Allopurinol Add-on 6-Mercaptopurine Strategy Improves Efficacy and Reduces Toxicity in Pediatric Patients With Acute...

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/m²/day is recommended for those with BSA ≤ 1 m², and 15-20 mg/m²/day for those with BSA > 1 m², when co-administered with allopurinol (50 mg/m²/day).