Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk of tMN is high in recipients of autologous hematopoietic stem cell transplantation (aHSCT). Acquisition of genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly in the context of preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified. We studied a cohort of 1507 patients undergoing aHSCT and a cohort of 263 patients who developed tMN without aHSCT to determine clinico-molecular features unique to post-aHSCT tMN. We show that tMN occurs in up to 2.3% of patients at median of 2.6 years post-AHSCT. Age ≥ 60 years, male sex, radiotherapy, high treatment burden ( ≥ 3 lines of chemotherapy), and graft cellularity increased the risk of tMN. Time to evolution and overall survival were shorter in post-aHSCT tMN vs. other tMN, and the earlier group’s mutational pattern was enriched in PPM1D and TP53 lesions. Preexisting CH increased the risk of adverse outcomes including post-aHSCT tMN. Particularly, antecedent lesions affecting PPM1D and TP53 predicted tMN evolution post-transplant. Notably, CH-derived tMN had worse outcomes than non CH-derived tMN. As such, screening for CH before aHSCT may inform individual patients’ prognostic outcomes and influence their prospective treatment plans. Presented in part as an oral abstract at the 2022 American Society of Hematology Annual Meeting, New Orleans, LA, 2022.

治疗相关的骨髓肿瘤（tMN）是细胞毒性治疗的并发症。自体造血干细胞移植 (aHSCT) 受者发生 tMN 的风险较高。基因组突变的获得是一个关键的致病驱动因素，但其起源、时间和动态，特别是在先前存在或出现的克隆造血 (CH) 的背景下，尚未得到充分阐明。我们研究了 1507 名接受 aHSCT 的患者和 263 名未经 aHSCT 发生 tMN 的患者，以确定 aHSCT 后 tMN 特有的临床分子特征。我们发现，在 AHSCT 后中位 2.6 年时，高达 2.3% 的患者发生 tMN。年龄≥60岁、男性、放疗、高治疗负担（≥3线化疗）和移植细胞构成会增加tMN的风险。与其他 tMN 相比，aHSCT 后 tMN 的进化时间和总生存期较短，并且早期组的突变模式在PPM1D和TP53病变中丰富。先前存在的 CH 增加了不良后果的风险，包括 aHSCT 后 tMN。特别是，影响PPM1D和TP53 的先前病变预测了移植后 tMN 的演变。值得注意的是，CH 衍生的 tMN 的结果比非 CH 衍生的 tMN 更差。因此，aHSCT 前的 CH 筛查可能会告知个体患者的预后结果并影响他们的前瞻性治疗计划。在 2022 年美国血液学会年会上（洛杉矶新奥尔良，2022 年）以口头摘要形式部分提出。