Allopurinol Add‐on 6‐Mercaptopurine Strategy Improves Efficacy and Reduces Toxicity in Pediatric Patients With Acute Lymphoblastic Leukemia

The short‐term efficacy of allopurinol add‐on thiopurine therapy has been well documented; however, the long‐term effects and dose recommendations are poorly detailed. This study aimed to elucidate the long‐term implications of this combination therapy and to develop initial dose applying pharmacokinetic modeling. Forty‐two pediatric patients with acute lymphoblastic leukemia, treated with 6‐mercaptopurine (6‐MP) and allopurinol, were enrolled in this prospective before‐after pharmacokinetic study. Metabolite levels (6‐thioguanine nucleotides (6‐TGNs), methyl mercaptopurine nucleotides (6‐MMPN), DNA‐thioguanine (DNA‐TG)), thiopurine methyltransferase (TPMT) activity were measured pre‐ and post‐combination. Another retrospective cohort of 40 patients receiving 6‐MP monotherapy was taken as controls. Compared with the control group, the combination therapy showed a similar myelosuppression effect (( P = 0.060, adjusted Hazard Rates, aHR = 0.94 (0.89–1.00)), while markedly reducing the cumulative hazard of severe neutropenia ( P = 0.009, aHR = 0.49 (0.28–0.83)) and hepatotoxicity ( P < 0.001, aHR = 0.54 (0.40–0.73)). Allopurinol combination led to a fourfold reduction in TPMT activity, the 6‐MMPN:6‐TGNs ratios, and 6‐MMPN: DNA‐TG ratios. This metabolic adjustment improved control of white blood cell (WBC) counts, neutrophil counts (ANC), and aminotransferase levels. LOESS regression estimates indicated significant fluctuations in WBC, ANC, and 6‐MP/allopurinol dosage ratios following 3 months of combination therapy ( P < 0.001), reflecting the need for close monitoring and frequent dose adjustments. Pharmacokinetic analysis further reinforces the benefits of allopurinol add‐on 6‐MP strategy, and suggested that, for patients with normal or high TPMT activity, an initial 6‐MP dose of 20–30 mg/m 2 /day is recommended for those with BSA ≤ 1 m 2 , and 15–20 mg/m 2 /day for those with BSA > 1 m 2 , when co‐administered with allopurinol (50 mg/m 2 /day).