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

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.

Keywords: 6-Mercaptopurine; ALL; Maintenance therapy; Methotrexate; Myelosuppression.