Effects of allopurinol on 6-mercaptopurine metabolism in unselected patients with pediatric acute lymphoblastic leukemia: a prospective phase II study

Abstract

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 6MP metabolism.

Fifty-one patients from Sweden and Finland were enrolled in this prospective beforeafter trial during ALL MT. Mean e-TGN increased from 280 nmol/mmol 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 9481 nmol/mmol Hb to 2791 (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 WBC 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.