On the Road to New Drugs in Acute Myeloid Leukemia

The outcome of therapy for acute myeloid leukemia (AML) has improved over the years, mainly in patients of younger age. There is no question, however, that the challenges in the area of developmental therapeutics in AML have remained considerable. Thesechallengesrelatetopatientswhofromthestartoftreatment, fail to respond to currently available drugs or combinations of drugs.Theoutlookoftheseprimarilyrefractorypatientsisnotably dismal. The majority of patients (75%) age 60 years or younger, however, do attain an initial complete remission. Unfortunately, mostoftheseresponders(onaverage,60%)willultimatelypresent withdiseaserelapse,usuallyoccurringwithinthefirst2years.Both groups, initial nonresponders and secondary nonresponders, represent the notorious difficulty of chemotherapy resistance. Age of the patient and certain acquired genetic characteristics of the leukemia are important predictors of failure. The unmet therapeutic need is by any measure greatest among the large population of patients with AML of older age, in whom response rates are comparatively low (average 50% for those older than 60 years of age), relapseratesareexceedinglyhigh(morethan85%),andlong-term survival rates are less than 10%. The traditional chemotherapeutic approach to the patient with AML has been based on treatment with a combination of an anthracycline or anthracenedione (daunorubicin, idarubicin, mitoxantrone) with cytarabine. Scientists are permanently on the road to discover new drugs with different modes of action that can overcomethelimitationsofthecurrentselectionofdrugs.Numerous new drugs are currently in early clinical development with the aim of circumventing chemotherapy resistance. In the coming years, some of these compounds are expected to become members of the standard armamentarium of drugs available to the patient with AML. New drugs may be designed with the deliberate objective of affecting a known molecular lesion or signaling pathway in the neoplastic cell, thus critically inhibiting leukemia cell survival. These therapeutic compounds may tackle distinct molecular subsetsofleukemia;researchersanticipatethattheirgreaterspecificity