Association of delivered drug dose and outcome for children with acute lymphoblastic leukemia and unfavorable presenting features

Abstract

Dose and dose intensity are believed critical for attaining a maximal therapeutic effect in drug-responsive tumor systems. Childhood acute lymphoblastic leukemia may be an example of such a drug-responsive system as it is cured with current chemotherapy in a majority of cases. Between August 1981 and May 1983, the Childrens Cancer Study Group enrolled 209 children with ALL and unfavorable presenting features in CCG-193P, a trial based on the Berlin Frankfurt Munster 76/79 regimen. The cumulative delivered dose of each medication was recorded prospectively. Patients who completed the intensive portion of therapy in continuous complete remission were ranked by the percentage of protocol required drug delivered from the initiation of therapy to that date. No association was found between delivery of any single drug and subsequent disease-free survival. However, when patients were ranked by the sum of the percentages of protocol vincristine, l-asparaginase, and anthracycline delivered, children in the approximate middle and lower tertiles were 3 and 5 times more likely to have had a subsequent relapse than were those in the upper tertile (P = 0.025, test for trend). Delivery of the full protocol prescribed dose of these agents may have been critical, but corroboration is certainly needed. Only prospective trials can determine if children with acute lymphoblastic leukemia and unfavorable presenting features might benefit from greater use of vincristine, l-asparaginase, and/or anthracycline.

The Clinical and Cellular Pharmacology Of Vincristine, Corticosteroids, l‐Asparaginase, Anthracyclines and Cyclophosphamide In Relation To Childhood Acute Lymphoblastic Leukaemia

“…The potential importance of primary drug resistance, as measured by the methylthiazol tetrazoliumbromide (MTT) assay, has been investigated as a determinant of potential response to remission induction therapy and overall prognosis (Pieters et al , 1991; Kaspers et al , 1997). Moreover, an association between the delivered drug dose of vincristine, l ‐asparaginase and anthracycline has been described for children with higher risk ALL (Gaynon et al , 1991). However, there have been no studies of the importance of the clinical and cellular pharmacology of the antileukaemic agents that form the mainstay of remission induction and intensification/consolidation therapy for childhood ALL.…”

Emerging treatment approaches in acute lymphoblastic and acute myeloid leukemias

“…A pediatric study showed that the sum of the percentages of three induction drugs (vincristine, L-asparaginase and anthracyclines) delivered were critical in predicting relapse, supporting the concept that the dose intensity of the drugs delivered in induction is important for long-term prognosis. 110 In an effort to improve upon the outcome, modifications of these standard treatments have been proposed by the addition of known chemotherapy drugs, intensification of chemotherapy doses, submit your manuscript | www.dovepress.com or incorporation of novel 'targeted' drugs. Although, the addition of other cytotoxic drugs does not increase CR rates substantially, the highest remission rates have been achieved with multidrug induction regimens.…”

Comprehensive analysis of dose intensity of acute lymphoblastic leukemia chemotherapy

“… 1-8 There is, however, a lack of data comparing administered dosages to planned dosages, and the last comprehensive analysis (for only 209 patients) was published in 1991. 9 Hence, it is difficult to compare feasibility of protocol delivery among cooperative treatment groups, between adults and children, and across different countries. Most ALL drugs can cause myelosuppression, and thus comparisons of administered dose intensity across protocols that are limited to a single agent, e.g., mercaptopurine or asparaginase, may be misleading if the dosages of other possibly “compensating” agents are not also accounted for across protocols.…”