Schmiegelow Kjeld, Nielsen Stine N, Frandsen Thomas L, Nersting Jacob
*Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet †Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark.
J Pediatr Hematol Oncol. 2014 Oct;36(7):503-17. doi: 10.1097/MPH.0000000000000206.
The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients' ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens to improve therapy for the individual patient.
6-巯基嘌呤（6MP）和甲氨蝶呤（MTX）维持治疗的抗白血病机制尚不清楚，但多年的骨髓抑制维持治疗对急性淋巴细胞白血病的益处已得到充分证实。目前，关于药物剂量尚无国际共识。由于药物处置和药效学存在显著的个体间和个体内差异，需要进行积极的剂量调整以达到目标骨髓抑制程度。由于正常白细胞计数因患者年龄和种族而异，且在年龄组内也有所不同，两名患者相同的白细胞水平可能并不反映相同的治疗强度。测量6MP和MTX细胞内细胞毒性代谢物水平可识别不依从的患者，但治疗目标水平仍有待确定。维持治疗期间血清转氨酶水平升高很常见，且通常与甲基化6MP代谢物水平升高有关。然而，除低血糖发作外，严重肝功能障碍很少见，永久性肝损伤风险低，且转氨酶水平通常在停药后几周内恢复正常。6MP和MTX剂量增加应导致白细胞减少或转氨酶升高，如果两者均未出现，则应考虑治疗依从性差。许多决定6MP和MTX处置、疗效及毒性的基因多态性使得药物基因组学无法应用于治疗，唯一的例外是硫嘌呤甲基转移酶纯合缺陷的患者需大幅降低6MP剂量，硫嘌呤甲基转移酶是使6MP及其几种代谢物甲基化的酶。总之，维持治疗与早期强度更大且毒性更高的治疗阶段同样重要，且往往更具挑战性。正在进行的研究涉及药物代谢物测量用于剂量调整的适用性、广泛的宿主基因组分析以了解治疗疗效和毒性的多样性，以及替代硫嘌呤给药方案以改善个体患者的治疗。
