Prospective evaluation of residual disease in intensively treated patients with acute myeloid leukemia (AML) as surrogate endpoint for survival

急性髓性白血病是一种遗传和表型异质性疾病，发病率为3 - 4/100 000男性，每年警告，诊断时的中位年龄约为70岁。预后，特别是老年患者的预后仍然很差。在认为适合强化化疗的患者中，蒽环类药物和阿糖胞苷的联合治疗仍然是标准治疗。对于达到完全缓解（CR）的患者，需要从化疗到异基因造血干细胞移植的缓解后治疗（PRT）;在老年患者中，强化PRT仍在争论中。除了治疗前基于遗传学的风险分层外，治疗和随访期间残留疾病（RD）的测量是首次CR的重要预后因素。此外，RD可以提供用于读出治疗功效的工具。在本诊断研究中，我们打算在5项前期随机临床试验中使用多参数流式细胞术测量RD，这些试验将招募1000多例患者。根据诊断时的白血病相关表型，将在治疗期间的早期（诱导后）和晚期（巩固后）评估RD。该研究的目的是显示在治疗期间早期测量的RD水平与总生存期密切相关，因此可以作为早期替代指标。越来越多的公众要求尽快批准有前途的新药用于治疗。因此，基于早期生物标志物终点（如RD）而非长期生存终点获得这些批准具有重大意义。

Acute myeloid leukemia is a genetically and phenotypically heterogeneous disorder with an incidence of 3 to 4 per 100 000 men and warnen per year and a median age at diagnosis of about 70 years. Prognosis, especially in older patients, has remained very poor. In patients considered suitable for intensive chemotherapy, the combination of an anthracycline and cytarabine remains the standard of care. For patients achieving a complete remission (CR), postremission therapy (PRT) ranging from chemotherapy to allogeneic hematopoietic stem cell transplantation is required; intensive PRT is still under debate in older patients. Beyond pre-treatment geneticsbased risk stratification, measurement of residual disease (RD) during treatment and follow up emerges as an important prognostic factor in first CR. Furthermore, RD may provide a tool for a read-out of therapeutic efficacy. In this diagnostic study we intend to measure RD using multiparameter flow cytometry across 5 up-front randomized clinical trials which will accrue more than 1000 patients. According to the leukemia-associated phenotype at diagnosis, RD will be assessed early (after induction) and late (after consolidation) during treatment. The aim of the study is to show that levels of RD measured early during treatment are closely related to overall survival and thus may serve as an early surrogate. There is a growing public demand that new, promising drugs are approved for therapy as rapidly as possible. Therefore, it is of great interest to obtain these approvals based on early biomarker endpoints such as RD rather than on longterm survival endpoints.