Maintenance therapy of childhood acute lymphoblastic leukemia revisited—Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?
- 22 July 2016
- journal article
- research article
- Published by Wiley in Pediatric Blood & Cancer
- Vol. 63 (12), 2104-2111
- https://doi.org/10.1002/pbc.26139
Abstract
Background 6-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. Procedure To 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 × 109/l. Results After 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 × 109/l rise [1.00–1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 109/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, rs = 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. Conclusions This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.Keywords
Funding Information
- Danish Childhood Cancer Foundation
- Swedish Childhood Cancer Foundation (53/91, 62/94, 72/96, 98/59)
- Danish Cancer Society (91-048, 92-017, 93-017, 95-100-28)
- Lundbeck Foundation (38/99)
- Nordic Cancer Union (56-9257, 56-100-03-9102)
- University Hospital Rigshospitalet
- US National Institutes of Health; (U19 GM61388, RO1 GM28157)
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