Novel prognostic factors in chronic myeloid leukemia

...........................................................................................................................7 Introduction .....................................................................................................................9 Review of the literature ..................................................................................................10 1. History of CML..................................................................................................................10 2. Clinical characteristics of CML .........................................................................................12 2.1. Epidemiology ........................................................................................................................... 13 2.2. Clinical course of CML............................................................................................................. 13 2.3. Risk scores ............................................................................................................................... 14 2.4. Immunological background of CML.......................................................................................... 15 3. The cytogenetics of CML ...................................................................................................16 3.1. Standard Ph translocation.......................................................................................................... 16 3.2. Variant Ph translocations .......................................................................................................... 16 3.3. Ph negative, BCR-ABL fusion positive CML ............................................................................. 17 3.4. Deletions of the derivative chromosome 9 ................................................................................. 18 3.4.1. When are der(9) deletions formed? .................................................................................... 20 3.4.2. The clinical impact of der(9) deletions ............................................................................... 20 3.5. Clonal evolution ....................................................................................................................... 20 3.6. Clonal chromosomal changes in Ph negative cells ..................................................................... 21 3.7. Ph chromosome in other hematological malignancies ................................................................ 22 4. Molecular genetics and pathology of CML ........................................................................22 4.1. Oncogenic tyrosine kinases in hematological malignancies........................................................ 22 4.2. Abelson murine leukemia viral oncogene homolog 1 (ABL) gene............................................... 22 4.3. Breakpoint cluster region (BCR) gene........................................................................................ 24 4.4. The BCR-ABL fusion gene ........................................................................................................ 24 4.5. Cellular signaling pathways affected by BCR-ABL ................................................................... 26 5. The role of genetic analyses in diagnostics and follow-up of CML....................................27 5.1. Analyses performed at the diagnostic phase............................................................................... 27 5.2. Follow-up studies and minimal residual disease analyses ........................................................... 27 5.2.1. Cytogenetic follow-up analyses ......................................................................................... 27 5.2.2. Molecular genetic follow-up studies................................................................................... 28 5.2.3. International standardization of RQ-PCR assays in minimal residual disease analytics........ 29 6. Treatment of CML .............................................................................................................30 6.1. Imatinib: the current gold standard of CML treatment................................................................ 30 6.1.1. The mechanism of imatinib kinase inhibition ..................................................................... 31 6.1.2. The IRIS (International Randomized Study of Interferon and STI571) trial......................... 32 6.2. Allogeneic hematopoietic stem cell transplantation (alloHSCT)................................................. 33 7. Imatinib resistance.............................................................................................................33 7.1. BCR-ABL gene amplification .................................................................................................... 34 7.2. Mutations in the kinase domain of BCR-ABL............................................................................ 35 7.3. BCR-ABL independent resistance mechanisms ......................................................................... 37 8. Second generation tyrosine kinase inhibitors.....................................................................39 8.1. Dasatinib .................................................................................................................................. 39 8.2. Nilotinib ................................................................................................................................... 39 8.3. Other second generation tyrosine kinase inhibitors .................................................................... 40 8.4. Resistance against second generation tyrosine kinase inhibitors ................................................. 40