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01-11-2016 | Original Article

Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia

Authors: Stine Nygaard Nielsen, Kathrine Grell, Jacob Nersting, Thomas Leth Frandsen, Lisa Lyngsie Hjalgrim, Kjeld Schmiegelow

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2016

Abstract

Purpose

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-MTXpg_2–6).

Results

On-therapy WBC was correlated with ANC and ALC (r _s = 0.84 and r _s = 0.33, p values <0.001), whereas ANC was weakly correlated with ALC (r _s = −0.11, p < 0.001), and neither significantly correlated with age. Off-therapy ALC, but not ANC, was strongly correlated with age (r _s = −0.68 and −0.18, p < 0.001 and p = 0.22). Delta-ALC decreased with increasing age (r _s = −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-MTXpg_2–6 (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.

Conclusion

Measurements of 6MP/MTX metabolites could supplement blood counts in assessing therapy intensity, but require prospective validation.

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Title: Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia
Authors: Stine Nygaard Nielsen
Kathrine Grell
Jacob Nersting
Thomas Leth Frandsen
Lisa Lyngsie Hjalgrim
Kjeld Schmiegelow
Publication date: 01-11-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-3151-2

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