Analysis of Two Types of Granulocyte Transfusions in Patients with Acute Leukemia and Septicemia

Transcription

1 ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 12, No. 2 Copyright 1982, Institute for Clinical Science, Inc. Analysis of Two Types of Granulocyte Transfusions in Patients with Acute Leukemia and Septicemia EDWARD E. MORSE, M.D.,* E. SNYDER,f N. BLUMBERG,* and ALFRED J. KATZ, M.D. *University o f Connecticut School o f Medicine and Connecticut Red Cross Blood Services, Farmington, CT \Blood Bank, Yale University School o f Medicine, New Haven, CT \Blood Bank, University o f Rochester School of Medicine, Rochester, NY American Red Cross Blood Services, Washington, DC ABSTRACT In a study of over 300 patient episodes where filtration granulocytes or centrifuged granulocytes were transfused to neutropenic patients with fever, 81 cases of culture proven septicemia in patients with acute leukemia were analyzed. Age, sex, organisms, interval betw een fever and transfusion, average num ber of transfusion, and antibiotics were similar in the two groups. Centrifuged granulocytes produced a statistically significantly better recovery rate when compared with filtration granulocytes. Introduction tion. Those that have been done suggest no difference in the effectiveness of Granulocyte transfusions, given under the two types of preparations.1,13,16,18 Although large doses of granulocytes can be appropriate guidelines, have been shown to be effective, supportive therapy for obtained by filtration, the cells often appear damaged and vacuolated1,10,15,17,24 neutropenic patients whose bone marrow is unable to produce granulocytes normally.2,4 8 11,12 13'21 Clinical effectiveness obtained by centrifugation.10 and do not circulate as effectively as those has been most satisfactorily demonstrated The present report is a retrospective in animal experiments3,6,7 and in patients study of a group of patients with acute with septicemia.2,8,11,12 Few comparison leukemia and docum ented septicemia studies have been made betw een the two taken from a larger series of patients randomly assigned one or the other type of major types of granulocyte transfusions prepared by centrifugation or by filtra transfusion. The patients all had granulo /82/ $00.90 Institute for Clinical Science, Inc.

2 GRANULOCYTE TRANSFUSIONS IN LEUKEMIA AND SEPTICEM IA 1 07 cytopenia less than 500 per cumm5 owing to disease in the marrow or as a result of chemotherapy. These patients received granulocyte transfusions prepared either by continuous flow filtration* or by intermittent flow centrifugation, f but not both. Methods Through a cooperative program between the Connecticut Division of the American Red Cross Blood Services, the University of Connecticut, Yale University, and the hospitals and hematologists of the State, two types of granulocyte transfusions have been provided to patients, as previously described.18 The patients were selected because they had marrow hypoplasia, neutropenia with absolute granulocyte count of less than 500 per cumm,5 fever unresponsive to antibiotics, and a reasonable likelihood of recovery. In a three year period, over 300 patient episodes were treated with either centrifuged granulocytes obtained by interm ittent flow centrifugation using hydroxyethyl starch as segm enting agent or by granulocytes obtained by continuous flow filtration and heparin anticoagulant, but not both. Donors were pretreated with prednisone or dexamethasone. The type of granulocyte used was determ ined at random in the Blood Center. An attempt was made to give at least four daily transfusions, each containing approximately 1 x 1010 granulocytes, as previously published.18 Transfusions were given, in fact, until a patient died or recovered. Outcome was determ ined by almost daily telephone contact with the hospitals. In an effort to determine the effectiveness of these two types of granulocytes in a severely ill population, an analysis was carried out on patients with acute leukemia and culture proven septicemia. Accurate clinical information was * Fenwal Laboratories, Morton Grove, IL. f Haemonetics Model 30 Cell Separator, Haemonetics Corp., Braintree, MAobtained by direct contact with each patient s physician, and positive blood cultures were documented by direct review of laboratory records. Eight-one episodes were selected because the patient criteria were met, and the patients had received at least three daily transfusions or 75 percent of the planned transfusion program. Three other patients with culture proven septicemia were not included because they received only one or two transfusions. Statistical analyses were made by computer using Chi square (X2) determination or non-paired t test.20 Results Organisms grown from the blood of these patients are shown in table I. Twenty-three episodes involved gram positive cocci, 55 involved gram negative rods, and three involved fungi (Candida albicans). There was no statistically significant distribution of organisms between the two types of transfusions, although there were more gram positive organisms found in patients receiving centrifuged granulocytes. Gram negative organisms were equally distributed between the two types of transfusions. There were a few more Escherichia coli in patients receiving filtration cells and a few more Klebsiella in patients receiving centrifuged granulocytes. TABLE I Organisms in Blood C ultures Centrifuga ti on Filtrations Gram postive Staphylococci 12 4 Streptococci Gram negative E. coli 8 13 Klebsiella 13 7 Other 8 6 (Aeromonas, serratia proteus, pseudomonas) Fungi Candida 0 3

3 1 08 M ORSE, SNYDER, BLUM BERG, AND KATZ Three patients, all of whom received filtration granulocytes, were found to have Candida albicans septicemia. Initial antibiotic therapy was similar, in that virtually all patients received carbenicillin and gentamycin, and many received cephalothin as well. If organisms grown showed other antibiotic sensitivities, those antibiotics were also employed. The characteristics of the patients are summarized in table II. There were 45 patients who received centrifuged granulocytes and 36 who received filtration granulocytes. There were no statistically significant differences in age or sex distribution, although more females received centrifuged granulocytes. The mean interval between onset of fever and the beginning of transfusion therapy was similar in each group. The average num ber of transfusions actually given was the same in each group. The recovery from infection, as judged by defervescence, was significantly better by statistics in patients receiving centrifuged granulocytes (p < 0.05). Even if the three episodes involving fungi are eliminated from consideration, the data show a statistically significant advantage for the centrifuged granulocytes. Separate analysis of gram negative and gram positive Transfusion T A B L E II Characteristics of Patients Centrifugation Filtration Statistics Number of patients Age (range) 41 ± 21 yrs 46 ± 19 yrs NS tt) Sex F/M 26/19 14/22 NS (X2) Interval 6 ± 8 days 5 ± 6 days NS (t) (fever-*- transfusion Number of transfusions 8 ± 7 NS (t) Organisms 16/29/0 7/26/3 NS (X2) gram pos/neg/ fungi Outcome recovered/ failed +i CO <0 32/13 16/ (x2) P < 0.05 septicemias show similar trends which fail to reach statistical significance at the 0.05 level. Seventeen of 29 patients (59 percent) with gram negative septicemia receiving centrifuged granulocytes recovered, but only 11 of 26 (42 percent) of those receiving filtration granulocytes recovered. Fifteen of 16 patients (94 percent) with gram positive septicemia receiving centrifuged granulocytes recovered, while only four of seven (57 percent) receiving filtration cells recovered. Discussion As with any study in which a group of patients is subsequently selected for analysis, there is the possibility that factors not considered or m easured during the course of the treatment, may play a role in the outcome. Thus, interpretation of the data obtained must be cautious. In the present study, however, patients were initially selected randomly to receive centrifuged or filtration granulocytes on the basis of fever and neutropenia. Proof of septicemia by positive blood culture often took several days to, in most instances, a week and, therefore, was not part of the randomization process. Nevertheless, there is a reasonably good distribution of patient episodes between the two types of transfusions, the patient characteristics are similar, and the only statistically significant observation is the recovery rate. In the present study, the data are suggestive that granulocytes produced by centrifugation are more effective in determining the recovery of patients with acute leukemia from an episode of culture proven septicemia. This suggestion deserves further investigation. Our own previous study18 of treatm ent of a variety of infections in a large group of patients with different hematological diseases showed no difference in recovery between patients receiving centrifuged granulocytes and those receiving filtration granulocytes. In that

4 GRANULOCYTE TRANSFUSIONS IN LEUKEMIA AND SEPTICEM IA study, however, the large number of patients with diseases not directly affecting the bone marrow and with infections other than septicemia may have obscured the potentially real differences between the two types of granulocyte preparations. Çeveral studies of serious infection in patients with acute leukemia have failed to show any difference in response rate when centrifuged granulocytes are compared with filtration granulocytes,1,12*16 but the numbers of patients have been fewer than those in the present study. On the other hand, Appelbaum and Diesseroth3 have demonstrated in rats that Pseudomonas septicemia is more controllable when centrifuged granulocytes are infused than w hen filtration granulocytes aré infused, and twice the dose of filtration granulocytes must be used to achieve the same effect in animals. These observations are in keeping with in vitro function studies comparing these two types of granulocyte preparations,10,14,17 24 Recent reviews of granulocyte transfusion13,19 have emphasized their costs and thé relative lack of evidence of efficacy except in patients with septicemia. In addition, severe reactions sometimes accompany the transfusion of granulocytes,9,22,23 some of which can be lethal.25 It seems important, then, to use this mode of therapy with good indication as well as good intentions and to consider cost, efficacy, and toxicity in the decision making process. The data presented here suggest that further development of centrifugation or sedimentation techniques is the wise course of action to produce larger doses of undamaged granulocytes for treatm ent of patients with septicemia. References 1. A i s n e r, J., S c h i f f e r, C. A., and W ie r n i k, P. H.: Granulocyte transfusions: evaluation offactors influencing results and a comparison of filtration and interm ittent centrifugation leukapheresis. Brit. J. Haemat. 38: , A l a vi, J. B., R o o t, R. K., D j e r a s s i, I., e t a l : Leukocyte transfusions in acute leukemia. New Eng. J. Med. 296: , A p p e lb a u m, R. F., B o w l e s, C. A., M a k u c h, R. W., and DlESSEROTH, A. B.: Granulocyte transfusion therapy of experimental pseudomonas septicemia: Study of cell dose and collection technique. Blood 52:323, B e n b u n a n, M., e t a l : Granulocyte transfusions an established or still an experimental therapeutic procedure? International Forum. Vox Sang. 38:40-56, B o d e y, G., B u c k l e y, M., S a t h e r, Y. S., and FREIREICH, E. J.: Quantitative relationship between circulating leukocytes and infection in patients with acute leukemia. Ann. Int. Med. 64: , D e b e l a k, K. M., E p s t e i n, R. B., and A n d e r s o n, B. R.: Granulocyte transfusion therapy in neutropenic dogs. In vivo and in vitro function of granulocytes obtained by continuous flow filtration leukapheresis. Blood 43: , E p s t e i n, R. B., W a x m a n, F. J., B e n n e t, B. T., and ANDERSON, B. R.: Pseudomonas septicemia in neutropenic dogs. I. Treatment with granulocyte transfusions. Transfusion 14:51-57, G r a w, R. G., H e r z i g, G., P e r r y, S., and H e n d e r s o n, E. S.: Normal granulocyte transfusion therapy: Treatment of septicemia due to gram negative bacteria. New Eng. J. Med. 287: , Herzig, G. P.: Leukocyte donor and recipient reactions with filtration leukapheresis: Their character, frequency and management. Exp. Hematol. 7 (Suppl 4):31-35, H e r z i g, G. P., B u l l, M. I., L o h r m a n n, H. P., H e r z i g, R. H., D e c t e r, J. A., and G r a w, R. G.: Impaired transfusion response to granulocytes collected by filtration leukapheresis. Leucocytes: Separation, Collection and Transfusion. Goldman, J. M. and Lowenthal, R. M., eds. London, Academic Press, 1975, pp H e r z i g, R., H e r z i g, G., G r a w, R. G., B u l l, M. I., and R a y, K. K.: Efficacy of granulocyte transfusion therapy for gram negative sepsis: A prospectively randomized controlled study. New Eng. J. Med. 296: , Higby, D. J.: Controlled perspective studies of granulocyte transfusion therapy. Exp. Hematol. 5 (Suppl l):57-64, H ig b y, D. J. and B u r n e t t, D.: Granulocyte transfusions: Current status. Blood 55:2-8, H ig b y, D. J., S a l v a t o r i, V., B u r n e t t, D., and P a r k, B. H.: Improvement in the quality of granulocytes obtained by filtration leukapheresis. Exp. Hematol. 7 (Suppl 4):36-41, H ig b y, D. J., Y a t e s, J., H e n d e r s o n, E. S., and H o l l a n d, J. F.: Filtration leukapheresis for granulocyte transfusion therapy. New Eng. J. Med. 292: , M c C u l l o u g h, J., W e i b l e n, J., D e i n a r d, A. R., B o e n, J., F o r t u n y, I. E., and Q u ie, P. G.:In vitro function and posttransfusion survival of

5 110 M ORSE, SNYDER, BLUM BERG, AND KATZ granulocytes collected by continuous flow centrifugation and by filtration leukapheresis. Blood 48: , MORSE, E. E. and K atz, A. J.: Clinical effectiveness of granulocyte transfusions. Conn. Med. 43: , M o r s e, E. E., K a t z, A. J., B u c h h o l z, D. H., and Houx, J.: Clinical effectiveness of transfusion of granulocytes obtained by filtration or interm ittent flow centrifugation. Cancer 47: , R o s e n s h e i n, M. S., F a r e w e l l, V. T., P r i c e, T. H., L a r s o n, E. B., and D a l e, D. C.: The cost effectiveness of therapeutic and prophylactic leukocyte transfusion. New Eng. J. Med. 302: , S n e d e c o r, G. W. and C o c h r a n, W. G.: Statistical Methods, 6th ed. Ames, IA, Iowa State University Press, VOGLER, W. R. and W ln TO N, E. F.: The efficacy of granulocyte transfusions in neutropenic patients. Amer. J. Med. 63: , WARD, H. N.: Pulmonary infiltrates associated with leukoagglutinin transfusion reaction. Ann. Int. Med. 73: , W il t b a n k, T. B., N u s b a c h e r, J., H i g b y, D. J., and M a c P h e r SON, J. L.: Abdominal pain in donors during filtration leukapheresis. Transfusion 27: , W r i g h t, D. G., K a u f f m a n, J. C., C h u s i d, M. J., H e r z i g, G. P., and G a l l i n, J. I.: Functional abnormalities of human neutrophils collected by continuous flow filtration leukapheresis. Blood 46: , W r i g h t, D. G., R o b i c h a u d, K. J., Pizzo, P. A., and D lesse R O T H, A. B.: Lethal pulmonary reactions associated with the combined use of Amphotericin B and leukocyte transfusions. New Eng. J. Med. 304: , 1981.