Hematology Laboratory, Unité 1277-Cancer Heterogeneity Plasticity and Resistance to Therapies (CANTHER), Centre Hospitalier Universitaire (CHU) de Lille, University of Lille, INSERM, Lille, France.
Hematology Laboratory, CHU de Toulouse-Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France.
Blood. 2022 Aug 18;140(7):756-768. doi: 10.1182/blood.2021015328.
DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL 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 DDX41MutGL 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 (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/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. DDX41MutGL 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) DDX41WT 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 DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT 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).
DDX41 种系突变（DDX41MutGL）是骨髓增生异常综合征和急性髓系白血病（AML）最常见的遗传易感性因素。最近的报告表明，DDX41MutGL 髓系恶性肿瘤可以被视为一种独特的实体，即使它们的具体表现和结局仍有待确定。我们在这里描述了 191 例 DDX41MutGL AML 患者的临床和生物学特征。对其中 86 例接受 5 项急性白血病法国协会/法国创新白血病组织前瞻性强化化疗治疗的患者的基线特征和结局进行了分析，并与 1604 例 DDX41 野生型（DDX41WT）AML 患者进行了比较，占 5%。DDX41MutGL AML 患者多为男性（75%），年龄在 70 岁，白细胞计数低（中位数为 2×109/L），骨髓原始细胞浸润低（中位数为 33%），细胞遗传学正常（75%），且仅有少量其他体细胞突变（中位数为 2 个）。82%的患者发现存在第二个体细胞 DDX41 突变（DDX41MutSom），克隆结构推断提示其可能是 AML 进展的主要驱动因素。DDX41MutGL 患者的完全缓解率更高（94% vs 69%；P<0.0001），且限制性平均总生存期（在造血干细胞移植[HSCT]时进行校正）也更长（与 2017 年欧洲白血病网中危/高危（Int/Adv）DDX41WT 患者相比，5 年差异为 13.6 个月；P<0.001）。在 HSCT 时校正的 1 年复发率在 DDX41MutGL 患者中较低（15% vs 44%），但在 3 年时与 Int/Adv DDX41WT 患者相似（82% vs 75%）。在首次完全缓解时进行 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）。
