Effects of allopurinol on 6-mercaptopurine metabolism in unselected patients with pediatric acute lymphoblastic leukemia: a prospective phase II study.
AI interpretation is pending for this paper.
Open original publication →What the AI sees
Not AI summarized yet.
Research significance
Pending deeper interpretation.
Source abstract
Allopurinol can be used in maintenance therapy (MT) for pediatric acute lymphoblastic leukemia (ALL) to mitigate hepatic toxicity in patients with skewed 6-mercaptopurine metabolism. Allopurinol increases the erythrocyte levels of thioguanine nucleotides (e-TGN), which is the proposed main mediator of the antileukemic effect and decreases methyl mercaptopurine (e-MeMP) levels, associated with hepatotoxicity. We investigated the effects of allopurinol in thiopurine methyltransferase (TPMT) wild-type patients without previous clinical signs of skewed 6-mercaptopurine metabolism. Fifty-one patients from Sweden and Finland were enrolled in this prospective before-after trial during ALL MT. Mean e-TGN increased from 280 nmol/mmol hemoglobin (Hb) after 12 weeks of standard MT to 440 after 12 weeks of MT with addition of allopurinol 50 mg/ m2 (P<0.001). Mean e-MeMP decreased simultaneously from 9,481 nmol/mmol Hb to 2,791 (P<0.001) and mean alanine aminotransferase declined by almost 50%. Primary endpoint, defined as e-TGN >200 nmol/mmol Hb, was reached for 91% of the patients after 12 weeks of allopurinol (week 25) compared to 67% before (week 13) (P<0.001). This level was chosen as the median e-TGN in a previous NOPHO ALL-2008 study was just below 200 nmol/mmol Hb. During weeks on allopurinol a slightly higher proportion of the patients had a white blood cell count within target 1.5-3.0×109/L. Allopurinol did not increase severe adverse events and no life-threatening events were reported. In conclusion, allopurinol add-on treatment is safe and leads to increased e-TGN and reduced e-MeMP also in ALL-patients without previous signs of skewed thiopurine metabolism and is a promising approach to increase antileukemic effect and reduce toxicity.