儿童急性淋巴细胞白血病中6-巯基嘌呤和甲氨蝶呤维持治疗强度的测量
Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia.
作者信息
Nielsen Stine Nygaard, Grell Kathrine, Nersting Jacob, Frandsen Thomas Leth, Hjalgrim Lisa Lyngsie, Schmiegelow Kjeld
机构信息
Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, JMC-4072, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
出版信息
Cancer Chemother Pharmacol. 2016 Nov;78(5):983-994. doi: 10.1007/s00280-016-3151-2. Epub 2016 Sep 6.
PURPOSE
Normal white blood cell counts (WBC) are unknown in children with acute lymphoblastic leukemia (ALL). Accordingly, 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy is adjusted by a common WBC target of 1.5-3.0 × 10/L. Consequently, the absolute degree of myelosuppression is unknown for the individual child and we wanted to evaluate this.
METHODS
A median of 22 (range 8-27) 6MP/MTX metabolite samples and 100 (range 25-130) blood counts during therapy and 10 (range 2-15) off therapy were collected in 50 children with ALL. Differences between off-therapy and on-therapy WBCs [including absolute neutrophil (ANC) and lymphocyte counts (ALC)] were used to retrospectively approximate the absolute myelosuppression (="delta-") and association with age, sex and 6MP/MTX doses explored. We applied linear mixed models to estimate on-therapy counts by 6MP/MTX metabolites: DNA-incorporated thioguanine nucleotides (DNA-TGN), erythrocyte thioguanine nucleotides (ery-TGN), erythrocyte-methylated 6MP metabolites (ery-MeMP) and erythrocyte MTX polyglutamates with 2-6 glutamate residues (ery-MTXpg).
RESULTS
On-therapy WBC was correlated with ANC and ALC (r = 0.84 and r = 0.33, p values <0.001), whereas ANC was weakly correlated with ALC (r = -0.11, p < 0.001), and neither significantly correlated with age. Off-therapy ALC, but not ANC, was strongly correlated with age (r = -0.68 and -0.18, p < 0.001 and p = 0.22). Delta-ALC decreased with increasing age (r = -0.69, p < 0.001). Incorporation of DNA-TGN was positively associated with ery-TGN (p < 0.001), ery-MeMP (p < 0.001) and ery-MTXpg (p = 0.047). On-therapy ALC decreased with increasing DNA-TGN level (p < 0.001, model adjusted for off-therapy ALC), whereas on-therapy ANC could not be modeled reliably.
CONCLUSION
Measurements of 6MP/MTX metabolites could supplement blood counts in assessing therapy intensity, but require prospective validation.
目的
急性淋巴细胞白血病（ALL）患儿的正常白细胞计数（WBC）尚不明确。因此，6-巯基嘌呤（6MP）和甲氨蝶呤（MTX）维持治疗是根据1.5 - 3.0×10⁹/L这一常见的WBC目标进行调整的。然而，个体患儿的骨髓抑制绝对程度尚不清楚，我们希望对此进行评估。
方法
收集了50例ALL患儿治疗期间的中位数为22份（范围8 - 27份）6MP/MTX代谢物样本和100份（范围25 - 130份）血常规计数，以及治疗结束后10份（范围2 - 15份）血常规计数。用治疗结束后与治疗期间的WBC差异[包括绝对中性粒细胞（ANC）和淋巴细胞计数（ALC）]来回顾性估算绝对骨髓抑制（=“delta-”），并探讨其与年龄、性别以及6MP/MTX剂量的关联。我们应用线性混合模型通过6MP/MTX代谢物来估算治疗期间的计数：DNA掺入的硫鸟嘌呤核苷酸（DNA-TGN）、红细胞硫鸟嘌呤核苷酸（ery-TGN）红细胞甲基化6MP代谢物（ery-MeMP）以及具有2 - 6个谷氨酸残基的红细胞MTX多聚谷氨酸（ery-MTXpg）。
结果
治疗期间的WBC与ANC和ALC相关（r = 0.84和r = 0.33，p值<0.001），而ANC与ALC的相关性较弱（r = -0.11，p < 0.001），且两者均与年龄无显著相关性。治疗结束后的ALC与年龄密切相关，但ANC与年龄无关（r = -0.68和 -0.18，p < 0.001和p = 0.22）。Delta-ALC随年龄增长而降低（r = -0.69，p < 0.001）。DNA-TGN的掺入与ery-TGN（p < 0.001）、ery-MeMP（p < 0.001）和ery-MTXpg（p = 0.047）呈正相关。随着DNA-TGN水平升高，治疗期间的ALC降低（p < 0.001，模型已根据治疗结束后的ALC进行调整），而治疗期间的ANC无法可靠建模。
结论
6MP/MTX代谢物的测量在评估治疗强度方面可补充血常规计数，但需要前瞻性验证。
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