Pharmacodynamics inChildhood Acute Lymphoblastic Leukemia

Pharmacokinetic variability clearly influences the outcome of treatment for acute lymphoblastic leukemia (ALL) , but its utility as a clinical risk factor is limited when pa­ tients receive complex multiagent regimens of chemotherapy. However, judicious use of pharmacodynamic measures can increase the precision of risk assessment and guide the selection of therapy. For example, patients with slow reduction of their initial leukemic cell burden are excellent candidates for inten­ sified chemotherapy. Also, recent studies indi­ cate that the level of minim al residual leuke­ mia, as measured by immunological or molecular methods at the time of remission induction, is highly pred ictive of treatment outcome. Patients achieving a "molecular" or "immunologic" remission, defined as leuke­ mic involvement of less than 0.01% of mononucleated bone marrow cells, are pre­ dicted to have a better clinical outcome than those in whom remission is identified solely by blast cell morphologic criteria. A related approach is to measure specific biochemical endpoints that correlate closely with drug­ induced cytotoxicity. This is well illustrated by experience with methotrexate, whose accumulation as poly­ glutamates (active metabolites) in leukemic blast cells correlates positively with antileuke­ mic responses. Ongoing studies will determine the opti­ mal dosage of methotrexate for the major phenotypic or genotypic subtypes of ALL. Although the erythrocyte concentration of 6­ thioguan ine nucleotides, the active meta­ bolites of 6-mercaptopruine, correlates posi- tively with long-term event-free survival, a recent study shows that the dose intensit y of oral 6-mercaptopurine is an even more important determinant of clinical outcome, particularly among patients with a homo ­ zygous wild-type thiopurine methyltrans­ ferase phenotype, a cytosolic enzyme that inactivates 6-mercaptopurine and 6-thiogua­ nine. Consistent adm inistration of full proto­ col doses of daily oral 6-mercaptopurine is important in achieving optimal clinical res­ ponses; however, care must be taken to avoid excessive neutropenia, which can decrease dose intensity overall, leading to a poorer cli­ nical outcome. For pat ients who tolerate thio ­ purine therapy poorly, molecular methods are available to diagnose a deficiency of thio­ purine methyltransferase, allowing rational adjustment of drug dosages. Prospective cli­ nical trials are needed to determine the opti­ mal integration of pharmacodynamic measu­ rements with more conventional predictors of the clinical relapse hazard in patients with ALL.