Hematopoietic Stem Cell Transplantation by Robert J. Soiffer

Author:Robert J. Soiffer
Language: eng
Format: epub
Publisher: Humana Press, Totowa, NJ

2 2. Patterns of Immune Reconstitution

2.1 2.1. Neutrophil Recovery

Neutrophils are essential as a first line of defense against bacterial and fungal infection. Historically, most patients were conditioned for transplant using myeloablative doses of chemotherapy, with or without irradiation, resulting in a period of from nine to 14 days of nearly absolute neutropenia during which there is a high risk of infection. Without an HSCT rescue, the patient would not be expected to recover hematopoiesis. With myeloablation, the kinetics of neutrophil engraftment are influenced primarily by the graft source, dose of CD34+ progenitor cells, use of hematopoietic growth factors, use of post-HSCT GVHD prophylaxis and, to a lesser extent, by the underlying disease [4]. In general, recipients of mobilized peripheral blood stem cell (PBSC) grafts engraft neutrophils and platelets earlier than recipients of bone marrow (BM) [5, 6], a result of the larger dose of CD34+ progenitors in the PBSC graft as well as to the more differentiated status of peripheral progenitors compared to BM. There is a dose-dependent increase in the rate of neutrophil engraftment up to a ccccthreshold number of CD34+ cells (approximately 2.0 × 106/kg) in most studies [7]. Hematopoietic growth factors (primarily granulocyte colony-stimulating factor (G-CSF) and granulo-cyte-macrophage colony-stimulating factor (GM-CSF) have been widely used to enhance the kinetics of neutrophil engraftment [8], but may be associated with a delay in platelet engraftment [4]. Drugs such as methotrexate that are widely used to prevent acute GVHD are marrow suppressive and may further delay neutrophil engraftment even when growth factors are used [9]. Antiviral agents used to prevent or treat vial infections may likewise be myelosuppressive. The patient's primary disease and the extent of pre-transplant therapy may also affect the rate of neutrophil recovery with patients transplanted for aplasia recovering granulocytes more quickly than those transplanted for acute or chronic leukemia [10]. However, even under the most optimal conditions, one can expect from nine to 16 days during which the absolute neutrophil count (ANC) is below 0.5 × 109/L. Once engraftment occurs, the ANC generally rises rapidly to protective levels above 109/L rapidly. With nonmyeloablative stem cell transplant (NST) regimens, the period of neutropenia is considerably shortened or is eliminated, a major factor in the reduced toxicity of these regimens [11].

The ability of the engrafted neutrophils to phagocytize and kill bacteria returns early post-HSCT and neutrophil chemotaxis normalizes by four months unless the patient is experiencing active GVHD or infection [12,14]. Zimmerli, et al. [14] demonstrated that patients who subsequently developed pyogenic infections had poorer neutrophil function than those who did not. In this study, defective skin window migration or combined defects in migration and killing were predictive for late pyogenic infections. Neutrophil migration may be further reduced during infusion of GM-CSF, but normalizes quickly after infusions are stopped [15]. Prophylactic supportive care with antimicrobial agents is of most importance during the engraftment period and for patients with active GVHD.

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