Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion
Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion
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DOI：
10.1182/blood-2015-04-640128
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发表时间：
2016-02-11
期刊：
影响因子：
20.3
通讯作者：
Fontenay, Michaela
中科院分区：
文献类型：
--
作者：
Chesnais, Virginie;Renneville, Aline;Fontenay, Michaela
非del（5 q）输血依赖性低/中1型骨髓增生异常综合征（MDS）患者在25%的病例中使用来那度胺获得红系反应。添加红细胞生成刺激剂可提高应答率。在患病克隆中鉴定的对来那度胺应答的复发性体细胞突变的影响以及药物对克隆进化的影响仍然未知。我们通过下一代测序研究了94例在GFM-Len- Epo-08临床试验中随机分配至来那度胺或来那度胺加依泊苷β治疗的非del（5 q）MDS患者的复发性突变。在42例病例中，在4个周期的治疗后分析了克隆演变，并在18例病例中在稍后的时间点重新分析。5例同时测定了单个CD 34（+）CD 38（-）造血干细胞克隆结构的命运。突变频率>10%：SF 3B 1（74.5%）、TET 2（45.7%）、DNMT 3A（20.2%）和ASXL 1（19.1%）。变异等位基因频率分析表明，在4个周期后，20个应答者中有15个的主要突变减少，而22个无应答者中有10个。应答者中主要突变的变异等位基因频率的降低比无应答者更显著（P <0.001）。单个CD 34（+）CD 38（-）细胞衍生集落的基因分型表明，优势亚克隆大小的减少可能与创始克隆或缺乏复发突变的造血干细胞的增加有关。这些影响仍然是短暂的，疾病逃逸与重新出现的优势亚克隆。总之，我们表明，虽然药物最初调节亚克隆的分布，治疗效果的损失与占主导地位的亚克隆的再扩张相一致。本试验在twww.clinicaltrials.gov上注册为#NCT 01718379。
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 beta. 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 a twww.clinicaltrials.gov as #NCT01718379.