Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

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.

• Authors: Kjeld Schmiegelow, Jacob Nersting, Stine Nygaard Nielsen, Mats Heyman, Finn Wesenberg, Jon Kristinsson, Kim Vettenranta, Henrik Schrøeder, Richard Weinshilboum, Katrine Lykke Jensen, Kathrine Grell, Susanne Rosthoej
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 63 Issue 12 Pg. 2104-2111 (12 2016) ISSN: 1545-5017 [Electronic] United States
• PMID: 27447547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2016 Wiley Periodicals, Inc.

Chemical References

• Mercaptopurine
• Methotrexate

Topics

• Adolescent
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Leukocyte Count
• Lymphocyte Count
• Male
• Mercaptopurine (administration & dosage)
• Methotrexate (administration & dosage)
• Neutrophils
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (blood, drug therapy)
• Proportional Hazards Models