11 results on '"Leukemia, Myeloid, Chronic-Phase genetics"'
Search Results
2. Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells.
- Author
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Wang J, Lu L, Kok CH, Saunders VA, Goyne JM, Dang P, Leclercq TM, Hughes TP, and White DL
- Subjects
- Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cells, Cultured, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl metabolism, Gene Expression Regulation, Leukemic, HL-60 Cells, Humans, Imatinib Mesylate pharmacokinetics, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myeloid, Chronic-Phase genetics, Leukemia, Myeloid, Chronic-Phase metabolism, Leukemia, Myeloid, Chronic-Phase pathology, Leukocytes, Mononuclear metabolism, Organic Cation Transporter 1 genetics, Organic Cation Transporter 1 metabolism, PPAR gamma agonists, PPAR gamma antagonists & inhibitors, Fusion Proteins, bcr-abl antagonists & inhibitors, Imatinib Mesylate pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Leukocytes, Mononuclear drug effects, PPAR gamma metabolism
- Abstract
Imatinib is actively transported by organic cation transporter-1 (OCT-1) influx transporter, and low OCT-1 activity in diagnostic chronic myeloid leukemia blood mononuclear cells is significantly associated with poor molecular response to imatinib. Herein we report that, in diagnostic chronic myeloid leukemia mononuclear cells and BCR-ABL1
+ cell lines, peroxisome proliferator-activated receptor γ agonists (GW1929, rosiglitazone, pioglitazone) significantly decrease OCT-1 activity; conversely, peroxisome proliferator-activated receptor γ antagonists (GW9662, T0070907) increase OCT-1 activity. Importantly, these effects can lead to corresponding changes in sensitivity to BCR-ABL kinase inhibition. Results were confirmed in peroxisome proliferator-activated receptor γ-transduced K562 cells. Furthermore, we identified a strong negative correlation between OCT-1 activity and peroxisome proliferator-activated receptor γ transcriptional activity in diagnostic chronic myeloid leukemia patients (n=84; P <0.0001), suggesting that peroxisome proliferator-activated receptor γ activation has a negative impact on the intracellular uptake of imatinib and consequent BCR-ABL kinase inhibition. The inter-patient variability of peroxisome proliferator-activated receptor γ activation likely accounts for the heterogeneity observed in patient OCT-1 activity at diagnosis. Recently, the peroxisome proliferator-activated receptor γ agonist pioglitazone was reported to act synergistically with imatinib, targeting the residual chronic myeloid leukemia stem cell pool. Our findings suggest that peroxisome proliferator-activated receptor γ ligands have differential effects on circulating mononuclear cells compared to stem cells. Since the effect of peroxisome proliferator-activated receptor γ activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, caution should be applied when combining these therapies, especially in patients with high peroxisome proliferator-activated receptor γ transcriptional activity., (Copyright© Ferrata Storti Foundation.)- Published
- 2017
- Full Text
- View/download PDF
3. Low leukotriene B4 receptor 1 leads to ALOX5 downregulation at diagnosis of chronic myeloid leukemia.
- Author
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Lucas CM, Harris RJ, Giannoudis A, McDonald E, and Clark RE
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arachidonate 5-Lipoxygenase metabolism, Blast Crisis, Disease Progression, Down-Regulation, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Leukemia, Myeloid, Chronic-Phase diagnosis, Leukemia, Myeloid, Chronic-Phase genetics, Male, Middle Aged, RNA, Messenger genetics, Receptors, Leukotriene B4 genetics, Treatment Outcome, Young Adult, Arachidonate 5-Lipoxygenase genetics, Gene Expression Regulation, Leukemic, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Receptors, Leukotriene B4 blood
- Abstract
ALOX5 is implicated in chronic myeloid leukemia development in mouse leukemic stem cells, but its importance in human chronic myeloid leukemia is unknown. Functional ALOX5 was assessed using an LTB4 ELISA and ALOX5, and LTB4R1 mRNA expression was determined via a TaqMan gene expression assay. LTB4R1 and 5-LOX protein levels were assessed by cell surface flow cytometry analysis. At diagnosis ALOX5 was below normal in both blood and CD34(+) stem cells in all patients. On treatment initiation, ALOX5 levels increased in all patients except those who were destined to progress subsequently to blast crisis. LTB4 levels were increased despite low ALOX5 expression, suggesting that the arachidonic acid pathway is functioning normally up to the point of LTB4 production. However, the LTB4 receptor (BLT1) protein in newly diagnosed patients was significantly lower than after a period of treatment (P<0.0001). The low level of LTB4R1 at diagnosis explains the downregulation of ALOX5. In the absence of LTB4R1, the arachidonic acid pathway intermediates (5-HEPTE and LTA4) negatively regulate ALOX5. ALOX5 regulation is aberrant in chronic myeloid leukemia patients and may not be important for the development of the disease. Our data suggest caution when extrapolating mouse model data into human chronic myeloid leukemia., (Copyright© Ferrata Storti Foundation.)
- Published
- 2014
- Full Text
- View/download PDF
4. Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors.
- Author
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Kim SH, Menon H, Jootar S, Saikia T, Kwak JY, Sohn SK, Park JS, Jeong SH, Kim HJ, Kim YK, Oh SJ, Kim H, Zang DY, Chung JS, Shin HJ, Do YR, Kim JA, Kim DY, Choi CW, Park S, Park HL, Lee GY, Cho DJ, Shin JS, and Kim DW
- Subjects
- Adult, Aged, Antineoplastic Agents adverse effects, Benzamides adverse effects, Benzamides therapeutic use, Female, Follow-Up Studies, Fusion Proteins, bcr-abl genetics, Humans, Imatinib Mesylate, Leukemia, Myeloid, Chronic-Phase genetics, Leukemia, Myeloid, Chronic-Phase mortality, Male, Middle Aged, Mutation, Piperazines adverse effects, Piperazines therapeutic use, Protein Kinase Inhibitors adverse effects, Pyrazines adverse effects, Pyrazines therapeutic use, Pyrimidines adverse effects, Pyrimidines therapeutic use, Remission Induction, Treatment Outcome, Young Adult, Antineoplastic Agents therapeutic use, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl antagonists & inhibitors, Leukemia, Myeloid, Chronic-Phase drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2014
- Full Text
- View/download PDF
5. The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis.
- Author
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Nicolini FE, Ibrahim AR, Soverini S, Martinelli G, Müller MC, Hochhaus A, Dufva IH, Kim DW, Cortes J, Mauro MJ, Chuah C, Labussière H, Morisset S, Roche-Lestienne C, Lippert E, Hayette S, Peter S, Zhou W, Maguer-Satta V, Michallet M, Goldman J, Apperley JF, Mahon FX, Marin D, and Etienne G
- Subjects
- Adolescent, Adult, Aged, Cohort Studies, Drug Resistance, Neoplasm genetics, Female, Humans, Leukemia, Myeloid, Chronic-Phase mortality, Male, Middle Aged, Prospective Studies, Protein Kinase Inhibitors pharmacology, Retrospective Studies, Survival Rate, Young Adult, Fusion Proteins, bcr-abl genetics, Genes, abl, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase genetics, Mutation, Protein Kinase Inhibitors therapeutic use
- Abstract
The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact of this mutation on survival in early stages of disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64 patients with chronic phase chronic myelogenous leukemia harboring a T315I mutation and resistant to imatinib mesylate was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according to age at diagnosis, interval between disease diagnosis and start of imatinib treatment, and duration of imatinib therapy. Kaplan-Meier survival analyses demonstrated the significant negative impact of the presence of the T315I mutation on overall survival (since imatinib-resistance: 48.4 months for T315I(+) patients versus not reached for T315I(-) ones; P=0.006) and failure-free survival (since imatinib-resistance: 34.7 months for T315I(+) patients versus not reached for T315I(-) patients; P=0.003). In addition, Cox proportional hazard models adjusted on overall survival demonstrated the negative influence of the T315I mutation (P=0.02, HR=2.54). These results confirm early assumptions concerning the poor prognosis of chronic phase chronic myelogenous leukemia patients with the T315I mutation who are not eligible for allogeneic transplantation, and demonstrate the need for more therapeutic options.
- Published
- 2013
- Full Text
- View/download PDF
6. The response to imatinib and interferon-alpha is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive chronic myeloid leukemia patients in early chronic phase.
- Author
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Palandri F, Castagnetti F, Iacobucci I, Martinelli G, Amabile M, Gugliotta G, Poerio A, Testoni N, Breccia M, Bocchia M, Crugnola M, Rege-Cambrin G, Martino B, Pierri I, Radaelli F, Specchia G, Pane F, Saglio G, Rosti G, and Baccarani M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Benzamides, Clinical Trials as Topic, Female, Fusion Proteins, bcr-abl genetics, Humans, Imatinib Mesylate, Interferon-alpha administration & dosage, Kaplan-Meier Estimate, Leukemia, Myeloid, Chronic-Phase genetics, Male, Middle Aged, Piperazines administration & dosage, Prognosis, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors therapeutic use, Pyrimidines administration & dosage, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Chronic-Phase drug therapy, Piperazines therapeutic use, Pyrimidines therapeutic use
- Abstract
Before the introduction of imatinib, interferon alpha-based regimens were the gold standard for treatment of early chronic phase chronic myeloid leukemia patients. The combination of IFN-alpha with imatinib is currently being investigated in at least two large clinical trials, the German CML Study IV and the French SPIRIT trial. We reviewed the cytogenetic and molecular responses of 76 early chronic phase chronic myeloid leukemia patients who were treated with imatinib and interferon-alpha and of 419 early chronic phase chronic myeloid leukemia patients treated with imatinib alone front-line. The complete cytogenetic response rate was higher in the IM+IFN-alpha group than in the imatinib group at six months (60% vs. 42%; P=0.003), but not at 48 months (88% vs. 88%). The durability of the complete cytogenetic response was similar in the two groups with 94% and 91% of complete cytogenetic responders in continuous complete cytogenetic response at 48 months (P=0.56). The major molecular response rate was higher in the IM+IFN-alpha group at six months (58% vs. 34%; P=0.0001) and 12 months (67% vs. 47%; P=0.001) but not later on (65% vs. 57% at 48 months; P=0.25). Overall and progression free survival were comparable in the two groups; a significant trend to a better event free survival was observed in patients treated with PegIFNalpha (91% vs. 78%; P=0.02). These data suggest that the response to the combination treatment is more rapid. It is not yet known how much a rapid reduction will influence the longer-term overall and progression free survival, and the cure rate.
- Published
- 2010
- Full Text
- View/download PDF
7. Mobilization of autologous hematopoietic progenitors and subsequent transplantation is a safe and feasible procedure in chronic phase chronic myelogenous leukemia patients with cytogenetic resistance to imatinib.
- Author
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Prebet T, Tigaud I, Hayette S, Clapisson G, Philip I, Michallet M, and Nicolini FE
- Subjects
- Adult, Antimetabolites, Antineoplastic therapeutic use, Antineoplastic Agents pharmacology, Benzamides, Combined Modality Therapy, Cytarabine therapeutic use, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl antagonists & inhibitors, Fusion Proteins, bcr-abl genetics, Granulocyte Colony-Stimulating Factor pharmacology, Humans, Imatinib Mesylate, Interferons therapeutic use, Lenograstim, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase genetics, Male, Piperazines pharmacology, Pyrimidines pharmacology, Recombinant Proteins pharmacology, Remission Induction, Antineoplastic Agents therapeutic use, Hematopoietic Stem Cell Mobilization, Leukemia, Myelogenous, Chronic, BCR-ABL Positive surgery, Leukemia, Myeloid, Chronic-Phase surgery, Peripheral Blood Stem Cell Transplantation, Piperazines therapeutic use, Pyrimidines therapeutic use, Transplantation, Autologous
- Published
- 2005
8. Clinical significance of development of Philadelphia-chromosome negative clones in patients with chronic myeloid leukemia treated with imatinib mesylate.
- Author
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Perel JM, McCarthy C, Walker O, Irving I, Williams B, and Kennedy GA
- Subjects
- Acute Disease, Aged, Antineoplastic Agents pharmacology, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzamides, Bone Marrow pathology, Cytarabine administration & dosage, Disease Progression, Fatal Outcome, Fusion Proteins, bcr-abl antagonists & inhibitors, Fusion Proteins, bcr-abl genetics, Granulocyte Colony-Stimulating Factor administration & dosage, Humans, Hydroxyurea administration & dosage, Imatinib Mesylate, In Situ Hybridization, Fluorescence, Interferons administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive enzymology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myeloid pathology, Leukemia, Myeloid, Chronic-Phase enzymology, Leukemia, Myeloid, Chronic-Phase genetics, Leukemia, Myeloid, Chronic-Phase pathology, Male, Middle Aged, Neoplastic Stem Cells enzymology, Piperazines pharmacology, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Selection, Genetic, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Agents therapeutic use, Clone Cells ultrastructure, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid genetics, Leukemia, Myeloid, Chronic-Phase drug therapy, Neoplastic Stem Cells drug effects, Philadelphia Chromosome, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use
- Published
- 2005
9. Complex variant Philadelphia translocation involving the short arm of chromosome 9 in a case of chronic myeloid leukemia.
- Author
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Cianciulli AM, Marzano R, Merola R, Orlandi G, Petti MC, Guadagni F, and Pisani F
- Subjects
- Adult, Female, Humans, In Situ Hybridization, Fluorescence, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myeloid, Chronic-Phase genetics, Philadelphia Chromosome
- Abstract
Here we describe how we detected the BCR/ABL fusion gene on the short arm of der(9) combining classical GTG banding and Fluorescence In Situ Hybridization (FISH) in a case of chronic myeloid leukemia (CML). To our knowledge, variant translocations involving the short arm of chromosome 9, in literature, are almost rare in chronic myeloid leukemia. It is not clear if this complex genetic translocation represents clonal evolution or a unique, initial presentation variant of the Philadelphia chromosome (Ph).
- Published
- 2004
10. Lack of Bcr-Abl point mutations in chronic myeloid leukemia patients in chronic phase before imatinib treatment is not predictive of response.
- Author
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Agirre X, Fontalba A, Andreu EJ, Odero MD, Larráyoz MJ, Montiel C, Calasanz MJ, Fernández-Luna JL, and Prósper F
- Subjects
- Amino Acid Substitution, Benzamides, Clone Cells chemistry, Clone Cells ultrastructure, DNA Mutational Analysis, Drug Resistance, Neoplasm, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid, Chronic-Phase drug therapy, Mutation, Missense, Polymerase Chain Reaction, Protein Structure, Tertiary genetics, Treatment Outcome, DNA, Neoplasm genetics, Fusion Proteins, bcr-abl genetics, Genes, abl, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myeloid, Chronic-Phase genetics, Piperazines therapeutic use, Point Mutation, Pyrimidines therapeutic use
- Published
- 2003
11. Chronic myeloid leukemia in chronic phase with a partial trisomy 9 mosaicism.
- Author
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Vargas MT, Gonzalez-Ruano J, and Fernandez-Nóvoa MC
- Subjects
- Aged, Female, Gene Deletion, Humans, Mosaicism, Chromosomes, Human, Pair 9, Leukemia, Myeloid, Chronic-Phase genetics, Trisomy
- Published
- 1999
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