Expression of the multidrug transporter P-glycoprotein is highly correlated with clinical outcome in childhood acute lymphoblastic leukemia: results of a long-term prospective study.
The improved cure rate in childhood ALL may be attributed largely to the effective multidrug regimens currently applied in well-designed clinical trials. However, in a minority of patients with ALL, chemotherapy failure remains a leading cause of cancer related death, most probably due to cellular drug resistance. The better-known mechanism of such resistance is mediated by P-glycoprotein (P-gp). In a long term prospective study (mean time of follow-up: 65 months) the multidrug efflux pump P-gp was examined immunocytochemically in leukemic cells of 102 protocol-treated children with de novo acute lymphoblastic leukemia (ALL) and of 37 children with relapsed ALL. Fourteen percent expressed P-gp at initial diagnosis and 35% were P-gp positive at relapse. The patients being P-gp positive at initial diagnosis had a higher rate of leukemic relapse than the P-gp negative patients (P = 0.02). In the relapsing patients, those who were P-gp positive had a 2.18-fold greater risk for leukemic death than those who were P-gp negative. Paired analysis on diagnostic and relapsed samples from 20 patients did not support the hypothesis of P-gp mediated expression being a chemotherapy induced phenomenon. The cumulative event free survival for de novo ALL patients was significantly higher in the P-gp negative patient group. Multivariate analysis showed that P-gp expression is independent of other known risk factors. In conclusion we strongly advise that tests for P-gp in leukemic blasts should be conducted for every child with ALL, since this parameter selects a subgroup of patients with increased risk for leukemic relapse.
Dhooge
Catharina
C
Department of Pediatrics, Ghent University Hospital, Belgium. catharina.dhooge@rug.ac.be
De Moerloose
Barbara
B
Laureys
Geneviève
G
Ferster
Alice
A
De Bacquer
Dirk
D
Philippe
Jan
J
Leroy
Jules
J
Benoit
Yves
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D016555:Matched-Pair Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D016019:Survival Analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1