Page 1967 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 114 Principles of Neutrophil (Granulocyte) Transfusions 1741

who were pretransplantation recipients. PMNs were collected from dictated for each arm) were nearly identical (p > .99) with 42% in
donors stimulated with G-CSF and dexamethasone. Although donors the GTX arm versus 43% of controls having a favorable response.
were selected without regard for leukocyte compatibility, recipients Similarly, by per-protocol analysis (i.e., only patients actually treated
were documented not to exhibit evidence of leukocyte alloimmuniza- as intended), results were not different (p = .64), with 49% favorable
tion at study entry. Bacterial infections responded well, and yeast in the GTX arm versus 41% of controls. No differences in success
infections responded modestly. Despite very high PMN doses, success rates were noted when subsets of subjects were analyzed per specific
for other invasive fungal infections was dismal. type of infection (i.e., bacteremia, fungemia, invasive/tissue bacterial
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Hubel et al expanded the study of Price et al to a total of 74 infections, or invasive/tissue fungal infections).
patients (see Table 114.5) with HPC transplants. Controls were 74 Although results appeared to be “negative” (i.e., no advantage for
historical patients not given GTX. Donors were either family GTX), 32% of patients in the GTX arm received less than the
members or unrelated individuals stimulated with G-CSF with or intended dose of PMNs/granulocytes. When patients actually given
without dexamethasone. Comparative favorable responses varied with the intended “high-dose” GTX were compared with those given the
family versus unrelated donors but were approximately 70% for unintended lower doses of GTX, the “high-dose” GTX patients had
bacterial, 50% for yeast, and 20% for other fungal infections, values significantly higher success rates (p = .01). Specifically the success rate
similar to the historical control patients not given GTX. was 58% for 26 patients given at least three GTX with an average
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The report of Safdar et al did not lend itself to presentation in dose per transfusion of at least 5 × 10 compared with 11% success
Table 114.5 because many aspects of the patients and their infections for 9 patients receiving lower leukocyte doses.
are quite heterogeneous. The study was a case-control retrospective The reasons for the poor PMN/granulocyte doses given in the
analysis of 491 cancer patients with candidemia—29 given GTX and RING trial could not be determined, but the findings suggest that
462 not. Donors were stimulated with G-CSF plus dexamethasone, the potential benefits of high-dose GTX still remain a possibility,
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and GTX were given either daily or on alternate days. Not all patients provided high-dose GTX (at least 4 × 10 neutrophils per transfu-
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were evaluable, but unexpectedly only 35% of patients given GTX sion) are actually given. The findings also demonstrate that the
resolved their infections versus 67% of those not given GTX (p < collection of quality neutrophil/granulocyte concentrates requires
.001). expertise and careful quality assessment to consistently provide a
No firm conclusions can be drawn from these somewhat anecdotal product with any hope of benefit.
and very heterogeneous reports of modern therapeutic GTX, but on As a case in point, in a retrospective review of patients with
the basis of these preliminary findings, bacterial infections appeared invasive Fusarium infections, 11 patients with severe neutropenia and
to respond well to modern GTX, relatively mild yeast and other failure to respond to antifungal drugs received a median of seven
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fungal infections responded modestly well, whereas, serious and/or GTX containing a mean of 6.84 × 10 granulocytes per GTX. Ten
invasive fungal infections with tissue damage often resisted even the of eleven patients (91%) had a favorable response, compared with an
large doses of PMNs transfused with modern GTX. 15–17 Accordingly expected response of <50% when antifungal drugs are given without
the precise role of modern therapeutic GTX, collected from donors GTX. Over 98% of donors were unrelated community donors who
stimulated with G-CSF plus corticosteroids, was addressed by two were given 480 µg G-CSF subcutaneously plus 8 mg dexamethasone
randomized clinical trials. orally, 12–18 hours and 12 hours before leukapheresis, respectively.
As background for judging the quality and recognizing the short- Seven liters of donor blood were processed by continuous-flow leu-
comings of the randomized trials, modern therapeutic GTX is defined kapheresis using 500 mL of 6% hetastarch and anticoagulated with
as PMNs collected from donors stimulated with G-CSF, preferably 30 mL of 46.7% trisodium citrate at a hetastarch to donor blood
combined with dexamethasone, by means of centrifugation leuka- ratio of 1 : 12 throughout the procedure.
pheresis using an erythrocyte-sedimenting agent, while processing Conclusions regarding the role of modern therapeutic GTX at this
large volumes of donor blood. An ideal PMN collection should time are as follows. The use of G-CSF plus dexamethasone to stimu-
include: (1) 300–480 µg G-CSF given subcutaneously plus 8 mg late PMN donors has brought GTX therapy into a new era, as it is
dexamethasone given orally to the donor approximately 12 hours now possible to collect relatively large numbers of PMNs (granulo-
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before leukapheresis begins; (2) hetastarch plus concentrated citrate cytes) (>4 × 10 ). However, definitive quality data to provide firm
infused throughout the entire leukapheresis procedure at a ratio of 1 guidelines for clinical practice remain elusive. Randomized clinical
part hetastarch to 12 to 14 parts donor blood; and (3) processing of trials have proven extremely difficult to complete because of poor
8 to 10 L of donor blood. The goal should be to transfuse 6 to 8 × and/or slow patient enrollment and the lack of dependable neutrophil/
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10 neutrophils per GTX, with a lower limit of 4 × 10 . granulocyte leukapheresis products. There are strong hints that
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Two randomized clinical trials have been reported, but both have transfusing >4 × 10 neutrophils/granulocytes daily to severely
shortcomings or flaws that preclude firm guidelines for clinical neutropenic infected patients may be beneficial and, despite lack of
practice. The first published randomized clinical trial of modern definitive proof of efficacy, should be considered in clinical settings
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GTX provided no definitive guidelines for transfusion practices where severely neutropenic patients suffer significant morbidity and/
because of problems including: (1) lack of completion due to poor or mortality from infections.
enrollment; (2) donors stimulated only with G-CSF and not dexa-
methasone resulting in relatively low PMN doses for individual GTX;
and (3) GTX were given every other day, not daily, resulting in low THERAPEUTIC GTX IN INFANTS AND CHILDREN
PMN doses for the overall course of GTX. Thus the trial failed to
test efficacy of modern “high-dose” GTX. 21 Children with severe neutropenia due to marrow failure during
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The second and most recent randomized clinical trial (RING), chemotherapy or HPC transplantation suffer infections similar to
like the first trial, was stopped before completion due to slow enroll- those of adult patients, and the principles for therapeutic GTX are
ment and, accordingly, failed to provide definitive guidelines for comparable to those discussed in the previous section. Accordingly,
clinical practice. RING is a multicenter (14 clinical sites in the United they will not be reiterated other than to note that GTX, generally,
States) randomized clinical trial in which 114 infected neutropenic are transfused infrequently with doses of PMNs/granulocytes
(<500 neutrophils/µL blood) patients were randomly allocated to decreased commensurate with smaller body size. Alternatively, it may
treatment either with daily GTX collected from donors stimulated be wise to transfuse an entire standard leukapheresis collection to
with G-CSF plus dexamethasone plus antibiotics (n = 56) or with provide very high doses of PMNs, assuming the overall condition of
antibiotics alone (n = 58). The primary endpoint was composite, the patient permits the large volume of the GTX.
consisting of survival at 42 days after randomization plus a favorable An indication for GTX is severe infection occurring in children
microbial response determined by a blinded adjudication panel. with congenital disorders of PMN dysfunction, who have adequate
Results by intention-to-treat analysis (i.e., all subjects enrolled into numbers of blood PMNs, but are susceptible to serious infection
the two arms, regardless of whether or not they received the therapy because their PMNs fail to kill pathogenic microorganisms. Patients