Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3–4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3–4) was seen in 54.9% of patients. The NUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105’T’) carrier status along with NUDT15c.415T allele [HR = 2.7 (1.5–4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

中文翻译：

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印度急性淋巴细胞白血病患者在 6-MP 和低剂量甲氨蝶呤维持治疗期间 NUDT15*3 和 FPGS 2572C>T 变体与早期血液学毒性风险的关联

影响急性淋巴细胞白血病 (ALL) 治疗中使用的化疗药物的药代动力学和/或药效学的遗传变异通常会导致治疗相关毒性 (TRT) 的发生。在这项研究中，我们探讨了候选遗传变异与在低剂量甲氨蝶呤和 6-巯基嘌呤维持治疗（n = 73）的前 100 天内发生的早期血液学 TRT（3-4 级）的关联。使用实时 PCR 的等位基因鉴别分析对以下候选基因中的 14 个变体进行基因分型：ABCB1、DHFR、GGH、FPGS、MTHFR、RFC1、SLCO1B1、TPMT 和 NUDT15。通过 LC-MS/MS 测量红细胞中的甲氨蝶呤聚谷氨酸 (MTXPG3-5) 水平。54.9% 的患者出现早期血液学 TRT（3-4 级）。NUDT15c。415T 等位基因与早期 TRT 发生相关 [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]。通过考虑 FPGS 变体 (rs1544105'T') 携带者状态以及 NUDT15c.415T 等位基因 [HR = 2.7 (1.5–4.7, p = 0.008)]，早期 TRT 预测的灵敏度提高（从 30.7% 到 89.7%）。所考虑的遗传变异均与 MTXPG3-5 水平无关，而 MTXPG3-5 水平又与早期 TRT 无关。NUDT15c.415T 等位基因携带者状态可用作印度 ALL 患者的分层标记，以区分发生早期血液学 TRT 的高风险或低风险患者。所考虑的遗传变异均与 MTXPG3-5 水平无关，而 MTXPG3-5 水平又与早期 TRT 无关。NUDT15c.415T 等位基因携带者状态可用作印度 ALL 患者的分层标志物，以区分发生早期血液学 TRT 的高风险或低风险患者。所考虑的遗传变异均与 MTXPG3-5 水平无关，而 MTXPG3-5 水平又与早期 TRT 无关。NUDT15c.415T 等位基因携带者状态可用作印度 ALL 患者的分层标记，以区分发生早期血液学 TRT 的高风险或低风险患者。