RESUMEN
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.
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Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Pirimidinas , Humanos , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Adulto , Anciano , Resultado del Tratamiento , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Puntaje de Propensión , Supervivencia sin Progresión , Adulto JovenRESUMEN
BACKGROUND: In Nigeria, since 2002, Imatinib mesylate (glivec®) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria. METHOD: This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002-2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1-1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant. RESULTS: The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal (r = 0.733, p = 0.011) and EUTOS (r = 0.102, p = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively. CONCLUSION: This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria.
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Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Mesilato de Imatinib/uso terapéutico , Nigeria , Pronóstico , Resultado del Tratamiento , Anciano , Adulto Joven , Antineoplásicos/uso terapéutico , Adolescente , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , PobrezaRESUMEN
BACKGROUND: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the BCR::ABL1 fusion gene arising from the Philadelphia chromosome (Ph) translocation t(9:22)(q34;q11), exhibits diverse clinical courses often influenced by additional chromosomal aberrations (ACAs). This report presents a case of CML har-boring a novel four-way Ph translocation involving the X chromosome, offering insights into the interplay between complex karyotypes and treatment response and emphasizing the need for further research into the role of ACAs in CML management. METHODS: A 42-year-old man diagnosed with CML in the accelerated phase presented a novel four-way Ph translocation involving chromosomes X, 5, 9, and 22: 46,Y,t(X;5;9;22)(q26;q15;q34;q11.2). Despite achieving a major molecular response initially with imatinib and nilotinib, BCR::ABL1 levels (international scale) increased up to 24.0%, which prompted the use of second-line nilotinib. RESULTS: Follow-up bone marrow (BM) studies revealed clonal evolution with trisomy 8 and an unclassified ABL1 mutation (E292V), potentially contributing to resistance. Though a transient major molecular response (MMR) occurred after a switch to third-line dasatinib, this change failed to achieve a deep molecular response, and BCR-ABL1 levels were elevated above the MMR. CONCLUSIONS: This case highlights the challenge of ACAs impacting CML treatment response and prognosis. Limited knowledge exists on complex Ph translocations involving the X chromosome, but this report contributes data for further research. Understanding ACA effects on therapeutic response and prognosis requires a detailed study of such complex chromosomal aberrations.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Cromosoma Filadelfia , Translocación Genética , Humanos , Masculino , Adulto , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Evolución Clonal/genética , Proteínas de Fusión bcr-abl/genética , Mesilato de Imatinib/uso terapéutico , Pirimidinas/uso terapéutico , Cromosomas Humanos X/genética , Antineoplásicos/uso terapéuticoAsunto(s)
Antineoplásicos , Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Humanos , Mesilato de Imatinib/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patologíaRESUMEN
Imatinib-induced skin rash poses a significant challenge for patients with gastrointestinal stromal tumor, often resulting in treatment interruption or discontinuation and subsequent treatment failure. However, the underlying mechanism of imatinib-induced skin rashes in gastrointestinal stromal tumor patients remains unclear. A total of 51 patients (27 with rash and 24 without rash) were enrolled in our study. Blood samples were collected concomitantly with the onset of clinical manifestations of rashes, and simultaneously collecting clinical relevant information. The imatinib concentration and untargeted metabolomics were performed by ultra-high-performance liquid chromatography-tandem mass spectrometry. There were no significant differences in age, gender, imatinib concentration and white blood cells count between the rash group and the control group. However, the rash group exhibited a higher eosinophil count (P<0.05) and lower lymphocyte count (P<0.05) compared to the control group. Untargeted metabolomics analysis found that 105 metabolites were significantly differentially abundant. The univariate analysis highlighted erucamide, linoleoylcarnitine, and valine betaine as potential predictive markers (AUC≥0.80). Further enriched pathway analysis revealed primary metabolic pathways, including sphingolipid signaling pathway, sphingolipid metabolism, cysteine and methionine metabolism, biosynthesis of unsaturated fatty acids, arginine and proline metabolism, and biosynthesis of amino acids. These findings suggest that the selected differential metabolites could serve as a foundation for the prediction and management of imatinib-induced skin rash in gastrointestinal stromal tumor patients.
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Antineoplásicos , Exantema , Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Metabolómica , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Exantema/inducido químicamente , Neoplasias Gastrointestinales/tratamiento farmacológico , Anciano , AdultoRESUMEN
BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
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Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Inhibidores de Proteínas Quinasas , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/mortalidad , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Francia , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/mortalidad , Supervivencia sin Progresión , Adulto , Factores de Tiempo , Resistencia a Antineoplásicos , Privación de Tratamiento/estadística & datos numéricos , Esquema de MedicaciónRESUMEN
Understanding the determinants of long-term liver metastasis (LM) outcomes in gastrointestinal stromal tumor (GIST) patients is crucial. We established the feature selection model of intratumoral microbiome at the surgery, achieving robust predictive accuracies of 0.953 and 0.897 AUCs in discovery (n = 74) and validation (n = 34) cohorts, respectively. Notably, despite the significant reduction in LM occurrence with adjuvant imatinib (AI) treatment, intratumoral microbiome exerted independently stronger effects on post-operative LM. Employing both 16S and full-length rRNA sequencing, we pinpoint intracellular Shewanella algae as a foremost LM risk factor in both AI- and non-AI-treated patients. Experimental validation confirmed S. algae's intratumoral presence in GIST, along with migration/invasion-promoting effects on GIST cells. Furthermore, S. algae promoted LM and impeded AI treatment in metastatic mouse models. Our findings advocate for incorporating intratumoral microbiome evaluation at surgery, and propose S. algae as a therapeutic target for LM suppression in GIST.
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Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Neoplasias Hepáticas , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/microbiología , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/microbiología , Animales , Ratones , Femenino , Masculino , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/microbiología , Quimioterapia Adyuvante/métodos , Persona de Mediana Edad , Microbiota/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , AncianoRESUMEN
BCR-ABL1-independent resistance to imatinib has no effective treatment due to its complexity and diversity. We previously reported that the CDH13 oncogene was expressed at low levels in BCR-ABL1-independent resistant CML cell lines. However, its effects on CML resistant cells and mechanisms remain unknown. This study investigated the effects of saRNA-based CDH13 activation on BCR-ABL1-independent imatinib resistance in CML and its underlying mechanism, and proposes a unique treatment method to overcome imatinib resistance. Specifically, this study demonstrated that using the DSIR (Designer of Small Interfering RNA) website tool, saRNAs targeting the CDH13 promoter region were generated and validated using qPCR and western blotting. Among the predicted sequences, C2 and C3 efficiently elevated CDH13 mRNA and protein expression, as well as inhibited the relative vitality of cells and the ability to form clones. After promoting CDH13 expression in K562-IMR cells, it inhabited the NF-κB signaling pathway and induced apoptosis in imatinib-resistant CML cells. LNP-saRNA (C3) was also observed to limit the growth of K562-IMR cells in vivo. From the above, the activation of CDH13 expression by saRNA promotes cell apoptosis by inhibiting the NF-κB signaling pathway to overcome to BCR-ABL1-independent resistance to imatinib in patients with CML.
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Cadherinas , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Transducción de Señal , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Cadherinas/metabolismo , Cadherinas/genética , Transducción de Señal/efectos de los fármacos , Proteínas de Fusión bcr-abl/metabolismo , Proteínas de Fusión bcr-abl/genética , Células K562 , ARN Interferente Pequeño/metabolismo , Animales , Apoptosis/efectos de los fármacos , Ratones , FN-kappa B/metabolismo , Ratones Desnudos , Línea Celular TumoralRESUMEN
BACKGROUND Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, which results from the fusion of the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, forming the BCR-ABL gene on chromosome number 22, which accounts for approximately 95% of CML cases. Complex translocation involving other chromosomes can occur. CASE REPORT We present a rare case of CML with a variant Ph chromosome, in which chromosome 16 was involved with the usual translocation. A 34-year-old woman presented with a history of left upper quadrant pain and excessive sweating, with no hepatosplenomegaly on examination. She was found to have leukocytosis, with elevated neutrophils (34 000/mm³), basophils (1460/mm³), and eosinophils (2650/mm³). Karyotyping showed a translocation (16;22) (q24,q11.2), and FISH analysis showed BCR-ABL fusion as a result of (9,22) translocation, with a third chromosome (chromosome 16) involved and fused with chromosome 22, with a different breakpoint, which has never been reported in the literature, affecting the long arm of chromosome 16. The patient was treated with a first-generation tyrosine kinase inhibitor (imatinib) and achieved a deep molecular remission. The repeated FISH analysis confirmed the disappearance of both translocations (9,22) and (16,22). CONCLUSIONS The impact of the additional chromosomal aberration in CML is widely heterogeneous, and the outcome is dependent on multiple factors. Larger studies are needed to clarify the outcome in CML with variant Ph chromosomes, as most of the available data come from reported cases.
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Cromosomas Humanos Par 16 , Leucemia Mielógena Crónica BCR-ABL Positiva , Cromosoma Filadelfia , Translocación Genética , Humanos , Femenino , Adulto , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Cromosomas Humanos Par 16/genética , Mesilato de Imatinib/uso terapéutico , Proteínas de Fusión bcr-abl/genéticaRESUMEN
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.
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Apoptosis , Neoplasias Colorrectales , Subunidad alfa del Factor 1 Inducible por Hipoxia , Mesilato de Imatinib , Imágenes de Resonancia Magnética Multiparamétrica , Pericitos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Animales , Pericitos/metabolismo , Pericitos/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/diagnóstico por imagen , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Humanos , Ratones Desnudos , Microambiente Tumoral/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Imatinib (IM), a breakthrough in chronic myeloid leukemia (CML) treatment, is accompanied by discontinuation challenges owing to drug intolerance. Although BCR-ABL1 mutation is a key cause of CML resistance, understanding mechanisms independent of BCR-ABL1 is also important. This study investigated the sphingosine-1-phosphate (S1P) signaling-associated genes (SphK1 and S1PRs) and their role in BCR-ABL1-independent resistant CML, an area currently lacking investigation. Through comprehensive transcriptomic analysis of IM-sensitive and IM-resistant CML groups, we identified the differentially expressed genes and found a notable upregulation of SphK1, S1PR2, and S1PR5 in IM-resistant CML. Functional annotation revealed their roles in critical cellular processes such as proliferation and GPCR activity. Their network analysis uncovered significant clusters, emphasizing the interconnectedness of the S1P signaling genes. Further, we identified interactors such as BIRC3, TRAF6, and SRC genes, with potential implications for IM resistance. Additionally, receiver operator characteristic curve analysis suggested these genes' potential as biomarkers for predicting IM resistance. Network pharmacology analysis identified six herbal compounds-ampelopsin, ellagic acid, colchicine, epigallocatechin-3-gallate, cucurbitacin B, and evodin-as potential drug candidates targeting the S1P signaling genes. In summary, this study contributes to efforts to better understand the molecular mechanisms underlying BCR-ABL1-independent CML resistance. Moreover, the S1P signaling genes are promising therapeutic targets and plausible new innovation avenues to combat IM resistance in cancer clinical care in the future.
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Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Transducción de Señal , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Humanos , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Transducción de Señal/efectos de los fármacos , Lisofosfolípidos/metabolismo , Perfilación de la Expresión Génica/métodos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Femenino , Esfingosina/análogos & derivadosRESUMEN
BACKGROUND: Medication-related oral pigmentation is a unique yet benign finding in the dental setting. As new antineoplastic agents emerge, it is likely that this documented manifestation will continue to grow. CASE DESCRIPTION: Here, we describe two case presentations of imatinib-related hyperpigmentation of the palate. Both patients had been on imatinib, an antineoplastic agent for 10-14 years and presented with asymptomatic diffuse blue-black discoloration of the hard palate. Both cases demonstrated biopsy-proven pigment changes localized to the superficial connective tissue with evidence of melanin and hemosiderin deposits. Of note, this is a benign finding that does not require intervention. CONCLUSION: These two cases illustrate intraoral findings associated with imatinib. Increased awareness of this side effect will enable clinicians to appropriately council patients regarding the benign nature of this process.
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Antineoplásicos , Hiperpigmentación , Mesilato de Imatinib , Humanos , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/uso terapéutico , Antineoplásicos/efectos adversos , Hiperpigmentación/inducido químicamente , Hiperpigmentación/patología , Femenino , Biopsia , Persona de Mediana Edad , Paladar Duro/patología , Paladar Duro/efectos de los fármacos , Masculino , Diagnóstico DiferencialRESUMEN
ETV6::ABL1 fusion gene is a rare but recurrent genomic rearrangement in hematological malignancies with poor prognosis. Here, we report 1 case of Ph negative myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) who carry ETV6::ABL1 fusion gene. The patient achieved clinical remission after treatment with imatinib. However, disease progression of blast crisis was observed around 2 years later. The patient was treated with second-generation tyrosine kinase inhibitor of flumatinib, yielded a short term second therapeutic response. ETV6::ABL1 positive myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) is rare and may be misdiagnosed by conventional cytogenetical analysis. Early treatment with TKIs, particularly second-generation TKIs, may be beneficial to improve treatment results.
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Crisis Blástica , Proteína ETS de Variante de Translocación 6 , Proteínas de Fusión Oncogénica , Proteínas Proto-Oncogénicas c-ets , Humanos , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/genética , Proteínas de Fusión Oncogénica/genética , Masculino , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Persona de Mediana Edad , Mesilato de Imatinib/uso terapéutico , Aminopiridinas/uso terapéutico , FemeninoRESUMEN
OBJECTIVES: We studied the short- and long-term effects of imatinib in hospitalized COVID-19 patients. METHODS: Participants were randomized to receive standard of care (SoC) or SoC with imatinib. Imatinib dosage was 400 mg 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 randomized trials studying imatinib for 30-day mortality in hospitalized COVID-19 patients. RESULTS: We randomized 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 hospitalized COVID-19 patients.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Hospitalización , Mesilato de Imatinib , Calidad de Vida , SARS-CoV-2 , Humanos , Mesilato de Imatinib/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , COVID-19/mortalidad , Hospitalización/estadística & datos numéricos , Anciano , Resultado del Tratamiento , AdultoRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory bowel disease usually treated by azathioprine. It is a well-established risk factor for colorectal cancers and extraintestinal malignancies. Nevertheless, the risk of myeloid leukemia in patients with UC is less known. We report a case of a 51-year-old patient, with a history of extensive ulcerative colitis, who was treated with azathioprine at a dose of 2.5 mg/kg/day. Seven years later, he presented an increased count of white blood cells at 25,400/µL and of platelets at 1,382,000/µL. Peripheral blood smear showed 1% blasts and 20% myelemia. The karyotype showed the Philadelphia chromosome and the RT-PCR revealed the BCR-ABL transcript. Thus, chronic myeloid leukemia (CML) was confirmed and imatinib was prescribed. This case reported a rare and serious event in a UC patient and illustrates the importance of closely monitoring this population.
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Azatioprina , Colitis Ulcerosa , Mesilato de Imatinib , Inmunosupresores , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Persona de Mediana Edad , Azatioprina/efectos adversos , Azatioprina/uso terapéutico , Masculino , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/efectos adversos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéuticoRESUMEN
OBJECTIVE: To explore the different treatment modalities for esophageal gastrointestinal stromal tumors (E-GIST) and their respective applicability and clinical outcomes. METHODS: This is a retrospective study in which consecutive patients diagnosed with E-GIST at our hospital from January 2017 to August 2023 were included. The clinical characteristics of all the patients as well as long-term quality of life were recorded and analyzed. RESULTS: A total of 23 (12 males, 11 females) E-GIST patients with a mean age of 56.7 ± 12.0 years were included in this study. Common symptoms, including upper abdominal pain, acid reflux, and heartburn, accounted for over 60 % of cases. Fifteen patients underwent endoscopic resection, five patients underwent surgical resection, two patients underwent surgical resection after receiving preoperative imatinib therapy, and one patient received conservative management. CONCLUSION: Different treatment strategies may be applied to the patients with E-GIST depending on the their clinical features. Our study provides insights into precise treatment for different patients. However, due to the rarity of the disease, it is challenging to collect a large sample size from a single center, necessitating more multicenter prospective large-scale studies.
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Neoplasias Esofágicas , Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Humanos , Masculino , Persona de Mediana Edad , Femenino , Tumores del Estroma Gastrointestinal/terapia , Tumores del Estroma Gastrointestinal/cirugía , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Estudios Retrospectivos , Mesilato de Imatinib/uso terapéutico , Anciano , Calidad de Vida , Antineoplásicos/uso terapéutico , Adulto , Pirosis/etiología , Dolor Abdominal/etiología , Reflujo Gastroesofágico/terapia , Esofagectomía/métodos , Tratamiento Conservador/métodosRESUMEN
BACKGROUND: For gastric gastrointestinal stromal tumors (GISTs), neoadjuvant imatinib is most often reserved for tumors near the gastroesophageal junction, multivisceral 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 7203 patients, 762 (10.6%) received NAT followed by resection. On multivariable analysis, increasing tumor size was associated with NAT use (<2.0 cm vs 2.0-5.0 cm [odds ratio {OR}, 2.03; 95% CI, 1.19-3.47; P = .010] vs >5 cm [OR, 16.87; 95% CI, 10.02-28.40; P < .001]). After propensity score matching, 1506 patients remained. Median OS for NAT was 46.0 months vs 43.0 months for resection (P = .059), which was independently predictive of improved survival on multivariable analysis (hazard ratio [HR], 0.89; 95% CI, 0.80-0.99; P = .041). Subgroup analysis by tumor size showed no survival differences for tumors <2.0 cm or from 2.0 to 5.0 cm. Median OS was higher for tumors > 5.0 cm treated with NAT (NAT, 45.4 months [IQR, 29.5-65.9] vs upfront resection, 42.3 months [IQR 26.9-62.8]) and associated with improved survival on multivariable analysis (HR, 0.88; 95% CI, 0.78-0.99; P = .040). CONCLUSION: Although patients who received NAT had improved survival, this was primarily due to tumors >5.0 cm. Expanding NAT selection criteria to include localized gastric GISTs >5.0 cm may improve outcomes and warrants investigation through clinical trials.
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Tumores del Estroma Gastrointestinal , Terapia Neoadyuvante , Neoplasias Gástricas , Humanos , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/terapia , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/cirugía , Femenino , Masculino , Persona de Mediana Edad , Anciano , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Gastrectomía , Tasa de Supervivencia , Puntaje de Propensión , Carga Tumoral , Estudios Retrospectivos , Mesilato de Imatinib/uso terapéutico , Estimación de Kaplan-MeierRESUMEN
INTRODUCTION: We conducted an open-label, single-arm, multi-center phase II trial to evaluate the efficacy and safety of imatinib chemotherapy-refractory or metastatic solid tumor patients with c-KIT mutations and/or amplification. METHODS: c-KIT mutations and amplification were detected using NGS. Imatinib (400 mg daily) was administered continuously in 28-day cycles until disease progression, unacceptable adverse events, or death by any cause. The primary endpoint was the objective response rate (ORR). RESULT: In total, 18 patients were enrolled on this trial. The most common tumor type was melanoma (n = 15, 83.3%), followed by ovarian cancer, breast cancer, and metastasis of unknown origin (MUO) (each n = 1, 5.5%). The total number of evaluable patients was 17, of which one patient had a complete response, six patients had partial response, and two patients had stable disease. The overall response rate (ORR) of 41.2% (95% CI 17.80-64.60) and a disease control rate of 52.9% (95% CI 29.17-76.63). The median progression-free survival was 2.2 months (95% CI 1.29-3.20), and median overall survival was 9.1 months (95% CI 2.10-16.11). The most common adverse events were edema (31.3%), anorexia (25.0%), nausea (18.8%), and skin rash (18.8%). CONCLUSION: Imatinib demonstrated modest anti-tumor activity and a manageable safety profile in chemotherapy-refractory solid tumors with c-KIT mutation, especially in melanoma patients.
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Mesilato de Imatinib , Mutación , Neoplasias , Proteínas Proto-Oncogénicas c-kit , Humanos , Proteínas Proto-Oncogénicas c-kit/genética , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/administración & dosificación , Femenino , Persona de Mediana Edad , Masculino , Adulto , Anciano , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Neoplasias/mortalidad , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , República de Corea , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan. METHODS: Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan-Meier method. Cox regression analysis was used to analyze the prognostic factors of survival. RESULTS: A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01-14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39-10.89). CONCLUSIONS: We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.
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Tumores del Estroma Gastrointestinal , Mutación , Recurrencia Local de Neoplasia , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-kit , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas , Sistema de Registros , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Femenino , Masculino , Taiwán/epidemiología , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Proteínas Proto-Oncogénicas c-kit/genética , Adulto , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Sunitinib/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Pronóstico , Anciano de 80 o más Años , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/mortalidad , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Tasa de Supervivencia , Supervivencia sin Progresión , Estimación de Kaplan-MeierRESUMEN
BACKGROUND: Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy. METHODS: In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011. FINDINGS: Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm2 or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm2. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 years of treatment conferred the most benefit. INTERPRETATION: If the identified patient subgroups were applied in clinical practice, as many as a third of the current cohort of candidates who do not benefit from adjuvant imatinib would be encouraged to not receive imatinib, subsequently avoiding unnecessary toxicity on patients and financial strain on health-care systems. Our finding that 5 years is the optimal duration of imatinib treatment could be the best source of evidence to inform clinical practice until 2028, when a randomised controlled trial with the same aims is expected to report its findings. FUNDING: National Cancer Institute.