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As an important determinant of the response to chemotherapy, measurements of cellular drug resistance may provide prognostically significant information, which could be useful for optimal risk-group stratification. The objective of this report is to determine the relation between in vitro resistance to 12 drugs, measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and long-term clinical response to chemotherapy in 152 children with newly diagnosed acute lymphoblastic leukemia. At risk-group stratified analyses, in vitro resistance to prednisolone, L-asparaginase, and vincristine were each significantly (P < .01) related to the probability of disease-free survival (pDFS) after combination chemotherapy. The combination of data for prednisolone, L-asparaginase, and vincristine provided a drug-resistance profile with prognostic independent significance superior to that of any single drug or any other factor. The 3-years pDFS was 100% for the group with the most sensitive profile, 20% of all patients, 84% (SE 6%) for the group with an intermediately sensitive profile, 40% of all patients, and 43% (SE 8%) for the remaining group with the most resistant profile (P < .001). In conclusion, the extent of in vitro cellular resistance to prednisolone, L-asparaginase, and vincristine, measured using the MTT assay, was significantly related to the clinical response to combination chemotherapy. Treatment failure in newly diagnosed childhood ALL can be predicted based on cellular drug resistance data.

As an important determinant of response to chemotherapy, accurate measurement of cellular drug resistance may provide clinically relevant information. Our objectives in this study were to determine the relationship between in vitro resistance to prednisolone (PRD) measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and (1) short-term clinical response to systemic PRD monotherapy, (2) long-term clinical outcome after combination chemotherapy within all patients and within the subgroups of clinical good and poor responders to PRD, and (3) in vitro resistance to 12 other drugs in 166 children with newly diagnosed acute lymphoblastic leukemia (ALL). The 12 clinical poor PRD responders had ALL cells that were median 88-fold more in vitro resistant to PRD than 131 good responders (P = .013). Within all patients, increased in vitro resistance to PRD predicted a significantly worse long-term clinical outcome, at analyses with and without stratification for clinical PRD response, and at multivariate analysis (P ≤ .001). Within both the clinical good and poor responder subgroups, increased in vitro resistance to PRD was associated with a worse outcome, which was significant within the group of clinical good responders (P < .001). LC50 values, ie, lethal concentrations to 50% of ALL cells, for PRD and each other drug correlated significantly with those of all other 12 drugs, with an average correlation coefficient of 0.44 (standard deviation 0.05). The highest correlations were found between structurally related drugs. In conclusion, in vitro resistance to PRD was significantly related to the short-term and long-term clinical response to chemotherapy, the latter also within the subgroup of clinical good responders to PRD. There was a more general in vitro cross-resistance between anticancer drugs in childhood ALL, although drug-specific activities were recognized.

The clinical relevance of cellular drug resistance in children with acute lymphoblastic leukaemia (ALL) is unknown. The relation between in-vitro sensitivity to chemotherapeutic drugs at initial diagnosis and long-term clinical outcome was investigated in 44 children with ALL. The short-term MTT assay was used to assess sensitivity to prednisolone, vincristine, colaspase (asparaginase), daunorubicin, and thioguanine (instead of mercaptopurine which is unstable in vitro). For vincristine and colaspase there was no difference in outcome (probability of continuous complete remission) between sensitive and resistant patients. However, the probability of continuous complete remission was significantly lower in patients with resistant cells than in those with sensitive cells for thioguanine (p<0·01), daunorubicin (p<0·02), and prednisolone (p<0·05). For prednisolone there was a significant worsening of the prognosis (p<0·05) from the extremely sensitive patients through an intermediate group to the most resistant group. The prognostic significance of cellular drug resistance was independent of white-blood-cell count, age, sex, and hepatosplenomegaly. Leukaemic cells from boys were more resistant to thioguanine than those from girls. Thus, the short-term highly efficient MTT assay can help to predict long-term response to chemotherapy in childhood ALL.

The incidence of childhood leukaemia in The Netherlands in the period 1973-1986 was studied by means of the DCLSG nationwide register, which lists all patients according to bone marrow slides classified in the DCLSG central laboratory. Acute lymphocytic leukaemia (ALL) accounted for 81% of cases, acute non-lymphocytic leukaemia (ANLL) for 13%, chronic myelocytic leukaemia (CML) for 2.5%, and acute unclassifiable leukaemia (AUL) for 3%. The peak incidence of ALL was at age 3, common-ALL and pre B-ALL comprising about 95% of the immunophenotypes at this age. Incidence rates for ALL remained stable between 1973 and 1978 at 2.85 cases per 10(5) children per year, exhibited a temporary increase between 1979 and 1984 to 3.60 and dropped back to the lower, previous level in 1985 and 1986. This rise was seen mainly among children in the 1-4 year age group, especially at age 3, and those with common-ALL and an initial WBC less than 5.0 x 10(9) l-1. Cumulative incidence rates per year of birth were fairly homogeneous up to age 6, except for the 1978 birth cohort which exhibited higher rates. Incidence rates for ANLL, CML and AUL remained stable over time. Changes in ascertainment, declining birth rates and a 50% decrease in childhood mortality, e.g. from infectious diseases, could not explain this temporary variation. Moreover, incidence rates in this survey appeared to be similar to those reported in various developed countries for the same period. As far as the aetiology of childhood common-ALL is concerned, therefore, the Dutch data appear to support the hypothesis of 'random mutation' as well as that of a limited role of environmental factors.