Page 1964 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 114

PRINCIPLES OF NEUTROPHIL (GRANULOCYTE) TRANSFUSIONS

Ronald G. Strauss

Current leukapheresis technology and donor management/ the historical and modern experiences with GTX are reviewed, and
stimulation permit collection of large numbers of several types of the current technology of PMN collection is discussed.
blood leukocytes (e.g., neutrophils, hematopoietic progenitors/
stem cells, and lymphocytes) from either healthy donors (allogeneic
use) or patients (autologous use)—who often are stimulated with THERAPEUTIC GTX FOR NEUTROPENIC INFECTIONS:
recombinant cytokines such as granulocyte colony-stimulating factor HISTORICAL EXPERIENCE
(G-CSF)—to be used for transfusion and transplantation or for
further processing (e.g., ex vivo expansion and genetic manipulation). The historical experience with GTX will be critically reviewed because
Polymorphonuclear neutrophils (PMNs) are granulocytic leukocytes it provides the underpinnings for continued interest in this mode of
that are collected from healthy donors and issued as a standard therapy, despite its lack of universal acceptance over the 40 or so years
blood component (granulocytes, pheresis). This chapter analyzes since publication of the first controlled trials. In the third edition of
the use of neutrophil (i.e., granulocyte) transfusions (GTX) as an this book, 34 papers were reviewed that reported the therapeutic use
adjunct to antimicrobial drugs in the treatment and prevention of of GTX—collected before the advent of G-CSF donor stimulation—
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progressive infections in patients with severe neutropenia or PMN in severely neutropenic patients (<5 × 10 /L blood PMNs), and only
dysfunction. a summary of their findings will be presented here to lay the basis for
Life-threatening infections with bacteria, yeast, or other fungi modern GTX therapy.
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continue to be a consequence of severe neutropenia (<0.5 × 10 /L Results of the historical studies were tabulated (Table 114.1)
blood PMNs), most commonly occurring after intense chemotherapy according to the index infection that prompted GTX therapy. Patients
or hematopoietic progenitor cell (HPC) transplantation, and disor- were counted only once (e.g., patients with septicemia were listed
ders of PMN dysfunction such as chronic granulomatous disease. The only in the septicemia group, even if they had another infection, such
most frequent clinical situation today is neutropenic fever and infec- as pneumonia). As an exception, all patients with invasive fungal
tion following intense chemotherapy or HPC transplantation given infections were counted together because it was impossible to accu-
to treat hematologic malignancies. Neutropenic infections cause rately separate sepsis, pneumonia, sinusitis, and so forth into distinct
considerable morbidity, occasionally are fatal, and add considerable categories. All patients given GTX for a designated type of infection
cost to the management of these patients. However, because of were enumerated in the “Treated” column. The treated patients, those
improved antifungal prophylaxis and therapy immediately following for whom the actual course and mortality of the index infection could
HPC transplantation, severe fungal infections often occur later after be clearly documented, were enumerated again in the “Evaluable”
neutrophil engraftment (i.e., due primarily to long-standing immu- column. GTX therapy was considered successful if so stated by the
nodeficiency, not to severe neutropenia), and neutrophil transfusions authors. Combining data from multiple reports of varying experi-
(GTX), of course, are not warranted during this later time in the mental design, admittedly, is of limited value for drawing firm con-
posttransplant period. Thus the number of patients with severe fungal clusions, and it was done simply to document the surprising breadth
infections, for whom GTX previously were considered, has decreased, of historical reported experience.
further questioning the need in some physicians’ opinions for GTX To obtain more definitive information regarding efficacy of his-
therapy. torical GTX (i.e., collected without G-CSF), the seven controlled
1–7
Previous attempts to prevent infections in severely neutropenic studies were analyzed in more detail. In these seven studies, the
patients by transfusing PMN concentrates (i.e., prophylactic GTX) response of infected neutropenic patients to treatment with GTX
achieved only questionable success. Although rates of certain infec- plus antibiotics (study group) was compared with that of comparable
tions were significantly reduced by prophylactic GTX, many adverse patients given antibiotics alone and evaluated concurrently (control
effects, such as pulmonary infiltrates and cytomegalovirus infections, group). The design, size, and results of these seven studies are pre-
were reported, and GTX were expensive. Thus prophylactic GTX sented in Tables 114.2 and 114.3. Despite the limited donor stimula-
have gained little support over the years. Similarly, use of therapeutic tion and somewhat primitive leukapheresis technology, three of the
4–6
GTX to resolve existing infections has not gained lasting acceptance, seven studies reported a significant overall benefit for GTX. In two
1,3
despite many reports, including randomized clinical trials, docu- additional studies, overall success was not demonstrated for GTX,
menting significant benefit for some patients. This lack of enthusiasm but certain subgroups of patients were found to benefit significantly.
for GTX can be explained by the continuing development of new Thus some measure of success for GTX was evident in five of the
and very effective antimicrobial drugs to prevent and treat infections seven controlled studies. However, this success was counterbalanced
2,7
and by the availability of recombinant hematopoietic growth factors by four studies that were negative in some respect—two totally and
and peripheral blood hematopoietic progenitor cell (PBHPC) two partially negative. 1,3
transfusions—both of which hasten patient recovery from myelotoxic An explanation of these inconsistent results is evident on critical
therapy and, thereby, shorten the period of severe neutropenia and analysis of the adequacy of GTX support (see Table 114.3). Patients
consequent risk of neutropenic infections. in the three successful trials received relatively high doses of PMNs
4–6
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Historically, PMN concentrates were collected for transfusion (generally ≥1.7 × 10 /day). Donors were selected to be both
from unstimulated donors or those stimulated only with corticoste- erythrocyte and leukocyte compatible. By contrast, the four con-
roids, and contained woefully inadequate numbers of PMNs. Cur- trolled studies yielding negative results can legitimately be criticized.
rently, very large numbers of PMNs can be collected from normal Two of the four studies with negative conclusions used PMNs col-
1,3
donors using G-CSF plus corticosteroid (i.e., dexamethasone) marrow lected by filtration leukapheresis for some patients. It is now known
stimulation followed by large-volume leukapheresis, during which that such PMNs are defective, and they are no longer transfused. In
several liters (e.g., 7 L) of donor blood are processed. In this chapter the negative studies using PMNs collected by centrifugation
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