Author(s): Christophe Roumier 1 , Meyling H Cheok [[dagger]] 2
acute myeloid leukemia; pharmacogenetics; pharmacogenomics; treatment response
The efficacy of antileukemic drugs is determined by the interplay of numerous gene products that influence each treatment's pharmacokinetics (drug metabolism or disposition) and pharmacodynamics (drug efficacy or toxicity). Pharmaco-genetics and -genomics focuses on the genetic variation of drug-metabolizing enzymes, targets and transporters, and how these genetic variations interact to produce specific drug-related phenotypes. Additionally, prospective genetic markers may be used to provide a mechanistic subclassification of patients by their disease, which subsequently affects the choice and intensity of chemotherapy. Finally, these genetic markers may point to new drug targets or drug modifiers, which have the potential to alter drug efficacy and toxicity (e.g., reverse drug resistance or increase cellular uptake). The promise of pharmaco-genetics and -genomics is to develop polygenic models that accurately predict drug efficacy and toxicity for each patient, and to use these models to prospectively individualize chemotherapy with the intent to optimize treatment efficacy and safety through better understanding of the patient's pharmaco-genetic and -genomic characteristics. A wealth of work in this area has been performed in pediatric acute lymphoblastic leukemia (ALL), with one of the pioneering institutions being St Jude Children's Research Hospital (TN, USA) but many other great institutions have also contributed to important pharmaco-genetic and -genomic findings that have improved treatment outcome and are routinely used in clinical practice, reviewed in [1-4] . The hope is that some of these ideas will transfer to acute myeloid leukemia (AML) in adults. Further information on the different general aspects of pharmaco-genetics and -genomics are reviewed elsewhere  . In this review we have outlined recent advances in pharmacogenomics applied to AML.
Acute myeloid leukemia
Acute leukemia occurs when a hematopoietic stem cell undergoes malignant transformation into a primitive, undifferentiated cell with abnormal longevity. Lymphoid cells (ALL) or myeloid cells (AML) proliferate abnormally, replacing normal bone marrow tissue and hematopoietic cells. The goal of treatment is complete remission (CR), including resolution of abnormal clinical features, restoration of normal blood counts and normal hematopoiesis with less than 5% blast cells, and elimination of the leukemic clone. Acute leukemias have been widely explored owing to the relatively easy access to leukemic material. Because of well organized clinical trials there is a wealth of phenotypic, genotypic and functional data available concerning leukemogenic pathways and the development of targeted therapies.
Acute myeloid leukemia is a relatively rare cancer. The incidence of AML increases with age, with a median age at diagnosis of 63 years. There are approximately 0.7-3.9 cases per 100,000 between 0 and 60 years and from 6.7 to 19.2 cases per 100,000 above 60 years with a median of more than 70 years. AML accounts for 1.2% of all cancer deaths in Western countries  . AML is the most common acute leukemia in adults (about 90%), but is rare in children. AML may also occur as a secondary cancer after chemotherapy or irradiation for a different type of cancer (therapy-induced secondary [t]-AML), and this...