德国汉堡埃本多夫大学医学中心Nicolaus Kröger团队研究了骨髓纤维化移植后驱动基因突变的清除。相关论文发表在2025年1月9日出版的《新英格兰医学杂志》上。

异基因造血干细胞移植是治疗骨髓纤维化的唯一有效方法。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。

研究组使用高灵敏度聚合酶链反应技术分析了324名骨髓纤维化患者（73%有JAK2突变，23%有CALR突变，4%有MPL突变）外周血样本中驱动突变的动态，这些患者在降低强度条件后接受移植。在移植前和移植后30、100和180天检测突变，以评估清除率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。

移植后第30天，42%的JAK2突变患者、73%的CALR突变患者和54%的MPL突变患者发现突变清除；第100天的相应百分比分别为63%、82%和100%。在移植后第30天突变清除的患者中，1年的累积复发率为6%（95%置信区间[CI]，2至10），在第30天没有突变清除的人中，复发率为21%（95%CI，15至27）。在移植后第30天突变清除的患者中，6年的无病生存率和总生存率分别为61%和74%，在第30天没有突变清除的人中，分别为41%和60%。

作为反应的衡量标准，第30天的突变清除率似乎优于传统的供体嵌合体；它与复发或进展风险的降低独立相关（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（JAK2与MPL或CALR）的预后差异。

研究结果表明，在骨髓纤维化患者中，移植后第30天清除驱动突变似乎会影响复发和生存，而与潜在的驱动突变无关。

附：英文原文

Title: Clearance of Driver Mutations after Transplantation for Myelofibrosis

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

Issue&Volume: 2025-01-09

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 JAK2 mutations, 23% with CALR mutations, and 4% with MPL 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 JAK2 mutations, 73% of those who had CALR mutations, and 54% of those who had MPL 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 (JAK2 vs. MPL or CALR).

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.

DOI: NJ202501093920210

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2408941