Type 1 interferon to prevent leukemia relapse after allogeneic transplantation.
Type 1 interferon to prevent leukemia relapse after allogeneic transplantation.
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1型干扰素可以防止同种异体移植后白血病复发。
DOI：
10.1182/bloodadvances.2021004908
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发表时间：
2021-12-14
期刊：
影响因子：
7.5
通讯作者：
Reddy, Pavan
中科院分区：
文献类型：
--
作者：
Magenau, John M.;Peltier, Dan;Riwes, Mary;Pawarode, Attaphol;Parkin, Brian;Braun, Thomas;Anand, Sarah;Ghosh, Monalisa;Maciejewski, John;Yanik, Gregory;Choi, Sung Won;Talpaz, Moshe;Reddy, Pavan
预防性1型IFN增强早期GVL应答可能降低极高危AML患者HCT后白血病复发率。交互毒性，包括急性GVHD和非复发死亡率，没有增加后1型IFN治疗。有效的移植物抗白血病（GVL）反应是预防复发的关键，复发是成功的异基因造血细胞移植（HCT）的主要障碍。在临床前研究中，1型干扰素（IFN-α）增强了CD 8 α树突状细胞（DC）对白血病特异性抗原的交叉呈递，并扩增了GVL。这一观察结果被转化为一项在接受HCT治疗高危急性髓性白血病（AML）患者中使用长效IFN-α（聚乙二醇化IFN-α [pegIFNα]）的概念验证I/II期临床试验。未缓解的耐药AML患者或低风险白血病患者从HCT前第-1天开始每14天给予4剂pegIFNα。通过适应性设计确定剂量选择，在整个试验期间持续评估剂量限制性毒性的概率。通过测定最大耐受剂量（MTD）下6个月的复发率来评价疗效。36例患者（中位年龄60岁）接受了pegIFNα治疗。25%的患者发生3级或以上严重不良事件，确定180 μg为MTD。在II期，6个月时复发率为39%，持续至HCT后1年。移植相关死亡率为13%，严重的III-IV级急性移植物抗宿主病（GVHD）发生率为11%。HCT后供体和受体的配对血液样本显示1型IFN水平升高，伴有细胞应答，交叉呈递DC和循环白血病抗原特异性T细胞的持续存在。这些数据表明，在围HCT期预防性给予pegIFNα是可行的。在高危AML中，未观察到毒性增加，初步证据表明HCT后白血病复发减少。本试验在www.clinicaltrials.gov上注册为#NCT02328755。
Augmenting early GVL response by prophylactic type 1 IFN may reduce the rates of leukemic relapse after HCT in very high–risk AML. Reciprocal toxicities, including acute GVHD and nonrelapse mortality, were not increased after type 1 IFN treatment. A potent graft-versus-leukemia (GVL) response is crucial in preventing relapse, the major impediment to successful allogeneic hematopoietic cell transplantation (HCT). In preclinical studies, type 1 interferon (IFN-α) enhanced cross-presentation of leukemia-specific antigens by CD8α dendritic cells (DCs) and amplified GVL. This observation was translated into a proof-of-concept phase 1/2 clinical trial with long-acting IFN-α (pegylated IFN-α [pegIFNα]) in patients undergoing HCT for high-risk acute myeloid leukemia (AML). Patients with treatment-resistant AML not in remission or those with poor-risk leukemia were administered 4 dosages of pegIFNα every 14 days beginning at day −1 before HCT. Dose selection was established by adaptive design that continuously assessed the probability of dose-limiting toxicities throughout the trial. Efficacy was evaluated by determining the 6-month incidence of relapse at the maximum tolerated dose (MTD). Thirty-six patients (median age, 60 years) received pegIFNα treatment. Grade 3 or greater severe adverse events occurred in 25% of patients, establishing 180 μg as the MTD. In phase 2, the incidence of relapse was 39% at 6 months, which was sustained through 1-year post-HCT. The incidence of transplant-related mortality was 13%, and severe grade III-IV acute graft-versus-host disease (GVHD) occurred in 11%. Paired blood samples from donors and recipients after HCT revealed elevated levels of type 1 IFN with cellular response, the persistence of cross-presenting DCs, and circulating leukemia antigen-specific T cells. These data suggest that prophylactic administration of pegIFNα is feasible in the peri-HCT period. In high-risk AML, increased toxicity was not observed with preliminary evidence for reduction in leukemia relapse after HCT. This trial was registered at www.clinicaltrials.gov as #NCT02328755.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
20.3
作者：
Kayser, Sabine;Zucknick, Manuela;Schlenk, Richard F.
通讯作者：
Schlenk, Richard F.
影响因子：
45.3
作者：
Ji, Yuan;Wang, Sue-Jane
通讯作者：
Wang, Sue-Jane
影响因子：
20.3
作者：
Armand, Philippe;Kim, Haesook T.;Saber, Wael
通讯作者：
Saber, Wael
影响因子：
82.9
作者：
Reddy, P;Maeda, Y;Ferrara, JLM
通讯作者：
Ferrara, JLM