Division of Hematologic Neoplasia, Department of Medical Oncology, and.
Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.
Blood. 2022 Jun 16;139(24):3546-3557. doi: 10.1182/blood.2021014520.
Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.
老年急性髓系白血病 (AML) 患者在接受异基因造血细胞移植 (HCT) 后复发风险高且生存状况较差。年轻患者可能会接受清髓性预处理以降低与高危遗传学或可测量残留疾病 (MRD) 相关的复发风险，但老年患者通常会接受强度降低的预处理 (RIC) 以限制毒性。为了确定哪些因素会影响老年患者的 HCT 结局，我们对 295 名年龄≥60 岁且在首次完全缓解期接受 HCT 的 AML 患者的诊断样本进行了靶向突变分析 (变异等位基因分数≥2%)，其中 91%的患者接受了 RIC，在包含 192 名患者的亚组中进行了缓解时的靶向双测序。在包含基线遗传和临床变量的无白血病生存 (LFS) 的多变量模型中，我们将患者分为低危 (3 年 LFS，85%)、中危 (55%)、高危 (35%) 和极高危 (7%)。在 HCT 前，79.7%的患者存在持续的基线突变，其中 18.3%仅有 DNMT3A 或 TET2 (DT) 突变，61.4%有其他突变 (MRD 阳性)。在单变量分析中，与 DT 和 MRD 阴性突变相比，MRD 阳性与更高的复发和较差的 LFS 相关。然而，在考虑基线风险的多变量模型中，MRD 阳性对 LFS 没有独立影响，这很可能是因为它与诊断遗传特征密切相关，包括 MDS 相关基因突变、TP53 突变和高危核型。总之，与 MRD 阳性和老年 AML 患者 HCT 结局相关的分子关联主要由基线遗传学决定，而不是由缓解期的突变决定。在这群患者中，高强度预处理会带来很大的毒性风险，因此需要采取其他方法来降低与 MRD 相关的复发风险。
