Abstract
BackgroundThe 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.MethodsWe 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 μg/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/μl and platelet count >20,000/μl. 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.ResultsThirty 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.ConclusionsOur 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.Trial registrationClinicalTrials.gov NCT01280955
Highlights
IntroductionThe binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/ progenitor cells (HSPCs) in a quiescent state
The binding of CXCR4 with its ligand maintains hematopoietic stem/ progenitor cells (HSPCs) in a quiescent state
The massive cytokine storm from conditioning has deleterious effects on hematopoiesis [7,8,9,10]. Consistent with these hypotheses, we demonstrated in our preclinical murine study that administration of AMD3100 following myeloablative stem cell transplantation resulted in improved animal survival, reduced pro-inflammatory cytokine/chemokine production, and enhanced recovery of all donor cell lineages [11]
Summary
The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/ progenitor cells (HSPCs) in a quiescent state. Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is associated with a high incidence of morbidity and mortality [1, 2]. 25 % of patients will die within 1 year of transplant-related complications. Many of these complications arise during the period of bone marrow aplasia that precedes donor cell engraftment. The speed of hematopoietic recovery and donor cell engraftment has been correlated with the length of the hospital stay, the severity of illness during the stay, incidence of infection, and the patient’s survival [3]. Reduction in the period of bone marrow aplasia would be expected to reduce transplant-related mortality. There is urgent need to develop novel approaches for enhancing hematological recovery in HSCT
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