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

Abstract

BACKGROUND: 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. METHODS: 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 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280955.

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Citation

Published Version (Please cite this version)

10.1186/s13045-016-0301-2

Publication Info

Green, Michael MB, Nelson Chao, Saurabh Chhabra, Kelly Corbet, Cristina Gasparetto, Ari Horwitz, Zhiguo Li, Jagadish Kummetha Venkata, et al. (2018). Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery. J Hematol Oncol, 9(1). p. 71. 10.1186/s13045-016-0301-2 Retrieved from https://hdl.handle.net/10161/16168.

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Scholars@Duke

Li

Zhiguo Li

Associate Professor of Biostatistics & Bioinformatics

survival analysis, dynamic treatment regimes, clinical trials

Long

Gwynn Douglas Long

Professor of Medicine

1. High dose therapy and autologous and allogeneic stem cell rescue for hematologic malignancies (especially multiple myeloma) and solid tumors.
2. Non-myeloablative allogeneic transplants for hematologic malignancies and solid tumors.
3. Supportive care for hematopoietic stem cell transplants.
4. Prevention and therapy of graft versus host disease.

Sung

Anthony D Sung

Adjunct Associate Professor of Medicine

I am dedicated to the treatment of hematologic malignancies through cellular therapies such as hematopoietic stem cell transplantation (HCT). My research focuses on strategies to reduce complications of HCT and ranges from preclinical studies using murine models of HCT to Phase 1 and Phase 2 clinical trials. Areas of interest include the role of the microbiota (the trillions of bacteria living in and on our bodies), nutrition, and exercise in modulating HCT outcomes such as graft-versus-host disease (GVHD) and infections. In addition to advancing new pharmacological and cellular immunotherapies in support of these goals, we also are developing mobile health technologies (mHealth) to monitor patients at home, both as part of our innovative home transplant program as well as to improve follow up care of all our patients when they return home after transplant.

Sullivan

Keith Michael Sullivan

James B. Wyngaarden Distinguished Professor Emeritus of Medicine

Research areas

  • Late effects of cancer treatment and stem cell transplantation 
  • Chronic graft-versus-host disease 
  • Transplantation for sickle cell and autoimmune diseases 
  • Knowledge engineering
Overview
Early on, Dr. Sullivan and the team at Fred Hutchinson Cancer Research Center developed a systematic investigative approach for the diagnosis and treatment of chronic graft-versus-host disease (GVHD), the major cause of late morbidity and non-relapse mortality following allogeneic stem cell transplantation (SCT). As a result of this work, it became clear that blood and marrow transplant recipients require systematic long-term follow-up to evaluate and treat late complications of high-dose chemoradiotherapy and SCT.

The program grew into a large multidisciplinary team, resulting in improvement in patient outcome and quality of life. Through the late events project, he also contributed to outcomes research, computer decision support systems, and knowledge engineering for follow-up care. With quality of life as a focus, research pursued the application of SCT to diseases with high morbidity but little immediate mortality. For young patients with advanced, symptomatic sickle cell disease, myeloablative conditioning and SCT from an HLA-identical sibling has led to an 86% long-term survival free of sickle cell disease. For individuals with autoimmune diseases such as multiple sclerosis, scleroderma, and systemic lupus erythematosus, current therapy is often incomplete and significant morbidity from the disease or its treatment is observed.

Recent preclinical and clinical data suggest that high-dose immunosupression and SCT can halt the progression and, in some settings, reverse the course of autoimmune diseases. Since his arrival at Duke University, over 30 centers nationwide are participating in Duke-led phase II and III trials to test the toxicity, efficacy, and quality of life following autologous and allogeneic stem cell transplantation for autoimmune diseases.

These trials will also serve as platforms to study the immune repertoire and mechanistic pathways before and after SCT to gain greater insight into the basic mechanisms of autoimmunity.

A national repository of tissue and cell specimens is also part of these NIH-supported trials to further promote scientific study from these unique patients.

Kang

Yubin Kang

Professor of Medicine

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