General AML

Imaging of CXCR4 expression in patients with AML using targeted positron emission tomography

The CXCR4 chemokine receptor is reported to play a significant role in survival and apoptosis of both healthy and malignant hematopoietic cells in the Bone Marrow (BM). Moreover, it has been implicated in the pathogenesis of Acute Myeloid Leukemia (AML). The specific role of CXCR4 in AML may be related to the preservation of AML cells within the BM microenvironment. Thus, this receptor is of interest with regards to developing new prognostic tools and identifying new therapeutic targets in AML.

Herhaus et al. evaluated cell lines from 67 patients with Myelodysplastic Syndromes (MDS), de Novo AML or secondary AML for CXCR4 expression. The findings were published in Haematologica in August 2016. Their key published results revealed a correlation between high CXCR4 expression and chemotherapeutic resistance and poor prognosis.

In addition, they report that CXCR4 has been identified as a new therapeutic target. The drug AMD3100 (plerixafor), a CXCR4 antagonist licensed in the EU for stem cell mobilization, has now been evaluated for use in AML. The drug has been used in combination with Granulocyte Colony Stimulating Factor (G-CSF) in relapsed/refractory AML for chemosensitization to help overcome chemotherapeutic resistance in a phase1/2 clinical trial (clinical trial registration number NCT00906945).

Abstract

Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression. The wide range of CXCR4 surface expression in patients was reflected in cell lines of acute myeloid leukemia. Next, we evaluated the CXCR4-specific peptide Pentixafor by positron emission tomography imaging in mice harboring CXCR4 positive and CXCR4 negative leukemia xenografts, and in 10 patients with active disease. [68Ga]Pentixafor-positron emission tomography showed specific measurable disease in murine CXCR4 positive xenografts, but not when CXCR4 was knocked out with CRISPR/Cas9 gene editing. Five of 10 patients showed tracer uptake correlating well with leukemia infiltration assessed by magnetic resonance imaging. The mean maximal standard uptake value was significantly higher in visually CXCR4 positive patients compared to CXCR4 negative patients. In summary, in vivo molecular CXCR4 imaging by means of positron emission tomography is feasible in acute myeloid leukemia. These data provide a framework for future diagnostic and theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche.

References
  1. Herhaus P. et al. Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia. Haematologica. 2016 Aug; 101(8): 932-40. DOI: 10.3324/haematol.2016.142976.