Impact of mercaptopurine schedule on hypoglycemia in leukemic children: randomized trial and risk factor analysis

Children with acute lymphoblastic leukemia (ALL) may develop hypoglycemia, potentially attributable to mercaptopurine (6-MP) during long-term maintenance chemotherapy. Since hypoglycemia is harmful to childhood neurodevelopment, it is necessary to examine its occurrence during chemotherapy with and without 6-MP beyond the maintenance stage for ALL, along with the risk factors.

ALL patients received CAM-1 regimen (cyclophosphamide, cytarabine, and 6-MP). 6-MP was randomized to conventional administration at night before bedtime (Group A) or in the afternoon between lunch and dinner (Group B). Children with acute myeloid leukemia received non-6MP-containing chemotherapy (Group C).

Group C showed no hypoglycemia. Among patients on CAM-1, 33% developed hypoglycemia, 48% of whom were symptomatic. There was no significant difference in hypoglycemic incidence (P = 0.933) between Groups A and B. No further hypoglycemic episodes were observed after shortening overnight fasting period in most cases. Multivariate analysis identified young age, higher serum bilirubin levels, and longer overnight fasting as significant risk factors for hypoglycemia in children receiving 6-MP.

Hypoglycemia is also prevalent in children exposed to short-term 6-MP but not in those without such exposure. Shortening overnight fasting period, rather than changing 6-MP schedule, is more critical in preventing hypoglycemia in young children.

This study reveals that hypoglycemia occurs frequently in children with ‌short-term exposure to 6-MP‌, as documented for long-term exposure‌ in published literature. The data demonstrate that it is 6-MP that is directly associated with hypoglycemia. Prolonged durations of overnight fasting, especially in younger individuals with hepatotoxicity, constitute a risk factor for developing hypoglycemia. Shortening the overnight fasting period, rather than changing the 6-MP schedule, is critical to prevent hypoglycemia and adverse neurodevelopment in children, even if they are receiving short-term 6-MP treatment.