169 results on '"Imatinib treatment"'
Search Results
2. Molecular Biology and Pathology of Gastrointestinal Stromal Tumors
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Zhang, Paul J., Sepulveda, Antonia R., editor, and Lynch, John P., editor
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- 2013
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3. Gastrointestinal Stromal Tumors
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Antonescu, Cristina, Mellinghoff, Ingo K., editor, and Sawyers, Charles L., editor
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- 2012
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4. Deep molecular response on imatinib treatment — results from a real-life retrospective study
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Joanna Gora-Tybor, Joanna Niesiobedzka-Krezel, and Aleksandra Gołos
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medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Imatinib ,Retrospective cohort study ,Hematology ,Real life setting ,Imatinib treatment ,Discontinuation ,Oncology ,Internal medicine ,Molecular Response ,Major Molecular Response ,embryonic structures ,Medicine ,business ,medicine.drug - Abstract
Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically changed the outcome of chronic myeloid leukemia (CML) patients. Recent research focused on TKI discontinuation after achieving a deep molecular response (DMR) has revealed that about half of the patients maintain the response. DMR is a key criterion for TKI discontinuation. Our retrospective, ‘real-life’ study was aimed at to estimating the proportion of patients treated with first-line imatinib (IM) who achieved DMR and thus may be candidates for discontinuation of TKI treatment in a real life setting. Material and methods: Two hundred and twenty-three patients were enrolled. All patients started IM at 400 mg daily. The median age at the time of diagnosis was 57 years (range: 17–92). Results: Eighty-five patients (43%) in the whole group achieved DMR. Early molecular response (EMR) was achieved by 136 (69%) patients and correlated with the DMR rate (53% with EMR vs 14% without, p < 0.001). Major molecular response (MMR) after a year of treatment was confirmed in 108 (55%) patients, and was predictive for achieving DMR at any time (69% with MMR vs. 24% without, p < 0.001). Conclusion: DMR can be achieved in a significant proportion of patients in a real-life setting. We observed that both the achievement of an EMR at three months and MMR at 12 months were associated with a significant advantage in terms of DMR.
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- 2021
5. MiR-150 Expression in Chronic Myeloid Leukemia: Relation to Imatinib Response
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Dalia E Sherief, Eman M Habib, Atef Taha, Muhammad Tarek Abdel Ghafar, Manal A Eid, Nahla A Nosiar, and Asmaa E Hassan
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Oncology ,medicine.medical_specialty ,Treatment response ,business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Area under the curve ,Myeloid leukemia ,Imatinib ,Control subjects ,Imatinib treatment ,MicroRNAs ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,miR-150 ,Internal medicine ,Imatinib Mesylate ,medicine ,Humans ,In patient ,business ,medicine.drug - Abstract
Objective To assess the circulating micro-RNA-150 (miR-150) expression in patients with chronic myeloid leukemia (CML) in relation to imatinib response. Methods Sixty patients with CML and 20 age- and sex-matched control subjects were enrolled. Circulating miR-150 levels were assessed by quantitative real-time polymerase chain reaction on days 0, 14, and 90 of imatinib therapy for patients and once for control subjects. Results The baseline miR-150 expression was significantly lower in patients with CML than in control subjects with subsequent elevation at 14 and 90 days after the start of imatinib treatment. Early treatment response (ETR) at 90 days was the main study outcome. The miR-150 expression had a significantly higher level in patients with CML with ETR. On multivariate analysis, miR-150 on day 14 was significantly related to ETR in patients with CML with predictive efficacy (area under the curve = 0.838, 72.9% sensitivity, and 84.2% specificity). Conclusion We found that miR-150 expression on day 14 of imatinib treatment is a useful early predictive candidate for imatinib response in patients with CML.
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- 2021
6. Imatinib-mesylate enhances the maintenance of chronic myeloid leukemia stem cell potential in the absence of glucose.
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Bono, Silvia, Dello Sbarba, Persio, and Lulli, Matteo
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The introduction of BCR/Abl tyrosine kinase inhibitors (TKI), such as imatinib-mesylate (IM), has revolutioned the treatment of chronic myeloid leukemia (CML). However, although extremely effective in inducing CML remission, IM is unable to eliminate leukemia stem cells (LSC). This is largely due to the suppression of BCR/Abl protein, driven by the reduction of energy supply due to oxygen or glucose shortage, in stem cell niches of bone marrow. Here, we investigated whether, in K562 and KCL22 CML cell cultures, glucose shortage induces refractoriness of stem cell potential to IM. In the absence of glucose, IM, while maintaining its detrimental effect on CML cell bulk, actually enhanced colony formation ability and stem cell potential. This was paralleled by an increased expression of the Nanog and Sox-2 stem cell markers. These evidences stress further the importance of developing strategies alternative to TKI capable to target LSC of CML. [ABSTRACT FROM AUTHOR]
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- 2018
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7. Caveolin-1 expression predicts favourable outcome and correlates withPDGFRAmutations in gastrointestinal stromal tumours (GISTs)
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Simona Osella-Abate, Antonella Barreca, Luca Bertero, Mauro Papotti, Alessandro Gambella, Patrizia Lista, Paola Francia di Celle, Paola Cassoni, and Luigi Chiusa
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Oncology ,medicine.medical_specialty ,business.industry ,General Medicine ,PDGFRA ,Relapse rate ,Gastrointestinal stromal tumours ,Imatinib treatment ,Mitotic Count ,Pathology and Forensic Medicine ,gastrointestinal neoplasms ,Internal medicine ,immunohistochemistry ,Caveolin 1 ,medicine ,Overall survival ,molecular ,pathology ,Immunohistochemistry ,business - Abstract
AimsNovel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours.MethodsCaveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate.ResultsThirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence ofPDGFRAmutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48).ConclusionCaveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with thePDGFRAoncogenic pathway.
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- 2021
8. Optimal duration of imatinib treatment/deep molecular response for treatment‐free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial
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Igor Novitzky-Basso, Elena Liew, Eshetu G. Atenafu, Lambert Busque, Pierre Laneuville, Kristjan Paulson, Dennis Dong Hwan Kim, Mary-Margaret Keating, Isabelle Bence-Bruckler, Robert Delage, Suzanne Kamel-Reid, Tracy Stockley, Jeffrey H. Lipton, Donna L. Forrest, Brian Leber, Taehyung S Kim, Lynn Savoie, and Anargyros Xenocostas
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Adult ,Male ,Canada ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Gastroenterology ,Imatinib treatment ,Disease-Free Survival ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,Child ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,Log reduction ,business.industry ,Imatinib ,Hematology ,Middle Aged ,Predictive value ,Discontinuation ,Survival Rate ,030220 oncology & carcinogenesis ,Molecular Response ,Major Molecular Response ,Imatinib Mesylate ,Female ,business ,Follow-Up Studies ,030215 immunology ,medicine.drug - Abstract
Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).
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- 2021
9. Outcome of Imatinib Treatment in Yemeni Patients With Chronic Myeloid Leukemia and the Influence of Nonadherence to Treatment and Duration of Previous Hydroxyurea Therapy
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Jameel Al-Ghazaly, Leila Al-Gharasi, Yousr Noaman, Gianantonio Rosti, Waled Al-Dubai, and Munasser Abdullah
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Yemen ,Adolescent ,medicine.drug_class ,Imatinib treatment ,Tyrosine-kinase inhibitor ,Medication Adherence ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Overall survival ,medicine ,Humans ,Hydroxyurea ,Longitudinal Studies ,Longitudinal cohort ,Aged ,Aged, 80 and over ,business.industry ,Myeloid leukemia ,Hematology ,Middle Aged ,Progression-Free Survival ,Medication possession ratio ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Major Molecular Response ,Imatinib Mesylate ,Female ,Disease characteristics ,business ,030215 immunology - Abstract
In a developing country like Yemen, data are limited regarding the outcome of imatinib treatment of chronic myeloid leukemia and the effect of nonadherence to imatinib treatment and previous duration of hydroxyurea treatment.A longitudinal cohort study, which included 164 Yemeni patients, was performed. Data regarding the disease characteristics, adherence to treatment (the medication possession ratio) and outcome were analyzed.After a median follow-up of 60 months and a median duration of imatinib treatment of 46 months, 79 (48.2%) patients were adherent to treatment. In adherent patients, the overall survival and progression-free survival (PFS) were 78 (98.7%) and 73 patients (92.4%), respectively and major molecular response (MMR) rates at 12 months and at 46 months were 32 (41.0%) and 45 patients (57.0%), respectively, compared with 67 (78.8%), 51 (60%), 5 (6.9%), and 2 patients (2.4%), respectively, in nonadherent patients (P .001 for all parameters). Nonadherence to imatinib treatment and duration of hydroxyurea treatment of more than 12 months before starting imatinib were found to adversely affect PFS in univariate (hazard ratio [HR], 7.5 and 9.7, respectively and P .001 for both) and multivariate (HR, 5.6 and 9.3; P = .001 and P .001, respectively) analysis. High risk Sokal score was found to adversely affect PFS in univariate analysis (HR of high to low risk, 2.8; P .022) but not in multivariate analysis.Yemeni patients who were adherent to imatinib therapy achieved response rates similar to that of international standards. Nonadherence to imatinib treatment and previous duration of hydroxyurea treatment for more than 12 months, as a proxy of long interval between diagnosis and starting imatinib treatment, reduced the optimal response to imatinib therapy.
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- 2020
10. Comprehensive analyses of safety and efficacy toward individualizing imatinib dosage in patients with chronic myeloid leukemia
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Soo Young Choi, Soo-Hyun Kim, Dong-Wook Kim, Hayeon Noh, Jangik I. Lee, Kyung-Mi Kee, Dae Young Zang, Hyejin Shin, Su Young Jung, and Seon-Young Yang
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Adult ,Male ,medicine.medical_specialty ,Neutropenia ,Time Factors ,Adolescent ,Imatinib treatment ,Gastroenterology ,Young Adult ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,In patient ,Precision Medicine ,Aged ,Aged, 80 and over ,Leukopenia ,Hematology ,business.industry ,Body Weight ,Age Factors ,Myeloid leukemia ,Imatinib ,Middle Aged ,medicine.disease ,Thrombocytopenia ,Treatment Outcome ,Major Molecular Response ,Imatinib Mesylate ,Female ,Safety ,medicine.symptom ,business ,medicine.drug - Abstract
Safety and efficacy outcomes of imatinib treatment were evaluated using extensive clinical data collected from a total of 1003 patients with newly diagnosed chronic myeloid leukemia in chronic phase between 2001 and 2018. By 12 months of imatinib treatment at a fixed dose of 400 mg/day, 45.4% of patients experienced at least one type of dose-limiting toxicities (DLTs). The DLTs that frequently occurred first were thrombocytopenia (40.0%), neutropenia/leukopenia (14.3%) and dermatological reactions (12.1%). Patients with lighter body weight (≤ 64 kg) and older age (> 43 years) experienced a markedly higher occurrence of first DLTs by 12 months than heavier and younger patients (57.9% vs. 30.1%, p
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- 2019
11. The Outcomes of Chronic Myeloid Leukemia Patients With Molecular Warning Responses During Imatinib Treatment According to the European LeukemiaNet 2013 Recommendations
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Teoman Soysal, Isil Erdogan Ozunal, Zafer Baslar, Sevil Sadri, Muhlis Cem Ar, Ahmet Emre Eskazan, Ugur Ozbek, Şeniz Öngören, Yildiz Aydin, Dilek Keskin, Ayse Salihoglu, Istemi Serin, Nurgul Ozgur Yurttas, and Selin Berk
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Imatinib treatment ,Tyrosine-kinase inhibitor ,Young Adult ,03 medical and health sciences ,European LeukemiaNet ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,In patient ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Myeloid leukemia ,Cancer ,Imatinib ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Treatment Outcome ,030220 oncology & carcinogenesis ,Major Molecular Response ,Imatinib Mesylate ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Background In the European LeukemiaNet (ELN) 2013 recommendations, chronic myeloid leukemia (CML) patients with warning response (WR) were suggested to be monitored closely continuing with the same tyrosine kinase inhibitor (TKI). Differently, the guidelines of the National Comprehensive Cancer Network considers switching to another TKI as an option. Patients and Methods We retrospectively evaluated 73 CML patients receiving first-line imatinib, who were followed and managed in accordance with ELN recommendations. We compared patients with molecular WR with patients with optimal response (OR) and failure regarding short- and long-term outcomes. Results The cumulative major molecular response (MMR) rates in patients with OR were significantly higher at any time point than those achieved by the WR group. Patients with WR at 3 months had significantly inferior failure-free survival (FFS) than optimal responders, but overall survival (OS) was similar. For 6 and 12 months, the WR and OR groups had similar FFS and OS. Twenty of 23 patients with WR at 12 months achieved MMR during imatinib treatment. Conclusion It takes longer to get to ELN time points with imatinib than second-generation TKIs (2GTKIs). Treatment might fail in a small proportion of the patients with WR during imatinib treatment, but close and careful monitoring and timely switching to 2GTKIs might translate into favorable outcomes. Avoiding early switch to 2GTKIs would prevent patients from experiencing potential toxicities. There is still a need for prospective comparative studies (ie, continuing imatinib treatment vs. switching to 2GTKIs) in patients with WR, to justify the validity of this response category and to explore the benefit of treatment change in these patients.
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- 2019
12. Tumores del estroma gastrointestinal
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Jorge Luis Soriano-Lorenzo, Vilma Fleites-Calvo, Mayte Lima-Pérez, Karla Zaldivar-Blanco, and Jorge Luis Soriano-García
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Gynecology ,Medicine (General) ,medicine.medical_specialty ,Gastrointestinal tract ,GiST ,Sunitinib ,business.industry ,Standard treatment ,Imatinib ,Imatinib treatment ,R5-920 ,medicine ,Medicine ,General Earth and Planetary Sciences ,Surgical excision ,Relapse risk ,business ,neoplasms ,General Environmental Science ,medicine.drug - Abstract
espanolLos tumores del estroma gastrointestinal (GIST) son neoplasias mesenquimales originadas en el tracto gastrointestinal. Su localizacion mas frecuente es en estomago e intestino delgado. Pueden originarse a cualquier edad, pero mas del 80% de los casos son mayores de 50 anos sin predileccion de sexo, aunque puede observarse en pacientes mas jovenes asociados a sindromes que predisponen el desarrollo de estos tumores. Presentan sintomatologia inespecifica. La tomografia axial computarizada esta recomendada para realizar el estudio de extension y seguimiento de estos pacientes. Los marcadores inmunohistoquimicos mas sensibles y especificos son el KIT y DOG1. El tratamiento en caso de lesiones primarias localizadas es la reseccion quirurgica, con o sin terapia adyuvante con imatinib durante 3 anos en dependencia del riesgo de recidiva. En los casos avanzados o metastasicos se recomienda terapia neoadyuvante con imatinib por tiempo indefinido; el tratamiento en casos de progresion o intolerancia a imatinib es el sunitinib EnglishGastrointestinal stromal tumors (GIST) are mesenchymal neoplasms that arise in the gastrointestinal tract, usually in the stomach or the small intestine. GISTs can arise at any age, but more than 80% are reported in individuals older than 50 years men and women are affected at a roughly similar frequency. The few patients are who younger frequently have GIST associated with a syndrome. The clinical manifestations are non-specifics. The computer-tomography is recommended for staging and follow-up. The KIT and DOG1 are the most sensitive and specific immunohistochemistry markers. The standard treatment of localized GIST is complete surgical excision of the lesion, with or without adjuvant imatinib in dependence with the relapse risk. Neoadjuvant imatinib is the standard treatment for locally advanced and metastatic disease. In locally advanced and metastatic disease the imatinib treatment should be continued indefinitely. Following confirmed progression, or intolerance, to imatinib the standard second-line treatment is sunitinib.
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- 2019
13. No role of 3435C>T and 2677G>T ABCB1 (MDR1) gene single nucleotide polymorphisms in imatinib treatment response: A case control study on CML patients of Kashmir
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Mohsin S. Khan, Zafar A. Shah, Roohi Rasool, and Niyaz A. Azad
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Subfamily ,business.industry ,Case-control study ,Cytogenetics ,Single-nucleotide polymorphism ,Imatinib treatment ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Statistical significance ,Internal medicine ,Genetics ,medicine ,Multiplex ,business ,Gene ,Genetics (clinical) - Abstract
Studies on polymorphisms in ABCB1 (ATP Binding Cassette subfamily B member 1) gene have shown importance in CML treatment. 42 CML patients comprising 18 males (42.86%) and 24 females (57.14%) aged from 7 to 75 years, of which 19 (45.24%) belonged to age group of ≤45 years and the rest 23 (54.76%) were >45 years of age. A case-control analysis of 3435C>T and 2677G>T ABCB1 single nucleotide polymorphisms (SNPs) with respect to imatinib treatment outcome and evaluation of correlation, if any, with molecular (both qualitative & quantitative) and cytogenetic responses of the patients at 01 year was done by Multiplex RT-PCR, PCR-RFLP, quantitative real time PCR and cytogenetics. No association of any statistical significance was noted between either of the two SNPs and the imatinib treatment outcome.
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- 2019
14. Hypocalcemia with imatinib treatment in chronic myeloid leukemia patients
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Iffat Jamal
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Surgical pathology ,Oncology ,medicine.medical_specialty ,Clinical pathology ,business.industry ,Internal medicine ,Medicine ,Myeloid leukemia ,business ,Medical science ,Imatinib treatment - Published
- 2021
15. Dedifferentiated gastrointestinal stromal tumour with features mimicking malignant PEComa/alveolar soft part sarcoma: An unusual type of morphological transformation following imatinib treatment
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Kesavan Sittampalam and Kankanamage Malinda Amesh Karasinghe
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0301 basic medicine ,Stromal cell ,GIST dedifferentiation ,Imatinib treatment ,Pathology and Forensic Medicine ,Morphological transformation ,03 medical and health sciences ,0302 clinical medicine ,Alveolar soft part sarcoma ,lcsh:Pathology ,Medicine ,neoplasms ,Gastrointestinal tract ,GiST ,biology ,business.industry ,CD117 ,Mesenchymal stem cell ,medicine.disease ,digestive system diseases ,Malignant PEComa ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,business ,lcsh:RB1-214 - Abstract
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Dedifferentiation is a rare phenomenon in GISTs, most often following long-term Imatinib therapy and less frequently in de-novo fashion. According to the literature, the process of dedifferentiation is likely associated with genetic instability, rather than a result of acquisition of novel mutations in the common driver oncogenes. However, the exact underlying molecular basis of dedifferentiation is not well-established. Dedifferentiated GISTs show anaplastic features with loss of immunoreactivity for CD117 and DOG1. In this report, we present a rare and unique case of dedifferentiated metastatic GIST with a very unusual malignant PEComa/alveolar soft part sarcoma-like morphology. The molecular findings of our case also support the concept that dedifferentiation of GIST is independent of acquisition of additional novel mutations in the common driver oncogenes.
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- 2021
16. Letter to the editor: new response evaluation criteria using early morphological change in imatinib treatment for patients with gastrointestinal stromal tumor
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Lisong Teng and Junjie Jiang
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Oncology ,Cancer Research ,medicine.medical_specialty ,Letter to the editor ,Gastrointestinal Stromal Tumors ,business.industry ,Gastroenterology ,MEDLINE ,General Medicine ,Imatinib treatment ,Piperazines ,Stomach Neoplasms ,Surgical oncology ,Internal medicine ,Benzamides ,Imatinib Mesylate ,Humans ,Medicine ,Stromal tumor ,business ,Abdominal surgery - Published
- 2021
17. New response evaluation criteria using early morphological change in imatinib treatment for patients with gastrointestinal stromal tumor
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Kazuyoshi Yamamoto, Shinsuke Sato, Yujiro Nakahara, Koji Tanaka, Masaaki Motoori, Tomoki Makino, Kiyokazu Nakajima, Takuro Saito, Makoto Yamasaki, Atsushi Takeno, Toshirou Nishida, Yukinori Kurokawa, Hidetoshi Eguchi, Kotaro Yamashita, Yuichiro Doki, Yutaka Kimura, Hiromitsu Ohnishi, Tsuyoshi Takahashi, Yasuhiro Miyazaki, Tomo Ishida, and Takahiro Tsuboyama
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Oncology ,Cancer Research ,medicine.medical_specialty ,Gastrointestinal Stromal Tumors ,Antineoplastic Agents ,Imatinib treatment ,Piperazines ,Surgical oncology ,Stomach Neoplasms ,Internal medicine ,medicine ,Humans ,Stage (cooking) ,Stromal tumor ,neoplasms ,Gastrointestinal Neoplasms ,Retrospective Studies ,Predictive marker ,GiST ,business.industry ,Gastroenterology ,Imatinib ,General Medicine ,Pyrimidines ,Treatment Outcome ,Benzamides ,Imatinib Mesylate ,business ,Abdominal surgery ,medicine.drug - Abstract
The introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal stromal tumor (GIST), and based on the different response image, the methods of response evaluation have been established for GISTs. Furthrmore, the best response evaluation using them has been reported to be associated with progression-free survival (PFS) in imatinib treatment. However, since it is more important to predict the clinical outcomes of imatinib treatment in “early treatment phase”, new predicting factor in earlier stage is desired to work out the whole strategy of each patient. Early morphological change (EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer. The purpose of the present study was to verify the efficacy of EMC in predicting the outcome in patients with GIST receiving imatinib at early evaluation. We retrospectively reviewed 66 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups: active MR (morphological response) (+) group and active MR (−) group. We investigated the association between the presence of active MR and clinical outcomes. Forty-five patients had active MR ( +). The median progression-free survival (PFS) in patients with/without active MR was 49/23 months (P = 0.0039). The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with unresectable GIST.
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- 2020
18. Resection of a giant gastrointestinal stromal tumor after failed imatinib treatment during the COVID-19 pandemic: a case report
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Abbas E. Abbas, Heather Ann Hartman, Juhi Mittal, Facundo Iriarte, Antonio Di Carlo, and Katie Yusun Kwon
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Oncology ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Internal medicine ,Pandemic ,medicine ,Stromal tumor ,business ,Imatinib treatment ,Resection - Published
- 2022
19. Author response for 'A Phase 1 study to evaluate the feasibility and efficacy of the addition of ropeginterferon alpha 2b to imatinib treatment in patients with chronic phase chronic myeloid leukemia not achieving a deep molecular response (MR 4.5) – AGMT_CML 1'
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Gudrun Piringer, Stefan Schmidt, Richard Greil, Josef Thaler, Gerald Webersinke, Thomas Melchardt, Thomas Kuehr, Sonja Heibl, Dominik Wolf, Veronika Buxhofer-Ausch, and Thomas Lion
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business.industry ,Molecular Response ,Cancer research ,Alpha (ethology) ,Medicine ,In patient ,Chronic phase chronic myeloid leukemia ,business ,Imatinib treatment - Published
- 2020
20. Regulation of miR-126 and miR-122 Expression and Response of Imatinib Treatment on Its Expression in Chronic Myeloid Leukemia Patients
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Sameer Ahmad Guru, Irfan Ahmad, Aliya Rizvi, Amit Kumar Verma, Mirza Masroor Ali Beg, Yamini Goyal, Saleh Mohammed Abdullah, and Juheb Akhter
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Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid leukemia ,Imatinib ,Antineoplastic Agents ,Hematology ,Disease ,Blastic Phase ,Imatinib treatment ,Fold change ,MicroRNAs ,Drug Resistance, Neoplasm ,hemic and lymphatic diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,microRNA ,MiR-122 ,medicine ,Imatinib Mesylate ,Humans ,medicine.drug - Abstract
Background: MicroRNAs (miRNAs) have been observed to exhibit altered expression patterns in chronic myeloid leukemia (CML). Therefore, this study was aimed to evaluate the clinical importance of miR-126 and miR-122 expression in concert to imatinib response in CML patients. Methods: The present study included 100 CML and 100 healthy subjects. The expression of the 2 miRNAs was performed using TaqMan probe chemistry, and snU6 was used as internal control. Results: The expression of miR-126 and miR-122 was downregulated in CML patients, with a mean fold change ± SD 0.20 ± 0.33 and 0.22 ± 0.37, respectively. While the expression of both miRNAs was analysed before and after imatinib treatment, it was observed that the expression levels of both were increased after imatinib treatment by 26.25-fold (5.33 against 0.20) and 13.95-fold (3.07 against 0.22) and the increase was statistically significant (p < 0.0001 and p < 0.0001, respectively). The expression of miR-126 was not conclusive when compared in different clinical stages of the CML disease as it showed a decreased expression in patients with accelerated phase compared to chronic phase (mean fold change = 0.03 and 0.27, respectively), but patients with chronic phase and blastic phase had comparable expression (mean fold change = 0.27 and 0.24, respectively). We also observed an increased expression of both miRNAs after imatinib therapy in each clinical phase. Conclusion: The study concludes that expression of miR-126 and miR-122 increases after imatinib treatment in CML patients and that miR-126 defines the good responders of imatinib therapy.
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- 2020
21. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia
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Andrija Bogdanovic, Boris Labar, Martin Höglund, Edgar Faber, Hele Everaus, Richard E. Clark, Adriana Colita, Rüdiger Hehlmann, Sonja Heibl, Anna G. Turkina, Ulla Olsson-Strömberg, Francisco Cervantes, Michele Baccarani, Tomasz Sacha, Verena S. Hoffmann, Michael Lauseker, Daniela Zackova, Markus Pfirrmann, Andreas Hochhaus, Laimonas Griskevicius, Perttu Koskenvesa, Susanne Saussele, Irena Preložnik Zupan, Joerg Hasford, Andrey Zaritskey, Gert J. Ossenkoppele, Fausto Castagnetti, Witold Prejzner, François Guilhot, Joelle Guilhot, Hematology laboratory, CCA - Cancer Treatment and quality of life, HUS Comprehensive Cancer Center, Department of Oncology, Hematologian yksikkö, University of Helsinki, Helsinki University Hospital Area, Pfirrmann M., Clark R.E., Prejzner W., Lauseker M., Baccarani M., Saussele S., Guilhot F., Heibl S., Hehlmann R., Faber E., Turkina A., Ossenkoppele G., Hoglund M., Zaritskey A., Griskevicius L., Olsson-Stromberg U., Everaus H., Koskenvesa P., Labar B., Sacha T., Zackova D., Cervantes F., Colita A., Zupan I., Bogdanovic A., Castagnetti F., Guilhot J., Hasford J., Hochhaus A., and Hoffmann V.S.
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Registrie ,Male ,Cancer Research ,Epidemiology ,European LeukemiaNet ,0302 clinical medicine ,Risk groups ,BOSUTINIB ,Registries ,CML ,Aged, 80 and over ,0303 health sciences ,DASATINIB ,Hazard ratio ,FRONTLINE ,Myeloid leukemia ,Hematology ,IMATINIB TREATMENT ,Middle Aged ,Prognosis ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Female ,PROGNOSTIC DISCRIMINATION ,Sokal Score ,Human ,Adult ,medicine.medical_specialty ,Adolescent ,Prognosi ,Concordance ,MODELS ,3122 Cancers ,Protein Kinase Inhibitor ,VALIDATION ,Article ,03 medical and health sciences ,Young Adult ,Survival prognosis ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Long term survival ,medicine ,Humans ,Hematologi ,Protein Kinase Inhibitors ,030304 developmental biology ,Aged ,Probability ,business.industry ,Risk factors ,business - Abstract
Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
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- 2020
22. Generalized lentigines associated with familial gastrointestinal stromal tumors dramatically improved by imatinib treatment
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Akira Shimizu, Michiko Hasegawa, Kyoko Shibusawa, Atsushi Tamura, Akemi Ishida-Yamamoto, Keisuke Ieta, and Osamu Ishikawa
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Oncology ,medicine.medical_specialty ,Stromal cell ,business.industry ,Internal medicine ,medicine ,Dermatology ,General Medicine ,business ,Imatinib treatment - Published
- 2020
23. A rare case of cardiac toxicity in a patient with imatinib treatment: Case report
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Emir Celik, ZeynepHande Turna, Murat Guliyev, NilaySengul Samanci, and Ezgi Degerli
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Cardiac toxicity ,Rare case ,medicine ,Radiology, Nuclear Medicine and imaging ,General Medicine ,business ,Imatinib treatment - Published
- 2022
24. Chronic Myeloid Leukemia With P190 BCR-ABL Translocation and Persistent Moderate Monocytosis: A Case Report
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Sara Marinoni, Alessandra Movilia, Annalisa Citro, Arianna Gatti, Lucia Roncoroni, and Bruno Brando
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0301 basic medicine ,Dasatinib ,Chronic myelomonocytic leukemia ,Chromosomal translocation ,Case Report ,Imatinib treatment ,03 medical and health sciences ,0302 clinical medicine ,Monocytosis ,hemic and lymphatic diseases ,Medicine ,neoplasms ,business.industry ,Chronic myeloid leukemia ,Myeloid leukemia ,Imatinib ,P190 BCR-ABL ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,business ,medicine.drug - Abstract
Chronic myeloid leukemia (CML) with p190 BCR-ABL is rare. In some cases it is associated with peripheral monocytosis, while bone marrow shows features intermediate between CML and chronic myelomonocytic leukemia. The prognosis is controversial, but in the most recent literature p190 BCR-ABL CML seems associated with a poor outcome. We report a case of p190 BCR-ABL CML characterized by moderate monocytosis, without deep molecular response (DMR) to an initial imatinib treatment. After imatinib was replaced by dasatinib, a DMR was achieved, however without appreciable effects on monocytosis.
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- 2018
25. Assessment of BCR-ABL1 Fusion Transcripts and Their Association with Response to Imatinib Treatment in Chronic Myeloid Leukemia Patients
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Sailaja Kagita, Tulasi Krishna Mamidi, Raghunadharao Digumarti, Leela Digumarti, and S. Gundeti
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0301 basic medicine ,Oncology ,Sanger sequencing ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Imatinib ,Imatinib treatment ,Reverse transcriptase ,03 medical and health sciences ,symbols.namesake ,030104 developmental biology ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,symbols ,Platelet ,Mutation frequency ,business ,Tyrosine kinase ,medicine.drug - Abstract
Objectives: BCR-ABL1 fusion transcripts with contrasting data on response to imatinib therapy have been reported from different parts of the world. Hence, the present study aimed to determine the frequencies of transcripts and their association with response to imatinib therapy in chronic myeloid leukemia (CML) patients. Methods: A total of 170 (76 follow-up and 94 imatinib-resistant) CML samples were included in the study. BCR-ABL1 fusion transcripts and expression status were analyzed in all cases using multiplex reverse transcriptase PCyR and real-time PCyR. Sanger sequencing was used for tyrosine kinase domain (TKD) mutation screening in imatinib mesylate-resistant patients. Results: Of 170 CML patients, 36.36% showed b2a2, 63.53% had b3a2, and 2.94% had b2a2 + b3a2 isoforms. Mean platelet counts and blasts were significantly lower in b2a2 carriers (P = 0.0092; P ≤ 0.0001). Patients with b2a2 transcript were found to be more in responders group (both hematological and cytogenetic), whereas b3a2 patients were more in partial responders group and death (P = 0.763; P = 0.309). In follow-up patients, mean baseline BCR-ABL1 expression levels are significantly higher in b2a2 versus b3a2 carriers (P = 0.0351). Of 94 imatinib-resistant patients, 36 (38.29%) had acquired TKD mutations. Among 36 patients, mean BCR-ABL1 levels are significantly higher in b2a2 and b2a2 + b3a2 group (P = 0.0002; P ≤ 0.0001). TKD mutation frequency was more in b3a2 (61.11%) compared to other types. With respect to follow-up status in 36 patients, 17 patients died while 19 were on imatinib higher doses or 2nd-generation tyrosine kinase inhibitors. Of 17 patients, 41.66% had b2a2 transcript and 54.54% had b3a2 transcript. Conclusion: Patients with b3a2 transcripts might be associated with poor response and worse prognosis in CML with imatinib treatment.
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- 2018
26. Philadelphia chromosome-negative acute promyelocytic leukemia manifesting after long-term imatinib treatment for chronic myeloid leukemia: a case report and literature review
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Kiyomi Morita, Junji Koya, Takashi Toya, Fumihiko Nakamura, and Mineo Kurokawa
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Oncology ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Hematology ,business.industry ,Philadelphia Chromosome Negative ,Myeloid leukemia ,General Medicine ,medicine.disease ,Philadelphia chromosome ,Imatinib treatment ,03 medical and health sciences ,Leukemia ,Myelogenous ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,030215 immunology - Published
- 2018
27. Disappearing pigmentary mosaicism during imatinib treatment for gastrointestinal stromal tumors
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Shawn E. Cowper, Jonathan S. Leventhal, Jill Lacy, Gauri Panse, and Emily Coleman
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Stromal cell ,GiST ,business.industry ,pigmentary mosaicism ,GIST - Gastrointestinal stromal tumor ,Case Report ,Imatinib ,Dermatology ,Imatinib treatment ,GIST, gastrointestinal stromal tumor ,gastrointestinal stromal tumors ,imatinib ,c-kit ,Cancer research ,Medicine ,business ,medicine.drug - Published
- 2019
28. The Rate of Cellular Energy Production of Muscle Cells Is Attenuated By Carnitine Intracellular Deficiency Caused By Imatinib Treatment
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Vaclava Polivkova, Nikola Curik, Pavel Burda, Alzbeta Hlavackova, Jitka Koblihova, Jiri Suttnar, Hana Klamova, and Katerina Machova
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Chemistry ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,Biochemistry ,Imatinib treatment ,hemic and lymphatic diseases ,medicine ,Myocyte ,Carnitine ,Cellular energy ,Intracellular ,medicine.drug - Abstract
Introduction: Previous works identified that imatinib intake through the carnitine-specific OCTN2 (SLC22A5) transporter resulted in a significant decrease of carnitine intracellular concentrations in chronic myeloid leukemia (CML) and muscle cell lines. On contrary, even high doses of carnitine in preincubation did not influence imatinib cell intake capacity. Specifically performed inhibition of OCTN2 activity by vinorelbine resulted in block of carnitine cell intake, while imatinib intake was only slightly reduced (13-30%). This observation is in line with the knowledge that imatinib is transported also through other known SLC transporters. OCTN2 transporter is the major transporter for carnitine, an essential compound in cell energy metabolism. Presented work follows a hypothesis that non-equal competition between imatinib and carnitine intake through OCTN2 can lead to the carnitine intracellular deficiency, which can be in CML patients manifested by a disruption of skeletal muscle mitochondrial density and cause side effects like fatigue, muscle pain and cramps reported up to 80% of patients treated with imatinib (Kekale et al., 2015). Methods: Muscle cell HTB-153 (human rhabdomyosarcoma, ATCC HS 729), CML cell line KCL-22 (DSMZ ACC 519) were used for in vitro experiments. Intracellular concentration of imatinib, carnitine and metabolites were measured by chromatographic separation using XBridge Amide column (50x2.1mm, 3.5µm; Waters, Milford (MA), USA) and ZIC-pHILIC column (50x2.1mm, 5 µm; Merck, Darmstadt, Germany) coupled to tandem mass spectrometer (QTRAP 4000; Sciex, USA). Results: Carnitine, resp. L-carnitine transports long-chain fatty acids to mitochondria and its high rate is required especially in energetically demanding tissues such as skeletal and cardiac muscles. The concentrations of citric acid cycle (CAC) metabolites (citrate, malate, alpha-ketoglutarate, succinate, fumarate, 2-hydroxyglutarate, cis-aconitate), glycolysis (phosphoenolpyruvate, 3- phosphoglycerate, lactate), production of ATP, ADP and AMP were measured in HTB-153 cells 3 and 24 hours after imatinib treatment in vitro. The significant decrease of malate (CAC), lactate (glycolysis) and ATP levels were found at both time points after imatinib treatment compared to baseline. The same observations were found in KCL-22, which was used for comparison as BCR-ABL1 positive cell line. Additionally, significant decrease of succinate and 2-hydroxyglutarate (CAC) was detected in KCL-22 after imatinib treatment. Next, HTB-153 was incubated with imatinib (1-8 µM) for 24 hours and carnitine (8 µM) was supplied for last 3 hours of incubation, i.e., after 21 hours of imatinib treatment start. No significant changes were found in any metabolites of CAC and glycolysis. Production of ATP, ADP and AMP was not changed as well. Conclusions: Imatinib treatment of muscle (rhabdomyosarcoma) and CML cell lines caused a significant decrease of intracellular concentrations of carnitine. Significant decrease of ATP levels and of certain metabolites of CAC and glycolysis outlined that cells struggle from attenuated mitochondria energy production after imatinib treatment. This has not happened, if carnitine was supplied to the culture for final 3 hours of 24 hours incubation with imatinib. Observed data strongly support the hypothesis that decreased carnitine intake to the muscle cells due to competition with imatinib transport through OCTN2 attenuated mitochondria energy production. Interestingly, the clinical trial NCT03426722 (Chae H et al. 2019) showed that L-carnitine could effectively relieve imatinib-related muscle cramps and significantly increase QoL in patients with advanced gastrointestinal stromal tumor. Supported by GACR18-18407S, MZCR00023736 Disclosures No relevant conflicts of interest to declare.
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- 2021
29. Inadequate response to imatinib treatment in chronic myeloid leukemia due to a drug interaction with phenytoin
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Vicente Escudero-Vilaplana, E González-Arias, J L Díez, Ignacio Gómez-Centurión, X García-González, and Santiago Osorio
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Male ,Phenytoin ,Antineoplastic Agents ,Pharmacology ,Imatinib treatment ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Drug Interactions ,Pharmacology (medical) ,Protein Kinase Inhibitors ,neoplasms ,Aged, 80 and over ,business.industry ,Myeloid leukemia ,Imatinib ,Drug interaction ,Imatinib mesylate ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,business ,Tyrosine kinase ,030215 immunology ,medicine.drug - Abstract
Imatinib mesylate and the newer BCR-ABL tyrosine kinase inhibitors are the standard therapy for chronic myeloid leukemia. Although these are remarkably effective drugs, some mechanisms of resistance have been identified including drug-to-drug interactions. Here we present the case of a chronic myeloid leukemia patient with an inadequate response to imatinib due to concurrent phenytoin administration. Conspicuously low imatinib plasma trough levels were documented. Imatinib dose was increased from 400 to 800 mg with good response. In conclusion, drug-to-drug interactions should be ruled out in cases of resistance to tyrosine kinase inhibitor treatment. Potent inducers of cytochrome P450 isoenzyme CYP3A4, as phenytoin, could induce inadequate responses due to increased imatinib clearance and low imatinib trough plasma levels. Thus, this interaction should be avoided. When this is not possible, dose escalation of imatinib and measurement of plasma levels, if available, is recommended.
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- 2017
30. Identification of novel target genes of nerve growth factor (NGF) in human mastocytoma cell line (HMC-1 (V560G c-Kit)) by transcriptome analysis.
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Dutta, Priyanka, Koch, Alexandra, Breyer, Bjoern, Schneider, Heike, Dittrich-Breiholz, Oliver, Kracht, Michael, and Tamura, Teruko
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- *
NERVE growth factor , *CELL lines , *KRUPPEL-like factors , *HEMATOPOIETIC system , *PROGENITOR cells - Abstract
Background: Nerve growth factor (NGF) is a potent growth factor that plays a key role in neuronal cell differentiation and may also play a role in hematopoietic differentiation. It has been shown that NGF induced synergistic action for the colony formation of CD34 positive hematopoietic progenitor cells treated with m acrophage-c olony s timulating f actor (M-CSF or CSF-1), or s tem c ell f actor (SCF). However, the exact role of NGF in hematopoietic system is unclear. It is also not clear whether NGF mediated signals in hematopoietic cells are identical to those in neuronal cells. Results: To study the signal transduction pathways induced by NGF treatment in hematopoietic cells, we utilized the mastocytoma cell line HMC-1(V560G c-Kit) which expresses the NGF receptor, t ropomyosin-r eceptor-k inase (Trk)A, as well as the constitutively activated SCF receptor, V560G c-Kit, which can be inhibited completely by treatment with the potent tyrosine kinase inhibitor imatinib mesylate (imatinib). NGF rescues HMC-1(V560G c-Kit) cells from imatinib mediated cell death and promotes proliferation. To examine the NGF mediated proliferation and survival in these cells, we compared the NGF mediated upregulated genes (30 and 120 min after stimulation) to the downregulated genes by imatinib treatment (downregulation of c-Kit activity for 4 h) by transcriptome analysis. The following conclusions can be drawn from the microarray data: Firstly, gene expression profiling reveals 50% overlap of genes induced by NGF-TrkA with genes expressed downstream of V560G c-Kit. Secondly, NGF treatment does not enhance expression of genes involved in immune related functions that were down regulated by imatinib treatment. Thirdly, more than 55% of common upregulated genes are involved in cell proliferation and survival. Fourthly, we found Kruppel-like factor (KLF) 2 and Smad family member 7 (SMAD7) as the NGF mediated novel downstream genes in hematopoietic cells. Finally, the downregulation of KLF2 gene enhanced imatinib induced apoptosis. Conclusion: NGF does not induce genes which are involved in immune related functions, but induces proliferation and survival signals in HMC-1(V560G c-Kit) cells. Furthermore, the current data provide novel candidate genes, KLF2 and SMAD7 which are induced by NGF/TrkA activation in hematopoietic cells. Since the depletion of KLF2 causes enhanced apoptosis of HMC-1(V560G c-Kit), KLF2 may play a role in the NGF mediated survival signal. [ABSTRACT FROM AUTHOR]
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- 2011
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31. Targeted Therapies: The Rare Cancer Paradigm
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Pierotti, Marco A., Negri, Tiziana, Tamborini, Elena, Perrone, Federica, Pricl, Sabrina, and Pilotti, Silvana
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TARGETED drug delivery , *IMATINIB , *TREATMENT of chronic myeloid leukemia , *PROTEIN-tyrosine kinases , *ENZYME activation , *COLON cancer treatment - Abstract
Abstract: This review analyzes the state of the art of targeted therapies for several tumors, starting from the paradigmatic example of Imatinib treatment in chronic myelogenous leukemia (CML). We discuss how rare tumors can be models for various mechanisms of receptor tyrosine kinase (RTK) activation, and provide the opportunity to develop new therapies also for more common cancer types. We discuss the activation of the downstream RTK effectors as further targets for therapies in colorectal cancer. Finally, we highlight how a novel multidimensional approach which adds an in silico dimension to the in vitro and in vivo approach, can predict clinical results. [Copyright &y& Elsevier]
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- 2010
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32. Chromosomal complexity as a biomarker to de-escalate adjuvant imatinib treatment in high-risk gastrointestinal stromal tumor
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Sverre Heim, Ioannis Panagopoulos, Toto Hølmebakk, Francesca Micci, Jeanne-Marie Berner, Ivar Hompland, Bodil Bjerkehagen, Ludmila Gorunova, and Kjetil Boye
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Cancer Research ,Stromal cell ,business.industry ,Growth factor ,medicine.medical_treatment ,Alpha (ethology) ,PDGFRA ,Imatinib treatment ,Oncology ,medicine ,Cancer research ,Biomarker (medicine) ,High Risk Gastrointestinal Stromal Tumor ,business ,Adjuvant - Abstract
11535 Background: Gastrointestinal stromal tumors (GISTs) are characterized molecularly by oncogenic KIT or platelet-derived growth factor alpha ( PDGFRA) mutations. Malignant progression of primary GISTs occurs through stepwise accumulation of additional chromosomal aberrations, such as losses of chromosome arms 14q, 22q, 1p, 15q and Xp. After surgical resection of primary GIST, three years of adjuvant imatinib treatment is recommended for patients with an estimated high risk of recurrence. Still, nearly half of high-risk patients are cured by surgery alone, indicating that selection of patients could be improved. We hypothesized that high-risk GISTs with few chromosomal aberrations had a favorable outcome, and might not benefit from adjuvant therapy. The aim of the study was to investigate if chromosomal complexity could be used as a biomarker in de-escalation of adjuvant imatinib treatment. Methods: GIST patients undergoing surgical resection of their primary tumor between 1998 and 2020 were identified in the sarcoma database at Oslo University Hospital. All samples with available karyotype analysis made on fresh tumor tissue were included. Karyotypes were categorized as simple if they had ≤5 chromosomal changes, and complex if there were > 5 chromosomal aberrations. Results: Chromosomal aberrations were detected in 226 tumors, of which 181 (80.1 %) were gastric. The most frequent resulting imbalances were loss of 14q (75.9 %), 22q (43.5 %), 1p (36.6 %), and 15q (29.6 %). One-hundred and thirty-six tumors (60.2 %) had simple karyotypes whereas 90 (39.8 %) were complex. Cytogenetically complex tumors were larger ( P< 0.001), had a higher mitotic count ( P= 0.009), and were more often non-gastric ( P< 0.001). There was a strong association between chromosomal complexity and risk classification according to the modified NIH criteria ( P< 0.001). Thirty-eight of 58 (65.5 %) high-risk tumors were karyotypically complex compared to 37 of 144 (25.7 %) tumors that were not high-risk. In the high-risk group, 17 patients experienced disease recurrence, of whom one had a simple and 16 had a complex tumor karyotype. Estimated 5-year recurrence-free survival (RFS) for patients with simple tumor karyotypes was 94 % compared to 51 % for patients with cytogenetically complex tumors ( P= 0.004). Adjuvant and/or neoadjuvant imatinib treatment was administered to 40 high-risk patients with a median treatment duration of 33 months (range 2-60 months). A complex karyotype was associated with poor RFS both in patients with ( P= 0.016) and without ( P= 0.046) adjuvant imatinib. Conclusions: Chromosomal complexity was strongly associated with poor RFS in localized, high-risk GIST. Recurrences were infrequent for tumors with simple karyotypes, indicating that de-escalation of adjuvant imatinib treatment should be further explored in patients with cytogenetically simple GISTs.
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- 2021
33. Novel application of Kaplan-Meier methods to model tolerance for nonadherence to imatinib in patients with chronic myeloid leukemia (CML) in the ADAGIO study
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Mavis Obeng-Kusi, Marie-Anne van Lierde, Karen MacDonald, and Ivo Abraham
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Oncology ,Cancer Research ,medicine.medical_specialty ,Treatment response ,business.industry ,Myeloid leukemia ,Imatinib ,Imatinib treatment ,Internal medicine ,medicine ,In patient ,business ,medicine.drug - Abstract
7038 Background: Although adherence to imatinib treatment has been shown to be critical for attaining treatment response among patients with CML, some studies have suggested a 7.3-9.9% nonadherence tolerance margin before loss of treatment effects. We aimed to model probabilistically the margin of tolerance required to ensure treatment response among patients prescribed imatinib and the margin, if any, before treatment response is at risk. Methods: We performed a post hoc analysis of the ADAGIO study conducted in Belgium on 169 evaluable patients ( Blood 2009). Using the pill count ratio as, what in conventional survival analysis would be, the time variable, we modeled the cumulative likelihood of treatment response as a function of increasing pill count adherence. We applied Kaplan-Meier methods to model the likelihood of complete cytogenetic (CCyR), complete hematological (CHR), major molecular (MMR) and optimal (OR) (as defined by the European Leukemia Net) response as a function of 90-day pill count adherence. Kaplan-Meier methods thus estimated the tolerance for nonadherence to imatinib by calculating the 1 minus Kaplan-Meier estimate for treatment response. Results: Analyses (see Table) showed that ̃100% adherence of prescribed dose is associated with probabilities (rounded) of 0.84 for CHR, 0.83 for CCyR, 0.82 for OR, and 0.77 for MMR; compared to, 0.37 (CHR and CCyR), 0.35 (OR), and 0.39 (MMR) at 90% adherence. (of 0.7698 (MMR). Increasing the intake of imatinib from 90% to 100% of the prescribed dose increased the likelihood of the various treatment responses by 1.95 to 2.35-fold. Conclusions: Our findings challenge any previously estimated tolerance for nonadherence. There is virtually no margin for nonadherence if the objective is to optimize the likelihood of treatment response, and only a minimal margin to avoid impaired treatment response. Under such adherence, response rates similar to those in the pivotal IRIS trial can be obtained. Clinicians must assess and promote patient adherence, and patients must be perfectly adherent.[Table: see text]
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- 2021
34. Pathogenesis, treatment effects, and resistance dynamics in chronic myeloid leukemia - insights from mathematical model analyses.
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Roeder, Ingo and Glauche, Ingmar
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CHRONIC myeloid leukemia , *PROTEIN-tyrosine kinases , *PATHOLOGY , *MATHEMATICAL models , *CLINICAL trials - Abstract
Mathematical models and simulation studies are powerful tools to investigate dynamic properties of complex systems. Specifically, they can be used to test alternative hypotheses on underlying biological mechanisms for their consistency with real data and therefore to effectively guide the design of new experimental strategies or clinical trials. In this study, we present an overview of recently published mathematical approaches applied to the description of chronic myeloid leukemia (CML). We discuss three different fields relevant to clinical issues: the pathogenesis of the malignancy, the treatment effects of the tyrosine kinase inhibitor imatinib, and the process of acquired treatment resistance highlighting both the differences and the consistencies in the proposed hypotheses and the resulting conclusions. The mathematical models presented agree that CML can adequately be described as a clonal competition between normal and leukemic stem cells for a common resource. Furthermore, a certain therapeutic effect of imatinib on leukemic stem cells turned out to be necessary to consistently explain clinical data on the long-term response of CML patients under imatinib treatment. However, the approaches described cannot resolve the question whether or not this effect is sufficient to ultimately eradicate malignant stem cells. A number of different hypotheses have been proposed concerning the initiation and the dynamics of treatment-resistant malignant stem cell clones. The theoretical results clearly indicate that further experimental effort with the particular focus on the quantitative monitoring of resistant clones will be required to definitely distinguish between these hypotheses. [ABSTRACT FROM AUTHOR]
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- 2008
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35. CML-368: Response to Imatinib Treatment in Chronic Myeloid Leukemia According to BCR-ABL Transcript
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Carlos Roberto Best Aguilera, Bárbara García Reyes, Saribethe Mahely Visuetti Pimentel, Areli Sarai Calderón Valdez, Alicia Elizabeth Guzmán Hernández, Arianna Robles Rodríguez, Laura Adriana Rivera Mendoza, Titania del Carmen Acosta Hernández, Luis Mario Villela Martínez, Oscar Rodrigo Gómez Vázquez, Juan Carlos López Hernández, and Aldo Fernando Adrián Gutiérrez Alatorre
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Disease Response ,business.industry ,Disease progression ,Myeloid leukemia ,Imatinib ,Context (language use) ,Hematology ,Imatinib treatment ,Imatinib mesylate ,hemic and lymphatic diseases ,Internal medicine ,Molecular Response ,medicine ,business ,medicine.drug - Abstract
Context The chronic myeloid leukemia (CML) cytogenetic hallmark t (9; 22) (q34; q11.2) generates different transcripts, which had been postulated to play a role in imatinib treatment response. Objective To assess the molecular response, loss of response, and disease progression as a function of the BCR-ABL transcript variant in a group of CML patients treated with imatinib. Patients and methods 61 CML chronic-phase patients were analyzed for imatinib molecular response according to the variant of the transcript detected by RT-PCR. Square Chi test was used to evaluate a set of variables that included the following: major molecular response (MMR), major molecular response according to imatinib dose, time to MMR, deep molecular response (DMR), loss of response, and disease progression. Results All three variants of the transcript were identified. However, the b3a2/b2a2 variant was only presented in 1 case and is, therefore, excluded from the analysis. E13a2 (b2a2) variant was identified in 27 (45%) patients and E14a2 (b3a2) in 33 (55%) patients. Results are as following: E13a2 (b2a2) variant: MMR, 74%; major molecular response by dose 400 mg, 63%; 600 mg, 3%; 800 mg, 12%; time to MMR 48 months, 22%; loss of MMR, 8%; progression, 18%; DMP, 63%. E14a2 (b3a2) variant: MMR, 78%; major molecular response by dose 400 mg, 44%; 600 mg, 18%; 800 mg, 11%; time to MMR 48 months, 42%; loss of MMR, 3%; progression, 9%; DMP, 63%. No significate statistical differences were found between these variants regarding the set of analyzed variables. Conclusions In this group of patients, the BCR-ABL p210 transcript variants had no impact on disease response to imatinib mesylate.
- Published
- 2020
36. Imatinib-induced Gastrointestinal Vascular Ectasia in a Patient with Advanced GIST: Case Report and Literature Review
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Gil Bar-Sela, Mahmoud Abu-Amna, and Halim Awadie
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Cancer Research ,medicine.medical_specialty ,Gastrointestinal Stromal Tumors ,Anemia ,Antineoplastic Agents ,Imatinib therapy ,Multimodal Imaging ,Gastroenterology ,Imatinib treatment ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Ectasia ,medicine ,Humans ,neoplasms ,Aged ,GiST ,business.industry ,Gastric antral vascular ectasia ,Imatinib ,General Medicine ,medicine.disease ,Surgery ,Oncology ,Positron-Emission Tomography ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,Female ,030211 gastroenterology & hepatology ,Upper gastrointestinal bleeding ,Tomography, X-Ray Computed ,business ,Gastric Antral Vascular Ectasia ,medicine.drug - Abstract
BACKGROUND Imatinib is generally well tolerated in the treatment of advanced gastrointestinal stromal tumors (GIST). Gastrointestinal vascular ectasia (GIVE) and gastric antral vascular ectasia (GAVE), while rare, are significant under-reported complications of imatinib therapy. CASE REPORT We present one patient with GIVE complicating imatinib therapy with a literature review of this rare side-effect. RESULTS A 68-year-old woman was diagnosed with advanced GIST, wild-type CKIT. After 3 months of treatment with imatinib, she had partial response. However, she was diagnosed with GAVE and, later, also with GIVE. During her 3-year imatinib treatment, she suffered from severe anemia and required blood transfusions. Conservative treatments were not helpful and the ectatic lesions resolved only with cessation of imatinib. CONCLUSION This confirms a causal relationship between GIVE and imatinib. GIVE and GAVE should be considered possible causes of anemia and upper gastrointestinal bleeding in patients receiving imatinib therapy.
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- 2016
37. Long-term adjuvant imatinib treatment for a patient who underwent complete resection of a localized recurrent gastrointestinal stromal tumor after preoperative imatinib treatment: A case report
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Chunhui Shou, Jiren Yu, Kai Li, Welda E H Tjhoi, and Wei-Li Yang
- Subjects
Male ,medicine.medical_specialty ,Gastrointestinal Stromal Tumors ,medicine.medical_treatment ,Antineoplastic Agents ,Complete resection ,Imatinib treatment ,gastrointestinal stromal tumor ,surgery ,03 medical and health sciences ,0302 clinical medicine ,Neoplasm Recurrence ,Text mining ,recurrent ,medicine ,Humans ,long-term treatment ,030212 general & internal medicine ,Clinical Case Report ,neoplasms ,Chemotherapy ,GiST ,business.industry ,General Medicine ,Middle Aged ,digestive system diseases ,Surgery ,imatinib ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,Recurrent Gastrointestinal Stromal Tumor ,Neoplasm Recurrence, Local ,business ,Adjuvant ,Research Article - Abstract
Rationale: The efficiency and tolerance of long-term adjuvant imatinib treatment for patient who underwent complete resection of a localized recurrent gastrointestinal stromal tumor (GIST) was unknown. Patient concerns: A 45-year-old man underwent complete resection of an intestinal GIST in August 2001. Four years later, a giant (11 × 8 × 6 cm) recurrent GIST located in the retroperitoneum was detected. Diagnosis: The recurrent tumor was positive for CD117 by immunohistochemistry. Interventions: The recurrent tumor was completely resected after 4 months of effective imatinib treatment (400 mg/day), and the patient continued imatinib treatment postoperatively. In June 2011, imatinib treatment was stopped for 3 weeks because of hepatitis B infection, and resumed with a reduced dose level of 300 mg/day when liver function recovered. In March 2017, imatinib treatment was interrupted again for 12 days because the patient underwent cholecystectomy. Outcomes: In December 2017, a computed tomography scan showed no signs of tumor recurrence. To date, the patient has been under adjuvant imatinib treatment for >12 years without severe side effects. The plasma concentration of imatinib (detected in February 2018) was trough concentration (Cmin) 1015.7 ng/mL and peak concentration (Cmax) 1550.5 ng/mL. Lessons: This case report highlights the active role of long-term (>12 years) imatinib treatment after complete resection of localized recurrent GIST.
- Published
- 2019
38. The intracellular negative regulator genes of the Wnt signaling in imatinib treatment
- Author
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Burcu Çerçi, Melek Pehlivan, and Hakki Ogun Sercan
- Subjects
Cancer research ,Wnt signaling pathway ,General Medicine ,Biology ,Imatinib treatment ,Gene ,Intracellular ,Negative regulator - Published
- 2021
39. Partial response to imatinib treatment in a patient with unresectable gastrointestinal stromal tumor: A case report and mini literature review
- Author
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Dong Xia, Libo Feng, Liang Xu, Xiaolong Wu, and Qing Liu
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Imatinib treatment ,03 medical and health sciences ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,hemic and lymphatic diseases ,Internal medicine ,Partial response ,medicine ,Stromal tumor ,neoplasms ,GiST ,business.industry ,Cancer ,Imatinib ,Articles ,General Medicine ,medicine.disease ,digestive system diseases ,Clinical trial ,030104 developmental biology ,Imatinib mesylate ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
The aim of the present study was to evaluate the efficacy and safety of imatinib mesylate in unresectable gastrointestinal stromal tumor (GIST) and to discuss its therapeutic regimen. A patient with unresectable GIST is described, and several key clinical studies are reviewed, including the clinical trials B2222 and S0033, which contain recently reported results of the long-term clinical outcome of imatinib in patients with unresectable or metastatic GIST. The recent results of the two studies demonstrate the long-term efficacy and safety of imatinib for unresectable or metastatic GIST. A positive response to imatinib treatment was observed in the present patient, which is consistent with the data of the B2222 and S0033 trials. However, further long-term, large-scale, multicenter and controlled trials are required to determine the relative efficacy of combining imatinib agents with surgical procedures or administering imatinib alone.
- Published
- 2016
40. The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment
- Author
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Deborah L. White, Andrew Grigg, Laura N Eadie, Timothy P. Hughes, David T Yeung, Michael Osborn, Verity A Saunders, and Phuong Dang
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,First line ,Hematology ,Imatinib treatment ,Outcome (game theory) ,Surgery ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical significance ,business ,neoplasms - Abstract
The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment
- Published
- 2016
41. Granulocytic Sarcoma of Ovary Associated with Chronic Myelogenous Leukaemia Mimicking Carcinoma: A Rare Case Report
- Author
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Surendra Nath Senapati, Kirti Ranjan Mohanty, Tapan Kumar Sahoo, Diptirani Samanta, K. Roopesh, and Chaitali Bose
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,medicine.disease ,Chronic myeloid leukaemia ,Imatinib treatment ,hemic and lymphatic diseases ,Rare case ,Primary infertility ,medicine ,Carcinoma ,Neoplasm ,Sarcoma ,business ,Chronic myelogenous leukaemia - Abstract
Granulocytic sarcoma is a rare haematological neoplasm due to extramedullary leukemic deposits. Granulocytic Sarcoma of ovary is even rare associated with chronic myeloid leukaemia and responds to imatinib treatment. A strong vigilance is required. Here we report a case of granulocytic sarcoma of ovary in a 31 year old female with primary infertility being provisionally diagnosed as
- Published
- 2016
42. Hair loss associated with imatinib treatment: a dermoscopic study
- Author
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Shiang-Yu Yang, Shih-Ying Chen, and Shih-Tsung Cheng
- Subjects
medicine.medical_specialty ,business.industry ,MEDLINE ,Dermatology ,medicine.disease ,Imatinib treatment ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Hair loss ,medicine.anatomical_structure ,Text mining ,030220 oncology & carcinogenesis ,Scalp ,medicine ,business - Published
- 2017
43. Imatinib Treatment of Lymphomatoid Papulosis Associated with Myeloproliferative Hypereosinophilic Syndrome Presenting the FIP1L1-PDGFRA Fusion Gene
- Author
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Enric Llistosella, Dolors Sitjas, Pablo García-Martínez, Ramon M. Pujol, Fernando Gallardo, Blanca Espinet, Maria I. Hernández-Muñoz, and María Rodríguez-Rivera
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Receptor, Platelet-Derived Growth Factor alpha ,Skin Neoplasms ,Oncogene Proteins, Fusion ,Biopsy ,Treatment outcome ,Limfomes -- Tractament ,Antineoplastic Agents ,Dermatology ,Imatinib treatment ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,Myeloproliferative Disorders ,Lymphomatoid Papulosis ,hemic and lymphatic diseases ,Hypereosinophilic Syndrome ,Biomarkers, Tumor ,medicine ,Humans ,Lymphomatoid papulosis ,Protein Kinase Inhibitors ,In Situ Hybridization, Fluorescence ,mRNA Cleavage and Polyadenylation Factors ,Hypereosinophilic syndrome ,business.industry ,General Medicine ,medicine.disease ,Immunohistochemistry ,Fip1l1 pdgfra ,Treatment Outcome ,Imatinib mesylate ,RL1-803 ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,Cancer research ,Gene Fusion ,business ,030215 immunology - Abstract
Peripheral blood eosinophilia has been reported to occur in a wide range of haematological malignancies including primary cutaneous lymphomas. The concurrence of lymphomatoid papulosis (LyP) with peripheral blood eosinophilia seems to be an uncommon phenomenon. Atypical lymphocytes in LyP display the phenotype of activated T-helper cells, consistently express CD30 antigen, have a Th2 cytokine profile, and secrete eosinophilstimulating cytokines. Cases of LyP have been reported in association with myeloproliferative hypereosinophilic syndrome (M-HES) presenting the Fip1-like 1/plateletderived growth factor receptor-α (FIP1L1-PDGFRA) fusion gene. In such cases, imatinib treatment may lead to a complete and persistent resolution of LyP lesions.
- Published
- 2017
44. Long-Term Imatinib Treatment for Patients with Unresectable or Recurrent Gastrointestinal Stromal Tumors
- Author
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Toru Yanoma, Hiroyuki Kuwano, Nobuhiro Nakazawa, Mitsuhiro Yanai, Kyoichi Ogata, Kiyohito Iwamatsu, Yasunari Ubukata, Akiharu Kimura, Norimichi Kogure, and Masaki Suzuki
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Multivariate analysis ,Stromal cell ,Time Factors ,Gastrointestinal Stromal Tumors ,Antineoplastic Agents ,Disease ,Imatinib treatment ,03 medical and health sciences ,0302 clinical medicine ,Clinical Trials, Phase II as Topic ,Japan ,Gastrectomy ,Internal medicine ,Medicine ,Humans ,neoplasms ,Protein Kinase Inhibitors ,Aged ,Gastrointestinal Neoplasms ,Retrospective Studies ,Aged, 80 and over ,GiST ,business.industry ,Gastroenterology ,Imatinib ,Middle Aged ,Prognosis ,Long-Term Care ,Survival Analysis ,030104 developmental biology ,Imatinib mesylate ,Treatment Outcome ,Clinical Trials, Phase III as Topic ,Tumor progression ,030220 oncology & carcinogenesis ,Disease Progression ,Imatinib Mesylate ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug ,Follow-Up Studies - Abstract
Background: Only limited data are available concerning the long-term outcomes of imatinib treatment among Japanese or Asian patients with advanced or recurrent gastrointestinal stromal tumors (GIST). Our multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent GIST. Summary: The clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001 to 2011 were retrospectively reviewed (GREAT study). Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The patients treated with imatinib (n = 41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3, 74.9, and 53.8% respectively. In univariate and multivariate analyses, imatinib continuation with dose reduction and achieving a complete or partial response were found to be associated with increased OS. The results of 2 large-scale, long-term trials demonstrate that the risk of tumor progression decreases with increased treatment duration. Furthermore, the interruption of imatinib treatment in responsive and controlled patients results in a high risk of disease progression. Key Messages: Long-term imatinib treatment is recommended for patients with nonprogressive disease. If patients experience significant toxicities, temporary dose reduction and treatment continuation might be useful.
- Published
- 2018
45. Imatinib Treatment of Chronic Myeloid Leukemia Reveals a Preexisting CALR-mutated Essential Thrombocythemia
- Author
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Anne Bouvier, Damien Luque Paz, Rébecca Jouanneau-Courville, Bénédicte Ribourtout, Laurane Cottin, Odile Blanchet, Anaïse Blouet, Valérie Ugo, Marie-Christine Rousselet, Yannick Le Bris, Service d'Oncologie Médicale [CH Cholet], Centre Hospitalier de Cholet (CHC), Laboratoire d’anatomopathologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), UFR Santé [UNIV Angers], Université d'Angers (UA), Laboratoire d'Hematologie [CHU Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), Laboratoire d'Hématologie Biologique (Hémato - ANGERS), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
- Subjects
0301 basic medicine ,business.industry ,Essential thrombocythemia ,lcsh:RC633-647.5 ,Myeloid leukemia ,Case Report ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,medicine.disease ,Imatinib treatment ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Text mining ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,business ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2018
46. Gender andBCR-ABLtranscript type are correlated with molecular response to imatinib treatment in patients with chronic myeloid leukemia
- Author
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Peter Ainsworth, Ronald F. Carter, Jocob Dyck, Randa Stringer, Maria Harvey, Christopher M. Hillis, Brian Leber, Jenny Sjaarda, Guillaume Paré, Bekim Sadikovic, and Hanxin Lin
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Fusion Proteins, bcr-abl ,Gene Expression ,Antineoplastic Agents ,Imatinib treatment ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Break point ,Recurrence ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,In patient ,RNA, Messenger ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,business.industry ,Myeloid leukemia ,Imatinib ,Hematology ,General Medicine ,Middle Aged ,Alternative Splicing ,Regimen ,Treatment Outcome ,030220 oncology & carcinogenesis ,Molecular Response ,Major Molecular Response ,Immunology ,Imatinib Mesylate ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Objectives Achieving a major molecular response (MMR) is the goal of imatinib therapy for chronic myeloid leukemia. However, the association between gender, BCR-ABL transcript type, and age with MMR is not well understood and often controversial. Methods We retrospectively analyzed 166 patients who have been treated with imatinib for up to 10 yr. Results Men had a lower MMR rate than women (63.3% vs. 81.6%, P = 0.006) and a shorter time to relapse (median 354 vs. 675 d, P = 0.049), while patients with b3a2 or with both b3a2 and b2a2 break point transcripts had higher MMR rate than those with b2a2 (81.8%, 77.1% vs. 60.7%, P = 0.023 for b3a2 vs. b2a2, P = 0.043 for both vs. b2a2). A striking difference was found between men with b2a2 and women with both b2a2 and b3a2 in terms of MMR rate (43.8% vs. 88.9%), MMR rate within 6 months (7.1% vs. 62.5%) and the time to MMR (median d 493 vs. 159, P = 0.036). Conclusions Both gender and BCR-ABL transcript, but not age, were significantly associated with the molecular response. Men with b2a2 represent a less favorable group in their response to imatinib treatment and may need alternative therapy regimen and closer monitoring.
- Published
- 2015
47. A multicenter long-term study of imatinib treatment for Japanese patients with unresectable or recurrent gastrointestinal stromal tumors
- Author
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Hiroyuki Ando, Kyoichi Ogata, Minoru Fukuchi, Hitoshi Ojima, Erito Mochiki, Norimichi Kogure, Yoshitaka Toyomasu, Nobuyuki Uchida, Takehiko Yokobori, Hiroyuki Kuwano, Tetsuro Ohno, Ryuusuke Aihara, Norihiro Haga, Masaki Suzuki, and Akiharu Kimura
- Subjects
medicine.medical_specialty ,Stromal cell ,Multivariate analysis ,GiST ,business.industry ,Imatinib ,General Medicine ,Disease ,Gastroenterology ,Imatinib treatment ,Surgery ,Imatinib mesylate ,Long term learning ,Oncology ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Background and Objectives This multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent gastrointestinal stromal tumors (GIST). Methods The clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001–2011 were retrospectively reviewed. Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The median follow-up period was 4.0 years. Results After a median follow-up period of 4.0 years, the patients treated with imatinib (n = 41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3%, 74.9%, and 53.8%, respectively. In univariate and multivariate analyses, imatinib dose reduction and achieving a complete or partial response were found to be associated with increased OS. Conclusions Long-term imatinib treatment is recommended for patients with non-progressive disease. If patients experience significant toxicities, temporary dose reduction might be useful. J. Surg. Oncol. 2014; 110:942–946. © 2014 Wiley Periodicals, Inc.
- Published
- 2014
48. Concomitant ATM Mutations Identified by Next Generation Sequencing in a Patient With New-Onset Acute Myeloid Leukemia Following Imatinib Treatment for Chronic Myeloid Leukemia
- Author
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Eric Vick, Matthew K Stein, Melissa Crawley, and Michael Gary Martin
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Imatinib treatment ,DNA sequencing ,New onset ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Text mining ,030220 oncology & carcinogenesis ,Concomitant ,Internal medicine ,Medicine ,business ,Letter to the Editor - Published
- 2018
49. Imatinib Mesylate for Patients With Unresectable or Recurrent Gastrointestinal Stromal Tumors: 10-Year Experience From Vietnam
- Author
-
Phuong Nguyen Thi Bich, Kien Do Hung, Gia Nguyen Hoang, and Quang Le Van
- Subjects
Adult ,Male ,Oncology ,unresectable or recurrent ,medicine.medical_specialty ,Time Factors ,Stromal cell ,Gastrointestinal Stromal Tumors ,Imatinib treatment ,03 medical and health sciences ,0302 clinical medicine ,imatinib mesylate ,hemic and lymphatic diseases ,Internal medicine ,Overall survival ,Humans ,Medicine ,Protein Kinase Inhibitors ,neoplasms ,GISTs ,Aged ,Gastrointestinal Neoplasms ,Retrospective Studies ,Aged, 80 and over ,Response rate (survey) ,Performance status ,business.industry ,Imatinib ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,Survival Analysis ,Progression-Free Survival ,Clinical Practice ,Imatinib mesylate ,Vietnam ,030220 oncology & carcinogenesis ,Special Collection on Cancers in Vietnam: Burden and Control Efforts ,Female ,030211 gastroenterology & hepatology ,Neoplasm Recurrence, Local ,business ,Research Article ,medicine.drug - Abstract
Only limited data are available concerning the long-term outcomes of imatinib treatment among Vietnamese or Asian patients with unresectable or recurrent gastrointestinal stromal tumors (GISTs). Our study, which was conducted in 188 patients, aimed to assess the efficacy of imatinib mesylate against unresectable or recurrent GISTs. Imatinib had a high response rate and long survival. Some predictors favorable for progression-free survival and overall survival are good performance status and response with imatinib. Findings are discussed in relation to clinical practice in low- and middle-income country.
- Published
- 2019
50. Second Attempt of TKI Discontinuation with Dasatinib for Treatment-Free Remission after Failing First Attempt with Imatinib: Treatment-Free Remission Accomplished By Dasatinib (TRAD) Trial
- Author
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Lynn Savoie, Donna L. Forrest, Anargyros Xenocostas, Elena Liew, Suzanne Kamel-Reid, Robert Delage, Pierre Laneuville, Stephen Couban, Kristjan Paulson, Jeffrey H. Lipton, Isabelle Bence-Bruckler, Lambert Busque, Brian Leber, and Dennis Dong Hwan Kim
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Imatinib treatment ,Discontinuation ,Clinical trial ,Dasatinib ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Imatinib mesylate ,030220 oncology & carcinogenesis ,Internal medicine ,Relapse pattern ,medicine ,Risk factor ,business ,medicine.drug - Abstract
Introduction: A Canadian tyrosine kinase inhibitor (TKI) discontinuation trial is ongoing to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation after imatinib (IM) treatment. The preliminary result indicate : 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4. We report here the preliminary analysis of the TFR rate at 6 months after DA discontinuation for the second TFR attempt. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level < MR4.0 on 2 consecutive occasions, or a single increase in BCR-ABL transcript level < MR3.0. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving > MR4 for a 2nd TFR attempt. The null hypothesis was a TFR2 rate of 17.5% while the alternative hypothesis was a TFR2 rate of 35.0% and the study was designed to reject our null hypothesis if > 28% of patients remain in TFR after DA discontinuation. Results: As of Jun 15, 2018, 53 (40.4%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 58.0% at 12 months (95% CI, 42.1-71.0%). Of the 53 patients who lost response, 51 patients received DA. The incidence of MMR, MR4 and MR4.5 at 3 months was 97.7%, 89.9%, and 84.6%, respectively. 25/ 51 patients receiving DA attained MR4.5 for 12 months or longer and discontinued it for a 2nd TFR attempt (TFR2). 21/25 (84.0%) of these patients lost molecular response at a median of 3.7 months after DA discontinuation. The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months (95% CI [7.9-39.5%], Fig 1A). Thus we cannot reject our null hypothesis based on this result. For risk factor analysis for maintaining TFR2, the variables analysed included Sokal risk score, IM duration, MR4/MR4.5 duration, monthly doubling time after IM discontinuation, time to molecular relapse after IM discontinuation, molecular relapse pattern after IM discontinuation (MMR loss vs MR4 loss), and BCR-ABL1 qPCR value prior to DA discontinuation. 1) Time to molecular relapse after IM discontinuation correlates with TFR2 (p 2) Molecular relapse pattern after IM discontinuation correlates with TFR2. The group who had loss of MMR after IM discontinuation lost molecular response faster after DA discontinuation (n=19; median 3.0 months) compared to those with two consecutive losses of MR4(n=6; 6.43 months; p=0.0435, HR 2.991; Fig 3B). 3) The group with 5.5 log reduction or deeper in BCR-ABL1 qPCR transcripts prior to DA discontinuation (n=19) showed a TFR2 rate of 28.7% at 6 months (median TFR2 duration of 4.04 months) versus 0% in the group with qPCR transcript level between 4.5 and 5.4 log reduction (n=6, median TFR2 duration of 2.89 months; p=0.017; Fig 3C). We did not identify any other risk factor for molecular relapse after DA discontinuation . The expansion kinetics of the leukemic clone after DA discontinuation is similar to that after IM discontinuation. Conclusion: These preliminary results suggest that rechallenge with DA after failing a first IM discontinuation attempt for TFR is well tolerated and effective as most cases rapidly regained at least MR4. However, more strict criteria should be considered for TFR2 attempt, including achievement of a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the 2nd TKI discontinuation attempt, and a MR4 duration of more than 12 months. Disclosures Kim: Pfizer: Consultancy; Paladin: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Bence-Bruckler:Lundbeck: Membership on an entity's Board of Directors or advisory committees. Delage:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Liew:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Laneuville:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Paladin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees.
- Published
- 2018
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