Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia.
OBJECTIVE
Normal white blood cell counts (WBC) are unknown in children with acute lymphoblastic leukemia (ALL). Accordingly, 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy is adjusted by a common WBC target of 1.5-3.0 × 109/L. Consequently, the absolute degree of myelosuppression is unknown for the individual child and we wanted to evaluate this.


METHODS
A median of 22 (range 8-27) 6MP/MTX metabolite samples and 100 (range 25-130) blood counts during therapy and 10 (range 2-15) off therapy were collected in 50 children with ALL. Differences between off-therapy and on-therapy WBCs [including absolute neutrophil (ANC) and lymphocyte counts (ALC)] were used to retrospectively approximate the absolute myelosuppression (="delta-") and association with age, sex and 6MP/MTX doses explored. We applied linear mixed models to estimate on-therapy counts by 6MP/MTX metabolites: DNA-incorporated thioguanine nucleotides (DNA-TGN), erythrocyte thioguanine nucleotides (ery-TGN), erythrocyte-methylated 6MP metabolites (ery-MeMP) and erythrocyte MTX polyglutamates with 2-6 glutamate residues (ery-MTXpg2-6).


RESULTS
On-therapy WBC was correlated with ANC and ALC (rs= 0.84 and rs= 0.33, p values <0.001), whereas ANC was weakly correlated with ALC (rs= -0.11, p < 0.001), and neither significantly correlated with age. Off-therapy ALC, but not ANC, was strongly correlated with age (rs= -0.68 and -0.18, p < 0.001 and p = 0.22). Delta-ALC decreased with increasing age (rs= -0.69, p < 0.001). Incorporation of DNA-TGN was positively associated with ery-TGN (p < 0.001), ery-MeMP (p < 0.001) and ery-MTXpg2-6(p = 0.047). On-therapy ALC decreased with increasing DNA-TGN level (p < 0.001, model adjusted for off-therapy ALC), whereas on-therapy ANC could not be modeled reliably.


CONCLUSIONS
Measurements of 6MP/MTX metabolites could supplement blood counts in assessing therapy intensity, but require prospective validation.
Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, JMC-4072, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Stine Nygaard
SN
Nielsen
Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, JMC-4072, Blegdamsvej 9, 2100, Copenhagen, Denmark.|Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
Kathrine
K
Grell
Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, JMC-4072, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Jacob
J
Nersting
Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, JMC-4072, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Thomas Leth
TL
Frandsen
Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, JMC-4072, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Lisa Lyngsie
LL
Hjalgrim
Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, JMC-4072, Blegdamsvej 9, 2100, Copenhagen, Denmark. kjeld.schmiegelow@regionh.dk.|Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. kjeld.schmiegelow@regionh.dk.
Kjeld
K
Schmiegelow
D000293:Adolescent; D000375:Aging / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D001772:Blood Cell Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007958:Leukocyte Count; D007970:Leukopenia / Q000139:chemically induced; D060046:Maintenance Chemotherapy / Q000379:methods*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects; D008727:Methotrexate / Q000009:adverse effects; D009504:Neutrophils; D051059:PTEN Phosphohydrolase / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011446:Prospective Studies; D018570:Risk Assessment; D017027:Protein Tyrosine Phosphatases
D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008727:Methotrexate; D051059:PTEN Phosphohydrolase; C000612027:Ptpmt1 protein, human; D017027:Protein Tyrosine Phosphatases
6-Mercaptopurine; ALL; Maintenance therapy; Methotrexate; Myelosuppression