The intensification of post-
remission induction therapy has been shown to improve the relapse-free survival for childhood acute lymphoblastic leukaemia (ALL), and is now a standard component of the treatment of childhood acute lymphoblastic leukaemia. For
cytosine arabinoside (
ara-C),
methotrexate,
vincristine and
corticosteroids, in-vitro studies indicate that the extracellular
drug concentration and exposure time are important determinants of cytotoxicity for human leukaemia cell lines. For L-
asparaginase, epipodopyllotoxins and
cyclophosphamide, there have been few studies of the relationship between cellular pharmacology and cytotoxicity in relation to ALL. The clinical and cellular pharmacology of
methotrexate and
cytosine arabinoside have been studied in relation to
childhood ALL in vivo. For these drugs, there is evidence to suggest that maintenance of plasma concentrations that are biochemically optimal is necessary to maximize anti-leukaemic effects. For
cytosine arabinoside in particular, optimal extracellular fluid concentrations are not likely to be achieved or maintained by bolus or short-duration i.v. infusions. A potentially important example of this may be served by the success of
antimetabolite-based intrathecal
chemotherapy for CNS-directed treatment of
childhood ALL. Intrathecal administration of both
methotrexate and
cytosine arabinoside results in prolonged leukaemic cell exposure to cytotoxic concentrations of the
drug. For
vincristine,
anthracyclines and
asparaginase, the actual dose intensity received by children during consolidation
therapy may be important, and there is considerable interpatient variation in the pharmacokinetics of
cyclophosphamide and
teniposide in the
therapy of childhood
cancers. The importance of this relationship to
childhood ALL is not known. The pharmacological and cellular pharmacological studies performed at St Jude Children's Research Hospital (Memphis, TN, USA) have allowed investigation of the relationships between the clinical and cellular pharmacology of
methotrexate and prognosis, and have supported the individualization of consolidation
therapy with this
drug.
Cytosine arabinoside has been less well studied in relation to
childhood ALL, although evidence exists to suggest that the administration of conventional-dose bolus or infusion schedules may not be optimal in terms of the antileukaemic efficacy of this
antimetabolite. For L-
asparaginase, ongoing studies may allow the relationship between dose and schedule of administration to be related to pharmacodynamic measures such as
asparagine depletion and prognosis. Therefore, through knowledge of clinical and cellular pharmacological properties, it may be possible to optimize the consolidation phase of
therapy for
childhood ALL, without disrupting the fundamental principles by which the overall treatment is administered. This may be particularly important for children with disease that has inherent or acquired resistance to
therapy.