Christiane Querfeld, Joycelynne M Palmer, Zhen Han, Xiwei Wu, Yate-Ching Yuan, Min-Hsuan Chen, Chingyu Su, Ni-Chun Tsai, D Lynne Smith, Samantha N Hammond, Liliana Crisan, Joo Y Song, Raju K Pillai, Steven T T Rosen, Jasmine Zain
{"title":"Phase 1 trial of durvalumab (anti-PD-L1) combined with lenalidomide in relapsed/refractory cutaneous T cell lymphoma.","authors":"Christiane Querfeld, Joycelynne M Palmer, Zhen Han, Xiwei Wu, Yate-Ching Yuan, Min-Hsuan Chen, Chingyu Su, Ni-Chun Tsai, D Lynne Smith, Samantha N Hammond, Liliana Crisan, Joo Y Song, Raju K Pillai, Steven T T Rosen, Jasmine Zain","doi":"10.1182/bloodadvances.2024014655","DOIUrl":null,"url":null,"abstract":"<p><p>Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via PD1/PD-L1 blockade (durvalumab) may restore an anti-tumor immune response. The oral immunomodulator lenalidomide, which has activity in CTCL, may enhance durvalumab immune checkpoint blockade. Our phase 1/2 clinical trial of durvalumab and lenalidomide in patients with refractory/advanced CTCL (NCT03011814) sought to assess safety and tolerability and identify the maximum tolerated dose/recommended phase 2 dose (RP2D) of lenalidomide plus fixed-dose durvalumab. Secondary and tertiary objectives were to investigate efficacy and effects on the TME. Thirteen patients were evaluable for toxicities and 12 for dose decisions and response. No serious adverse events (SAEs) or dose-limiting toxicities (DLTs) were observed during cycles 1-3 (DLT evaluation period), and dose level 3 is the RP2D. The most frequent AEs were tumor flare, fatigue, neutropenia, and leukopenia. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Best overall and skin response rates were 58.3% (95% CI: 27.7% - 84.8%) and 75% (95% CI: 42.8% - 94.5%) respectively. Median cycles of treatment were 11 (range, 3-42+). Median duration of response was 25.5 (range 8-36.5) months. The combination showed clinical activity with 7 partial responses, and 4 stable disease. Potentially predictive immune signatures were downregulation of TNF-alpha signaling via NFκB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders vs up-regulation of MYC targets and pro-inflammatory pathways in non-responders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment response.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4000,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood advances","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1182/bloodadvances.2024014655","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via PD1/PD-L1 blockade (durvalumab) may restore an anti-tumor immune response. The oral immunomodulator lenalidomide, which has activity in CTCL, may enhance durvalumab immune checkpoint blockade. Our phase 1/2 clinical trial of durvalumab and lenalidomide in patients with refractory/advanced CTCL (NCT03011814) sought to assess safety and tolerability and identify the maximum tolerated dose/recommended phase 2 dose (RP2D) of lenalidomide plus fixed-dose durvalumab. Secondary and tertiary objectives were to investigate efficacy and effects on the TME. Thirteen patients were evaluable for toxicities and 12 for dose decisions and response. No serious adverse events (SAEs) or dose-limiting toxicities (DLTs) were observed during cycles 1-3 (DLT evaluation period), and dose level 3 is the RP2D. The most frequent AEs were tumor flare, fatigue, neutropenia, and leukopenia. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Best overall and skin response rates were 58.3% (95% CI: 27.7% - 84.8%) and 75% (95% CI: 42.8% - 94.5%) respectively. Median cycles of treatment were 11 (range, 3-42+). Median duration of response was 25.5 (range 8-36.5) months. The combination showed clinical activity with 7 partial responses, and 4 stable disease. Potentially predictive immune signatures were downregulation of TNF-alpha signaling via NFκB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders vs up-regulation of MYC targets and pro-inflammatory pathways in non-responders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment response.
期刊介绍：
Blood Advances, a semimonthly medical journal published by the American Society of Hematology, marks the first addition to the Blood family in 70 years. This peer-reviewed, online-only, open-access journal was launched under the leadership of founding editor-in-chief Robert Negrin, MD, from Stanford University Medical Center in Stanford, CA, with its inaugural issue released on November 29, 2016.
Blood Advances serves as an international platform for original articles detailing basic laboratory, translational, and clinical investigations in hematology. The journal comprehensively covers all aspects of hematology, including disorders of leukocytes (both benign and malignant), erythrocytes, platelets, hemostatic mechanisms, vascular biology, immunology, and hematologic oncology. Each article undergoes a rigorous peer-review process, with selection based on the originality of the findings, the high quality of the work presented, and the clarity of the presentation.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
