PO.CL01.03 · 临床研究

单细胞MRD分析识别CXCR4高表达AML为对Motixafortide CXCR4抑制有反应的人群

Single-cell MRD profiling identifies CXCR4-high AML as a responder population to CXCR4 inhibition with Motixafortide

编号 2440 展板 10 时间 4/20 09:00–12:00 区域 Section 40 主讲 Enise Ceran, MD

分会场 Biomarkers Predictive of Therapeutic Benefit 3

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作者与单位 Authors & Affiliations

Enise Ceran¹, Sonia Jaramillo-Segura¹, Anne Kahtrin Merbach¹, Christian Rohde¹, Robert Durruthy-Durruthy², Adam Sciambi², Marc Arribas-Layton², Michelle Lotze¹, Maxi Wass³, Kathrin Rieger⁴, Mathias Hänel⁵, Regina Herbst⁵, Christoph Röllig⁶, Edgar Jost⁷, Richard Schlenk¹, Katharina Götze⁸, Marina Scheller¹, Marion Subklewe⁹, Simone Kowoll¹⁰, Jörg Steighardt¹⁰, Bayram Edemir³, Lutz P. Müller³, Irit Glicko-Kabir¹¹, Abi Vainstein-Haras¹¹, Cora Gromann¹⁰, Ella Sorani¹¹, Shaul Kadosh¹¹, Andreas Wienke¹², Claudia Baldus¹³, Uwe Platzbecker¹⁴, Hubert Serve¹⁵, Martin Bornhäuser¹⁶, Carsten Müller-Tidow¹

¹Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany,²Mission Bio, San Francisco, CA,³Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany,⁴Department of Hematology, Oncology and Tumor Immunology, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany,⁵Klinik für Innere Medizin III, Klinikum Chemnitz, Chemnitz, Germany,⁶Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany,⁷Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine University Hospital RWTH Aachen, Aachen, Germany,⁸Department of Medicine III, Technical University Munich School of Medicine and Health, Munich, Germany,⁹Department of Medicine III, University Hospital LMU Munich, Munich, Germany,¹⁰Coordination Centre for Clinical Trials Halle, Martin-Luther University Halle-Wittenberg, Halle, Germany,¹¹BiolineRx, Modi'in, Israel,¹²Institute of Medical Epidemiology Biometrics and Informatics, Martin Luther University Halle-Wittenberg, Heidelberg, Germany,¹³Department of Hematology and Oncology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany,¹⁴Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany,¹⁵Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, University Hospital, Frankfurt am Main, Germany,¹⁶Med. Klinik und Poliklinik I, Carl Gustav Carus Univ. Hospital, Dresden, Germany

摘要 Abstract

中文摘要

背景：CXCL12-CXCR4轴介导骨髓龛对白血病干细胞的保护，并促成化疗耐药。Motixafortide是一种强效CXCR4拮抗剂，可破坏白血病细胞在微环境中的滞留。我们利用单细胞微小残留病（scMRD）分析，在BLAST试验（NCT02502968）中量化巩固治疗后的CXCR4表达和克隆持续存在，旨在定义Motixafortide反应的预测性生物标志物。方法：在128例随机分组、处于首次完全缓解（CR）的AML患者中，56例使用Tapestri平台（Mission Bio）接受骨髓scMRD分析，靶向40个复发突变热点和19个表面标志物（包括CXCR4）。以单细胞分辨率量化CXCR4表达，并按队列中位数二分。临床结局与治疗和scMRD指标进行相关分析。结果：尽管在ITT人群中各治疗组之间无复发生存（RFS）无差异（中位RFS：10.3 vs. 11.5个月，p=0.98），scMRD分析揭示了CXCR4依赖性的治疗效应。在安慰剂组中，高CXCR4表达与复发风险增加相关（p=0.02）。相反，在Motixafortide组中，高CXCR4表达与复发减少相关（p=0.047）。多变量Cox模型证实了治疗与CXCR4之间存在显著的交互作用（HRinteraction 0.032，95% CI 0.004至0.269，p=0.0015），支持CXCR4作为Motixafortide获益的预测性生物标志物。scMRD揭示了持续的克隆多样性，但常规MRD阳性与结局无关。结论：尽管BLAST试验显示RFS总体无差异，但单细胞MRD分析揭示了依据CXCR4表达的不同治疗效应。这些发现提示CXCR4可能作为Motixafortide反应的生物标志物，并凸显了单细胞分析在指导患者分层方面的潜力。

查看英文原文 English abstract

Background: The CXCL12-CXCR4 axis mediates bone marrow niche mediated protection of leukemic stem cells and contributes to chemoresistance. Motixafortide is a potent CXCR4 antagonist that disrupts leukemic cell retention in the microenvironment. We leveraged single-cell minimal residual disease (scMRD) profiling to quantify CXCR4 expression and clonal persistence after consolidation therapy within the BLAST trial (NCT02502968), aiming to define predictive biomarkers of Motixafortide response. Methods: Among 128 randomized AML patients in first complete remission (CR), 56 underwent bone marrow scMRD analysis using the Tapestri platform (Mission Bio) targeting 40 recurrent mutation hotspots and 19 surface markers including CXCR4. CXCR4 expression was quantified at single-cell resolution and dichotomized by cohort median. Clinical outcomes were correlated with treatment and scMRD metrics. Results: Although relapse-free survival (RFS) was not different between treatment arms in the ITT population (median RFS: 10.3 vs. 11.5 months, p=0.98), scMRD profiling uncovered a CXCR4 dependent treatment effect. In the placebo arm, high CXCR4 expression correlated with increased relapse risk (p=0.02). In contrast, in the Motixafortide arm, high CXCR4 expression was associated with reduced relapse (p=0.047). A multivariable Cox model confirmed a significant treatment by CXCR4 interaction (HRinteraction 0.032, 95% CI 0.004 to 0.269, p=0.0015), supporting CXCR4 as a predictive biomarker for Motixafortide benefit. scMRD revealed persistent clonal diversity, but conventional MRD positivity did not associate with outcome. Conclusion: While the BLAST trial showed no overall difference in RFS, single-cell MRD analysis revealed differential treatment effects according to CXCR4 expression. These findings suggest that CXCR4 may serve as a biomarker for response to Motixafortide and highlight the potential of single-cell profiling to inform patient stratification.

利益披露 Disclosure

E. Ceran, None.. S. Jaramillo-Segura, None.. A. Merbach, None.. C. Rohde, None.. R. Durruthy-Durruthy, None.. A. Sciambi, None.. M. Arribas-Layton, None.. M. Lotze, None.. M. Wass, None.. K. Rieger, None.. M. Hänel, None.. R. Herbst, None.. C. Röllig, None.. E. Jost, None.. R. Schlenk, None.. K. Götze, None.. M. Scheller, None.. M. Subklewe, None.. S. Kowoll, None.. J. Steighardt, None.. B. Edemir, None. L. P. Müller, Pfizer Advisory Role or Expert Testimony. Gilead Advisory Role or Expert Testimony. Novartis Advisory Role or Expert Testimony. Amgen Advisory Role or Expert Testimony. Gilead Travel. Amgen Financing of Scientific Research. I. Glicko-Kabir, BioLineRx Employment. A. Vainstein-Haras, BioLineRx Ltd Current Advisor Current equity holder in publicly traded company.. C. Gromann, None. E. Sorani, BioLineRx Ltd Employment. S. Kadosh, None.. A. Wienke, None.. C. Baldus, None.. U. Platzbecker, None.. H. Serve, None.. M. Bornhäuser, None.. C. Müller-Tidow, None.

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