New prognostic factors in chronic myeloid leukaemia

The tyrosine kinase inhibitor imatinib mesylate (IM) has proved a major advance in the management of patients with chronic myeloid leukaemia (CML) but about 15% of patients do not achieve complete cytogenetic responses (CCyR) (primary resistance) and a further 15-20% of those who do achieve CCyR eventually lose their response (secondary resistance). The best characterised mechanism of resistance is the expansion of a Ph-positive clone bearing an amino-acid substitution in the BCR-ABL1 kinase domain (KD). We screened over 300 CML patients for KD mutations and demonstrated that detection of a mutation after achieving CCyR is an independent prognostic factor for the loss of response and disease progression regardless of the level of mutant clone. In contrast this study found no difference in the level of IM-induced reduction of phospho-Crkl in diagnostic CD34+ cells from patients who achieved CCyR compared with those who failed to achieve such response. However, I also studied levels of human organic cation transporter 1 (hOCT1), a membrane protein responsible for facilitating entry of IM into cells. I showed that the level of hOCT1 at diagnosis predicted for 3 or more log reduction in BCR-ABL1 transcript level in the patients who achieved CCyR. I investigated the incidence of polymorphisms in the TP53 and MDM2 genes and showed an association between the TP53 P72R SNP and earlier age of onset of CML and an association between the MDM2 309 SNP and Sokal score in CML patients. Finally, I used array comparative genomic hybridisation to compare patterns in blood specimens obtained from 20 CML patients before treatment with patterns obtained from the same patients after induction of CCyR with IM; I showed aberrant patterns in several specific genes, most commonly NAMPT/PBEF1 on chromosome 7. I concluded that the results of these studies provided strong evidence that CML at diagnosis was a heterogeneous disease and that methods could be further refined to develop a model that would predict response to a given dose of IM