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 (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.