Impact of molecular profiling and cytogenetics in acute lymphoblastic leukemia.

Primary genetic abnormalities of leukemic cells have important prognostic significance. In B-cell precursor acute lymphoblastic leukemia (ALL), hyperdiploidy (more than 50 chromosomes) and TEL-AML1 fusion, which account for 25% and 23% of childhood cases but only 7% and 2% of adult cases, respectively, are associated with a favorable prognosis. Hypodiploidy (less than 44 chromosomes), found in less than 2% of pediatric or adult cases, confers an inferior outcome; the rare cases with low hypodiploidy (33 to 39 chromosomes) and near-haploidy (23 to 29 chromosomes) have a particularly poor prognosis. The t(4;11) with MLL-AF4 fusion which occur in 40% to 50% of infant cases, 2% of childhood and 5% to 6% of adult cases, and Philadelphia chromosome with BCR-ABL fusion whose incidence increases with age from 3% in children to 20% in adults to over 50% in those above 50 years of age, signify a poor prognosis. Interestingly, there is a marked influence of age on the prognosis of these genetic subtypes. In Philadelphia chromosome-positive ALL, children 1 to 9 years old with a low presenting leukocyte count have a better prognosis than adolescents, while adults have a dismal outcome. Among cases with MLL-AF4 fusion, infants fare considerably worse than older children, and adults have a particularly poor outcome. The basis for these differences may be related some combination of secondary genetic events, the development stage of the target cell undergoing malignant transformation, and the pharmacokinetic characteristics of the patients. In T-cell ALL, the presence of t(11;19) with the MLL-ENL fusion and the overexpression of HOX11 confer a good prognosis. Recent study demonstrates activating mutations of NOTCH1 gene in more than half of all T-cell ALL cases; its prognostic significance has yet to be determined. Gene-expression profiles can differentiate lineage and molecular genetic subtypes of ALL, and identify treatment-specific changes in gene expression in leukemic cells. Recent studies show that gene-expression profiling can also identify, within a given subtype of leukemia, previously unrecognized genes whose expression may have prognostic significance. Although gene-expression profile has not yet been used for risk classification, the findings already have led to efforts in identifying proteins that might serve as therapeutics targets or biologic markers. Host factors exert a crucial influence on the effectiveness of treatment. Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and drug targets result in wide inter-patient differences in drug disposition (absorption, distribution, metabolism, and excretion) and pharmacological effects. Patients who have homozygous or heterozygous deficiency of thiopurine methyltransferase, the enzyme that catalyses the S-methylation (inactivation) of mercaptopurine, have more rapid and profound reduction in leukemic cell burden after treatment with mercaptopurine in the early treatment phase and tend to have better event-free survival than those with wild-type enzyme activity, probably because they had, in effect, received a higher dose intensity of mercaptopurine. Glutathione S-transferases catalyze the inactivation of many antileukemic agents and their metabolites and protect the genome against oxidative stress. The null genotypes of these enzymes have been associated with a lower risk of relapse, perhaps because of the reduction in inactivation of cytotoxic chemotherapy. A tandem-repeat polymorphism within the enhancer region of the thymidylate synthase, one of the major targets of methotrexate, has been linked to increased