DNMT3A Mutational Status Affects the Results of Dose-Escalated Induction Therapy in Acute Myelogenous Leukemia.
DNMT3A Mutational Status Affects the Results of Dose-Escalated Induction Therapy in Acute Myelogenous Leukemia.
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DOI：
10.1158/1078-0432.ccr-14-0327
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发表时间：
2015-04-01
期刊：
影响因子：
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通讯作者：
Carroll M
中科院分区：
文献类型：
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作者：
Sehgal AR;Gimotty PA;Zhao J;Hsu JM;Daber R;Morrissette JD;Luger S;Loren AW;Carroll M
DNA甲基转移酶3A(DNMT3A)是急性髓系白血病(AML)中常见的突变基因之一。关于DNMT3A突变的预后意义的报道一直不一致，而且大多数数据仅适用于60岁或以下的患者。我们假设，这种不一致是由于诱导治疗中使用的蒽环类药物剂量和DNMT3A状态之间的相互作用造成的。我们研究了接受标准剂量的蒽环类药物治疗的DNMT3A突变AML患者是否比其他突变类型的患者或接受高剂量治疗的患者的存活率更低。在这项回顾性队列研究中，152名初治AML患者接受了诱导治疗和下一代测序，其中包括DNMT3A、Flt3-ITD、NPM1和IDH1/2等血液系统恶性肿瘤中常见的突变基因。用Cox回归分析DNMT3A突变的患者接受标准剂量蒽环类药物治疗后的生存率是否较低。在32%的患者中发现的DNMT3A突变与较低的存活率无关。在诱导方案中，蒽环类药物剂量的增加与DNMT3A突变患者的生存改善有关，但与野生型DNMT3A突变患者的生存率无关。接受标准剂量诱导的DNMT3A突变患者的生存时间比其他患者组短(10.1个月对19.8个月，p=0.0129)。在多变量控制下，这种关系仍然显著(HR：1.9，p=0.006)。DNMT3A突变的AML患者在接受标准剂量的蒽环类药物诱导治疗时存活率较低。这一群体应该考虑接受大剂量的诱导治疗。
DNA methyltransferase 3A ( DNMT3A) is one of the commonly mutated genes in acute myelogenous leukemia (AML). Reports on the prognostic significance of DNMT3A mutations have been inconsistent, and most of the data is available only for patients 60 years of age or younger. We hypothesized that this inconsistency is due to an interaction between the dose of anthracycline used in induction therapy and DNMT3A status. We studied whether patients with DNMT3A-mutated AML treated with standard dose anthracyclines had an inferior survival compared to patients with other mutation profiles or those who received high dose therapy. 152 patients in this retrospective cohort study (median age, 54 years) with de-novo AML underwent induction therapy and next-generation sequencing of 33 commonly mutated genes in hematologic malignancies, including DNMT3A, FLT3-ITD, NPM1, and IDH1/2. Cox regression was used to if those with DNMT3A mutations who were treated with standard dose anthracycline had inferior survival. DNMT3A mutations, found in 32% of patients, were not associated with an inferior survival. Dose escalation of anthracycline in the induction regimen was associated with improved survival in those with DNMT3A mutations but not those with wild-type DNMT3A. Patients with DNMT3A mutations who received standard dose induction had shorter survival time than other patient groups (10.1 months vs. 19.8 months, p=0.0129). This relationship remained significant (HR: 1.90, p=0.006) controlling for multiple variables. Patients with DNMT3A-mutated AML have an inferior survival when treated with standard-dose anthracycline induction therapy. This group should be considered for high-dose induction therapy.