Division of Pediatric Hematology and Oncology, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Cancer Chemother Pharmacol. 2019 Feb;83(2):341-348. doi: 10.1007/s00280-018-3732-3. Epub 2018 Nov 24.
Toxicity of 6-Mercaptopurine (6MP) is related to single nucleotide polymorphism (SNP) in genes coding for metabolizing enzymes, with TPMT analysis being recommended prior to maintenance therapy. However, ITPA and NUDT15 polymorphisms appear more important in the Asian population.
In this study 63 consecutive patients with ALL, entering maintenance phase of therapy, were evaluated for TPMT, ITPA and NUDT15 polymorphisms by PCR RFLP and confirmed by sequencing. Hematological and hepatic toxicities were monitored for 36 weeks. The groups with and without any of the three studied polymorphisms (Risk SNP + and Risk SNP-) were compared.
Eighteen (28.6%) patients had major polymorphisms, 17 being heterozygous. ITPA(198CA): 11(17.5%); NUDT (415CT): 6(9.5%) and TPMT*3C: in 2(3.1%). Mean cumulative dose of 6MP was lower: 10927 mg/m in group with one of the polymorphisms compared to 12533 mg/m in the group without a polymorphism (p = 0.009). The group with Risk SNP + tolerated lesser weeks of full-dose 6MP chemotherapy (20.81 vs 30.40 weeks; p = 0.001). Risk of neutropenia > 3 weeks was pronounced in Risk SNP + group. The individual TPMT, ITPA and NUDT15 polymorphism subgroups had similar cumulative 6MP dose and chemotherapy interruptions. There was no difference in the average cumulative dose of methotrexate in the two groups. No significant hepatotoxicity was noted.
Polymorphisms in ITPA and NUDT15 have a greater prevalence in the north Indian population. Patients with these SNPs tolerate lower doses of 6MP.
6-巯基嘌呤（6MP）的毒性与编码代谢酶的基因中的单核苷酸多态性（SNP）有关，建议在维持治疗前进行 TPMT 分析。然而，ITPA 和 NUDT15 多态性在亚洲人群中似乎更为重要。
本研究对 63 例连续接受 ALL 维持治疗的患者进行了 TPMT、ITPA 和 NUDT15 多态性的 PCR-RFLP 分析，并通过测序进行了验证。监测了 36 周的血液学和肝毒性。比较了有和没有三种研究多态性（风险 SNP+和风险 SNP-）的两组。
18 例（28.6%）患者存在主要多态性，其中 17 例为杂合子。ITPA(198CA)：11 例（17.5%）；NUDT（415CT）：6 例（9.5%）和 TPMT*3C：2 例（3.1%）。有一个多态性的组中 6MP 的累积剂量较低：与无多态性的组相比，有一个多态性的组的累积剂量为 10927mg/m，而无多态性的组为 12533mg/m（p=0.009）。Risk SNP+组耐受的全剂量 6MP 化疗周数较少（20.81 周 vs 30.40 周；p=0.001）。Risk SNP+组发生 3 周以上中性粒细胞减少的风险较高。单独的 TPMT、ITPA 和 NUDT15 多态性亚组的 6MP 累积剂量和化疗中断相似。两组的甲氨蝶呤平均累积剂量无差异。未观察到明显的肝毒性。
ITPA 和 NUDT15 多态性在印度北部人群中更为常见。携带这些 SNP 的患者耐受 6MP 的剂量较低。
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