Remission induction therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines

Abstract

Remission induction therapy with vincristine, a corticosteroid, L-asparaginase and an anthracycline has been the mainstay of the initial phase of treatment for childhood acute lymphoblastic leukaemia (ALL) for the past 25 years. The speed and depth of the early response to remission induction therapy has become an important determinant of the intensity of subsequent therapy in many protocols worldwide. Moreover, the detection of significant levels of minimal residual disease at the end of remission induction may have an important bearing on subsequent outcome. Although these clinical observations may reflect, in part, the inherent sensitivity of lymphoblasts to remission induction therapy, the pharmacology of these agents in relation to childhood ALL may also play an important part in early response to therapy. In-vitro studies of human leukaemia cell lines indicate that both the extracellular fluid concentration and duration of exposure to vincristine and anthracyclines are important determinants of cytotoxicity. For L-asparaginase and corticosteroids, the cellular and molecular pharmacological determinants of chemosensitivity have been partially characterized, but further work is needed in this area. The clinical pharmacology of vincristine and L-asparaginase have been well characterized in relation to childhood ALL, and considerable interpatient pharmacokinetic variability exists for these drugs. For corticosteroids and anthracyclines, pharmacology studies are needed in order to fully characterize and understand the factors influencing interpatient pharmacokinetic variability for these agents in relation to childhood ALL. Whereas the relationship between the clinical pharmacology, and potentially important pharmacodynamic effects such as asparagine depletion, has been well characterized for therapy with L-asparaginase, similar studies have yet to be performed for the other drugs that form the mainstay of remission induction therapy for childhood ALL. Therefore, further studies are required to investigate the relative importance of the clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines in the speed and depth of response to remission induction therapy for childhood ALL. Where these have been studied, interindividual differences in the clinical and cellular pharmacology of anticancer agents have been shown to be important determinants of the long-term disease-free survival for children with ALL.