Chronic Myelogenous Leukemia: Pathology and Genetics, Diagnosis and Treatment

Abstract

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm defined by the presence of the t(9;22)(q34.1;q11.2) reciprocal chromosomal translocation which generates the BCR-ABL1 fusion gene located on the so called Philadelphia (Ph) chromosome. CML accounts for 15%–20% of adult leukemias and is rare in children. Except for acute radiation exposure, CML etiology is unknown. The natural clinical course of the disease consists of a chronic phase and a blast phase which is usually (but not always) preceded by an accelerated phase. A majority of patients are diagnosed at chronic phase, up to a half of them incidentally, usually with increased white blood counts and/or splenomegaly. CML progression to the advanced phases is associated with additional chromosomal and genetic abnormalities, and manifests in particular with increasing basophilia and white blood cell counts, and an increasing proportion of blasts (myeloid in most cases). Rising numbers of abnormal megakaryocytes and increasing dysplasia are also observed. The boundaries between the three CML phases are not very sharp. A number of criteria has been proposed to differentiate them for clinical purposes but these may vary between centers. The mainstay of CML treatment are tyrosine kinase inhibitors (TKIs) whose introduction into clinical practice has significantly improved CML patients’ prognosis. Three generations of TKIs are now available, allowing to control chronic-phase disease in most cases. Blast-phase CML, however, is associated with an adverse prognosis. Chemotherapy and hematopoietic stem cell transplantation in addition to TKI therapy are the treatment options for advanced-phase patients. Identifying the means to target leukemic stem cells which are partially resistant to the currently available treatments and remain a source of recurrence, would be the next milestone in the management of CML.