阿扎胞苷指导下的治疗以预防骨髓增生异常综合征和急性髓系白血病患者血液学复发（RELAZA2）：一项开放标签、多中心、2 期试验。

Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial.

机构信息

Medical Clinic and Policinic 1, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany; Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.

Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.

出版信息

Lancet Oncol. 2018 Dec;19(12):1668-1679. doi: 10.1016/S1470-2045(18)30580-1. Epub 2018 Nov 12.

DOI:10.1016/S1470-2045(18)30580-1

PMID:30442503

Abstract

BACKGROUND

Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients.

METHODS

The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m per day subcutaneously on days 1-7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018.

FINDINGS

Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis p≤0·3). With a median follow-up of 13 months (IQR 8·5-22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32-59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82-94; hazard ratio 6·6 [95% CI 3·7-11·8], p<0·0001). The most common (grade 3-4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment.

INTERPRETATION

Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes.

FUNDING

Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.

摘要

背景

在达到形态学完全缓解的晚期骨髓增生异常综合征（MDS）或急性髓系白血病（AML）患者中监测可测量的残留疾病（MRD）可以预测血液学复发。在这项前瞻性研究中，我们旨在确定 MRD 指导的抢先治疗阿扎胞苷是否可以预防这些患者的复发。

方法

复发预防用阿扎胞苷（RELAZA2）研究是在德国九所大学健康中心进行的一项开放标签、多中心、2 期试验。年龄在 18 岁或以上的患有晚期 MDS 或 AML 的患者，在接受常规化疗或异基因造血干细胞移植后达到完全缓解，在基线后 24 个月内通过定量聚合酶链反应（qPCR）检测突变型 NPM1、白血病特异性融合基因（DEK-NUP214、RUNX1-RUNX1T1、CBFb-MYH11），或分析异基因造血干细胞移植患者流式细胞分选 CD34 阳性细胞中的供体嵌合体，前瞻性筛查 MRD。在确认完全缓解的 MRD 阳性患者中，接受阿扎胞苷 75 mg/m2 皮下注射，每天一次，在 29 天的周期中第 1-7 天给药，共 24 个周期。在 6 个周期后，重新评估 MRD 状态，MRD 反应良好（MRD 阴性）的患者有资格进行治疗降级。主要终点是在抢先治疗开始后 6 个月无复发和存活的患者比例。分析按方案进行。该试验在 ClincialTrials.gov 上注册，编号为 NCT01462578，于 2018 年 8 月 21 日完成招募。

结果

在 2011 年 10 月 10 日至 2015 年 8 月 20 日期间，我们筛查了 198 名患有晚期 MDS（n=26）或 AML（n=172）的患者，其中 60 名（30%）在 24 个月的筛查期间发生了 MRD，53 名（88%）有资格开始研究治疗。在开始阿扎胞苷治疗后 6 个月，53 名患者中有 31 名（58%，95%CI 44-72）无复发且存活（p<0.0001；零假设 p≤0.3 的单侧二项式检验）。在开始 MRD 指导治疗后的中位随访 13 个月（IQR 8.5-22.8）时，在 53 名 MRD 阳性且接受阿扎胞苷治疗的患者中，12 个月无复发生存率为 46%（95%CI 32-59）。在 MRD 阴性患者中，12 个月无复发生存率为 88%（95%CI 82-94；危险比 6.6 [95%CI 3.7-11.8]，p<0.0001）。最常见的（3-4 级）不良事件是中性粒细胞减少症，53 名患者中有 45 名（85%）发生。一名中性粒细胞减少症患者因感染死亡，该感染被认为可能与研究治疗有关。