Rapid Mobilization of CD34+ Cells Following Administration of the CXCR4 Antagonist AMD3100 to Patients With Multiple Myeloma and Non-Hodgkin's Lymphoma

Devine, Steven M.; Flomenberg, Neal; Vesole, David H.; Liesveld, Jane L.; Weisdorf, Daniel J.; Badel, Karin; Calandra, Gary B.; DiPersio, John F.

doi:10.1200/jco.2004.07.131

Cited by 402 publications

(278 citation statements)

References 53 publications

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“…The general feasibility and safety of such an approach has been demonstrated by recent studies in which CXCR4 antagonists were administered to patients or volunteers. 24,40,41 Stroma-mediated AML cell protection from chemotherapy can partially be reversed by CXCR4 antagonists in vitro. 42 As such, a clinical trial with administration of a CXCR4 antagonist in an attempt to mobilize AML cells from their protective environment prior to conventional therapy may be feasible in the near future, even though an increased toxicity to normal hematopoiesis due to simultaneous progenitor cell mobilization is a concern.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 is a prognostic marker in acute myelogenous leukemia

Spoo

Lübbert

Wierda

et al. 2006

Blood

295

213

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CXCR4 chemokine receptors retain hematopoietic progenitors and leukemia cells within the marrow microenvironment. We prospectively evaluated the prognostic implication of CXCR4 in 90 consecutive patients with acute myelogenous leukemia (AML) by flow cytometry. Patients were divided into groups with low (n ‫؍‬ 32), intermediate (n ‫؍‬ 26), or high (n ‫؍‬ 32) CXCR4 expression, as defined by CXCR4 mean fluorescence intensity ratio thresholds of less than 5, 5 to 10, or more than 10, respectively. We found that low CXCR4 expression on AML cells correlated with a better prognosis, resulting in a longer relapse-free and overall survival of 24.3 ؎ 2.9 months for low CXCR4-expressing patients, compared with 17.4 ؎ 3.4 months for intermediate and 12.8 ؎ 2 months (mean ؎ SEM) for patients with high expression. In univariate analyses, CXCR4 expression, cytogenetics, white blood cell count, and serum lactate dehydrogenase (LDH) predicted for shorter survival. Multivariate analysis revealed CXCR4 expression and unfavorable cytogenetics as independent prognostic factors. We conclude that CXCR4 expression in AML is an independent prognostic predictor for disease relapse and survival that can rapidly and easily be determined at disease presentation. These findings warrant further investigation into the role of CXCR4 in AML and suggest that CXCR4 should be incorporated into the risk assessment of AML patients. IntroductionDespite major improvements in the understanding and treatment of certain leukemias during the past years, the overall survival (OS) of patients with acute myelogenous leukemia (AML) remains poor, and new prognostic markers and therapeutic strategies are urgently needed. Several prognostic markers have been described in AML, including age, performance status, karyotype, white blood cell (WBC) count, serum lactate dehydrogenase (LDH), presence or absence of an antecedent hematologic disorder (eg, myelodysplasia), and the presence of distinct cytogenetic abnormalities. [1][2][3] Cytogenetic abnormalities can be detected in approximately 60% of AML patients and represent the most important predictor for responses to therapy and relapse probability. Depending upon cytogenetic characteristics, patients can be classified into low-risk, intermediate-risk, or high-risk groups. 4,5 However, there is substantial heterogeneity within these groups. About 35% to 50% of AML patients display a normal karyotype, which can further be subdivided using predictive molecular markers, such as mutations in the fetal liver tyrosine kinase-3 (FLT3) gene and the mixed-lineage leukemia (MLL) gene. 6,7 Several studies indicated that adhesion to marrow stromal cells affects the survival and proliferation of AML cells 8,9 and protects AML cells from chemotherapy in vitro 10 and in vivo. 11 Adhesion molecules, particularly the very late antigen-4 (VLA-4) and VLA-5 integrins, are considered essential for AML cell adhesion to respective stromal ligands (fibronectin) 12 and for protection of AML cells from spontaneous or drug-induced apoptosis....

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Section: Discussionmentioning

confidence: 99%

CXCR4 is a prognostic marker in acute myelogenous leukemia

Spoo

Lübbert

Wierda

et al. 2006

Blood

295

213

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“…Instead, AnorMED explored AMD3100 as a mobilizing agent for HSC, 88 and a subsequent series of preclinical and clinical trials demonstrated that AMD3100 alone and in combination with G-CSF mobilizes HSC. 34,89,90 AMD3100 (recently re-named as Plerixafor or Mozobil) is now owned by Genzyme Corporation (Cambridge, MA, USA) after a recent takeover of AnorMED by Genzyme in late 2006. Plerixafor is currently used in phase III trials in lymphoma and multiple myeloma patients undergoing autologous stem cell mobilization, and current plans are to file for US and European approval of the drug in 2008.…”

Section: Non-peptide Cxcr4 Antagonistsmentioning

confidence: 99%

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Burger

Peled²

2008

Leukemia

414

316

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“…Significant enhancement of PBSC mobilization was shown. [20][21][22][23][24][25][26] We evaluated the results of combined use of plerixafor and G-CSF in 20 patients who had previously failed to mobilize sufficient PBSCs, to allow the patients to proceed to auto-SCT, after obtaining consent for compassionate use of the experimental agent. Of the 20 patients, 5 had failed previous chemotherapy-based PBSC mobilization and 15 failed previous cytokine-only mobilization.…”

Section: Introductionmentioning

confidence: 99%