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1. Quintás-Cardama A, Cortes J: Management of patients with resistant or refractory chronic myelogenous leukemia. Oncology (Williston Park); 2008 Apr 15;22(4):430-7; discussion 437, 442, 446 passim
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  • [Title] Management of patients with resistant or refractory chronic myelogenous leukemia.
  • The introduction of imatinib mesylate (Gleevec) has dramatically changed the management and prognostic outlook of patients with chronic myeloid leukemia (CML).
  • Despite the outstanding results achieved with imatinib, approximately 20% to 30% of patients may either not respond to therapy or eventually develop resistance or intolerance to the drug.
  • Resistance to imatinib is mediated to a great extent by the emergence of mutations within the tyrosine kinase domain of the BCR-ABL oncogene.
  • A growing number of tyrosine kinase inhibitors (TKIs) with different pharmacokinetic and pharmacodynamic profiles are currently being investigated in clinical trials to determine their efficacy against CML resistant to imatinib therapy.
  • This review addresses the causes and consequences of imatinib resistance and current management of refractory CML with the second-generation TKIs.
  • [MeSH-major] Drug Resistance, Neoplasm. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Protein Kinase Inhibitors / therapeutic use
  • [MeSH-minor] Aniline Compounds / adverse effects. Aniline Compounds / therapeutic use. Benzamides. Dasatinib. Humans. Imatinib Mesylate. Nitriles / adverse effects. Nitriles / therapeutic use. Piperazines / pharmacology. Pyrimidines / adverse effects. Pyrimidines / pharmacology. Pyrimidines / therapeutic use. Quinolines / adverse effects. Quinolines / therapeutic use. Thiazoles / adverse effects. Thiazoles / therapeutic use. Treatment Outcome

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  • (PMID = 18472616.001).
  • [ISSN] 0890-9091
  • [Journal-full-title] Oncology (Williston Park, N.Y.)
  • [ISO-abbreviation] Oncology (Williston Park, N.Y.)
  • [Language] eng
  • [Grant] United States / NCI NIH HHS / CA / P30 CA016672
  • [Publication-type] Journal Article; Review
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; 0 / Aniline Compounds; 0 / Benzamides; 0 / Nitriles; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Quinolines; 0 / Thiazoles; 5018V4AEZ0 / bosutinib; 859212-16-1 / bafetinib; 8A1O1M485B / Imatinib Mesylate; RBZ1571X5H / Dasatinib
  • [Number-of-references] 55
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2. Deutsch E, Maggiorella L, Wen B, Bonnet ML, Khanfir K, Frascogna V, Turhan AG, Bourhis J: Tyrosine kinase inhibitor AG1024 exerts antileukaemic effects on STI571-resistant Bcr-Abl expressing cells and decreases AKT phosphorylation. Br J Cancer; 2004 Nov 1;91(9):1735-41
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  • [Title] Tyrosine kinase inhibitor AG1024 exerts antileukaemic effects on STI571-resistant Bcr-Abl expressing cells and decreases AKT phosphorylation.
  • Chronic myelogenous leukaemia (CML) is a clonal malignancy of the pluripotent haematopoietic stem cell, characterised by an uncontrolled proliferation and expansion of myeloid progenitors expressing a fusion oncogene, BCR-ABL, the molecular counterpart of the Ph1 chromosome.
  • The tyrosine kinase (TK) activity of BCR-ABL is known to activate several major signalling pathways in malignant cells, including Ras, JAK/STAT and PI3K/Akt with evidence of proteasome-mediated degradation of other targets such as the DNA repair protein DNA-PKcs and cyclin-dependent kinases inhibitor p27.
  • Targeting these abnormalities by blocking TK of BCR-ABL with STI571 provided a promising approach for the therapy of CML.
  • The recent development of resistance to STI571 illustrates, however, that the use of other TK inhibitors could be of major interest for therapeutic purposes.
  • To this end, the TK inhibitor Tyrphostin AG1024 was used to evaluate effect on regulation of BCR-ABL expression, inhibition of cell proliferation and tumour formation in vivo in human and murine BCR-ABL expressing cell lines.
  • Tyrphostin AG1024 was shown to downregulate expression of BCR-ABL and P-Akt, and to upregulate DNA-PKcs expression.
  • Thus, AG1024 is able to interfere with three major targets of BCR-ABL in leukaemic cells.
  • Interestingly, Tyrphostin AG1024 was also effective against cells resistant to STI571 by distinct mechanisms including Bcr-Abl mutation.
  • Therefore, these data suggest that Tyrphostin AG1024 could represent the basis of a novel therapy for STI571 refractory CML.
  • [MeSH-major] Drug Resistance, Neoplasm. Gene Expression Regulation, Leukemic. Leukemia, Erythroblastic, Acute / drug therapy. Protein-Serine-Threonine Kinases / metabolism. Protein-Tyrosine Kinases / antagonists & inhibitors. Protein-Tyrosine Kinases / metabolism. Proto-Oncogene Proteins / metabolism. Tyrphostins / therapeutic use
  • [MeSH-minor] Animals. Antineoplastic Agents / therapeutic use. Benzamides. Cell Proliferation / drug effects. DNA-Activated Protein Kinase. DNA-Binding Proteins / antagonists & inhibitors. Enzyme Inhibitors / therapeutic use. Fusion Proteins, bcr-abl. Humans. Imatinib Mesylate. Mice. Mice, Nude. Neoplasm Recurrence, Local / drug therapy. Neoplasm Recurrence, Local / metabolism. Neoplasm Recurrence, Local / pathology. Nuclear Proteins. Phosphorylation. Piperazines / pharmacology. Proto-Oncogene Proteins c-akt. Pyrimidines / pharmacology. Tumor Cells, Cultured

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  • (PMID = 15494718.001).
  • [ISSN] 0007-0920
  • [Journal-full-title] British journal of cancer
  • [ISO-abbreviation] Br. J. Cancer
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / DNA-Binding Proteins; 0 / Enzyme Inhibitors; 0 / Nuclear Proteins; 0 / Piperazines; 0 / Proto-Oncogene Proteins; 0 / Pyrimidines; 0 / Tyrphostins; 0 / tyrphostin AG 1024; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; EC 2.7.10.2 / Fusion Proteins, bcr-abl; EC 2.7.11.1 / AKT1 protein, human; EC 2.7.11.1 / DNA-Activated Protein Kinase; EC 2.7.11.1 / PRKDC protein, human; EC 2.7.11.1 / Protein-Serine-Threonine Kinases; EC 2.7.11.1 / Proto-Oncogene Proteins c-akt
  • [Other-IDs] NLM/ PMC2409959
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3. Borthakur G, Kantarjian H, Daley G, Talpaz M, O'Brien S, Garcia-Manero G, Giles F, Faderl S, Sugrue M, Cortes J: Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy. Cancer; 2006 Jan 15;106(2):346-52
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  • [Title] Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy.
  • BACKGROUND: Lonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models.
  • METHODS: In the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib.
  • Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily.
  • Ten patients had failed therapy with imatinib and 3 patients were intolerant to imatinib.
  • The median age of the patients was 62 years (range, 38-80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3-13 yrs).
  • In addition to imatinib mesylate, all patients had received prior therapy with interferon-alpha and seven patients had received other treatments.
  • The median duration of therapy with lonafarnib was 8 weeks (range, 2-41 wks).
  • One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months.
  • Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months.
  • Therapy was discontinued in one patient because of diarrhea not responding to dose adjustments.
  • CONCLUSIONS: Single-agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib.
  • [MeSH-major] Farnesyltranstransferase / antagonists & inhibitors. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperidines / therapeutic use. Pyridines / therapeutic use
  • [MeSH-minor] Adult. Aged. Aged, 80 and over. Antineoplastic Agents / therapeutic use. Benzamides. Drug Resistance, Neoplasm. Female. Humans. Imatinib Mesylate. Male. Middle Aged. Pilot Projects. Piperazines / therapeutic use. Pyrimidines / therapeutic use

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  • (PMID = 16342165.001).
  • [ISSN] 0008-543X
  • [Journal-full-title] Cancer
  • [ISO-abbreviation] Cancer
  • [Language] eng
  • [Publication-type] Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Piperidines; 0 / Pyridines; 0 / Pyrimidines; 193275-84-2 / lonafarnib; 8A1O1M485B / Imatinib Mesylate; EC 2.5.1.29 / Farnesyltranstransferase
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4. Ramchandren R, Schiffer CA: Dasatinib in the treatment of imatinib refractory chronic myeloid leukemia. Biologics; 2009;3:205-14
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  • [Title] Dasatinib in the treatment of imatinib refractory chronic myeloid leukemia.
  • The development of imatinib for the treatment of chronic myeloid leukemia (CML) has proven to be an example of medical success in the era of targeted therapy.
  • Additionally, patients who have progressed beyond the chronic phase of CML do relatively poorly with imatinib therapy.
  • Mechanisms of imatinib resistance include BCR-ABL point mutations resulting in decreased imatinib binding, as well as mutation-independent causes of resistance such as SRC family kinase dysregulation, BCR-ABL gene amplification, drug influx/efflux mechanisms and other poorly understood processes.
  • The options for therapy in these patients include stem cell transplantation, imatinib dose escalation as well as the use of second-generation tyrosine kinase inhibitors.
  • Moreover, several studies have evaluated dasatinib in patients who have progressed on imatinib therapy with encouraging results.
  • Although treatment options have increased, the choice of second-line therapy in patients with CML is influenced by concerns surrounding the duration of response as well as toxicity.

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  • (PMID = 19707409.001).
  • [ISSN] 1177-5475
  • [Journal-full-title] Biologics : targets & therapy
  • [ISO-abbreviation] Biologics
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] New Zealand
  • [Other-IDs] NLM/ PMC2726068
  • [Keywords] NOTNLM ; chronic myeloid leukemia (CML) / dasatinib / imatinib / nilotinib / resistance (imatinib resistance) / tyrosine kinase inhibitor
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5. Brixey AG, Light RW: Pleural effusions due to dasatinib. Curr Opin Pulm Med; 2010 Jul;16(4):351-6
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  • PURPOSE OF REVIEW: Dasatinib is a novel tyrosine-kinase inhibitor approved for treatment of BCR-ABL positive chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) after imatinib failure.
  • A twice-daily dosing regimen was found to significantly correlate with development of effusions, and therefore once-daily dosing is now approved for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia.
  • Management typically involves dose interruption or reduction, diuretics and short-term corticosteroid therapy.
  • SUMMARY: Dasatinib is a promising agent for the treatment of refractory chronic myeloid leukemia and acute lymphoblastic leukemia.
  • Incidence is decreasing with once-daily dosing, but when effusions do occur, most can be managed with specific measures without necessitating discontinuation of therapy.
  • [MeSH-minor] Clinical Trials as Topic. Dasatinib. Humans. Incidence. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Risk Factors

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  • (PMID = 20375898.001).
  • [ISSN] 1531-6971
  • [Journal-full-title] Current opinion in pulmonary medicine
  • [ISO-abbreviation] Curr Opin Pulm Med
  • [Language] eng
  • [Publication-type] Journal Article; Review
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 0 / Thiazoles; RBZ1571X5H / Dasatinib
  • [Number-of-references] 27
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6. Kim JA: Targeted therapies for the treatment of cancer. Am J Surg; 2003 Sep;186(3):264-8
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  • [Title] Targeted therapies for the treatment of cancer.
  • BACKGROUND: In contrast to conventional cytotoxic chemotherapy and radiation therapy, a new method of targeted cancer therapeutics is being directed towards molecular pathways that underlie the malignant phenotype.
  • These therapies target specific tumor cell receptors or signaling events that are critical to tumor progression while reducing toxicity to normal cells.
  • DATA SOURCES: The purpose of this review is to highlight several examples of novel targeted therapeutics that are currently approved by the FDA for treatment of patients with cancer.
  • Rituxan is a humanized monoclonal antibody that binds to the CD20 antigen present on B cell lymphomas and is currently approved for the treatment of patients with relapsed or refractory low-grade CD20 positive follicular lymphoma.
  • Finally, Gleevec is a tyrosine kinase inhibitor that inhibits abl-specific phosphorylation and is approved for use in select patients with chronic myelogenous leukemia that is refractory to interferon therapy.
  • CONCLUSIONS: The lessons learned from the use of these therapeutics will add to the growing knowledge of mechanistic approaches to the treatment of patients with cancer based upon targeted therapies, and herald a bright future that will improve the lives of patients with cancer.
  • [MeSH-major] Antineoplastic Agents / therapeutic use. Neoplasms / therapy
  • [MeSH-minor] Antibodies, Monoclonal / therapeutic use. Antibodies, Monoclonal, Humanized. Antibodies, Monoclonal, Murine-Derived. Benzamides. Breast Neoplasms / drug therapy. Female. Humans. Imatinib Mesylate. Lymphoma, B-Cell / drug therapy. Male. Piperazines / therapeutic use. Protein-Tyrosine Kinases / antagonists & inhibitors. Pyrimidines / therapeutic use. Rituximab. Trastuzumab

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  • (PMID = 12946830.001).
  • [ISSN] 0002-9610
  • [Journal-full-title] American journal of surgery
  • [ISO-abbreviation] Am. J. Surg.
  • [Language] eng
  • [Publication-type] Journal Article; Review
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antibodies, Monoclonal; 0 / Antibodies, Monoclonal, Humanized; 0 / Antibodies, Monoclonal, Murine-Derived; 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 4F4X42SYQ6 / Rituximab; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases; P188ANX8CK / Trastuzumab
  • [Number-of-references] 32
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7. Kreuzer KA, Le Coutre P, Landt O, Na IK, Schwarz M, Schultheis K, Hochhaus A, Dörken B: Preexistence and evolution of imatinib mesylate-resistant clones in chronic myelogenous leukemia detected by a PNA-based PCR clamping technique. Ann Hematol; 2003 May;82(5):284-9
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  • [Title] Preexistence and evolution of imatinib mesylate-resistant clones in chronic myelogenous leukemia detected by a PNA-based PCR clamping technique.
  • Recently, various mutations within the Abl sequence have been described that negatively affect imatinib binding to Bcr/Abl resulting in cellular resistance of chronic myeloid leukemia (CML) cells.
  • So far, little is known as to whether these mutations are preexisting or develop under imatinib therapy as current mutation analyses are limited by a low sensitivity of approximately 1:2 (50%) to 1:5 (20%).
  • By combining peptide nucleic acid (PNA)-based DNA clamping with a fluorescence hybridization probe assay, we developed a new and highly sensitive technique for the detection of known mutations within the Bcr/Abl kinase domain.
  • With this approach we investigated 19 cases of CML refractory to imatinib treatment before and during therapy.
  • By clamping of wild-type Abl through PNA we could effectively enhance the detection sensitivity for the Bcr/Abl mutations Thr315Ile, Glu255Lys, and Tyr253His such that 1 mutant cDNA molecule could be detected in 500 negatives (0.2%).
  • We observed in one case that a Gly255Lys mutation was detectable before treatment.
  • In two cases clonal evolution of known mutations developed gradually under treatment.
  • In another case an initially detectable Tyr253His mutation disappeared after therapy onset but was again observed after 6 weeks of imatinib treatment.
  • Preexisting and evolving Bcr/Abl mutations associated with an unfavorable prognosis could be safely detected by the presented technique.
  • This may facilitate risk stratification in CML and may serve as a model for individualized molecular monitoring and therapeutic strategies in other malignant diseases.
  • [MeSH-major] Drug Resistance, Neoplasm / genetics. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology. Peptide Nucleic Acids. Piperazines / therapeutic use. Pyrimidines / therapeutic use
  • [MeSH-minor] Adult. Aged. Aged, 80 and over. Benzamides. Binding, Competitive. Clone Cells. DNA Probes. Female. Fusion Proteins, bcr-abl / analysis. Fusion Proteins, bcr-abl / genetics. Humans. Imatinib Mesylate. Male. Middle Aged. Mutation. Nucleic Acid Hybridization / methods. Polymerase Chain Reaction / methods. Retrospective Studies. Sensitivity and Specificity

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  • [ErratumIn] Ann Hematol. 2003 Oct;82(10):660
  • (PMID = 12692682.001).
  • [ISSN] 0939-5555
  • [Journal-full-title] Annals of hematology
  • [ISO-abbreviation] Ann. Hematol.
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] Germany
  • [Chemical-registry-number] 0 / Benzamides; 0 / DNA Probes; 0 / Peptide Nucleic Acids; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.2 / Fusion Proteins, bcr-abl
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8. Liang YQ, Chen BA, Chen YL: [Research progress on aurora kinase inhibitor MK-0457 in therapy for some hematological malignancies -- review]. Zhongguo Shi Yan Xue Ye Xue Za Zhi; 2009 Jun;17(3):810-5
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  • [Title] [Research progress on aurora kinase inhibitor MK-0457 in therapy for some hematological malignancies -- review].
  • Recent work indicates that an Aurora kinase inhibitor MK-0457 (VX-680), a small-molecule inhibitor of Aurora kinases A, B, C and BCR-ABL, FLT-3, JAK-2, can block the progression of cell growth cycle, causing apoptosis in a range of human tumors.
  • MK-0457 has the activity against expressions of wild-type and mutated bcr-abl gene, including the T315I mutant, and can inhibit the activity of FLT-3, JAK-2 and their mutated types as well.
  • Clinical applications suggest that the MK-0457 has therapeutic effect on the highly refractory CML and CML with poor prognosis, Ph(+) ALL with T315I mutant, relapse refractory AML and JAK-2 positive myeloproliferative diseases (MPD).
  • The intensive preclinical studies and the on-going phase II clinical trials will open up a new vista of therapy for some hematological malignancies.
  • This review focuses on the pharmacologic action of MK-0457 and its clinical trial as well as combined application.

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  • (PMID = 19549414.001).
  • [ISSN] 1009-2137
  • [Journal-full-title] Zhongguo shi yan xue ye xue za zhi
  • [ISO-abbreviation] Zhongguo Shi Yan Xue Ye Xue Za Zhi
  • [Language] CHI
  • [Publication-type] English Abstract; Journal Article; Review
  • [Publication-country] China
  • [Chemical-registry-number] 0 / Piperazines; 0 / Protein Kinase Inhibitors; 639089-54-6 / VX680; EC 2.7.11.1 / Aurora Kinases; EC 2.7.11.1 / Protein-Serine-Threonine Kinases
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9. Curran MP, Croom KF, Goa KL: Spotlight on imatinib mesylate in chronic myeloid leukemia. BioDrugs; 2004;18(3):207-10
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  • [Title] Spotlight on imatinib mesylate in chronic myeloid leukemia.
  • Imatinib mesylate (Gleevec, Glivec) is an orally administered competitive inhibitor of the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukemia (CML).
  • In patients with newly diagnosed and previously untreated (apart from hydroxyurea and/or anagrelide) CML in the chronic phase, imatinib mesylate 400 mg/day, compared with interferon-alpha (IFNalpha) plus cytarabine, resulted in higher hematologic response (HR) and cytogenetic response (CR) rates and fewer patients progressing to the accelerated phase or blast crisis in a large comparative trial.
  • Preliminary results indicate that, compared with IFNalpha plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher health-related quality of life (HR-QOL).
  • Imatinib mesylate was also effective in patients with chronic-phase CML refractory to or intolerant of treatment with IFNalpha (as 400 mg/day) and in those with blast-crisis or accelerated-phase CML (600 mg/day).
  • In the latter groups, HR and CR rates were lower than those in patients with chronic-phase CML.
  • In patients with previously untreated chronic-phase CML, serious adverse events (both hematologic and nonhematologic) were less common with imatinib mesylate than with IFNalpha plus cytarabine treatment.
  • CONCLUSION: Imatinib mesylate is a valuable therapy for patients with newly diagnosed Ph+ chronic-phase CML.
  • It is better tolerated and produces higher HR, CR and freedom from progressive disease rates than conventional therapy with IFNalpha plus cytarabine.
  • Preliminary results indicate that, compared with IFNalpha plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher HR-QOL.
  • Imatinib mesylate is also effective in patients with accelerated-phase and blast-crisis CML, and patients with chronic-phase CML who have failed IFNalpha therapy.
  • Given its efficacy and generally manageable adverse event profile, imatinib mesylate offers an important early treatment option for patients with CML.
  • [MeSH-major] Antineoplastic Agents / therapeutic use. Enzyme Inhibitors / therapeutic use. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Protein-Tyrosine Kinases / antagonists & inhibitors. Pyrimidines / therapeutic use

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  • (PMID = 15161340.001).
  • [ISSN] 1173-8804
  • [Journal-full-title] BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
  • [ISO-abbreviation] BioDrugs
  • [Language] eng
  • [Publication-type] Journal Article; Review
  • [Publication-country] New Zealand
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Enzyme Inhibitors; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Protein-Tyrosine Kinases
  • [Number-of-references] 27
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10. Zonder JA, Schiffer CA: Practical aspects of the treatment of chronic myelogenous leukemia with imatinib mesylate. Curr Hematol Rep; 2003 Jan;2(1):57-64
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  • [Title] Practical aspects of the treatment of chronic myelogenous leukemia with imatinib mesylate.
  • Imatinib mesylate (Gleeve; formerly known as STI-571; Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration for chronic-phase chronic myeloid leukemia (CML) that is refractory to or intolerant of interferon-alpha, and with accelerated and blast-phase CML.
  • Imatinib is remarkably effective as treatment for chronic-phase and accelerated-phase CML at doses of 400 mg and 600 mg daily, respectively.
  • Although dramatic responses are noted in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia, the responses are usually incomplete and of short duration.
  • At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently long in some patients so that they are functionally "cured," and whether doses of imatinib higher than 400 mg daily will improve response rates in chronic-phase CML.
  • [MeSH-major] Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Piperazines / therapeutic use. Pyrimidines / therapeutic use
  • [MeSH-minor] Benzamides. Blast Crisis / drug therapy. Blast Crisis / therapy. Hematopoietic Stem Cell Transplantation. Humans. Imatinib Mesylate. Transplantation, Homologous. Treatment Outcome

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  • (PMID = 12901155.001).
  • [ISSN] 1540-3408
  • [Journal-full-title] Current hematology reports
  • [ISO-abbreviation] Curr. Hematol. Rep.
  • [Language] eng
  • [Publication-type] Journal Article; Review
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate
  • [Number-of-references] 41
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11. Talmadge JE: Hematopoietic stem cell graft manipulation as a mechanism of immunotherapy. Int Immunopharmacol; 2003 Aug;3(8):1121-43
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • Hematopoietic stem cell transplants (SCT) are used in the treatment of neoplastic diseases, in addition to congenital, autoimmune, and inflammatory disorders.
  • Both autologous and allogeneic SCT are used, depending on donor availability and the type of disease being treated, resulting in different morbidity and outcomes.
  • In both types of SCT, immune regulation via graft manipulation is being studied, although with highly different targeted outcomes.
  • In general, autologous SCT have lower treatment-related morbidity and mortality, but a higher incidence of tumor relapse, and graft manipulation targets immune augmentation and/or the reduction of immune tolerance.
  • In contrast, allogeneic SCT have a higher incidence of treatment-related morbidity and mortality and a significantly longer time of disease progression, and the targeted outcomes or graft manipulation focus on a reduction in graft versus host disease (GVHD).
  • One source of the increased relapse rate and shorter overall survival (OS) following high dose chemotherapy (HDT) and autologous SCT is the immune tolerance that limits host response, both innate and antigen (Ag) specific, against the tumor.
  • The immune tolerance that is observed is due in part to the tumor burden and prior cytotoxic therapy.
  • Therefore, graft manipulation, as an adjuvant therapeutic approach in autologous SCT, is primarily focused on non-specific or specific immune augmentation using cytokines and vaccines.
  • Recently, manipulation of the infused product as a form of cellular therapy has begun to also focus on approaches to reduce immune tolerance found in transplant patients, both prior to and following HDT and SCT.
  • Indeed, allogeneic SCT provide the only curative therapy for patients with chronic myelogenous leukemia (CML), refractory acute leukemia, and myelodysplasia.
  • The curative potential of allogeneic SCT is reduced, however, by the development of GVHD, a potentially lethal T-cell-mediated immune response targeting host tissues [Int. Arch.
  • The morbidity and mortality associated with GVHD limit this technology, resulting focus on those patients who have no alternative therapeutic options or who have advanced disease.
  • Thus, allogeneic SCT provide one of the few statistically supported demonstrations of therapeutic efficacy by T cells (comparison of allogeneic to autologous transplantation).
  • Additional strategies are examining the isolation and infusion of T cells with graft versus leukemia (GVL) activity to reduce GVHD and/or the infusion of genetically manipulated and/or selected cellular populations (monocytes or dendritic cells (DC)) to induce tolerance.
  • Therefore, depending upon the type of transplant, the goals associated with graft manipulation can be radically different.

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  • (PMID = 12860168.001).
  • [ISSN] 1567-5769
  • [Journal-full-title] International immunopharmacology
  • [ISO-abbreviation] Int. Immunopharmacol.
  • [Language] eng
  • [Publication-type] Journal Article; Review
  • [Publication-country] Netherlands
  • [Number-of-references] 219
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12. Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, Verstovsek S, Talpaz M, Garcia-Manero G, Kantarjian HM: Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol; 2005 Jun 10;23(17):3948-56
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  • [Title] Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate.
  • PURPOSE: To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia.
  • MATERIALS AND METHODS: Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase).
  • RESULTS: Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase).
  • Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy.
  • CONCLUSION: Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia.
  • We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.
  • [MeSH-major] Azacitidine / administration & dosage. Azacitidine / analogs & derivatives. Drug Resistance, Neoplasm. Enzyme Inhibitors / administration & dosage. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Neoplasm Recurrence, Local / drug therapy. Piperazines / therapeutic use. Protein Kinase Inhibitors / therapeutic use. Pyrimidines / therapeutic use
  • [MeSH-minor] Adult. Aged. Antimetabolites, Antineoplastic / therapeutic use. Benzamides. DNA Methylation. DNA Modification Methylases / antagonists & inhibitors. Dose-Response Relationship, Drug. Female. Humans. Imatinib Mesylate. Male. Middle Aged. Protein-Tyrosine Kinases / antagonists & inhibitors

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  • (PMID = 15883410.001).
  • [ISSN] 0732-183X
  • [Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • [ISO-abbreviation] J. Clin. Oncol.
  • [Language] eng
  • [Grant] United States / NCI NIH HHS / CA / P50CA100632
  • [Publication-type] Clinical Trial; Clinical Trial, Phase II; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antimetabolites, Antineoplastic; 0 / Benzamides; 0 / Enzyme Inhibitors; 0 / Piperazines; 0 / Protein Kinase Inhibitors; 0 / Pyrimidines; 776B62CQ27 / decitabine; 8A1O1M485B / Imatinib Mesylate; EC 2.1.1.- / DNA Modification Methylases; EC 2.7.10.1 / Protein-Tyrosine Kinases; M801H13NRU / Azacitidine
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