The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse.
Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (>or=10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 x 10(9)/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS(12y):0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r(S)=0.36, P=0.02), which became nonsignificant for those who relapsed (r(S)=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r(S)=0.38, P=0.02), which was not the case for those who developed a relapse (r(S)=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.
Department of Pediatric Oncology, The University Hospital Rigshospitalet, Copenhagen, Denmark. kschmiegelow@rh.dk
K
K
Schmiegelow
M
M
Heyman
G
G
Gustafsson
B
B
Lausen
F
F
Wesenberg
J
J
Kristinsson
K
K
Vettenranta
H
H
Schroeder
E
E
Forestier
S
S
Rosthoej
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007958:Leukocyte Count; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D008780:Methyltransferases / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy; D009504:Neutrophils / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome
D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D008727:Methotrexate