Department of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
Department of Hematology, Cleveland Clinic, Cleveland, Ohio.
Cancer. 2017 Oct 1;123(19):3662-3672. doi: 10.1002/cncr.30903. Epub 2017 Jul 31.
Hypomethylating agents (HMAs) have changed the landscape of the management of patients with higher-risk myelodysplastic syndromes (HR-MDS). HMAs have improved hematopoiesis and quality of life and, in the case of azacitidine, prolonged survival in a large randomized trial. However, multiple real-life and registry analyses have demonstrated minimal survival gains at the population level after the approval of HMAs. Furthermore, the 24-month median survival observed with azacitidine in the landmark AZA-001 trial has not been replicated in population-based studies or in other clinical trials using azacitidine monotherapy arms. Herein, we critically review the accumulating data suggesting that the actual survival impact of HMAs, especially azacitidine, in patients with HR-MDS is significantly lower than what was observed in the AZA-001 trial and what often is quoted to patients, and discuss the potential explanations for this discrepancy. We also present the rationale for why front-line clinical trial enrollment should be always considered and discussed with every newly diagnosed patient with HR-MDS rather than defaulting to the routine use of HMAs. Finally, we review the challenges to wider-scale enrollment in front-line HR-MDS clinical trials and suggest solutions to accelerate this process with the ultimate goal of achieving a real and substantial change in the natural history of this aggressive malignancy. Cancer 2017;123:3662-3672. © 2017 American Cancer Society.
低甲基化剂 (HMAs) 改变了高危骨髓增生异常综合征 (HR-MDS) 患者的治疗格局。HMAs 改善了造血功能和生活质量，在阿扎胞苷的情况下，在一项大型随机试验中延长了生存。然而，多项真实世界和登记分析表明，HMAs 获得批准后，人群水平的生存获益极小。此外，在具有里程碑意义的 AZA-001 试验中观察到的阿扎胞苷 24 个月中位生存期并未在基于人群的研究或使用阿扎胞苷单药治疗臂的其他临床试验中复制。在此，我们批判性地回顾了累积的数据，这些数据表明，HMAs（特别是阿扎胞苷）对 HR-MDS 患者的实际生存影响明显低于 AZA-001 试验中观察到的以及通常向患者报告的影响，并且讨论了这种差异的潜在解释。我们还提出了为什么应该始终考虑并与每例新诊断的 HR-MDS 患者讨论一线临床试验入组的理由，而不是默认常规使用 HMAs。最后，我们回顾了在一线 HR-MDS 临床试验中更广泛招募的挑战，并提出了加速这一过程的解决方案，最终目标是改变这种侵袭性恶性肿瘤的自然史，实现真正和实质性的改变。癌症 2017;123:3662-3672. © 2017 美国癌症协会。
