10 Administration of Plerixafor (a CXCR4 antagonist) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Enhances Platelet Recovery in a Phase I/II Trial

Track: BMT Tandem "Scientific" Meeting
Wednesday, February 11, 2015, 4:45 PM-6:45 PM
Seaport Ballroom ABC (Manchester Grand Hyatt)
Michael M.B. Green, MD , Division of Hematology, Medical Oncology, and Cellular Therapy, Duke University Medical Center, Durham, NC
Mitchell E. Horwitz, MD , Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
Yubin Kang, MD , Adult Stem Cell Transplant Program; Division of Cellular Therapy, Duke University Medical Center, Durham, NC
Nelson J. Chao, MD, MBA , Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC
Gwynn D Long, MD , Duke Univ Med Ctr BMT Prog, Durham, NC
David Rizzieri, M.D. , Duke Universtiy Medical Center, Durham, NC
Cristina Gasparetto, MD , Duke University Medical Center, Durham, NC
Anthony D. Sung, MD , Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC
Stefanie Sarantopoulos, MD, PhD , Duke Adult Blood and Marrow Transplant Program, Duke University, Durham, NC
Zhiguo Li, PhD , Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC
Kelly Corbet , Duke University, Durham, NC
Emily Riggan-Stuelke , Duke University, Durham, NC
Keith Sullivan, MD , Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC
Beth Wilson , Duke University, Durham, NC
Saurabh Chhabra, MD , Hematology and Oncology, MUSC, Charleston, SC
Luciano V Costa, MD , *, Troy, MI
Alice Mims , Hematology and Oncology, MUSC, Charleston, SC
Robert Stuart, MD , Medicine, Medical University of South Carolina, Charleston, SC

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

 

Disclosures:
M. E. Horwitz, Genzyme/Sanofi, Investigator: Research Funding

G. D. Long, Chimerix, Investigator: Research Funding
Sanofi, Speaking and teaching: Honoraria

D. Rizzieri, celgene, speaker: Advisory Board , Consultancy and Honoraria
gilead, speaker: Advisory Board and Honoraria
incyte, speaker: Advisory Board and Honoraria
spectrum, speaker: Advisory Board , Consultancy and Honoraria
seattle genetics, speaker: Advisory Board and Honoraria
sanofi, advisor: Consultancy
pfizer, dsmb: Consultancy

C. Gasparetto, celgene, advisory member: Advisory Board and Research Funding
millennium, speaker/teacher, advisory: Advisory Board and Honoraria
onyx, advisory board: Advisory Board
siattle genetic, spouse only: Advisory Board and Honoraria
incyte, spouse only: Advisory Board and Honoraria
spectrum, spouse only : Advisory Board and Honoraria
gilead, spouse only: Advisory Board and Honoraria
novartis, spouse only: Advisory Board

S. Sarantopoulos, pharmacyclics honorarium, ad hoc advisory board for chronic gvhd trial using ibrutinib: Advisory Board
Rigel, nothing financial, we are testing fostamatinib in preclinical studies, rigel may provide drug if we go to clinical trial: fostamatinib supply for lab and potential clinical trial

L. V. Costa, Sanofi-Aventis, Consultant: Consultancy and Honoraria

A. Mims, Incyte Corporation, Advisory Board Member: Advisory Board