骨髓纤维化移植后驱动突变的清除

Clearance of Driver Mutations after Transplantation for Myelofibrosis.

作者信息

Gagelmann Nico, Quarder Marie, Badbaran Anita, Rathje Kristin, Janson Dietlinde, Lück Catherina, Richter Johanna, Marquard Franziska, Oechsler Sofia, Massoud Radwan, Klyuchnikov Evgeny, Rudolph Ina, Schäfersküpper Mathias, Niederwieser Christian, Heidenreich Silke, Berger Carolina, Fehse Boris, Wolschke Christine, Ayuk Francis, Kröger Nicolaus

机构信息

From the Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

出版信息

N Engl J Med. 2025 Jan 9;392(2):150-160. doi: 10.1056/NEJMoa2408941.

DOI:10.1056/NEJMoa2408941

PMID:39778169

Abstract

BACKGROUND

Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for myelofibrosis. Driver mutations are the pathophysiological hallmark of the disease, but the role of mutation clearance after transplantation is unclear.

METHODS

We used highly sensitive polymerase-chain-reaction technology to analyze the dynamics of driver mutations in peripheral-blood samples from 324 patients with myelofibrosis (73% with mutations, 23% with mutations, and 4% with mutations) who were undergoing transplantation after reduced-intensity conditioning. Mutations were detected before transplantation and at 30, 100, and 180 days after transplantation to measure clearance and its effect on relapse and cure. The two primary end points were relapse and disease-free survival.

RESULTS

At day 30 after transplantation, mutation clearance was found in 42% of the patients who had mutations, 73% of those who had mutations, and 54% of those who had mutations; the corresponding percentages at day 100 were 63%, 82%, and 100%. The cumulative incidence of relapse at 1 year was 6% (95% confidence interval [CI], 2 to 10) among patients with mutation clearance at day 30 after transplantation and 21% (95% CI, 15 to 27) among those without mutation clearance at day 30. Disease-free and overall survival at 6 years were 61% and 74%, respectively, among patients with mutation clearance at day 30 after transplantation and 41% and 60%, respectively, among those without mutation clearance at day 30. Mutation clearance at day 30 appeared to outperform traditional donor chimerism as a measure of response; it was independently associated with a reduced risk of relapse or progression (hazard ratio, 0.36; 95% CI, 0.21 to 0.61) and appeared to overcome differences in prognosis based on the type of driver mutation ( vs. or ).

CONCLUSIONS

In patients with myelofibrosis, clearance of driver mutations at day 30 after transplantation appeared to influence relapse and survival, irrespective of the underlying driver mutation.

摘要

背景

异基因造血干细胞移植是骨髓纤维化唯一的治愈性治疗方法。驱动突变是该疾病的病理生理标志，但移植后突变清除的作用尚不清楚。

方法

我们使用高度敏感的聚合酶链反应技术分析了324例接受减低强度预处理后进行移植的骨髓纤维化患者（73%为突变型，23%为突变型，4%为突变型）外周血样本中驱动突变的动态变化。在移植前以及移植后30、100和180天检测突变，以测量清除情况及其对复发和治愈的影响。两个主要终点是复发和无病生存。

结果

移植后30天时，42%的突变型患者、73%的突变型患者和54%的突变型患者出现突变清除；100天时相应比例分别为63%、82%和100%。移植后30天有突变清除的患者1年时的累积复发率为6%（95%置信区间[CI]，2至10），30天无突变清除的患者为21%（95%CI，15至27）。移植后30天有突变清除的患者6年时的无病生存率和总生存率分别为61%和74%，30天无突变清除的患者分别为41%和60%。移植后30天的突变清除作为一种反应指标似乎优于传统的供体嵌合率；它与复发或进展风险降低独立相关（风险比，0.36；95%CI，0.21至0.61），并且似乎克服了基于驱动突变类型（与或）的预后差异。