Inhibition of high CXCR4 with motixafortide and absence of single-cell MRD predict outcome after AML consolidation
Abstract
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 (BM) microenvironment, largely orchestrated by the CXC chemokine receptor 4 (CXCR4)–CXC motif chemokine 12 axis (CXCL12), enables leukemia cell survival and chemoresistance by anchoring blasts in their protective BM 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 2 trial, 128 patients in first remission received high-dose cytarabine plus motixafortide or placebo. Median relapse-free survival did not substantially differ between groups: 10.3 months (95% confidence interval [CI], 8.0-12.0) for motixafortide and 11.5 months (95% CI, 8.6-24.1) for placebo (log-rank P = .98). But single-cell measurable residual disease (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 = .02), whereas in the motixafortide group, higher CXCR4 expression was linked to a reduced relapse rate (P = .047). Exploratory analyses identified scMRD levels at which higher MRD burden was associated with inferior overall survival. Taken together, combining functional MRD profiling with biomarker-driven patient selection, such as CXCR4 expression, may enable more precise and effective postremission interventions in AML. This trial was registered at www.clinicaltrials.gov as NCT02502968 and at EudraCT as 2014-002702-21.
Article Details
Authors (62)
Enise Ceran
1Department of Internal Medicine V, Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
Sonia Jaramillo Segura
1Department of Internal Medicine V, Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
Anne Kathrin Merbach
1Department of Internal Medicine V, Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
Christian Rohde
1Department of Internal Medicine V, Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
Maxi Wass
4Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Judith Schaffrath
4Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Robert Durruthy-Durruthy
5Mission Bio, South San Francisco, CA
Marc Arribas-Layton
5Mission Bio, South San Francisco, CA
Adam Sciambi
5Mission Bio, South San Francisco, CA
Kathrin Rieger
6Department of Hematology, Oncology, and Tumor Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Axel Nogai
Mathias Hänel
7Department III of Internal Medicine, Klinikum Chemnitz, Chemnitz, Germany
Regina Herbst
7Department III of Internal Medicine, Klinikum Chemnitz, Chemnitz, Germany
Friedrich Stölzel
8Department of Internal Medicine II, Hematology and Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Christoph Röllig
22Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany
Edgar Jost
Richard F. Schlenk
Michelle Lotze
1Department of Internal Medicine V, Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
Richard Noppeney
11Division of Hematology/Oncology, Medizinische Klinik I, Krankenhaus der Barmherzigen Brüder, Trier, Germany
Christian Brandts
12Department of Medicine, Hematology/Oncology, Goethe University Hospital Frankfurt, Frankfurt, Germany
Utz Krug
13German Bone Marrow Donor Collection Center, Cologne, Germany
Katharina S. Götze
Sebastian Buske
15Department of Medicine II, Community Hospital Kiel, Kiel, Germany
Axel Florschütz
16Department of Oncology, City Hospital Dessau, Dessau, Germany
Jörg Schubert
17Department of Internal Medicine II, Elbland Hospital Riesa, Riesa, Germany
Bernhard Opitz
18Department of Hematology and Oncology, Hospital St Elisabeth and St Barbara Halle, Halle, Germany
Eva Eßeling
19Department of Medicine A, Hematology, Oncology, and Respiratory Medicine, University Hospital Münster, Münster, Germany
Stephan von Witzendorff
20Department of Hematology/Oncology and Palliative Medicine, Evangelisches Stift St Martin, Gemeinschaftsklinikum Mittelrhein, Koblenz, Germany
Marion Subklewe
Ludwig Maximilian University Hospital, Munich, Germany
Martin Kaufmann
22Department of Hematology, Oncology and Palliative Medicine, Robert Bosch Hospital, Stuttgart, Germany
Norbert Frickhofen
23Department of Internal Medicine III, Dr Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
Christian W. Scholz
24Department of Hematology and Oncology, Vivantes Klinikum Am Urban, Berlin, Germany
Kerstin Schäfer-Eckart
25Department of Internal Medicine 5, Oncology, Hematology and Bone Marrow Transplantation, Klinikum Nürnberg Campus Nord, Paracelsus Medical University, Nürnberg, Germany
Volker Kunzmann
26Department of Internal Medicine II, Medical Oncology, Comprehensive Cancer Center Mainfranken Würzburg, University Hospital Würzburg, Würzburg, Germany
Martin Schmidt-Hieber
27Department of Hematology and Oncology, Medical University Lausitz–Carl Thiem, Cottbus, Germany
Herbert Sayer
28Department of Hematology, Oncology, and Stem Cell Transplantation, Helios Klinikum Erfurt, University Campus of the Health and Medical University Erfurt, Erfurt, Germany
Andreas Rank
Philipp Hemmati
30Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Academic Teaching Hospital of Charité University Medical School, Potsdam, Germany
Frank Schüler
31Department of Internal Medicine, Hematology and Oncology, KMG Klinikum Luckenwalde, Luckenwalde, Germany
Marina Scheller
1Department of Internal Medicine V, Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
Simone Kowoll
32Coordination Center for Clinical Trials, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Jörg Steighardt
32Coordination Center for Clinical Trials, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Bayram Edemir
4Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Beatrice Ludwig-Kraus
33Department of Laboratory Medicine, Central Laboratory, University Hospital Halle, Halle (Saale), Germany
Lutz P. Müller
4Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Sabine Edemir
4Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Abi Vainstein-Haras
34BioLineRx Ltd, Modi'in, Israel
Ella Sorani
34BioLineRx Ltd, Modi'in, Israel
Irit Glicko-Kabir
34BioLineRx Ltd, Modi'in, Israel
Shaul Kadosh
34BioLineRx Ltd, Modi'in, Israel
Sigal Tavor
35Department of Hematology, Assuta Medical Center, Tel Aviv, Israel
Cora Gromann
32Coordination Center for Clinical Trials, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Andreas Wienke
Marcus Bauer
Claudia Wickenhauser
Claudia D. Baldus
Uwe Platzbecker
Adelheid Cerwenka
Hubert Serve
Martin Bornhäuser
Christian Junghanß
40Department of Medicine, Clinic II, Hematology, Oncology, and Palliative Care, Rostock University Medical Centre, Rostock, Germany
Carsten Müller-Tidow