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Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

ABSTRACT: The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 ?g/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/?l and platelet count >20,000/?l. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis.Thirty patients received plerixafor following peripheral blood stem cell (n?=?28) (PBSC) or bone marrow (n?=?2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p?=?0.04) and platelet recovery >20 K (p?=?0.04) compared to the controls.Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted.ClinicalTrials.gov NCT01280955.

SUBMITTER: Green MM

PROVIDER: S-EPMC4989381 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

Green Michael M B MM Chao Nelson N Chhabra Saurabh S Corbet Kelly K Gasparetto Cristina C Horwitz Ari A Li Zhiguo Z Venkata Jagadish Kummetha JK Long Gwynn G Mims Alice A Rizzieri David D Sarantopoulos Stefanie S Stuart Robert R Sung Anthony D AD Sullivan Keith M KM Costa Luciano L Horwitz Mitchell M Kang Yubin Y

Journal of hematology & oncology 20160817 1

<h4>Background</h4>The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.<h4>Methods</h4>We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receivin ...[more]

PMID: 27535663

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Project description:BackgroundDiffuse large B-cell lymphoma (DLBCL) is an aggressive disease with variable clinical outcome, accounting for at least 25-30 % of adult non-Hodgkin lymphomas. Approximately one third of DLBCL patients are not cured by the currently used treatment regimen, R-CHOP. Hence, new treatment strategies are needed. Antagonizing the CXCR4 receptor might be promising since the CXCR4-CXCL12 axis is implicated in several aspects of tumor pathogenesis as well as in protection from chemotherapeutic response. In Burkitt lymphoma, the CXCR4 antagonist plerixafor has already been shown to enhance the therapeutic effect of rituximab, the immunotherapeutic agent of R-CHOP; but this is yet to be confirmed for DLBCL. We, therefore, investigated the effect of plerixafor on DLBCL cellular response to rituximab.MethodsIn this in vitro study, human DLBCL cell lines were treated with rituximab and/or plerixafor, concomitantly or in sequence. The trypan blue exclusion method and MTS-based assays were used to evaluate cellular proliferation, whereas flow cytometry was used for assessment of apoptosis status and CXCR4 surface expression level. Linear mixed effects models were used to assess statistical significance.ResultsWe observed that simultaneous addition of plerixafor and rituximab resulted in a significant decrease in DLBCL cellular proliferation, compared to monotherapeutic response. The effect was dose-dependent, and concomitant administration was observed to be superior to sequential drug administration. Accordingly, the fraction of apoptotic/dead cells significantly increased following addition of plerixafor to rituximab treatment. Furthermore, exposure of DLBCL cells to plerixafor resulted in a significant decrease in CXCR4 fluorescence intensity.ConclusionsBased on our results, implying that the anti-proliferative/pro-apoptotic effect of rituximab on DLBCL cells can be synergistically enhanced by the CXCR4 antagonist plerixafor, addition of plerixafor to the R-CHOP regimen can be suggested to improve treatment outcome for DLBCL patients.

Dataset Information

Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

Publications

Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

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