Posted by rob on August 27, 2009 under Uncategorized | 
Conclusion: This is the first report of development of LSetA, a sclerosing dermatosis, while receiving a therapeutic dose of imatinib mesylate, a drug thought to have anti-sclerotic properties. Skupsky H, Abuav R, High W, Pass C, Goldenberg G. Development of lichen sclerosus et atrophicus while receiving a therapeutic dose of imatinib mesylate for chronic myelogenous leukemia. (Source: Journal of Cutaneous Pathology)
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Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia.
Biologics. 2008 Sep;2(3):491-500
Authors: Karp JE, Lancet JE
Farnesyltransferase inhibitors (FTIs) represent a new class of signal transduction inhibitors that block the processing of cellular polypeptides that have cysteine terminal residues and, by so doing, interdict multiple pathways involved in proliferation and survival of diverse malignant cell types. Tipifarnib is an orally bioavailable, nonpeptidomimetic methylquinolone FTI that has exhibited clinical activity in patients with myeloid malignancies including elderly adults with acute myelogenous leukemia (AML) who are not candidates for traditional cytotoxic chemotherapy, patients with high-risk myelodysplasia, myeloproliferative disorders, and imatinib-resistant chronic myelogenous leukemia. Because of its relatively low toxicity profile, tipifarnib provides an important alternative to traditional cytotoxic approaches for elderly patients who are not likely to tolerate or even benefit from aggressive chemotherapy. In this review, we will focus on the clinical development of tipifarnib for treatment of newly diagnosed AML, both as induction therapy for elderly adults with poor-risk AML and as maintenance therapy following achievement of first complete remission following induction and consolidation therapies for poor-risk AML. As with all other malignancies, the optimal approach is likely to lie in rational combinations of tipifarnib with cytotoxic, biologic and/or immunomodulatory agents with non-cross-resistant mechanisms of action. Gene expression profiling has identified networks of differentially expressed genes and gene combinations capable of predicting response to single agent tipifarnib. The clinical and correlative laboratory trials in progress and under development will provide the critical foundations for defining the optimal roles of tipifarnib and in patients with AMl and other hematologic malignancies.
PMID: 19707379 [PubMed - in process]
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Inhibitors of Deacetylases Suppress Oncogenic KIT Signaling, Acetylate HSP90, and Induce Apoptosis in Gastrointestinal Stromal Tumors.
Cancer Res. 2009 Aug 25;
Authors: Mühlenberg T, Zhang Y, Wagner AJ, Grabellus F, Bradner J, Taeger G, Lang H, Taguchi T, Schuler M, Fletcher JA, Bauer S
Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA), and treatment with the tyrosine kinase inhibitor imatinib yields responses in the majority of patients. However, most patients develop secondary resistance, which is associated with a dismal prognosis. Histone deacetylase inhibitors (HDACI) have been shown to enhance imatinib activity in imatinib-resistant chronic myelogenous leukemia. Against this background, we explored whether HDACI might provide an alternative therapeutic strategy to KIT/PDGFRA kinase inhibitors in GIST. Inhibition of cell proliferation by HDACI was seen in KIT-positive but not in KIT-negative GIST cell lines, suggesting that HDACI activity is mainly conferred by targeting oncogenic KIT. KIT activity, expression, and activation of downstream pathways were strongly inhibited by several HDACI (SAHA, LBH589, VPA, trichostatin A, and NaButyrate). SAHA and LBH589 induced apoptosis in KIT-positive GIST, and strong synergism with imatinib was observed at low concentrations of SAHA and LBH589. Mechanistically, treatment with HDACI reduced KIT mRNA transcript levels and led to strong acetylation of HSP90, interfering with its activity as KIT chaperone. These results provide preclinical evidence for a disease-specific effect of HDACI in KIT-positive GIST, which could translate into therapeutic activity. [Cancer Res 2009;69(17):6941-50].
PMID: 19706776 [PubMed - as supplied by publisher]
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Development of lichen sclerosus et atrophicus while receiving a therapeutic dose of imatinib mesylate for chronic myelogenous leukemia.
J Cutan Pathol. 2009 Aug 23;
Authors: Skupsky H, Abuav R, High W, Pass C, Goldenberg G
Background: Imatinib mesylate (Gleevec((R))) is a selective Bcr-Abl protein tyrosine-kinase inhibitor, and it also inhibits the receptor tyrosine kinases for stem cell factor (c-kit) and platelet-derived growth factor (PDGFR). It is being investigated for use in the treatment of sclerosing dermatoses. Observation: A 44-year-old woman with a history of chronic myelogenous leukemia (CML) was referred for the evaluation of a pruritic eruption that developed over 6 months. Examination revealed atrophic plaques confined to the groin, vulva, axillae, inframammary region, trunk, antecubital and popliteal fossae, and posterior thighs bilaterally. A biopsy showed lichen sclerosus et atrophicus (LSetA). At the time of presentation, the patient was receiving imatinib mesylate 400 mg daily for CML. Conclusion: This is the first report of development of LSetA, a sclerosing dermatosis, while receiving a therapeutic dose of imatinib mesylate, a drug thought to have anti-sclerotic properties. Skupsky H, Abuav R, High W, Pass C, Goldenberg G. Development of lichen sclerosus et atrophicus while receiving a therapeutic dose of imatinib mesylate for chronic myelogenous leukemia.
PMID: 19703239 [PubMed - as supplied by publisher]
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New directions in the treatment of imatinib failure and/or resistance.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S27-33
Authors: Giles FJ
For the minority of chronic myeloid leukemia (CML) patients who demonstrate primary or secondary resistance or intolerance to first-line imatinib therapy, previously available treatment options were limited to cytotoxic chemotherapy, interferon alfa, or allogeneic hematopoietic stem cell transplantation. While the latter option remains a possibility for some, strong clinical efficacy data from recent phase II trials have led to the approval of two second-generation tyrosine kinase inhibitors (TKIs), nilotinib and dasatinib, for the treatment of CML following imatinib failure and/or resistance. Treatment guidelines now recommend either of these two agents as second-line therapy for most patients, although the decision of which second-generation agent to use remains subjective, and is often dependent on the agents’ tolerability profiles, as comparative efficacy data from head-to-head clinical studies are not available. Sequential treatment with all three TKIs over the course of the disease is also a possibility, as both nilotinib and dasatinib have shown activity in patients with resistance to imatinib and a subsequent TKI. Novel therapeutic options are continually being developed to expand the range of treatment options, and new tyrosine kinase inhibitors or agents with other mechanisms of action, such as histone deacetylase inhibitors, may prove effective in patients with resistance or intolerance to multiple agents.
PMID: 19621547 [PubMed - indexed for MEDLINE]
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Understanding the role of mutations in therapeutic decision making for chronic myeloid leukemia.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S22-6
Authors: Jabbour E, Soverini S
In patients with chronic myeloid leukemia (CML) resistant to imatinib, resistance is commonly associated with mutations in the BCR-ABL protein. Approximately 85% to 90% of resistance-associated mutations occur within the ABL kinase domain, and confer resistance either directly, by blocking imatinib binding, or indirectly, by altering the conformation of BCR-ABL. The degree of resistance depends on the mutation, with some remaining sensitive to imatinib. Imatinib dose escalation may overcome resistance in some of these patients or therapy can be switched to the second-generation tyrosine kinase inhibitors (TKIs) nilotinib or dasatinib. The long-term efficacy of second-generation TKIs may also be related to specific BCR-ABL mutations, with the T315I mutant remaining resistant to all currently available TKIs. Other treatments, including investigational agents, may be options for patients with this mutation. The choice of therapy should be guided by multiple factors, including mutational analysis, disease phase, patient characteristics, and the safety profile of the agents.
PMID: 19621546 [PubMed - indexed for MEDLINE]
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Practical considerations for the management of patients in the tyrosine kinase inhibitor era.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S16-21
Authors: O’Dwyer M, Atallah E
Most tyrosine kinase inhibitor (TKI)-associated adverse events are easily managed by symptomatic relief, although dose reductions or interruptions may be necessary in some patients. Long-term follow-up of early clinical trials has shown that the majority of imatinib-associated adverse events generally occur early, and the incidence decreases over the course of therapy, making imatinib the treatment of choice for long-term administration. A lack of patient adherence to imatinib, due to the occurrence of adverse events or for other reasons, can decrease response rates, and may cause resistance or disease relapse. Patient adherence to TKI therapies is a critical consideration for successful, long-term management of patients with chronic myeloid leukemia (CML). In patients who remain intolerant to imatinib, the differing tolerability profiles of second-generation TKIs should be considered when determining a therapeutic course of action. Throughout the course of therapy for CML, early and successful management of adverse events will increase dose optimization and patient adherence, and thereby optimize responses.
PMID: 19621545 [PubMed - indexed for MEDLINE]
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Clinical strategies to achieve an early and successful response to tyrosine kinase inhibitor therapy.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S11-5
Authors: Hughes T, Hochhaus A
Imatinib is the standard of care for previously untreated chronic myeloid leukemia (CML), with high response rates that lead to improved event-free and overall survival compared with interferon alfa. Imatinib dose is one important factor affecting response, and early clinical studies showed promising molecular response rates with high-dose therapy. Large, randomized trials are now ongoing to test this potential benefit and establish whether a starting dose of 800 mg/d improves long-term clinical outcomes compared with the current standard dose of 400 mg/d. Low plasma imatinib levels are associated with a decreased chance of response. The importance of imatinib dosing and plasma levels is likely due to their impact on intracellular concentrations of the drug. Cellular influx of imatinib is mediated by the OCT-1 protein, and patients with low OCT-1 activity may benefit from dose-intensive therapy. For nonresponding or slowly responding patients, dose escalation to 600 to 800 mg/d may lead to durable responses in patients with primary or secondary resistance. Regular monitoring of response is crucial to maximize therapeutic success, and improved understanding of the factors affecting response will guide future clinical strategies.
PMID: 19621544 [PubMed - indexed for MEDLINE]
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Optimizing first-line therapy for patients with chronic myeloid leukemia.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S5-10
Authors: Fava C, Cortes J
Imatinib is now established as the gold standard first-line therapy for patients with chronic myeloid leukemia (CML). Responses to imatinib are superior to those seen with interferon alfa and also occur earlier, demonstrating a stronger and deeper response to therapy. Imatinib therapy also provides long-term clinical benefit and outcomes, with improved progression-free survival (PFS) and overall survival (OS) compared with historical controls, at 6 years of follow-up. Recent data show that annual event rates decline over time with imatinib therapy, suggesting that long-term disease control is possible in continuously responding patients. Despite these treatment successes, new strategies are continually being evaluated to maximize responses to imatinib and ensure the best treatment outcomes for all patients. For example, high-dose imatinib therapy, with doses up to 800 mg/d, has been shown to improve response rates. Prospective, randomized trials are ongoing to assess the benefits of high-dose imatinib therapy and determine whether it extends PFS and OS compared with standard-dose imatinib.
PMID: 19621543 [PubMed - indexed for MEDLINE]
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New directions in the treatment of patients with chronic myeloid leukemia: introduction.
Semin Hematol. 2009 Apr;46(2 Suppl 3):S1-4
Authors: Baccarani M
PMID: 19621542 [PubMed - indexed for MEDLINE]
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Response dynamics in chronic-phase chronic myeloid leukemia.
Clin Lymphoma Myeloma. 2009 Jun;9(3):217-22
Authors: Mauro MJ
Cytogenetic response (CyR), especially complete CyR (CCyR), has historically and is currently associated with a significant survival advantage in patients with chronic-phase chronic myeloid leukemia (CP-CML). CCyR represents a critical level of disease reduction irrespective of treatment type, and timely achievement demonstrates treatment-sensitive disease. Guidelines from European LeukemiaNet and the National Comprehensive Cancer Network therefore state that alternative therapies should be considered for patients not achieving CCyR by 6 or 12 months. Data from clinical trials indicate that early CCyR affords the best benefit:risk ratio by minimizing the mounting risk of disease progression, and the duration of CCyR when achieved affects disease progression. Treatment options for patients who fail to achieve CCyR on standard-dose imatinib (400 mg/day) include imatinib dose escalation, dasatinib, nilotinib, stem-cell transplantation, or a clinical trial. While molecular testing gauges further risk reduction, disease stability, and often elimination of BCR-ABL transcripts below detection threshold, CCyR remains the most important surrogate for long-term survival and cytogenetic testing remains a key part of patient care in the management of CML, particularly early in response. Longerterm follow-up data will be required to confirm CCyR as a surrogate marker for survival in imatinib-resistant patients treated with the secondgeneration tyrosine kinase inhibitors, dasatinib and nilotinib.
PMID: 19525190 [PubMed - indexed for MEDLINE]
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Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia.
Eur Respir J. 2009 Mar;33(3):670-2
Authors: Daniels JM, Vonk-Noordegraaf A, Janssen JJ, Postmus PE, van Altena R
Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are several reports suggesting that imatinib might impair the immune system, leading to a variety of infections, including varicella zoster and hepatitis B. Control of TB in healthy individuals is achieved through acquired immunity, in which antigen-specific T-cells and macrophages arrest growth of Mycobacterium tuberculosis bacilli and maintain control over persistent bacilli. In the chronic stage of the infection, CD8+ T-cells assist macrophages in controlling intracellular mycobacteria. The T-cell receptor orchestrates this process. The fact that tyrosine kinases play an important role in T-cell receptor signal transduction and that imatinib has been shown to affect T-cell receptor signal transduction, presents a mechanism by which imatinib might impair control of Mycobacterium tuberculosis; thereby leaving the host susceptible to reactivation of tuberculosis.
PMID: 19251803 [PubMed - indexed for MEDLINE]
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