Kajetana Foryciarz

Imatinib Blood Level Testing - Current Perspectives and Key Questions

Imatinib is the gold standard for the treatment of chronic myeloid leukaemia. Several recent studies have revealed a correlation between imatinib trough plasma levels and clinical response, suggesting that measurement of plasma levels can be a useful tool for optimising imatinib dose. However, a number of important questions on the use of imatinib blood level testing (BLT) remain unanswered. These questions were discussed at a European expert meeting held in Bordeaux, France, under the auspices of the European Treatment and Outcome Study (EUTOS) for chronic myeloid leukaemia. The key views were that: imatinib blood level measured between days seven and 29 of treatment could be a prognostic indicator and an important baseline for evaluating subsequent measurements; an imatinib trough plasma threshold for optimal response of 1,000ng/ml has been proposed but needs further validation; there is insufficient evidence to define any relationship between imatinib plasma levels and adverse events; and, although it is not yet possible to define and validate a comprehensive algorithm for the application of BLT in clinical practice, a working model has been developed. Pan-European collaboration, data pooling and initiation of a prospective clinical trial would be important steps in addressing current uncertainties.

Molecular Biology of Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting from an acquired genetic aberration t(9;22)(q34;q11) (Philadelphia chromosome) in stem cells. As a result the BCR/ABL fusion gene is formed which encodes a specific mRNA, translated into BCR/ABL proteins with an abnormally high tyrosine kinase activity, playing a crucial role in leukemic transformation and neoplastic proliferation of hematopoietic stem cells. BCR/ABL protein activates a number of transcription factors and gene promoters; however, its expression does not explain all the biological mechanisms of the origin of CML and its progression. Trisomy of chromosome 8, 19, isochromosome 17, and an additional Ph chromosome are the most frequent additional chromosomal abnormalities detected in course of CML progression. Suppressor genes dysfunction may play a role in the progression of CML. There is a considerable heterogeneity of the molecular mechanism and the genes involved in the development and progression of CML.