Erythrocyte-incorporated 6-mercaptopurine metabolite levels are not affected by recent drug administration during maintenance therapy for childhood acute lymphoblastic leukemia

Abstract

Background: Childhood acute lymphoblastic leukemia (ALL) maintenance therapy with oral 6-mercaptopurine (6-MP) and methotrexate prevents leukemic relapse by acting against residual lymphoblasts. Non-adherence to oral maintenance therapy significantly increases ALL relapse risk. The levels of intracellular 6-MP metabolites erythrocyte incorporated (ery-) thioguanine nucleotides (ery-TGN) and methylated 6-MP metabolites (ery-MeMP) can be used to evaluate adherence to 6-MP, however, little is known on their short-term pharmacokinetics. The aim of this study was to assess the changes between trough levels and the levels at 2-hours after 6-MP intake when the 6-MP levels in plasma is expected to have peaked. Materials and methods: Ten ALL patients with stable 6-MP dose were prospectively included. Two blood samples were collected for ery-TGN and ery-MeMP analysis (before 6-MP intake and 2 h after). Results: The median trough ery-TGN was 173 (range 126–299) nmol/mmol hemoglobin (HGB), and 2 h after 6-MP intake the median level was 175 (range 120–293) nmol/mmol HGB. For ery-MeMP, the median trough and 2 h-concentrations were 9 239 (range 1 278–19 645) nmol/mmol HGB and 9 216 (range 1 215–19 519) nmol/mmol HGB, respectively. The median absolute percentual change for both ery-TGN and ery-MeMP were not statistically different from 0, p = 0.28 and p = 0.06, respectively. Conclusions: Intracellular 6-MP metabolites, ery-MeMP and ery-TGN, remain stable 2 h after oral 6-MP intake in patients with a stable 6-MP dose. This data support that blood samples may be used to assess patient adherence irrespective of the timing of 6-MP intake.

Keywords

• Leukemia
• Acute
• Lymphoblastic
• Maintenance therapy
• 6-mercaptopurine
• Relapse