Overexpression of CXCR4 predicts adverse overall and event‐free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype

Abstract

BACKGROUND.CXC chemokine receptor 4 (CXCR4) expression in acute myeloid leukemia (AML) is reported to correlate with FLT3 gene mutation and poorer prognosis. The prognostic significance of CXCR4 expression in patients with AML that have a normal karyotype and no evidence of FLT3 gene mutations was examined.METHODS.The prognostic significance of CXCR4 expression in 122 AML patients with normal karyotype and no evidence of FLT3 gene mutation treated at our institution between 1997 and 2003 was analyzed. All patients received intensive chemotherapy according to institutional protocols; 84% received cytarabine‐containing regimens. Bone marrow biopsy or clot specimens obtained before treatment were immunostained for CXCR4.RESULTS.There were 70 men and 52 women with a median age of 62 years (range, 22–82 years). Median follow‐up was 18 months (range, <1–97 months). Seventy‐six patients achieved complete remission (CR); 39 had recurrence. Sixty‐six patients died, including 9 with no evidence of disease. CXCR4 was positive in 70 and negative in 52 patients, with CR rates of 58% and 71%, respectively (P = .09). Multivariate analysis demonstrated that CXCR4 expression, presence of multilineage dysplasia, and high creatinine level predicted poorer overall (OS) and event‐free (EFS) survival.CONCLUSIONS.The results suggest that CXCR4 expression is associated with poor prognosis in AML patients with an unmutated FLT3 gene. Cancer 2007. © 2007 American Cancer Society.

The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation

“…12 Similarly, high level of CXCR4 expression in AML patients was found to be a factor of poor prognosis. 12,30,31 We also showed that the expression of cell surface elastase in AML cells is dependent on the SDF-1/CXCR4 axis, giving a first evidence for an important association between the SDF-1 and elastase pathways. In this study, we hypothesized that the inhibition of the SDF-1/ CXCR4 axis or elastase may regulate similar pathways and genes in AML cells.…”

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

“…AMLs with high CXCR4 cell surface expression, and with, therefore, a high tendency of stromal protection, have been shown to have a poor prognosis. 22,23 Inhibition of CXCR4 has been able to overcome resistance to numerous drugs. 24,25 CXCR4 inhibitors that target the stromal interaction and release the leukemic cells from the microenvironment have both a mobilizing and cell-cycle activating effect upon leukemic cells and may sensitize AML for chemotherapeutic cell killing.…”

“…[27][28][29] A mechanism of action for the beneficial effect of priming with GM-CSF could, therefore, be mediated through CXCR4-induced mobilization. CXCR4 expression in AML is correlated with FLT3 gene mutation, 23 and CXCR4 inhibition increased the sensitivity of FLT3-mutated leukemic cells to the apoptogenic effects of FLT3 inhibitors. Although the limited number of patients in each subgroups defined by molecular markers might lead to a cautious interpretation of data, our results regarding the advantage of priming in patients displaying FLT3-ITD mutation or MLL abnormalities are supporting these observations.…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…113 This function of CXCR4 could explain why CXCR4 surface expression on AML cells has such a profound negative prognostic impact in AML. [114][115][116] Plerixafor is currently used in an ongoing clinical trial for mobilization of AML cells from the protective marrow microenvironment to the blood, where the AML cells are then targeted by conventional cytotoxic drugs. The feasibility of using Plerixafor for AML cell mobilization to the blood in an animal model and in AML patients on this trial was recently reported.…”