A survival benefit for imatinib mesylate versus interferon-alpha therapy could not be demonstrated in the randomized study in newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML) due to the high rate of cross over (90%) from interferon-alpha to imatinib within a year of study entry. We compared survival in 279 patients with newly diagnosed CML treated with imatinib at our institution (2000 – 2004) to 650 patients treated with interferon-alpha (1982 – 1997). The complete cytogenetic response rates were 87% with imatinib and 28% with interferon-alpha (p < 0.0001). The estimated 3-year survival rates were 96% with imatinib and 81% with interferon-alpha (p < 0.01). Survival rates with imatinib were significantly better than with interferon-alpha within each of the CML prognostic risks groups. By multivariate analysis, imatinib therapy was identified as an independent favorable prognostic factor, after accounting for the impact of pretreatment factors (hazard ratio 0.04; p < 0.01). By landmark analysis at 12 months, survival within each cytogenetic response category was similar with imatinib or interferon-alpha, suggesting that the survival benefit of imatinib (versus interferon-alpha in newly diagnosed CML) is through improving cytogenetic response.

 

 

 

Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) are caused by the BCR-ABL oncogene. Imatinib inhibits the tyrosine kinase activity of the BCR-ABL protein and is an effective, frontline therapy for chronic-phase CML. However, accelerated or blast-crisis phase CML patients and Ph+ ALL patients often relapse due to drug resistance resulting from the emergence of imatinib-resistant point mutations within the BCR-ABL tyrosine kinase domain. This has stimulated the development of new kinase inhibitors that are able to over-ride resistance to imatinib. The novel, selective BCR-ABL inhibitor, AMN107, was designed to fit into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. In addition to being more potent than imatinib (IC50<30 nM) against wild-type BCR-ABL, AMN107 is also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. In preclinical studies, AMN107 demonstrated activity in vitro and in vivo against wild-type and imatinib-resistant BCR-ABL-expressing cells. In phase I/II clinical trials, AMN107 has produced haematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. Dasatinib (BMS-354825), which inhibits Abl and Src family kinases, is another promising new clinical candidate for CML that has shown good efficacy in CML patients. In this review, the early characterisation and development of AMN107 is discussed, as is the current status of AMN107 in clinical trials for imatinib-resistant CML and Ph+ ALL. Future trends investigating prediction of mechanisms of resistance to AMN107, and how and where AMN107 is expected to fit into the overall picture for treatment of early-phase CML and imatinib-refractory and late-stage disease are discussed.British Journal of Cancer advance online publication, 23 May 2006; doi:10.1038/sj.bjc.6603170 www.bjcancer.com.

 

It has recently been discovered that members of the hematopoietic serine protease superfamily, such as cathepsin G, neutrophil elastase, and proteinase 3, may play an important role in myeloid biology by suppressing granulopoiesis. Patients with hematological disorders, such as severe chronic neutropenia and myelogenous leukemia, may have mutations in genes encoding neutrophil serine proteases or alterations in the expression, localization or activity of the proteins. If these findings will stand the test of time, we may have caught a glimpse of the future regarding improved diagnosis, classification, and treatment of these severe blood disorders.

The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate launched the era of molecular targeted therapy and constitutes a milestone in oncology history. However, despite impressive cytogenetic response rates achieved with this agent in patients with chronic myelogenous leukemia (CML) in chronic phase, those with advanced-stage CML frequently obtain more modest responses that are in many instances of short duration. Several mechanisms of resistance to imatinib have been described among patients that develop clinical resistance to imatinib. Point mutations in the Bcr-Abl kinase domain that impair the ability of imatinib to inhibit the kinase activity represent the leading cause of resistance. Several approaches are being pursued to overcome these mutations. In addition, many other protein kinases implicated in signaling transduction downstream Bcr-Abl play critical roles in the pathogenesis of CML, thus representing potential therapeutic targets. Multiple compounds are being screened to identify inhibitors of these kinases. This article focuses on the current state of development of new kinase inhibitors for the therapy of CML.