Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?
PEDIATRIC BLOOD & CANCER(2016)
摘要
Background6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. ProcedureTo identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 x 10(9)/l. ResultsAfter a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N=83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P=0.003), WBC at diagnosis (HR=1.04 per 10 x 10(9)/l rise [1.00-1.09], P=0.048), the absolute neutrophil count (ANC; HR=1.7 per 10(9)/l rise [1.3-2.4], P=0.0007), and Ery thiopurine methyltransferase activity (HR=2.7 per IU/ml rise [1.1-6.7], P=0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r(s)=0.77; P<0.001), and only a borderline significant risk factor for relapse (HR=1.28 [95% CI: 1.00-1.64], P=0.046) when ANC was excluded from the Cox model. ConclusionsThis study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.
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关键词
ALL,ALL relapse,chemotherapy,molecular diagnosis and therapy,pharmacokinetics,pharmacology,white blood cell count
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