Advanced CML: Therapeutic options for patients in accelerated and blast phases

Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, 94143, USA.
Journal of the National Comprehensive Cancer Network: JNCCN (Impact Factor: 4.18). 03/2008; 6 Suppl 2:S31-S36.
Source: PubMed


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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    • "However, the potential for TKIs to effect cures is a matter of discussion. Allo-HSCT remains the only established curative approach for CML, especially in patients with CML in an advanced phase (accelerated phase (AP) and blast phase (BP)), and those in whom TKIs therapy has failed [7], [8]. The overall survival (OS) after allo-HSCT is estimated to range from 40% to 80%, with relapse and graft versus host disease (GVHD) as the main causes of death[9]–[11]. "
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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 · 3.23 Impact Factor
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    • "Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), dasatinib and nilotinib, which target the constitutively active Abl tyrosine kinase, are effective first-line therapy for CP CML (Druker et al., 2001). However, TKIs are significantly less effective in AP or BC CML where not only Bcr-Abl dependent, but also Bcr-Abl independent mechanisms are at work (Druker et al., 2006; Faderl et al., 1999; Hansen et al., 1998; Melo and Barnes, 2007; Quintas-Cardama and Cortes, 2009; Ren, 2005; Sawyers et al., 2002; Shah, 2008). Allogeneic hematopoietic stem cell transplantation (HSCT) is generally reserved for CP patients who are resistant to TKI therapy, or patients who have AP or BC CML. "
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    ABSTRACT: MOTIVATION: Selecting a small number of signature genes for accurate classification of samples is essential for the development of diagnostic tests. However, many genes are highly correlated in gene expression data, and hence, many possible sets of genes are potential classifiers. Because treatment outcomes are poor in advanced chronic myeloid leukemia (CML), we hypothesized that expression of classifiers of advanced phase CML when detected in early CML [chronic phase (CP) CML], correlates with subsequent poorer therapeutic outcome. RESULTS: We developed a method that integrates gene expression data with expert knowledge and predicted functional relationships using iterative Bayesian model averaging. Applying our integrated method to CML, we identified small sets of signature genes that are highly predictive of disease phases and that are more robust and stable than using expression data alone. The accuracy of our algorithm was evaluated using cross-validation on the gene expression data. We then tested the hypothesis that gene sets associated with advanced phase CML would predict relapse after allogeneic transplantation in 176 independent CP CML cases. Our gene signatures of advanced phase CML are predictive of relapse even after adjustment for known risk factors associated with transplant outcomes.
    Bioinformatics 01/2012; 28(6):823-30. DOI:10.1093/bioinformatics/bts059 · 4.98 Impact Factor
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    • "If the goal of the research study includes quantification of phosphorylated proteins, there are several useful techniques [e.g. Stable Isotope Labelling with Amino acids in cell Culture (SILAC), Isobaric Tag for Relative and Absolute (iTRAQ), Absolute Quantitation (AQUA), Multiple Reaction Monitoring (MRM), or Label-free quantification], which allow important large-scale phosphoproteomic studies [7-19] "
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    ABSTRACT: ABSTRACT: Reversible protein phosphorylation is one of the most important forms of cellular regulation. Thus, phosphoproteomic analysis of protein phosphorylation in cells is a powerful tool to evaluate cell functional status. The importance of protein kinase-regulated signal transduction pathways in human cancer has led to the development of drugs that inhibit protein kinases at the apex or intermediary levels of these pathways. Phosphoproteomic analysis of these signalling pathways will provide important insights for operation and connectivity of these pathways to facilitate identification of the best targets for cancer therapies. Enrichment of phosphorylated proteins or peptides from tissue or bodily fluid samples is required. The application of technologies such as phosphoenrichments, mass spectrometry (MS) coupled to bioinformatics tools is crucial for the identification and quantification of protein phosphorylation sites for advancing in such relevant clinical research. A combination of different phosphopeptide enrichments, quantitative techniques and bioinformatic tools is necessary to achieve good phospho-regulation data and good structural analysis of protein studies. The current and most useful proteomics and bioinformatics techniques will be explained with research examples. Our aim in this article is to be helpful for cancer research via detailing proteomics and bioinformatic tools.
    Journal of Clinical Bioinformatics 10/2011; 1(1):26. DOI:10.1186/2043-9113-1-26
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