ImportancePersistence of FLT3 internal tandem duplication (ITD) in adults with acute myeloid leukemia (AML) in first complete remission (CR) prior to allogeneic hematopoietic cell transplant (HCT) is associated with increased relapse and death after transplant, but the association between the level of measurable residual disease (MRD) detected and clinical outcome is unknown.ObjectiveTo examine the association between pre–allogeneic HCT MRD level with relapse and death posttransplant in adults with AML in first CR.Design, Setting, and ParticipantsIn this cohort study, DNA sequencing was performed on first CR blood from patients with FLT3-ITD AML transplanted from March 2013 to February 2019. Clinical follow-up was through May 2022. Data were analyzed from October 2022 to December 2023.ExposureCentralized DNA sequencing for FLT3-ITD in pre–allogeneic HCT first CR blood using a commercially available kit.Main Outcomes and MeasuresThe primary outcomes were overall survival and cumulative incidence of relapse, with non–relapse-associated mortality as a competing risk post–allogeneic HCT. Kaplan-Meier estimations (log-rank tests), Cox proportional hazards models, and Fine-Gray models were used to estimate the end points.ResultsOf 537 included patients with FLT3-ITD AML from the Pre-MEASURE study, 296 (55.1%) were female, and the median (IQR) age was 55.6 (42.9-64.1) years. Using the variant allele fraction (VAF) threshold of 0.01% or greater for MRD positivity, the results closely aligned with those previously reported. With no VAF threshold applied (VAF greater than 0%), 263 FLT3-ITD variants (median [range] VAF, 0.005% [0.0002%-44%]), and 177 patients (33.0%) with positive findings were identified. Multivariable analyses showed that residual FLT3-ITD was the variable most associated with relapse and overall survival, with a dose-dependent correlation. Patients receiving reduced-intensity conditioning without melphalan or nonmyeloablative conditioning had increased risk of relapse and death at any given level of MRD compared with those receiving reduced-intensity conditioning with melphalan or myeloablative conditioning.Conclusions and RelevanceThis study provides generalizable and clinically applicable evidence that the detection of residual FLT3-ITD in the blood of adults in first CR from AML prior to allogeneic HCT is associated with an increased risk of relapse and death, particularly for those with a VAF of 0.01% or greater. While transplant conditioning intensification, an intervention not available to all, may help mitigate some of this risk, alternative approaches will be necessary for this high-risk population of patients who are underserved by the current standard of care.

中文翻译：

---

急性髓系白血病同种异体移植前可测量的残留 FLT3 内部串联重复

重要性 持续性FLT3成人急性髓系白血病 (AML) 在同种异体造血细胞移植 (HCT) 之前首次完全缓解 (CR) 时的内部串联重复 (ITD) 与移植后复发和死亡增加相关，但可测量的残留水平与检测到疾病（MRD），临床结果未知。目的检查首次 CR 中患有 AML 的成人患者的同种异体 HCT 前 MRD 水平与移植后复发和死亡之间的关联。设计、设置和参与者在这项队列研究中，对以下对象进行了 DNA 测序：来自患者的第一批 CR 血液FLT3-2013年3月至2019年2月移植的ITD AML。临床随访截至2022年5月。数据分析时间为2022年10月至2023年12月。暴露集中DNA测序FLT3-使用市售试剂盒在同种异体 HCT 前的第一个 CR 血液中进行 ITD。 主要结果和测量主要结果是总生存率和累计复发率，非复发相关死亡率作为同种异体 HCT 后的竞争风险。 Kaplan-Meier 估计（对数秩检验）、Cox 比例风险模型和 Fine-Gray 模型用于估计终点。 结果 537 名患者包括以下患者：FLT3-Pre-MEASURE 研究中的 ITD AML，296 名 (55.1%) 为女性，中位 (IQR) 年龄为 55.6 (42.9-64.1) 岁。使用 0.01% 或更高的 MRD 阳性变异等位基因分数 (VAF) 阈值，结果与之前报道的结果非常一致。不应用 VAF 阈值（VAF 大于 0%），263FLT3-ITD变异（中位[范围] VAF，0.005% [0.0002%-44%]）和177名患者（33.0%）有阳性结果被识别。多变量分析表明，残差FLT3-ITD 是与复发和总生存期最相关的变量，具有剂量依赖性相关性。与接受马法兰或清髓性调理的降低强度调理的患者相比，接受不加美法仑或非清髓性调理的降低强度调理的患者在任何给定的 MRD 水平下复发和死亡的风险均增加。结论和相关性本研究提供了普遍且临床适用的证据，表明残留检测FLT3-同种异体 HCT 之前 AML 首次 CR 中成人血液中的 ITD 与复发和死亡风险增加相关，特别是对于 VAF 为 0.01% 或更高的患者。虽然移植调理强化（并非所有人都能获得的干预措施）可能有助于减轻部分风险，但对于当前护理标准服务不足的高危患者群体，需要采取替代方法。