Children's Cancer Centre, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Pediatrics, Institute for Clinical Sciences, University of Gothenburg.
Department of Pediatrics and Adolescents, Oulu University Hospital.
Haematologica. 2024 Sep 1;109(9):2846-2853. doi: 10.3324/haematol.2023.284390.
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.
别嘌醇可用于儿科急性淋巴细胞白血病（ALL）的维持治疗（MT），以减轻巯基嘌呤代谢偏倚患者的肝毒性。别嘌醇增加红细胞硫鸟嘌呤核苷酸（e-TGN）水平，这是抗白血病作用的主要介导物，并降低与肝毒性相关的甲基巯基嘌呤（e-MeMP）水平。我们研究了别嘌醇在没有先前巯基嘌呤代谢偏倚临床迹象的硫嘌呤甲基转移酶（TPMT）野生型患者中的作用。这项前瞻性前后对照试验共纳入了瑞典和芬兰的 51 名 ALL MT 患者。在标准 MT 治疗 12 周后，e-TGN 平均值从 280 nmol/mmol 血红蛋白（Hb）增加到加用别嘌醇 50 mg/m2 后 12 周的 440（P<0.001）。e-MeMP 平均值同时从 9481 nmol/mmol Hb 下降至 2791（P<0.001），丙氨酸氨基转移酶下降近 50%。主要终点定义为 e-TGN >200 nmol/mmol Hb，加用别嘌醇治疗 12 周（第 25 周）时 91%的患者达到，而治疗前（第 13 周）为 67%（P<0.001）。这一水平是基于先前 NOPHO ALL-2008 研究中中位数 e-TGN 刚刚低于 200 nmol/mmol Hb 而选择的。在使用别嘌醇的几周内，更多的患者白细胞计数在目标值 1.5-3.0×109/L 内。别嘌醇并未增加严重不良事件，也未报告危及生命的事件。总之，别嘌醇附加治疗是安全的，可增加 e-TGN 并降低 e-MeMP，即使在没有先前巯基嘌呤代谢偏倚迹象的 ALL 患者中也是如此，是增加抗白血病作用和降低毒性的有前途的方法。
