR, STAT3, MCL1, LAMC1, and KRAS which are already linked to imatinib resistance. MDR1 mRNA exhibited higher expression in Rexo compared to Sexo as well as in K562S cells treated with Rexo compared to K562S cells which may suggest exosomal transfer of MDR1 mRNA.

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.

The etiology for concurrent attacks of abdominal pain, nausea, vomiting, and diarrhea can be obscure. Mast cell activation syndrome is not usually considered in this differential diagnosis. A 53-year-old paint salesman suffered severe attacks of these symptoms for the 3 decades of his career. Nortriptyline, loperamide, hyoscyamine, and ondansetron failed to address his symptoms. Mast cell activation syndrome was ultimately diagnosed. Intravenous mast cell-targeted therapy reduced severity of attacks. Multiple oral mast cell-targeted treatments were ineffective, but addition of low-dose imatinib resulted in dramatic improvement. Recognition that paint-fume exposure-triggered attacks led to behavioral modifications which further reduced symptoms.

α1-Acid glycoprotein (AGP) is a primary binding protein for many basic drugs in plasma. The number of drugs that bind to AGP, such as molecular target anticancer drugs, has been continuously increasing. Since the plasma level of AGP fluctuates under various pathological conditions such as inflammation, it is important to evaluate the contribution of AGP to drug pharmacokinetics. Here, we generated conventional AGP-knockout (AGP-KO) mice and used them to evaluate the contribution of AGP. The pharmacokinetics of drugs that bind to two AGP variants (F1*S or A variants) or albumin were evaluated. Imatinib (a F1*S-binding drug) and disopyramide (an A-binding drug) or ibuprofen (an albumin-binding drug) were administered to wild-type (WT) and AGP-KO. The plasma level of imatinib and disopyramide decreased rapidly in AGP-KO as compared to WT. In AGP-KO, AUC and t1/2 were decreased, then CLtot was increased. Compared with disopyramide, imatinib pharmacokinetics showed more marked changes in AGP-KO as compared to WT. The results seemed to be due to the difference in plasma level of each AGP variant (F1*S:A = 2-3:1). No differences were observed in ibuprofen pharmacokinetics between the WT and AGP-KO mice. In vitro experiments using plasma from WT and AGP-KO showed that unbound fractions of imatinib and disopyramide were higher in AGP-KO. These results suggest that the rapid elimination of imatinib and disopyramide in AGP-KO could be due to decreased protein binding to AGP. Taken together, the AGP-KO mouse could be a potential animal model for evaluating the contribution of AGP to the pharmacokinetics of various drugs.

This article highlights the case of a 37-year-old male who presented with a recurrent, exponentially enlarging head mass, emphasizing the diagnostic and therapeutic challenges associated with a very rare type of tumor, fibrosarcomatous dermatofibrosarcoma protuberans (DFSP) of the head. Our patient presented with a rapidly growing head mass, initially diagnosed as a spindle cell tumor, and was managed with surgical excision and skin flap grafting. Follow-up revealed relapse and interval development of hemiparesis and hemisensory loss. MRI revealed tumor recurrence, with compression of the right parietal lobe and superior sagittal sinus. Histopathology revealed stroma with fascicles of spindle cells homogenous to fibrillar cytoplasm, with oval vesicular nuclei. Immunohistochemical staining showed positivity for CD34 and SMA. Oral chemotherapy with imatinib 800 mg/day was started. Follow-up imaging showed a marked reduction in the size of the tumor and resolution of the compression of the underlying brain parenchyma with cystic degeneration and decreased contrast enhancement. Future plans include possible surgical tumor debulking and/or radiation therapy. Although extremely rare, awareness of this tumor, with a multi-disciplinary approach to the management of the case, is vital to maximize treatment outcomes.