Effects of allopurinol on 6-mercaptopurine metabolism in unselected patients with pediatric acute lymphoblastic leukemia: a prospective phase II study
: Källström, Jonatan; Niinimäki, Riita; Fredlund, Johan; Vogt, Hartmut; Korhonen, Laura; Castor, Anders; Palle, Josefine; Harila, Arja; Borssén, Magnus; Abrahamsson, Jonas; Ek, Torben
Publisher: Ferrata Storti Foundation
: 2024
: Haematologica
: Haematologica
: 109
: 9
: 2846
: 2853
: 1592-8721
DOI: https://doi.org/10.3324/haematol.2023.284390
: https://haematologica.org/article/view/haematol.2023.284390p=85203028285&origin=inward
: https://research.utu.fi/converis/portal/detail/Publication/457860899
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.
:
Financial support was provided by the ARMEC Lindeberg Foundation, the Swedish Childhood Cancer Fund (Barncancerfonden) and Swedish governmental funding of clinical research (ALF).
