PO.CL01.03 · 临床研究

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

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

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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