Inhibition of high CXCR4 with Motixafortide and absence of single-cell MRD predict outcome after AML consolidation.

Relapse after remission remains the primary cause of treatment failure in acute myeloid leukemia (AML), underscoring the need for strategies to eliminate residual leukemic cells. The bone marrow microenvironment, largely orchestrated by the CXCR4-CXCL12 axis, enables leukemia cell survival and chemoresistance by anchoring blasts in their protective bone marrow niche. Motixafortide, a selective CXCR4 antagonist, mobilizes leukemic cells and disrupts tumor-microenvironment interactions in preclinical models. In this randomized, double-blind, placebo-controlled phase II trial (NCT02502968; registered at ClinicalTrials.gov), 128 patients in first remission received high‑dose cytarabine (HiDAC) plus Motixafortide or placebo. Median relapse-free survival (RFS) did not substantially differ between groups: 10.3 months (95% CI, 8.0-12.0) for Motixafortide and 11.5 months (95% CI, 8.6-24.1) for placebo (log-rank p=0.98). But scMRD analysis, performed before consolidation, demonstrated heterogeneity of CXCR4 inhibition benefit: in the placebo group, higher CXCR4 expression was associated with increased relapse risk (p=0.02), whereas in the Motixafortide group, higher CXCR4 expression was linked to a reduced relapse rate (p=0.047). Exploratory analyses identified scMRD levels at which higher MRD burden was associated with inferior overall survival (OS). Taken together, combining functional MRD profiling with biomarker-driven patient selection, such as CXCR4 expression, may enable more precise and effective post-remission interventions in AML. This clinical trial is registered at EudraCT number: 2014-002702-21.

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Journal
Blood
Published
2026-04-14
DOI
https://doi.org/10.1182/blood.2025032033
Primary Topic
Chemokine receptors and signaling
Type
article
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article

Inhibition of high CXCR4 with Motixafortide and absence of single-cell MRD predict outcome after AML consolidation.

Martin Schmidt‐Hieber, A Rank, Claudia Wickenhauser, Jörg Steighardt et al.
Blood
Chemokine receptors and signaling
article

Inhibition of high CXCR4 with Motixafortide and absence of single-cell MRD predict outcome after AML consolidation.

Martin Schmidt‐Hieber, A Rank, Claudia Wickenhauser, Jörg Steighardt, Utz Krug, Judith Schaffrath, Enise Ceran, Ella Sorani, Christoph Röllig, Martin Bornhäuser, Carsten Müller‐Tidow, Beatrice Ludwig‐Kraus, Stephan von Witzendorff, Irit Gliko-Kabir, Marc Arribas-Layton, Sigal Tavor, Friedrich Stölzel, Sonia Jaramillo, Shaul Kadosh, Edgar Jost, Adelheid Cerwenka, Bayram Edemir, Adam Sciambi, Sebastian Buske, Abi Vainstein‐Haras, Cora Gromann, Marcus Bauer, Christian Rohde, Sabine Edemir, Eva Eßeling, Katharina S. S. Götze, Axel Nogai, Volker Kunzmann, Michelle Lotze, Marina Scheller, N Frickhofen, Simone Kowoll, Christian Brandts, Richard Noppeney, Maxi Wass, Kathrin Rieger, Hubert Serve, Christian Junghanß, Philipp Hemmati, Axel Florschütz, Bernhard Opitz, Anne Kathrin Merbach, Richard Schlenk, Lutz P. Mueller, Herbert G. Sayer, Christian W Scholz, Martin Kaufmann, Kerstin Schäfer-Eckart, Mathias Hänel, Uwe Platzbecker, Frank Schüler, Jörg Ernst Albert Schubert, Claudia D Baldus, Regina Theresia Herbst, Marion Subklewe, Robert Durruthy-Durruthy
article en

Abstract

Relapse after remission remains the primary cause of treatment failure in acute myeloid leukemia (AML), underscoring the need for strategies to eliminate residual leukemic cells. The bone marrow microenvironment, largely orchestrated by the CXCR4-CXCL12 axis, enables leukemia cell survival and chemoresistance by anchoring blasts in their protective bone marrow niche. Motixafortide, a selective CXCR4 antagonist, mobilizes leukemic cells and disrupts tumor-microenvironment interactions in preclinical models. In this randomized, double-blind, placebo-controlled phase II trial (NCT02502968; registered at ClinicalTrials.gov), 128 patients in first remission received high‑dose cytarabine (HiDAC) plus Motixafortide or placebo. Median relapse-free survival (RFS) did not substantially differ between groups: 10.3 months (95% CI, 8.0-12.0) for Motixafortide and 11.5 months (95% CI, 8.6-24.1) for placebo (log-rank p=0.98). But scMRD analysis, performed before consolidation, demonstrated heterogeneity of CXCR4 inhibition benefit: in the placebo group, higher CXCR4 expression was associated with increased relapse risk (p=0.02), whereas in the Motixafortide group, higher CXCR4 expression was linked to a reduced relapse rate (p=0.047). Exploratory analyses identified scMRD levels at which higher MRD burden was associated with inferior overall survival (OS). Taken together, combining functional MRD profiling with biomarker-driven patient selection, such as CXCR4 expression, may enable more precise and effective post-remission interventions in AML. This clinical trial is registered at EudraCT number: 2014-002702-21.

Blood
Goethe University Frankfurt (DE), University of Mannheim (DE), Heidelberg University (DE), Protalix BioTherapeutics (Israel) (IL), Assuta Medical Center (IL), Helios Dr. Horst Schmidt Kliniken Wiesbaden (DE), Luther University (KR), University Hospital Augsburg (DE), University Hospital Heidelberg (DE), Robert Bosch Hospital (DE), LMU Klinikum (DE), Hochschule für Angewandte Wissenschaften Kiel (DE), Humboldt-Universität zu Berlin (DE), Krankenhaus der Barmherzigen Brüder Trier (DE), Städtisches Klinikum Dessau (DE), Nuremberg Hospital (DE), University Hospital Münster (DE), Priest Hospital (TH), Krankenhaus St. Elisabeth und St. Barbara (DE), Mission Bio (United States) (US), Vivantes Klinikum (DE), National Center for Tumor Diseases (DE), University Hospital Schleswig-Holstein (DE), Paracelsus Medizinische Privatuniversität (DE), University Hospital Leipzig (DE), Universitätsklinikum Würzburg (DE), Stadtwerke Köln (Germany) (DE), Klinikum Konstanz (DE), Medizinische Universität Lausitz - Carl Thiem (DE), Helios Klinikum Erfurt (DE), Gemeinschaftsklinikum Mittelrhein (DE), University Hospital in Halle (DE), Klinikum Ernst von Bergmann (DE), University Hospital Carl Gustav Carus (DE), Klinikum Chemnitz (DE), Clinical Research Center Kiel (DE), University of Rostock (DE), Technical University of Munich (DE), Martin Luther University Halle-Wittenberg (DE), Ludwig-Maximilians-Universität München (DE), RWTH Aachen University (DE), University of Lübeck (DE)
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