Therapy-related myeloid neoplasms (t-MN) are aggressive leukemia that develops as a complication of prior exposure to DNA-damaging agents. Clonal cytopenia of undetermined significance (CCUS) is a precursor of de novo myeloid neoplasms. Characteristics of CCUS that develop following cytotoxic therapies (therapy-related clonal cytopenia, t-CC) and outcomes following t-CC have not been described. We identified 33 patients with t-CC and compared to a cohort of the WHO-defined t-MN (n = 309). t-CC had a distinct genetic and cytogenetic profile: pathogenic variants (PV) in TET2 and SRSF2 were enriched in t-CC, whereas TP53 PV was more common in t-MN. Ten (30%) t-CC patients developed a subsequent t-MN, with a cumulative incidence of 13%, 23%, and 50% at 6 months, 1, and 5 years, respectively. At t-MN progression, 44% of evaluable patients had identifiable clonal evolution. The median survival following t-CC was significantly superior compared all t-MN phenotype including t-MDS with <5% bone marrow blasts (124.5 vs. 16.3 months, P < 0.001) respectively. The presence of cytogenetic abnormality and the absence of variants in DNMT3A, TET2, or ASXL1 (DTA-genes) were associated with a higher likelihood of developing a subsequent t-MN and an inferior survival. We describe a putative precursor entity of t-MN with distinct features and outcomes.
治疗相关髓系肿瘤（t-MN）是一种侵袭性白血病，作为先前接触DNA损伤剂后的并发症发生。意义未明的克隆性血细胞减少（CCUS）是原发髓系肿瘤的前兆。细胞毒治疗后出现的CCUS（治疗相关克隆性血细胞减少，t-CC）特征及其临床结局尚未被描述。我们确定了33例t-CC患者，并与WHO定义的t-MN队列（n=309）进行比较。t-CC具有独特的遗传和细胞遗传学特征：TET2和SRSF2的致病性变异在t-CC中富集，而TP53致病性变异在t-MN中更常见。10例（30%）t-CC患者后续进展为t-MN，其累积发生率在6个月、1年和5年分别为13%、23%和50%。在t-MN进展时，44%的可评估患者出现可识别的克隆进化。与所有t-MN表型（包括骨髓原始细胞<5%的治疗相关骨髓增生异常综合征）相比，t-CC后的中位生存期显著更优（分别为124.5个月 vs. 16.3个月，P<0.001）。细胞遗传学异常的存在以及DNMT3A、TET2或ASXL1（DTA基因）变异的缺失，与更高的后续t-MN发生风险和更差的生存率相关。我们描述了一种具有独特特征和结局的t-MN推定前体疾病。
Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms
肿瘤(癌症)患者之家