Hypomethylating agents (HMA) like azacitidine are licensed for the treatment of acute myeloid leukemia (AML) patients ineligible for allogeneic hematopoietic stem cell transplantation. Biomarker-driven identification of HMA-responsive patients may facilitate the choice of treatment, especially in the challenging subgroup above 60 years of age. Since HMA possesses immunomodulatory functions that constitute part of their anti-tumor effect, we set out to analyze the bone marrow (BM) immune environment by next-generation sequencing of T cell receptor beta (TRB) repertoires in 51 AML patients treated within the RAS-AZIC trial. Patients with elevated pretreatment T cell diversity (11 out of 41 patients) and those with a boost of TRB richness on day 15 after azacitidine treatment (12 out of 46 patients) had longer event-free and overall survival. Both pretreatment and dynamic BM T cell metrics proved to be better predictors of outcome than other established risk factors. The favorable broadening of the BM T cell space appeared to be driven by antigen since these patients showed significant skewing of TRBV gene usage. Our data suggest that one course of AZA can cause reconstitution to a more physiological T cell BM niche and that the T cell space plays an underestimated prognostic role in AML. Trial registration: DRKS identifier: DRKS00004519
诸如阿扎胞苷之类的去甲基化药物（HMA）已被批准用于治疗不适合接受异体造血干细胞移植的急性髓系白血病（AML）患者。通过生物标志物驱动识别对HMA治疗敏感的患者，可能有助于治疗选择，尤其是在60岁以上这一具有挑战性的亚组中。由于HMA具有构成其抗肿瘤作用部分的免疫调节功能，我们通过RAS-AZIC临床试验中51例接受治疗的AML患者的T细胞受体β链（TRB）库新一代测序技术，分析了其骨髓免疫环境。治疗前T细胞多样性较高的患者（41例中有11例）以及在阿扎胞苷治疗后第15天TRB丰富度显著提升的患者（46例中有12例）具有更长的无事件生存期和总生存期。无论是治疗前还是动态的骨髓T细胞指标，均被证明是比其他已知风险因素更好的预后预测因子。骨髓T细胞空间的有益扩增似乎由抗原驱动，因为这些患者显示出显著的TRBV基因使用偏斜。我们的数据表明，一个疗程的AZA治疗可以促使T细胞骨髓微环境重建至更接近生理状态，并且T细胞空间在AML中扮演着被低估的预后作用角色。试验注册号：DRKS标识符：DRKS00004519。
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