Title: Administration of Plerixafor (a CXCR4 antagonist) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Enhances Platelet Recovery in a Phase I/II Trial
Abstract: The binding of CXCR4 with its ligand (stromal derived factor-1 [SDF-1]) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. This effect of CXCR4/SDF-1 interaction may be undesirable during the early phase of hematopoietic stem cell transplantation (HSCT). We hypothesized that blocking CXCR4/SDF-1 interaction after HSCT promotes hematopoiesis by inducing HSPC proliferation. We have found that giving AMD3100 (plerixafor) after HSCT enhanced recovery of all donor cell lineages in murine transplant models (Kang, PLOS ONE 2010). We have further demonstrated that this enhanced donor cell recovery results from the combined effect of AMD3100 opening the marrow niche and inducing HSPC cell division. Based on these findings, we conducted a phase I/II trial of plerixafor on donor cell recovery following myeloablative allogeneic HSCT. Patients with various hematologic malignancies receiving myeloablative conditioning were enrolled in the study. Plerixafor 240 μg/kg subcutaneously every other day was administered beginning day +2 until day +21 or until ANC>500. The primary efficacy endpoints of the study were time to ANC>500 and time to platelets >20k. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a historical cohort of 106 patients from the Duke HSCT program who received similar conditioning and graft-versus host disease prophylaxis. Pre-engraftment relapse and death were the competing risks. Gray's test was used to compare the cohorts. Twenty-nine patients were evaluated in the study. Adverse events attributable to plerixafor were mild in nature and expected (GI upset, nausea, diarrhea, fatigue, and injection site reactions). They were difficult to distinguish from effects of the myeloablative conditioning regimen. There were no dose limiting toxicities of premature ventricular arrhythmias, primary or secondary graft failure, or mortality associated with plerixafor administration. Engraftment kinetics as demonstrated by cumulative incidence showed a trend toward faster neutrophil engraftment (p=0.07) and quicker platelet recovery >20K (p=0.04) Figures 1 and 2. Median time to ANC>500 with 95% CI for plerixafor treatment group and historical control group was 17 days (16, 18) and 17 days (16, 19), respectively. Median time to platelet count >20 was 18 days (15, 22) in the treatment cohort and 19 days (19, 21) historically. Transplant related mortality calculated at Day +100 with 95% CI was 0.069 (0.00, 0.157). In this study, there appeared to be limited toxicities with plerixafor following myeloablative HSCT. Plerixafor enhances platelet recovery, and may enhance neutrophil recovery as well. This study provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies are justified.Figure 2Cumulative incidence: time to platelet >20.View Large Image Figure ViewerDownload Hi-res image Download (PPT)