Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0854467 (myelosuppression)
5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2(V617F)) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments. We conducted a phase 2 clinical study of CEP-701 in 22 JAK2(V617F)-positive MF patients (80 mg orally twice daily), and 6 (27%) responded by International Working Group criteria (clinical improvement in all cases): reduction in spleen size only (n = 3), transfusion independency (n = 2), and reduction in spleen size with improvement in cytopenias (n = 1). Median time to response was 3 months, and duration of response was more than or equal to 14 months. No improvement was seen in bone marrow fibrosis or JAK2(V617F) allele burden. Phosphorylated STAT3 levels decreased from baseline in responders while on therapy. Eight patients (36%) experienced grade 3 or 4 toxicity, and 6 (27%) required dose reduction. Main side effects were myelosuppression (grade 3 or 4 anemia, 14%; and thrombocytopenia, 23%) and gastrointestinal disturbances (diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27%). In conclusion, CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients. The study was registered at http://clinicaltrials.gov as NCT00494585.
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PMID:Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. 2000 98

Chronic myeloid leukemia (CML) is treated effectively with tyrosine kinase inhibitors (TKIs); however, 2 key problems remain-the insensitivity of CML stem and progenitor cells to TKIs and the emergence of TKI-resistant BCR-ABL mutations. BCR-ABL activity is associated with increased proteasome activity and proteasome inhibitors (PIs) are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in chronic phase (CP) CD34+ CML cells at clinically achievable concentrations. We also show that bortezomib targets primitive CML cells, with effects on CD34+38(-), long-term culture-initiating (LTC-IC) and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cells. Bortezomib is not selective for CML cells and induces apoptosis in normal CD34+38(-) cells. The effects against CML cells are seen when bortezomib is used alone and in combination with dasatinib. Bortezomib causes proteasome but not BCR-ABL inhibition and is also effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. By targeting both TKI-insensitive stem and progenitor cells and TKI-resistant BCR-ABL mutations, we believe that bortezomib offers a potential therapeutic option in CML. Because of known toxicities, including myelosuppression, the likely initial clinical application of bortezomib in CML would be in resistant and advanced disease.
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PMID:Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells. 2006 23

IMATINIB MESYLATE (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, the so-called small molecules. They have a high selectivity against a specific molecular target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem-cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably Bcr-Abl. Imatinib has been shown to have remarkable clinical activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases.Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events (AE) include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression.Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of Bcr-Abl as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively. Improved understanding of the underlying mechanisms of resistance has led to the development of new second-generation tyrosine kinase inhibitors (see Chaps. 7-9).
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PMID:Imatinib mesylate. 2007 27

Ever since their description as "myeloproliferative syndromes" by William Dameshek in 1951, the myeloproliferative neoplasms (MPNs) have been managed by the selective use of rather mundane, nonspecific therapies that rely on either antiplatelet effects or myelosuppression. The year 2005 ushered in a new era of drug development and discovery for the MPNs after the description of the JAK2 V617F mutation and the role this constitutively active tyrosine kinase has in MPN pathogenesis. Subsequently, multiple pharmacologic agents have begun (or are about to begin) testing for the inhibition of JAK2 in an attempt to improve the treatment of MPNs. Both primary myelofibrosis and myelofibrosis following essential thrombocythemia or polycythemia vera have been the targets of the most extensive testing of these agents to date. Responses to these oral JAK2 inhibitors have been primarily intended to reduce splenomegaly and meaningfully improve symptoms; effects on the JAK2 V617F allele burden or marrow histology are limited. Toxicities have ranged from myelosuppression to significant diarrhea. Additional agents with other mechanisms of action are also targeting JAK2, including histone deacetylase inhibitors and mTOR inhibitors. The results of preliminary trials of JAK2 inhibitors in polycythemia vera and essential thrombocythemia have been mixed but are premature. Many questions remain as to the optimal JAK2 inhibitory strategy and the full extent of the benefit of single-agent JAK2 inhibition.
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PMID:Future therapies for the myeloproliferative neoplasms. 2108 Feb 42

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.
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PMID:Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: a case report. 2239 51

The outcome and quality of life of chronic myeloid leukemia (CML) patients has remarkably changed with the treatment of tyrosine kinase inhibitors (TKIs). Currently, hematopoietic stem cell transplantation (HSCT) is considered mainly as a third line salvage therapy in cases of TKIs resistance or intolerance. Here we describe a patient with chronic phase CML who developed both resistance and late occurrence of s severe thrombo-cytopenia on first and second generation TKIs and eventually underwent HSCT. Although the mechanism of the myelosuppression is not fully understood, we showed for the first time the development of dose dependent platelet antibodies in the presence of TKIs, suggesting the possibility of TKIs induced thrombocytopenia. Our case emphasizes that late development of severe myelosuppression during imatinib treatment is probably an important indication for consideration of early HSCT.
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PMID:Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia? 2259 20

CML (chronic myeloid leukaemia) in association with HIV (human immunodeficiency virus) infection (HIV-CML) is rarely described and is likely to be coincidental. The natural history and behaviour of HIV-CML is different, being more atypical and aggressive. Both conditions, and their respective treatments may cause myelosuppression. Concurrent treatment with cART (combination antiretroviral therapy) and the tyrosine kinase inhibitors (TKI's) can result in appropriate control of CML and HIV infection, as well as long term survival. However, drug interactions between ARV's and TKI's may require adjustment of treatment.
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PMID:Human immunodeficiency virus infection and chronic myeloid leukemia. 2286 99

Imatinib mesylate is a tyrosine kinase inhibitor used widely as the first-line treatment for chronic myeloid leukaemia (CML). The side-effect profile of this drug includes fluid retention, muscle cramps, diarrhoea, myelosuppression and skin rashes. Of these, rashes of the type maculo-papular eruptions and oedema developed most commonly. The cutaneous adverse reactions other than maculo-papular eruptions are rare with imatinib. Severe and life-threatening cutaneous reactions can occur in 5% cases. Here, the author reports a case of newly diagnosed CML that developed Steven-Johnsons syndrome due to imatinib therapy. Patient responded and discharged successfully on withdrawal of the culminating drug.
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PMID:Imatinib-induced Stevens-Johnsons syndrome. 2334 42

Because of their outstanding efficacy and low toxicity, tyrosine kinase inhibitors (TKIs) have replaced allogeneic hematopoietic cell transplant (HCT) as the standard frontline therapy for patients with newly diagnosed chronic myeloid leukemia (CML). Until a decade ago, HCT was the preferred treatment for CML, with 5-year overall survival rates of approximately 80%, 40%, and 20% for patients in chronic, accelerated, and blast crisis phases, respectively. Relapse after transplant is a problem for patients who undergo transplant in advanced phase disease and those undergoing a T-depleted transplant. Until the introduction of TKIs, therapy for relapsed CML after transplant relied on interferon and/or donor leukocyte infusion (DLI). Although effective in inducing remission, DLI is associated with clinically significant graft-versus-host disease or myelosuppression, with an accompanying treatment-related mortality of 5% to 20%. TKIs have emerged as an attractive alternative therapy for persistent or relapsing CML after HCT. Similar to DLI, the effectiveness of TKI posttransplant is largely determined by the phase of disease at relapse, showing very good response in patients experiencing relapse in the chronic phase, with high rates (>60%) of hematologic and cytogenetic remissions, but less favorable outcomes in patients with advanced disease, with only a minority experiencing durable cytogenetic or molecular remissions. Molecular monitoring of the BCR-ABL chimeric mRNA posttransplant is important for early detection of patients at high risk of relapse.
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PMID:Maintenance therapy with tyrosine kinase inhibitors after transplant in patients with chronic myeloid leukemia. 2348 57

Four breakpoint cluster region (BCR)-ABL1 tyrosine kinase inhibitors (TKIs) are currently available for the treatment of chronic myeloid leukemia (CML): imatinib, nilotinib, dasatinib, and bosutinib. Choosing the most appropriate TKI requires clinicians to consider a host of patient-, disease-, and treatment-related factors, not the least of which include the safety profiles of the agents. This review discusses the potential impact of treatment-, patient-, and disease-related characteristics on the emergence of adverse events during TKI therapy, with a focus on the underlying mechanisms believed to be responsible for a number of important adverse events associated with these agents and what implications they may have for treatment choice, particularly in the setting of first-line treatment. A literature search of the PubMed database was conducted to identify articles that described the molecular mechanisms of BCR-ABL1-mediated leukemic transformation, the efficacy and safety of imatinib, nilotinib, dasatinib, and bosutinib in patients with CML, the kinase-binding spectrum of each TKI, and evidence suggesting a link between the TKI-binding profile and adverse events. The pattern of adverse events associated with each agent is important when selecting treatment with a TKI. Clinical studies suggest that imatinib, nilotinib, dasatinib, and bosutinib have differing safety profiles, which are in part attributable to the specificity and selectivity of each agent. Although much basic research must be conducted to further illuminate the mechanisms responsible for TKI-related adverse events, on- and off-target effects are believed to be at least partly responsible for cardiovascular toxicity, myelosuppression, fluid retention, gastrointestinal toxicity, and dermatologic toxicity. Increased understanding of the factors that affect TKI-associated adverse events and long-term safety data will enable a more informed approach to the selection of therapy best suited to the individual needs of patients with CML.
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PMID:Treatment-, patient-, and disease-related factors and the emergence of adverse events with tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. 2355 55


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