Advanced CML: therapeutic options for patients in accelerated and blast phases.
ABSTRACT Tyrosine kinase inhibitor (TKI) therapy has impacted the natural course of chronic myelogenous leukemia (CML), because patients diagnosed as having chronic-phase disease can experience long-lasting responses. However, for patients with advanced CML (accelerated and blast phases), the efficacy of all current therapies is reduced. For these patients, allogeneic stem cell transplantation remains the preferred treatment if a donor is available, although TKIs play a valuable role as a bridging therapy. For patients with accelerated-phase CML, imatinib, dasatinib, and nilotinib have been shown to produce meaningful rates of hematologic and cytogenetic response. Imatinib and dasatinib are also approved for blast-phase CML. Studies with the newer agents have involved heavily pretreated patients; however, response rates have been at least comparable to those achieved with imatinib in previous studies. Therefore, these newer, more potent TKIs will probably be more likely to induce a deep response in previously untreated patients. Moreover, because fewer mechanisms appear to exist for secondary resistance to dasatinib and nilotinib, reducing the potential for disease to escape TKI therapy, these agents may result in improved longer-term outcomes. However, BCR-ABL-independent pathways may also become more important, indicating that other therapeutic targets may also have a future role in managing patients with advanced CML.
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ABSTRACT: Imatinib can induce complete molecular remission (CMR) in relapse chronic myelogenous leukemia (CML) after allogeneic hematopoietic stem cell transplantation, but it is indefinite whether imatinib is required to maintain CMR. We retrospectively reviewed 37 relapse CML post-transplants treated with imatinib (n = 20) or donor lymphocyte infusion (DLI) (n = 17). The rate of CMR was 85% and 76.47% (P = 0.509) and treatment-related mortality was 0% and 29.4% (P = 0.019), respectively, in imatinib and DLI groups. Fifteen patients obtaining CMR voluntarily ceased imatinib, and did not experience relapse. The 8-year overall survival (OS) after relapse was 85%±8% and 40.3±12.1% (P = 0.017), and disease-free survival (DFS) after relapse was 85%±8% and 40.3±12.1% (P = 0.011), respectively, in imatinib and DLI groups. Imatinib resulted in higher OS and DFS than that of DLI in relapse CML. Imatinib maintenance might not be required for patients with relapse CML post-transplants after they achieved full donor chimerism and CMR.PLoS ONE 06/2013; 8(6):e65981. DOI:10.1371/journal.pone.0065981 · 3.53 Impact Factor
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ABSTRACT: Protein phosphorylation plays key roles in the regulation of normal and cancer cells. It is a highly dynamic process. Protein kinases are the targets of several new cancer drugs and drug candidates. However, some of the main issues related to new drugs are how they function and the selection of those patients that will likely respond best to a particular treatment regime. There is an urgent need to understand and monitor kinase signalling pathways. Phosphoproteomics requires the enrichment of phosphorylated proteins or peptides from tissue or bodily fluids, and the application of technologies such as mass spectrometry (MS) to the identification and quantification of protein phosphorylation sites. As the field develops it will provide pharmacodynamic readouts of disease states and cellular drug responses in tumour samples. There have been a number of recent advances, but there are still technical hurdles and bioinformatics challenges that need to be addressed.Clinical and Translational Oncology 06/2009; 11(6):356-362. DOI:10.1007/s12094-009-0369-z · 1.60 Impact Factor
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ABSTRACT: The introduction of targeted agents such as the Bcr/Abl kinase inhibitor – imatinib mesylate – into the therapeutic armamentarium has revolutionized chemotherapeutic approaches to neoplastic diseases. However, as in the case of conventional chemotherapeutic agents, resistance mechanisms, either preexisting or those that develop following treatment, have limited the therapeutic potential of such agents. Over the last decade, it has become increasingly clear that survival signaling pathways do not exist in a vacuum, but instead exhibit strong evidence of cross-talk and mutual interdependence. In addition, a substantial body of evidence indicates that multiple dysregulated survival pathways may cooperate to trigger transformation. Such considerations raise the possibility that simultaneous interruption of more than one signaling pathway may represent an effective anticancer strategy. Indeed, numerous studies have now demonstrated that because many cancer cell types are not addicted to a single such pathway, simultaneous interruption of a constitutively activated and stimulated complementary pathway may effectively induce transformed cell death. Furthermore, this strategy may be particularly effective in the case of resistant disease. This chapter summarizes mechanisms of tumor cell resistance to novel agents, and provides examples of rational combination approaches involving targeted agents that might circumvent this problem. KeywordsLeukemia-Targeted agents-Drug resistance-Signal transduction-Combination therapy06/2011: pages 171-195;