Chesnais Virginie, Renneville Aline, Toma Andrea, Lambert Jérôme, Passet Marie, Dumont Florent, Chevret Sylvie, Lejeune Julie, Raimbault Anna, Stamatoullas Aspasia, Rose Christian, Beyne-Rauzy Odile, Delaunay Jacques, Solary Eric, Fenaux Pierre, Dreyfus François, Preudhomme Claude, Kosmider Olivier, Fontenay Michaela
Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France; Institut Cochin, INSERM U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France;
Laboratoire d'Hématologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France;
Blood. 2016 Feb 11;127(6):749-60. doi: 10.1182/blood-2015-04-640128. Epub 2015 Dec 1.
Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379.
非5q缺失的输血依赖型低/中危-1骨髓增生异常综合征（MDS）患者中，来那度胺可使25%的病例出现红系反应。添加促红细胞生成剂可能会提高反应率。疾病克隆中鉴定出的复发性体细胞突变对来那度胺反应的影响以及该药物对克隆进化的作用尚不清楚。我们通过下一代测序研究了94例非5q缺失的MDS患者中的复发性突变，这些患者在GFM-Len-Epo-08临床试验中被随机分配接受来那度胺或来那度胺加促红细胞生成素β治疗。42例患者在4个周期治疗后分析克隆进化情况，18例患者在后续时间点重新分析。还在5例患者中确定了单个CD34(+)CD38(-)造血干细胞克隆结构的命运。突变频率>10%的有：SF3B1（74.5%）、TET2（45.7%）、DNMT3A（20.2%）和ASXL1（19.1%）。分析变异等位基因频率表明，4个周期后，20例反应者中有15例主要突变减少，而22例无反应者中有10例减少。主要突变的变异等位基因频率下降在反应者中比在无反应者中更显著（P<.001）。对单个CD34(+)CD38(-)细胞衍生集落的基因分型显示，优势亚克隆大小的减小可能与起始克隆或无复发性突变的造血干细胞的增加有关。这些效应是短暂的，疾病逃逸与优势亚克隆的重新出现有关。总之，我们表明，虽然药物最初调节亚克隆的分布，但治疗效果的丧失与优势亚克隆的重新扩增同时发生。该试验在www.clinicaltrials.gov上注册，注册号为#NCT01718379。
