In Vitro Drug Resistance Profiles in Childhood Acute Lymphoblastic Leukemia

In 1987, the short-term MTT assay was adapted in our laboratory to study in vitro cellular drug resistance in childhood acute lymphoblastic leukemia (ALL). In this paper, some clinically relevant data obtained with this method are summarized: 1. In a small retrospective study we showed that in vitro drug resistance was related to the long-term clinical outcome. In 1989 a nationwide, prospective study including 128 patients was started to confirm these data. Patients with cells relatively in vitro resistant to prednisolone had a significantly lower 2-year probability of disease-free survival (pDFS 0.67) than sensitive cases (pDFS 0.98). In vitro resistance to L-asparaginase and daunorubicin were also significantly related to outcome; for vincristine the relation was borderline significant. Combining the results for prednisolone, L-asparaginase and vincristine, the pDFS was 100% for the sensitive, 83% for the intermediately sensitive and 60% for the in vitro resistant patients (p >.001). In vitro drug resistance was an independent prognostic factor at multivariate analysis. 2. In vitro resistance of a group of 99 children with relapsed ALL was compared to that of 137 children with untreated ALL. Cells from children with relapsed ALL were significantly more in vitro resistant to corticosteroids, anthracyclines, antimetabolites and L-asparaginase but not to vinca-alkaloids, epipodophyllotoxins and ifosfamide. Resistance profiles and the degree of resistance highly differed between individual patients. 3. The prognostic significance of several cell biological features can mainly be explained by drug resistance. DNA hyperdiploid cases have a better prognosis than non-hyperdiploid cases. Hyperdiploid cALL cases were significantly more in vitro sensitive to the antimetabolites 6TG, 6-MP and araC but not to other drugs. Immunophenotypic subgroups of ALL had their own specific drug resistance profiles that might explain the differences in prognosis related to phenotype.