背景:TP53突变,存在于5%至10%的急性髓性白血病(AML)患者中,与治疗抵抗和不良预后相关。TP53突变(TP53m)AML的一线治疗包括强化化疗(IC),低甲基化剂(HMA),或venetoclax结合HMA(VEN+HMA)。
方法:我们进行了系统评价和荟萃分析,以描述和比较新诊断的TP53mAML初治患者的治疗结果。随机对照试验,单臂试验,前瞻性观察性研究,和回顾性研究包括报道的完全缓解(CR),CR伴不完全血液学恢复(CRi),总生存期(OS),无事件生存(EFS),响应持续时间(DoR),接受IC一线治疗的TP53mAML患者的总反应率(ORR),HMA,或VEN+HMA。
结果:对EMBASE和MEDLINE的搜索确定了3006篇摘要,17份出版物描述12项研究符合纳入标准.随机效应模型被用来汇集反应率,和时间相关结局采用中位数方法进行分析.IC与43%的最大CR率相关,VEN+HMA和HMA的CR率分别为33%和13%。IC(46%)和VENHMA(49%)的CR/CRi率相当,但HMA(13%)较低。中位OS在治疗中一致较差:IC,6.5个月;VEN+HMA,6.2个月;和HMA,6.1个月。对于IC,EFS估计值为3.7个月;未报告VEN+HMA或HMA的EFS。IC的ORR为41%,VEN+HMA为65%,HMA为47%。IC的DoR为3.5个月,VEN+HMA5.0个月,并且没有报告HMA。
结论:尽管与HMA相比,IC和VEN+HMA的反应有所改善,生存率一直很差,新诊断患者的所有治疗方法的临床获益有限,治疗初治TP53mAML,证明了对这种难以治疗的人群的改进治疗的重大需求。
TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA).
We conducted a systematic
review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), duration of response (DoR), and overall response rate (ORR) among patients with TP53m AML receiving first-line treatment with IC, HMA, or VEN + HMA.
Searches of EMBASE and MEDLINE identified 3006 abstracts, and 17 publications describing 12 studies met the inclusion criteria. Random-effects models were used to pool response rates, and time-related outcomes were analyzed with the median of medians method. IC was associated with the greatest CR rate of 43%, and CR rates were 33% for VEN + HMA and 13% for HMA. Rates of CR/CRi were comparable for IC (46%) and VEN + HMA (49%) but were lower for HMA (13%). Median OS was uniformly poor across treatments: IC, 6.5 months; VEN + HMA, 6.2 months; and HMA, 6.1 months. For IC, the EFS estimate was 3.7 months; EFS was not reported for VEN + HMA or HMA. The ORR was 41% for IC, 65% for VEN + HMA, and 47% for HMA. DoR was 3.5 months for IC, 5.0 months for VEN + HMA, and was not reported for HMA.
Despite improved responses seen with IC and VEN + HMA compared to HMA, survival was uniformly poor, and clinical benefits were limited across all treatments for patients with newly diagnosed, treatment-naïve TP53m AML, demonstrating a significant need for improved treatment for this difficult-to-treat population.