Advanced CML: Therapeutic options for patients in accelerated and blast phases
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.
Available from: Jing Sun
- "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 , . 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–. "
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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.
Available from: onlinelibrary.wiley.com
- "Currently, she is waiting for a HSCT from a compatible donor. With the use of TKIs, 10–45% of patients in advanced phases of CML can achieve a CCyR, but the response duration is usually short (Druker et al, 2001; Shah, 2008). As a single agent, dasatinib induces CCyR in 20–40% of patients, with a higher rate of relapse occurring within 1 year of treatment and a median overall survival (OS) of 8 months (Saglio et al, 2010). "
Available from: Ailin Zhang
- "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.
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