Drug Resistance in Acute Leukemias

Drug resistance in acute leukemia was first described by Farber et al. (1) in cases of acute lymphoblastic leukemia (ALL) and is still the major cause of death in all types of acute leukemia. A mathematical model for the development of drug resistance in tumors was proposed in 1979 by Goldie and Coldman (2), based on the hypothesis that cancer cells have a high spontaneous mutation rate that leads, over time, to the emergence of cells resistant to chemotherapeutic drugs. To reduce the rate of emergence of resistant cells according to this hypothesis, the simultaneous administration of multiple drugs with different targets was suggested. Despite the introduction of combination chemotherapies, treatment failures continued to be observed. Rates of initial treatment failure and relapse were lowest in childhood ALL, whereas adults with ALL or acute myeloid leukemia (AML) mainly died of their disease, regardless of the treatment they received. Over the last 20 years, experimental models and clinical research have identified several causes of drug resistance in tumors. This improved understanding of the mechanisms involved in drug resistance has permitted the development of new therapeutic strategies.