Increased in vitro cellular drug resistance is related to poor outcome in high-risk childhood acute lymphoblastic leukaemia.
We determined the in vitro cellular drug resistance in 370 children with newly diagnosed acute lymphoblastic leukaemia (ALL). The resistance to each of 10 drugs was measured by the fluorometric microculture cytotoxicity assay (FMCA) and was related to clinical outcome. The median follow-up time was 41 months. Risk-group stratified analyses indicated that in vitro resistance to dexamethasone, doxorubicin and amsacrine were each significantly related to the probability of disease-free survival. In the high-risk (HR) group, increased in vitro resistance to dexamethasone (P = 0.014), etoposide (P = 0.025) and doxorubicin (P = 0.05) was associated with a worse clinical outcome. Combining the results for these drugs provided a drug resistance score with an independent prognostic significance superior to that of any other factor studied, with a relative risk of relapse in the most resistant group 9.8 times that in the most sensitive group (P = 0.007). The results in the intermediate-risk (IR) and standard-risk (SR) groups were less clear cut. In conclusion, our data indicate that in vitro testing of cellular drug resistance can be used to predict the clinical outcome in HR ALL, while the final evaluation of the results in IR and SR patients must await longer follow-up.
Frost
Britt-Marie
BM
Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden. Britt-Marie.Frost@kbh.uu.se
Nygren
Peter
P
Gustafsson
Göran
G
Forestier
Erik
E
Jonsson
Olafur G
OG
Kanerva
Jukka
J
Nygaard
Randi
R
Schmiegelow
Kjeld
K
Larsson
Rolf
R
Lönnerholm
Gudmar
G
D000293:Adolescent; D000677:Amsacrine / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003601:Cytotoxicity Tests, Immunologic; D003907:Dexamethasone / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005470:Fluorometry; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007958:Leukocyte Count; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D018709:Statistics, Nonparametric
D000677:Amsacrine; D003907:Dexamethasone; D004317:Doxorubicin