Neubauer Andreas, Maharry Kati, Mrózek Krzysztof, Thiede Christian, Marcucci Guido, Paschka Peter, Mayer Robert J, Larson Richard A, Liu Edison T, Bloomfield Clara D
Department for Hematology, Oncology and Immunology, Philipps University, Marburg, Germany.
J Clin Oncol. 2008 Oct 1;26(28):4603-9. doi: 10.1200/JCO.2007.14.0418. Epub 2008 Jun 16.
RAS mutations occur in 12% to 27% of patients with acute myeloid leukemia (AML) and enhance sensitivity to cytarabine in vitro. We examined whether RAS mutations impact response to cytarabine in vivo.
One hundred eighty-five patients with AML achieving complete remission on Cancer and Leukemia Group B study 8525 and randomly assigned to one of three doses of cytarabine postremission were screened for RAS mutations. We assessed the impact of cytarabine dose on cumulative incidence of relapse (CIR) of patients with (mutRAS) and without (wild-type; wtRAS) RAS mutations.
Thirty-four patients (18%) had RAS mutations. With 12.9 years median follow-up, the 10-year CIR was similar for mutRAS and wtRAS patients (65% v 73%; P = .31). However, mutRAS patients receiving high-dose cytarabine consolidation (HDAC; 3 g/m(2) every 12 hours on days 1, 3, and 5 or 400 mg/m(2)/d x 5 days) had the lowest 10-year CIR, 45%, compared with 68% for wtRAS patients receiving HDAC and 80% and 100%, respectively, for wtRAS and mutRAS patients receiving low-dose cytarabine (LDAC; 100 mg/m(2)/d x 5 days; overall comparison, P < .001). Multivariable analysis revealed an interaction of cytarabine dose and RAS status (P = .06). After adjusting for this interaction and cytogenetics (core binding factor [CBF] AML v non-CBF AML), wtRAS patients receiving HDAC had lower relapse risk than wtRAS patients receiving LDAC (hazard ratio [HR] = 0.67; P = .04); however, mutRAS patients receiving HDAC had greater reduction in relapse risk (HR = 0.28; P = .002) compared with mutRAS patients treated with LDAC.
AML patients carrying mutRAS benefit from higher cytarabine doses more than wtRAS patients. This seems to be the first example of an activating oncogene mutation favorably modifying response to higher drug doses in AML.
RAS突变发生在12%至27%的急性髓系白血病（AML）患者中，并在体外增强对阿糖胞苷的敏感性。我们研究了RAS突变是否会影响体内对阿糖胞苷的反应。
对参加癌症与白血病B组研究8525并在缓解后随机分配至三种阿糖胞苷剂量之一的185例AML患者进行RAS突变筛查。我们评估了阿糖胞苷剂量对有RAS突变（mutRAS）和无RAS突变（野生型；wtRAS）患者复发累积发生率（CIR）的影响。
34例患者（18%）存在RAS突变。中位随访12.9年，mutRAS和wtRAS患者的10年CIR相似（65%对73%；P = 0.31）。然而，接受大剂量阿糖胞苷巩固治疗（HDAC；第1、3和5天每12小时3 g/m²或400 mg/m²/d×5天）的mutRAS患者10年CIR最低，为45%，而接受HDAC的wtRAS患者为68%，接受小剂量阿糖胞苷（LDAC；100 mg/m²/d×5天）的wtRAS和mutRAS患者分别为80%和100%（总体比较，P < 0.001）。多变量分析显示阿糖胞苷剂量与RAS状态存在交互作用（P = 0.06）。在调整此交互作用和细胞遗传学（核心结合因子[CBF]AML与非CBF AML）后，接受HDAC的wtRAS患者复发风险低于接受LDAC的wtRAS患者（风险比[HR] = 0.67；P = 0.04）；然而，与接受LDAC治疗的mutRAS患者相比，接受HDAC的mutRAS患者复发风险降低幅度更大（HR = 0.28；P = 0.002）。
携带mutRAS的AML患者比wtRAS患者从更高剂量的阿糖胞苷中获益更多。这似乎是激活癌基因突变有利地改变AML对更高药物剂量反应的首个实例。
