Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study
Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study
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DOI：
10.1182/blood.2021015328
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发表时间：
2022-08-18
期刊：
影响因子：
20.3
通讯作者：
Sebert, Marie
中科院分区：
文献类型：
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作者：
Duployez, Nicolas;Largeaud, Laetitia;Sebert, Marie
DDX 41种系突变（DDX 41（MutGL））是骨髓增生异常综合征和急性髓性白血病（AML）最常见的遗传易感性。最近的报告表明，DDX 41（MutGL）骨髓恶性肿瘤可被视为一个独特的实体，即使其具体表现和结果仍有待确定。我们描述了191例DDX 41（MutGL）AML患者的临床和生物学特征。在5项前瞻性急性白血病法国协会/法国创新白血病组织试验中，将其中86例接受强化化疗的患者的基线特征和结局与1604例DDX 41野生型（DDX 41（WT））AML患者的基线特征和结局进行比较，后者的患病率为5%。DDX 41（MutGL）AML患者大多为70岁的男性（75%），白细胞计数低（中位数，2 x 10（9）/L），骨髓原始细胞浸润低（中位数，33%），细胞遗传学正常（75%），很少有额外的体细胞突变（中位数，2）。在82%的患者中发现了第二个体细胞DDX 41突变（DDX 41 MutSom），克隆结构推断表明它可能是AML进展的主要驱动因素。DDX 41（MutGL）患者的完全缓解率（94% vs 69%; P < .0001）和在造血干细胞移植（HSCT）时截尾的限制性平均总生存期长于2017年欧洲白血病网中间/不良（Int/Adv）DDX 41（WT）患者（限制性平均生存时间的5年差异为13.6个月; P < .001）。DDX 41（MutGL）患者在HSCT时删失的1年复发率较低（15% vs 44%），但随后增加至与Int/Adv DDX 41（WT）患者在3年时相似（82% vs 75%）。首次完全缓解的HSCT与无复发生存期延长相关（风险比，0.43; 95%置信区间，0.21-0.88; P = 0.02），但与总生存期延长无关（风险比，0.77; 95%置信区间，0.35-1.68; P = 0.5）。
DDX41 germline mutations (DDX41(MutGL)) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41(MutGL) myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41(MutGL) AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41(WT)) AML, representing a prevalence of 5%. Patients with DDX41(MutGL) AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 x 10(9)/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41(MutGL) patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41(WT) patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41(MutGL) patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41(WT) patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).