Chronic Myeloid Leukemia (CML) was the first human cancer to be associated with a consistent chromosomal abnormality, the Ph chromosome. Furthermore, CML is considered unusual because it is caused by a single genetic lesion, or “hit”, which occurs in a hematopoietic stem cell generating the BCR-ABL fusion oncogene. CML presents three distinct clinical phases: chronic phase (CP), accelerated phase (AP) and blast crisis (BC).
Most patients are initially diagnosed in the CP, the initial phase of CML. During CP, mature granulocytes are still being produced, however patients present increased number of myeloid progenitor cells in the peripheral blood. CP usually has an insidious onset, and the main clinical findings are enlarged spleen, fatigue and weight loss. The peripheral blood of patients shows leukocytosis, mostly neutrophils in different stages of maturation, as well as eosinophilia and basophilia. Blasts usually represent less than 2% of the white blood cells (WBCs). Platelet counts can be normal or increased. CP can last for years even without any treatment. As CML progresses, patients enter an AP, which is an intermediary stage of CML evolution, at this point the disease starts to become resistant to therapy. Accelerated phase is marked by an increase in spleen size and in total WBCs, blasts encompassing 10- 19% of WBCs, and circulating basophils more than 20%; there’s also persistent thrombocytopenia and/or the appearance of new clonal cytogenetic abnormalities. In the last stage of CML, blast crisis, hematopoietic differentiation has become arrested and immature blasts accumulate in the BM and escape into the circulation. BC may or may not be preceded by an accelerated phase. During blast crisis patients show deteriorated performance status, as well as worsening of symptoms related to thrombocytopenia and anemia, and also greater spleen enlargement. The World Health Organization issued criteria for BC diagnosis consists of: blasts in excess of 20% in peripheral blood or BM, and/or extramedullary blast proliferation, and/or large foci or clusters of blast in BM histological sections.
Acute myeloid leukemia (AML) is a heterogeneous disease marked by a highly variable clinical course and response to therapy. Approximately 12,000 adults, with a median age of 67, are diagnosed with AML in the United States annually. Among patients older than 60 years of age, 40%-50% of those with a favorable status can achieve complete remission, but cure rates are less than 10% and the median survival rate is less than 1 year. For patients younger than 60 years old, 70-80% can reach remission, however rate of relapse is high and the 5 year survival rate is 40%-45%. Recent discovery of new molecular lesions with prognostic significance in AML is enhancing our understanding of the disease biology and our ability to identify new therapeutic targets.
AML can be separated into different subtypes depending on two different classification systems. The French-American-British (FAB) classification breaks down the different AML subtypes by mainly the morphological phenotypes of the cells upon diagnosis.
Therapy-related acute myeloid leukemia (tAML) is a hematological malignancy that devel- ops following exposure to chemotherapeutic agents used as treatments for other tumors, most often breast cancer, Hodgkins disease (HD), non-Hodgkin Lymphoma (NHL) and acute lym- phoblastic leukemia (ALL). It is the most common secondary malignancy and accounts for 10 to 20% of all AML cases in the US.
Two forms of tAML are recognized: tAML caused by exposure to alkylators such as cy- clophosphamide, and tAML caused by exposure to topoisomerase II inhibitors such as etopo- side. Approximately 75% of tAML cases are linked to alkylator exposure. Alkylator- induced leukemia has an average latency of _ve years and is usually preceded by myelodys- plastic syndrome (MDS), in which the patient develops peripheral cytopenias and trilineage dysplasia without frank leukemia. Cytogenetically, this form of tAML is most often characterized by chromosome loss or deletion, particularly involving chromosomes 5 and 7. Topoisomerase II-induced disease is less common but has a much more rapid course, with a latency of only 2 years and no MDS stage. In general, topoisomerase II inhibitors result in a disease characterized by chromosomal rearrangements, especially rearrangements involving the mixed lineage leukemia (MLL) locus at 11q23, which confer a more favorable prognosis and a better response to chemotherapy.
Both classes of tAML carry a dire prognosis. This disease is resistant to treatment and has lower survival rates than de novo disease. Various studies have placed the four or five year survival rate at anywhere from below 10% to up to 24.5% in one German-Austrian study.