Hematopoietic progenitor cell mobilization for autologous transplantation – a literature review

摘要

The use of high-dose chemotherapy with autologous support of hematopoietic progenitor cells is an effective strategy to treat various hematologic neoplasms, such as non-Hodgkin lymphomas and multiple myeloma. Mobilized peripheral blood progenitor cells are the main source of support for autologous transplants, and collection of an adequate number of hematopoietic progenitor cells is a critical step in the autologous transplant procedure. Traditional strategies, based on the use of growth factors with or without chemotherapy, have limitations even when remobilizations are performed. Granulocyte colony-stimulating factor is the most widely used agent for progenitor cell mobilization. The association of plerixafor, a C-X-C Chemokine receptor type 4 (CXCR4) inhibitor, to granulocyte colony stimulating factor generates rapid mobilization of hematopoietic progenitor cells. A literature review was performed of randomized studies comparing different mobilization schemes in the treatment of multiple myeloma and lymphomas to analyze their limitations and effectiveness in hematopoietic progenitor cell mobilization for autologous transplant. This analysis showed that the addition of plerixafor to granulocyte colony stimulating factor is well tolerated and results in a greater proportion of patients with non-Hodgkin lymphomas or multiple myeloma reaching optimal CD34+ cell collections with a smaller number of apheresis compared the use of granulocyte colony stimulating factor alone. class="kwd-title">Keywords: Hematopoietic progenitor cell mobilization, Autologous transplant, Plerixafor, Multiple myeloma, Non-Hodgkin lymphomaHigh-dose chemotherapy with autologous hematopoietic stem cell transplantation is an effective strategy to treat various hematologic neoplasms, such as chemosensitive relapsed Hodgkin's lymphomas,1, 2 non-Hodgkin lymphomas (NHL)3, 4 and multiple myeloma (MM).5 Several clinical guidelines and consensus recommend the procedure as standard treatment in these conditions.6, 7, 8, 9, 10, 11 According to the Center for International Blood and Marrow Transplant Research (CIBMTR), 12,047 autologous hematopoietic stem cell transplantations (AHSCT) were carried out in the United States in 2011, with MM and NHL being the main indications.12 In Brazil, data from the Brazilian Transplant Registry show that 1144 AHSCT were performed in 2013, slightly higher than the year before.13The CIBMTR shows that peripheral blood progenitor cells are the main source used to support autologous transplants.12 In addition to the possible chemoresistance of the cancer, mobilization of hematopoietic progenitor cells (HPC) is another potentially limiting step for AHSCT, with high failure rates (between 5% and 40%) associated with historically used mobilization strategies.14A consensus published by the American Society for Blood and Marrow Transplantation (ASBMT) recommends collecting a minimum dose of 2?×?106?CD34+ cells/kg to perform AHSCT, but the decision to accept collections of between 1?×?106 and 2?×?106?CD34+ cells/kg can be individualized according to the circumstances of each patient. On the other hand, larger target numbers are needed if multiple transplants are planned.15Although the minimum dose of progenitor cells to be collected is well defined, the ideal target or the desirable maximum dose is less clear. Some data show that the use of ≥5?×?106?CD34+ cells/kg leads to quicker and more predictable grafting, achieving platelet transfusions independence significantly earlier with potential reductions in transplant costs.16, 17 Thus, adequate progenitor cell mobilization is a key step when planning an AHSCT.Biology related to mobilization of hematopoietic progenitor cells and therapeutic targetsAlthough mature hematopoietic cells are physiologically released from the bone marrow to the peripheral blood, immature cells are found in the circulation at a very low frequency. About 0.05% or less of the total circulating leukocytes are HPC and express the CD34+ surface marker.18 HPC adhere to the bone marrow microenvironment by a variety of adhesive interactions.19 Furthermore, they express a wide range of surface receptors, such as adhesion molecules associated with angiopoietin-1 lymphocytes, very late antigen 4 (VLA4), and Mac-1, C-X-C chemokine receptors type 4 (CXCR4) and type 2 (CXCR2), the surface glycoproteins CD44 and CD62L, and tyrosine kinase receptor c-kit.19 The bone marrow stroma contains stromal cell-derived factor 1 (SDF-1), CXC chemokine GRO-β, vascular cell adhesion molecule (VCAM-1), KIT-ligand, P-selectin glycoprotein ligand and hyaluronic acid, all of which are ligands for the stem cell adhesion molecules.20 Preclinical data show that inhibition of these receptor–ligand interactions results in increased mobilization of progenitor cells.19, 20, 21Growth factors [granulocyte colony-stimulating factor (G