The association between antimetabolite dose intensity (DI) and adverse events among children receiving maintenance therapy for acute lymphoblastic leukemia (ALL) remains unclear, especially in the context of antimetabolite adherence. Using Children’s Oncology Group AALL03N1 data, we examined the association between high DI during the first 4 study months and (i) treatment-related toxicities during the subsequent 2 study months; and (ii) relapse risk. Patients were classified into a high DI phenotype (either 6-mercaptopurine [6-MP] or methotrexate [MTX] DI ≥110% during the first 4 study months, or 6-MPDI or MTXDI 100%-110% at study enrollment and ≥25% increase over the 4 study months) and normal DI phenotype (all others). Only patients with wild-type TPMT and NUDT15 were included. 6-MP adherence data were available for 63.7% of study participants and used to stratify as adherent (median adherence ≥85%) and nonadherent (median adherence <85%) participants. Multivariable analyses were adjusted for sociodemographic and clinical prognosticators. Of the 644 patients, 29.3% were exposed to high DI. High DI was associated with a 2.1-fold greater odds of hematologic toxicity (95% confidence interval [CI] = 1.4-3.1; reference: normal DI) in the entire cohort and 2.9-fold higher among adherers (95% CI = 1.6-5.1); odds were comparable among nonadherers (2.1-fold; 95% CI = 0.4-10.1). Although high DI was not associated with relapse in the entire cohort (adjusted hazard ratio [aHR] = 1.4; 95% CI = 0.8-2.4), it was associated with a greater hazard of relapse among adherent participants (aHR = 2.4; 95% CI = 1.0-5.5) but not among nonadherent participants (aHR = 0.9; 95% CI = 0.2-3.8). Dose escalation above protocol doses during maintenance therapy for ALL should be done cautiously after assessing adherence to prescribed therapy.

中文翻译：

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急性淋巴细胞白血病儿童的抗代谢药物剂量强度和不良结局： COG-AALL03N1 报告


接受急性淋巴细胞白血病 （ALL） 维持治疗的儿童抗代谢药物剂量强度 （DI） 与不良事件之间的关联仍不清楚，尤其是在抗代谢药物依从性的情况下。使用儿童肿瘤组AALL03N1数据，我们检查了前 4 个研究月的高 DI 与 （i） 随后 2 个研究月的治疗相关毒性之间的关联;以及 （ii） 复发风险。患者被分为高 DI 表型 （6-巯基嘌呤 [6-MP] 或甲氨蝶呤 [MTX] DI ≥前 4 个研究月为 110%，或 6-MPDI 或 MTXDI 100%-110%，≥4 个研究月增加 25%）和正常 DI 表型 （所有其他）。仅纳入野生型 TPMT 和 NUDT15 患者。63.7% 的研究参与者有 6-MP 依从性数据，并用于分层为依从性 （中位依从性 ≥85%） 和非依从性 （中位依从性 <85%） 参与者。针对社会人口学和临床预后因素调整了多变量分析。在 644 例患者中，29.3% 暴露于高 DI。高 DI 与整个队列中血液学毒性的几率高 2.1 倍相关 （95% 置信区间 [CI] = 1.4-3.1;参考：正常 DI），在依从者中高 2.9 倍 （95% CI = 1.6-5.1）;非依从者之间的比值相当 （2.1 倍;95% CI = 0.4-10.1）。尽管高 DI 与整个队列的复发无关 （调整后的风险比 [aHR] = 1.4;95% CI = 0.8-2.4），但它与依从性参与者的复发风险更大相关 （aHR = 2.4;95% CI = 1.0-5.5），但在非依从性参与者中则无关 （aHR = 0.9;95% CI = 0.2-3.8）。 在评估对处方治疗的依从性后，应谨慎进行 ALL 维持治疗期间高于方案剂量的剂量递增。