LEUKOREDUCTION: the techniques used, their effectiveness and costs. Canadian Coordinating Office for Health Technology Assessment

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1 Canadian Coordinating Office for Health Technology Assessment LEUKOREDUCTION: the techniques used, their effectiveness and costs CCOHTA Report 1998: 6E

2 Cite as: Canadian Coordinating Office for Health Technology Assessment. Leukoreduction: the techniques used, their effectiveness and costs. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. Legal Deposit National Library of Canada ISBN

3 Canadian Coordinating Office for Health Technology Assessment LEUKOREDUCTION: the techniques used, their effectiveness and costs Bernhard Gibis, MD, CCOHTA Research Fellow Jean-François Baladi, MBA February 1998 This report was commissioned by the Canadian Blood Agency. The opinions and conclusions reached, however, are those of CCOHTA.

4 The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization, funded by the federal, provincial and territorial governments. It was established to encourage the appropriate use of health technology by influencing decision-makers through the scientific evaluation of medical procedures, devices and drugs. The effectiveness and cost of technology and its impact on health are examined. Additional copies of Leukoreduction: the techniques used, their effectiveness and costs are available from CCOHTA. Vous pouvez aussi vous procurer la version française, La réduction leucocytaire : les techniques, leur efficacité et les coûts, à l OCCÉTS. To obtain copies of publications please contact: CCOHTA Publications Green Valley Crescent Ottawa, Ontario, Canada K2C 3V4 Telephone (613) Facsimile (613) pubs@ccohta.ca or download full text from

5 REVIEWERS Dr. Walter Dzik, MD Director, Transfusion Medicine Harvard Medical School Boston, USA Dr. Sherill Slichter, MD Director, Division of Research and Education Puget Sound Blood Centre Seattle, USA Dr. Georges Andreu, MD Établissement de transfusion sanguine de l Assistance publique, Hôpitaux de Paris Paris, France Dr. Andreas Laupacis Chair, CCOHTA Scientific Advisory Panel Director, Clinical Epidemiology Unit Ottawa Civic Hospital Ottawa, Ontario Dr. Bernie O Brien CCOHTA Scientific Advisory Panel subcommittee member Associate Professor, McMaster University Centre for Evaluation of Medicines, St. Joseph s Hospital Hamilton, Ontario Dr. Murray Krahn CCOHTA Scientific Advisory Panel subcommittee member Toronto Hospital Toronto, Ontario This report was reviewed by external reviewers and by members of a subcommittee of CCOHTA s Scientific Advisory Panel. These individuals kindly provided comments on drafts of this report. This final document incorporates most of the reviewers comments; however CCOHTA takes sole responsibility for its form and content. ACKNOWLEDGEMENTS CCOHTA would like to thank the Scientific Advisory Committee and staff members of the Canadian Blood Agency for their valuable input. i

6 EXECUTIVE SUMMARY Leukocytes, as part of transfusions, can cause a variety of side-effects such as febrile reactions, platelet refractoriness, and transmission of viruses like the cytomegalovirus. In addition, transfused leukocytes may suppress the recipient s immune response thereby increasing the risk of infection or malignancy. Therefore, reduction of leukocytes in blood and platelet transfusions may potentially reduce the frequency of these adverse events and save costs. Currently, third generation adhesion filters exist which can achieve a three log reduction of the original leukocyte load. This study examines the efficacy of various filtration techniques and compares their costs and their potential savings. More specifically, it compares the efficacy of various filtration techniques in reducing the leukocyte load of transfused blood components (apheresis platelets, pooled platelets and red blood cells), their cost, as well as the savings associated with a reduction in treating the adverse events related to transfused leukocytes. Adverse events examined include febrile reactions, platelet refractoriness following alloimmunization and immunomodulation. The efficacy of leukoreduction in reducing these adverse events was obtained from an extensive literature search of published literature complemented with a number of interviews with Canadian stakeholders. Level of evidence was assessed and is indicated throughout the report. Canadian resource use and cost estimates were obtained from a number of Canadian sources. A retrospective analysis of patient charts was conducted for estimating the cost of treating febrile reaction. The cost of platelet-refractoriness due to allo-immunization was estimated by a panel of experts. The cost of immunomodulation was estimated by assuming that immunomodulation increases the likelihood of surgical site infections. The use of blood products was based on the annual Red Cross statistical report and data obtained from the CBA. The analysis is conducted from the perspective of the Canadian health care and blood transfusion systems. The efficacy of leukofiltrating three blood components (apheresis platelets, pooled platelets and red blood cells) was examined at three possible stages: in a regional blood centre before storage of the blood component, in a hospital blood bank following storage and prior to delivering it to the requesting ward, and at a patient s bedside just before the transfusion. Thus, nine filtration techniques are assessed, each one having its own clinical efficacy and its cost. Clinical Efficacy Non Hemolytic Febrile Transfusion Reactions: non Hemolytic Febrile Transfusion Reactions (NHFTR) are the most common leukocyte-related adverse effects of blood transfusions. Pre- or post-storage filtered transfusions prevent most febrile reactions to red blood cell transfusions and in this respect, the advantage of pre-storage filtration has not been proven in a randomized controlled trial. However, platelet transfusions are associated with a higher rate of adverse events, and post-storage filtration of platelets is not as effective as post-storage filtration of red blood cells. In the case of platelets, pre-storage filtration offers the advantage of preventing the production of some leukocyte mediated cytokines during the storage period. ii

7 Infections: the risk of transmission of leukocyte born viruses such as the cytomegalovirus (CMV) via transfusion of red blood cells and platelets is markedly decreased by leukofiltration. Consequently, leukofiltration is increasingly accepted as an alternative to CMV screening of blood components. However, for other viral or bacterial/protozoal infections, we found no evidence that leukofiltration is an alternative to existing screening programs. Thus, apart from CMV, the impact of leukofiltration on the prevention of transfusion-related infections remains unknown. Platelet-refractoriness: To prevent thrombocytopenic bleeding due to high dose chemotherapy, prophylactic platelet transfusions are usually given. The ability of these transfusions to increase the platelet count can be inhibited if the recipient has an immune response due to prior HLAalloimmunization to donor blood components, mainly leukocytes. Leukofiltration reduces the incidence of alloimmunization and therefore platelet refractoriness particularly in desensitized patients. However, despite several experimental and retrospective studies, no randomized controlled trial exists that has demonstrated an advantage of pre- over post-storage filtration. Immunomodulation: an immunomodulatory effect of blood transfusions in humans is still controversial. A recent meta-analysis of unconfounded randomized controlled trials concluded that any possible effect would be smaller than 25% (relative risk reduction of postoperative infection, cancer recurrence after surgery). At present, there is no evidence from clinical trials that the timing of filtration influences immunomodulation. Cost Comparison The cost of each of the nine filtration techniques was assessed in both single and multitransfused patients. This cost included the cost of filters, the cost of related activities such as inventory management and overhead costs and the cost of treating adverse reactions. The cost of treating adverse events is itself dependent on the number of transfusions, the efficacy of the leukoreduction technique and the cost of treating the particular adverse reaction. We then calculated the cost impact for three main strategies, the first being filtering all blood components in a blood centre, the second, filtering all components in a hospital blood bank, and the third, filtering all blood components at the patient bedside. This analysis focused on the costs associated with filtration and does not take into account the cost of producing different blood components. Thus the cost of one apheresis platelet cannot be compared directly with the cost of one pooled platelet. In addition, health-related-quality-of-life under different techniques were not examined. Costs are presented in 1997 Canadian dollars and have been estimated from the perspective of the health care system. For the purpose of the cost comparison, the benefit of the doubt was given to pre-storage filtration. A higher efficacy for pre-storage was used than for post-storage filtration in reducing adverse events although this has not been proven in randomized controlled trials. It was assumed that leukofiltration can prevent alloimmunization and thus platelet refractoriness in a certain percentage of patients at risk. Febrile reactions were assumed to occur more frequently in multitransfused patients than single-episode transfused patients. iii

8 This analysis revealed that the implementation of a 100% filtration strategy in a blood centre would cost $46.37 million and takes into account the savings resulting from a decrease in adverse events. Filtration at a hospital blood bank would cost $25.95 million, and at a hospital bedside, this cost would total $20.19 million. The much higher cost of pre-storage leukofiltration is mainly due to two factors that are specific to pre-storage filtration. Firstly, with pooled platelets, five filters have to be used instead of a single one for the production of one platelet concentrate. Also, since more blood components are produced than actually transfused to patients, 30% more pooled platelet concentrates have to be filtered in a blood centre level compared to hospital filtration. An examination of the cost of each filtration technique reveals that the impact of red blood cell filtration drives the overall cost of strategies. When looking at apheresis platelets in isolation, leukofiltration is cost saving regardless of the timing of leukofiltration. For pooled platelets, the case is different. Post-storage blood bank or bedside techniques are cost saving compared to pre-storage filtration. The fact that savings can be achieved with platelet transfusions is not surprising since around 70% of all platelet components are directed at multi-transfused patients. This is the patient group who benefit most from leukofiltration. On the other hand, 90% of all red blood cells are directed at single-transfused patients such as surgical or obstetric patients. This patient group does not benefit as much from leukofiltration, and as a result the savings achieved by filtration do not outweigh its costs. Since the impact of an immunomodulatory effect of transfused leukocytes is now not known the results could change if this effect is better understood. An extensive sensitivity analysis was performed and it showed that these results were robust. It can be concluded that a 100% filtration strategy is not cost-saving, whatever the timing of leukofiltration. However, for certain patient groups, notably those who require either frequent red blood cell or platelet transfusions, leukofiltration can be cost saving. iv

9 TABLE OF CONTENTS Reviewers... Acknowledgements... i i Executive summary... ii List of tables... vii List of figures... viii 1. Introduction Brief history of leukodepletion, the purpose of leukodepletion and the methods used Literature search The current situation Blood distribution Present users Current filtration activities in Canada International filter use Clinical issues associated with filtration and level of evidence for the efficacy of leukodepletion Non-hemolytic febrile transfusion reactions Leukocyte-transmitted infections Platelet-refractoriness Immunomodulation Filtration techniques Description of filtration techniques, stages of processing Filtration standards Cost-comparison analysis Methods Probabilities, unit costs and epidemiological assumptions Probabilities of adverse events Unit costs Epidemiological and transfusion assumptions Results Base case results Sensitivity analysis Threshold analysis Quality of life issues Financing considerations...44 v

10 6. Discussion Conclusion...50 References...51 Additional references...61 Appendices Appendix I Level of evidence scale...65 Appendix II Glossary...66 Appendix III Costing study on NHFTR...67 Appendix IV Sensitivity analysis...69 Appendix V Framework for categorizing economic study results Adopted from O Brien et al...79 vi

11 LIST OF TABLES Table 1 Expected blood components use for 1997/ Table 2 Distribution of platelet concentrates among patient groups...4 Table 3 Incidence of non-hemolytic febrile transfusion reactions (per transfusions, excluding allergic and other reactions)...9 Table 4 Platelet refractoriness in multi-transfused patients...14 Table 5 Leukocyte content of blood and blood components per transfused unit...16 Table 6 Considerations in the selection of timing of leukodepletion (adapted from Dzik)...22 Table 7 FDA recommendations and licensure requirements...23 Table 8 Council of Europe recommendation No. R(95)15 on the preparation, use and quality assurance of blood components...24 Table 9 Probabilities associated with developing NHFTR...29 Table 10 Probability of developing surgical site infection after surgery...30 Table 11 Probabilities associated with the development of platelet refractoriness...30 Table 12 Platelet filter unit prices...31 Table 13 Red blood cell filter unit prices...31 Table 14 Unit cost of related activities...32 Table 15 Cost of treating NHFTR...33 Table 16 Cost of treating refractoriness associated with allo-immunization...33 Table 17 Cost of treating surgical site infection...34 Table 18 Total number of blood units filtered and transfused per year...35 Table 19 Distribution of red blood cells among patient categories...35 Table 20 Distribution of blood components among patient categories...35 Table 21 Distribution of red blood cells among patient categories...35 Table 22 Number of transfusions per patient category...36 Table 23 Range for sensitivity analysis...36 Table 24 Filter and related costs of each strategy, in $ Table 25 Filter and related costs of each technique, in $ Table 26 Total cost of each strategy, in $ Table 27 Total cost of each technique, in $ Table 28 Number of adverse events avoided with each technique in Canada...39 Table 29 Cost per transfusion in dollars...40 Table 30 Budgetary impact of strategies with immunomodulation factor, in $ Table 31 Sensitivity analysis results...42 Table 32 Threshold analysis for filter prices...43 Table 33 Level of evidence scale...65 Table 34 Transfusions for leukemia and non-leukemia patients, , Ottawa General Hospital...67 Table 35 Costs of febrile reactions...68 Table 36 Sensitivity analysis: Costs per technique in $000, where NHFTR following pre-storage filtration equals 0% (all febrile reactions are avoided by pre-storage filtration)...69 Table 37 Costs per strategy in $ vii

12 Table 38 Sensitivity analysis: Costs per technique in $000, where NHFTR following pre-storage filtration is equal to that of blood bank filtration (no advantage of pre- over post-storage filtration)...70 Table 39 Costs per strategy in $ Table 40 Sensitivity analysis: Costs per technique in $000, where the number of platelet transfusions per multi-transfused patient equals 20 (this translates into that 3810 patients are at risk for suffering platelet refractoriness per year)...71 Table 41 Costs per strategy in $ Table 42 Sensitivity analysis: Costs per technique in $000, where the number of platelet transfusions per multi-transfused patient equals 50 (this translates into that 1524 patients are at risk for suffering platelet refractoriness per year)...72 Table 43 Costs per strategy in $ Table 44 Sensitivity analysis: Costs per technique in $000 where the cost of treating one episode of NHFTR is $ Table 45 Costs per strategy in $ Table 46 Sensitivity analysis: Costs per technique in $000 where the cost of treating platelet refractoriness is $5, Table 47 Costs per strategy in $ Table 48 Sensitivity analysis: Costs per technique in $000 where the cost of treating platelet refractoriness is $15, Table 49 Costs per strategy in $ Table 50 Sensitivity analysis: Costs per technique in $000 where the number of filters used for pre-storage filtration is equal to the actual number of transfused blood components...76 Table 51 Costs per strategy in $ Table 52 Sensitivity analysis: Costs per technique in $000 where one single filter is used for pre-storage pooled platelet production instead of five...77 Table 53 Costs per strategy in $ Table 54 Sensitivity analysis: Costs per technique in $000 where the utilization rate of pre-storage filtered platelet units is 70%...78 Table 55 Costs per strategy in $ LIST OF FIGURES Figure 1 Stages (used in the cost-comparison analysis), where leukofiltration of blood components is possible...17 Figure 2 Strategies used for cost comparison analysis...25 viii

13 1. INTRODUCTION 1.1 Brief history of leukodepletion, the purpose of leukodepletion and the methods used The introduction of transfusions as a medical technology has been associated with both beneficial effects and adverse reactions. Some of these adverse reactions are caused by donor leukocytes, which are residual blood cells in platelet or red blood cell transfusions. Leukocytes with their specific allogeneic structure (exposing the HLA Antigens class I and II on their surface) are main targets of the recipient s immune system. During or shortly after transfusion, some patients become febrile in response to leukocytes in the blood component. Repeated exposure to donor leukocytes can create an immune response which inactivates donor platelets. The state of refractoriness diminishes the effect of platelet transfusions - in spite of transfusing platelets, no therapeutic platelet increment is achieved. In addition, some viruses or bacteria are transmitted inside leukocytes. The cytomegalovirus (CMV), for example, survives in the leukocyte and is transmitted via blood transfusions. Another not so well established effect of transfused leukocytes is a modulating influence on the recipient s immune system. Leukocytes are believed to diminish the ability of the recipient s immune system to fight infection or cancer recurrence. In an attempt to prevent these problems, methods have been developed to remove transfused leukocytes ( unwanted passengers ). Filters were designed which are able to filter out 99.9% of all leukocytes, and as a result, leukocyte mediated adverse reactions can be prevented or delayed. However, this technology is not without cost and it is competing with other technologies which reduce the use of allogeneic blood components (for example erythropoetin or autologous blood donations) 1. The cost and clinical benefit of leukocyte filtration must be weighed against the costs saved by the avoidance of adverse events. Ideally, the costs saved by using the technology will be more than the cost of the technology itself. The aim of this report is to help identify the costs involved with and without filtration, to explore whether it is costly or cost saving to the Canadian health care system to introduce leukodepletion of blood components, and to compare these costs with the benefits involved. 1.2 Literature search The literature search was divided into three main topics: leucocyte depletion of blood transfusion and associated adverse events leucocyte depletion of platelet transfusion and associated adverse events costs associated with leukocyte depletion Canadian Coordinating Office for Health Technology Assessment 1

14 Each search was run on the following databases: MEDLINE HealthSTAR Cancerlit Toxline Dissertation Abstracts Pascal Embase SciSearch BIOSIS PREVIEWS The basic search terms used were: leu?ocyte? (? = various spellings and truncation) or blood in proximity with filt? or reduc? or deplet?; or leukotrap or buffy coat deplet? or leu?ofilt? blood transfusion? or blood component transfusion or blood component removal or erythrocyte transfusion? or blood storage or apheresis platelet transfusion or blood platelets or plateletpheresis These terms were combined with the following keywords for adverse events and costs: immunomodulat? or CMV or cytomegalovirus or contaminat? or infection? or alloimmun? or bacterial infection? or immunization or immunisation or immunity or adverse event? or FNH or non hemolytic febrile reaction? or safety or reaction or cytokine? cost? or economic? All searches were limited to references of studies with human subjects published from (searches were run April 30, 1997). Additional searches for new publications were run on Current Contents: Clinical Medicine, at monthly intervals during the project. Searches were also run on the Cochrane Library. Other references were obtained through contact with representatives of the Canadian Blood Agency and the Canadian Red Cross, through hand scanning of new journals received at the CCOHTA library, through searches of publications from agencies such as the American Association of Blood Banks, and from the reference lists of publications obtained in the course of this research. 2 Canadian Coordinating Office for Health Technology Assessment

15 2. THE CURRENT SITUATION 2.1 Blood distribution There is little epidemiological data about the use of blood components in Canada. Using statistics provided by the Canadian Blood Agency (CBA), we are using the expected production and utilization data 2 of platelets and red blood cells for 1997/1998 shown in Table 1. Table 1 Expected blood components use for 1997/1998 2,3 Product Expected utilization Blood components prepared by the Red Cross Apheresis platelets Red Cross utilization rate of 88% (1993/1994) Pooled platelets Red Cross utilization rate of 68% (1993/1994) Red blood cells Red Cross utilization rate of 87% (1993/1994) The utilization rate refers to the Blood Services Statistical Report 2 for the years 1993/1994. Platelet units are prepared from individual units of whole blood by centrifugation. Five platelet units are then pooled into one platelet concentrate. In this report we will refer to this as pooled platelets. Apheresis platelets are prepared by cytapheresis; we use the term apheresis platelets for this blood component. 2.2 Present users We estimated the distribution of red blood cell (RBC) concentrates to different patient groups from data from a cross-sectional survey done by Chiavetta in 1991/1992 surveying 45 Ontario teaching and non-teaching hospitals 4. In this study, information was collected from 439,373 patients discharged between September 1991 and August 1992, of whom 26,611 (6.1%) received at least one unit of red cells. Out of 101,116 red cell units, approximately 70% were given to surgical patients. In this study 50% of all RBC units were for clean and 20% for cleancontaminated operations. Transfused patients undergoing clean surgery (ie. heart surgery, hip replacement, etc.) received an average of 2.9 RBC units. Patients undergoing cleancontaminated surgery (ie. colon surgery, etc.) received an average of 4.7 RBC-units. Only 4.9 % of all RBC units were used for patients with diseases of blood and blood-forming organs. The study has several limitations. It was undertaken in 45 hospitals in central Ontario. Thus, it may not be representative of the Canada-wide use of blood-components. Since the data were collected in 1991/1992, changing medical procedures and practices, such as the increased Canadian Coordinating Office for Health Technology Assessment 3

16 use of blood components for high dose chemotherapy, could alter the blood distribution among recipients. In addition, it is likely that practice has changed in surgery and emergency medicine, so that clinicians are now less likely to transfuse for a given indication than they were in the past 5,6,7,8. With respect to platelets, no similar study with distributional data was found. Following conversations in Winnipeg (Dr. Blajchman and Dr. Growe at the Canadian Blood Agency meeting, May 12, 1997), we assume the percentages given in Table 2. Table 2 Distribution of platelet concentrates among patient groups Patient group Pooled platelets Apheresis platelets Leukemia patients 72% 100% Other patients (surgery/emergency etc.) 28% 0% 2.3 Current filtration activities in Canada In 1996, Medsep, a subsidiary of the Pall Corporation, one of the biggest manufacturers of leukocyte filters, surveyed the use of filters for platelet transfusions 4. Filters were used mostly to avoid febrile reactions, to prevent or delay alloimmunization (refractoriness), or in the case of transplantation, to provide cytomegalovirus (CMV)-safe platelets. The strategy of filtering is an ondemand one. Five out of 63 hospitals surveyed were using a 100% filtration strategy for oncology and long-term transfusion patients. The survey reported a 43% filtration rate of pooled platelets (post-storage) and a lower rate of filtration for apheresis platelets. In a current chart review done in the Ottawa General Hospital (Appendix III), a 439-bed university-affiliated tertiary care centre, 73% of all RBC units for leukemia patients were filtered versus 6.4% of RBC units for all other patients (surgery, emergency, etc.). 2.4 International filter use United States The American Red Cross is currently offering both pre-storage filtered RBC and platelets 10. We did not find actual information about the rate of either pre-storage or post-storage filtered blood components in the United States. However, the FDA released regulatory advice for the manufacturing of leukoreduced blood components Canadian Coordinating Office for Health Technology Assessment

17 Great Britain We found two documents regarding the filtration situation in Great Britain. During the annual scientific meeting of the British Society for Haematology in association with the British Blood Transfusion Society in Bournemouth on April 21, 1993, specific indications were stated for which leukofiltrated blood components should be used. A 100% filtration strategy was not promoted 12. In a technology assessment about pre-storage filtration of blood components prepared in 1996 by the NHS Executive South and West Research and Development Directorate, the authors outline the current service of the National Blood Service in Bristol 13. Most hospitals in this region already filter blood components at the bedside and for red blood cells the blood service currently leukofilters pre-storage a small number of units for a few hospitals. For platelets 80-90% are actually leukoreduced without need for leukofiltration and 20-30% of the pooled platelets are leukoreduced using the buffy coat technology. The authors do not state which level of leukoreduction is maintained. However, they regard a level of 1-5 x 10 8 leukocytes per unit as leukopoor. Denmark The Society of Clinical Immunology released in 1994 (published in 1996) indications for leukofiltered blood components that were established during a consensus conference 14. They did not recommend a 100% filtration strategy. Canadian Coordinating Office for Health Technology Assessment 5

18 3. CLINICAL ISSUES ASSOCIATED WITH FILTRATION AND LEVEL OF EVIDENCE FOR THE EFFICACY OF LEUKODEPLETION We have reviewed the literature about the efficacy of leukofiltration to prevent febrile reactions, leukocyte transmitted infections, platelet-refractoriness and immunomodulation. We have not addressed TRALI (Transfusion related lung injury) since it is due to preformed antigranulocyte antibodies in the donor plasma and thus is not preventable by leukofiltration 15. Also we do not refer to graft versus host disease since the standard preventive procedure remains irradiation of the blood component 12. Reperfusion injury in heart transplant surgery is related to donor leukocytes, but postoperative hemodynamics studies could not demonstrate a better clinical outcome in the leukoreduced-group 16. There are relatively small patient groups like thalassemia patients who seem to benefit more from leukofiltration than the majority of blood component recipients 17. In addition, patients after organ transplant or patients on a waiting list for organ transplant also benefit from leukofiltration. For these patients it is important to preserve the individual HLA-antibody status. Newly produced HLA-antibodies (for example, caused by receiving an allogeneic blood component) could induce a rejection of the donor-organ. Leukofiltration of blood components is more likely to prevent alloimmunization and thus the production of HLA-antibodies if such a patient should receive a blood transfusion. Although data about possible savings due to leukofiltration for this small group of patients groups is scarce, we would like to mention the importance of leukofiltration for these patients. We assessed the methodological quality of the retrieved studies using the level of evidence scale of Jovell 18. In the Jovell scale, randomized controlled trials (RCT) and metaanalyses of RCTs receive a score from I-III, while non-controlled clinical series receive a score of VIII. 3.1 Non-hemolytic febrile transfusion reactions (NHFTR) Non-hemolytic febrile reactions are the most common adverse effects of blood transfusions. These, along with allergic reactions, are clinical manifestations of alloimmunization 19. Symptoms following transfusions can be chills, a cold feeling, or discomfort. Discomfort often includes pain at the transfusion site, headache, nausea, and tightness of the chest 19. Allergic reactions, which occur at a higher rate after platelet transfusions than after RBC transfusions, are thought to be caused by soluble plasma proteins independent of leukocytes. Consequently, a reduction of allergic reactions could not be demonstrated in studies of leukofiltration 20, 21. In this summary, we will focus mainly on clinical data and not on experimental studies. Alloimmunization can occur after transfusion of leukocytes with their specific antigenic structure, during pregnancy, or after organ transplantation. More women than men are primarily sensitized 6 Canadian Coordinating Office for Health Technology Assessment

19 due to the transplacental transmission of fetal leukocytes during pregnancy and they react more frequently with febrile events 20,22. In particular, leukocytes induce the development of HLAantibodies by the recipient which leads to alloimmunization. The minimum number and type of white blood cells needed to generate a post-transfusion febrile reaction in an alloimmunized recipient of blood components remains unclear. It is also not known which role fragmented leukocytes play (i.e. whether they have an allogeneic structure which can induce alloimmunization or not) 23,15. Studies show that leukocytes are only one of the possible causes for febrile reactions 24. NHFTRs occurred in 32% of patients with antibodies and 37% of the patients without measurable antibodies in a study of 123 hematologic patients 25. The prevention of febrile reactions associated with platelet transfusions is more problematic than with RBC transfusions. The plasma remaining in the platelet transfusion after production from platelet rich plasma seem to cause more reactions than the leukocytes themselves 26. Another study in recipients who were already alloimmunized showed that 14% of patients who received bedside filtered pooled platelets still had febrile reactions, versus 20.3% who received unfiltered pooled platelets 27. There are fewer febrile reactions with leukofiltrated blood components, but a total prevention does not seem to be possible 20,24,28. As mentioned above, post-transfusion fever can be caused by a variety of underlying conditions, for example: the disease itself, infection, a hemolytic transfusion reaction or bacterial contamination of the applied blood component. Therefore, it is important to differentiate between fever caused by transfusions with that caused by other factors. Several diagnostic steps (depending on the severity, for example: blood sample, blood culture, chest x-ray, etc.) must be undertaken before a conclusion can be made that the fever is due to remaining leukocytes in the blood component. The estimated costs for the work up of a febrile reaction range from $300- $1000 in leukemia patients 29,30. We found no study related to costs for surgical patients. In a chart review undertaken in July 1997, we calculated the average cost of a febrile reaction to be $81 (Appendix III). While some studies found no valuable advantages in the leukofiltration of blood components 27,28, others point out that the timing of filtration is important for reducing rates of NHFTRs. The age of the blood component is an accepted risk factor. The older the component is, the more adverse reactions are observed. This is in particular the case for platelet concentrates which are stored at higher temperatures than RBC-units. Several studies found this to be a more obvious cause for a transfusion reaction than the number of remaining leukocytes 19,24,31. Since older blood components have higher rates of cytokines, the accumulation of soluble cytokines set free from leukocytes during storage may be the explanation for this result 24,26,30,32. Therefore, it seems reasonable that pre-storage filtration of blood components prevents cytokine accumulation during storage. Some clinical trials (not prospective, randomized controlled trials), were able to demonstrate positive effects of pre-storage filtration for RBC 24 even in previously sensitized patients 30. Canadian Coordinating Office for Health Technology Assessment 7

20 Despite the fact that transfusion reactions are more common in platelet than RBC transfusions 19 due to a higher storage temperature and higher cytokine levels 33, no conclusive studies in humans have shown the clear benefit of pre- over post-storage leukofiltration. In an experimental study, Hashemi et al demonstrated that with pre-storage leukoreduction of platelet concentrates, some cytokines (PAI-I, PAF, tpa) still accumulated similar to in unfiltered platelets 34. In contrast, Muir et al showed, in an abstract of a retrospective study, a 5.8-fold greater chance of a febrile reaction with post-storage filtered platelets than with pre-storage filtered ones in sensitized patients 30. The theory of preventing cytokine mediated NHFTR reactions with prestorage filtration of leukocytes is convincing. However, unfortunately, no randomized controlled trials exist to prove these advantages in a patient population. We found six studies in humans published after 1990 addressing the incidence of febrile reactions in the context of leukocyte filtration, with the results reported separately for platelets and RBC (Table 3). All studies achieved a level of leukoreduction of < 5 x 10 6 leukocytes in the applied blood component. In all studies, the real effect of leukoreduction is masked by the prophylactic use of antipyretics. Additionally, the definition of a febrile reaction is not always the same, resulting in different levels of occurrence. At minimum all studies showed a reduction of febrile events while using leukocyte filtration. Conclusion Leukofiltration prevents most febrile reactions to RBC-transfusions. This result can be achieved with post-storage filtered transfusions. The advantage of pre-storage filtration has not been proven in a randomized controlled trial. Platelet transfusions are associated with a higher rate of adverse events, and filtration is not as effective as in RBC. 8 Canadian Coordinating Office for Health Technology Assessment

21 Table 3 Incidence of non-hemolytic febrile transfusion reactions (per transfusions, excluding allergic and other reactions) Study Pre-storage filtration Post-storage filtration No filtration Level of evidence Platelets RBC Platelets RBC Platelets RBC % 59/ % 60/ % 139/6447 V % 82/ % 152/7080 VIII % 7/ /32 6.8% 8/117 VIII % 2/223 5% 14/ % 4/467 VIII [630] PP AP 19.4% 40/ % 14/ % 55/202 14% 26/207 VIII [582] % 7/4238 VIII + = apheresis platelets, FNHTR only; ++ = pooled platelets, all reactions; +++ = sensitized hematologic patients, apheresis platelets; ++++ = pooled platelets; PP= pooled platelets; AP= apheresis platelets 3.2 Leukocyte-transmitted infections Viruses The transmission of leukocyte-born viruses such as CMV, HTLV I or Epstein-Barr Virus (EBV) can be reduced by filtration 36,37. CMV pneumonia is a widely feared complication in immunosuppressed patients undergoing transplantation 38,39 or during high-dose chemotherapy. To avoid this complication, CMV-negative patients suitable for bone marrow transplant should receive only CMV-safe blood components 12,37. With a prevalence of 50-80% in the North American population 16,37, it is not always possible to obtain an appropriate CMV-seronegative donor. At the same time, the demand for CMV-seronegative blood components is rising because of the increase of transplants and physicians attempts to maintain the seronegative status of potential transplant candidates 36. Canadian Coordinating Office for Health Technology Assessment 9

22 Two prospective, randomized controlled trials showed that reduction of the leukocyte fraction of blood components (RBC and platelets), similar to the use of CMV-negative (laboratory antibody-screened) blood components, almost prevented CMV-infection in bone marrow transplant patients. One trial used platelets leukoreduced by centrifugation 39, the other by bedside 3logleukofiltration 36. In the latter trial, six of 250 patients who received leukofiltered blood developed CMV-disease and five of these six died of CMV pneumonia. In the group of 252 patients receiving CMV-seronegative blood, four developed CMV infection and none died of CMV pneumonia. The authors remarked in a response to a letter 40 that in the later follow-up, two more recipients of CMV seronegative blood became infected and both developed disease indicating that CMVseronegative blood also is not 100% safe. Although in a recent association bulletin 37 the American Association of Blood Banks felt that leukofiltration to a level < 5 x 10 6 was as safe as CMVseronegative components, others do not believe that leukofiltration should be a substitute for the already established practice of CMV-screening of blood components for patients who need CMVsafe blood components 40,41. For other viruses such as EBV and HTLV I and II, no conclusive studies exist that demonstrate a similar efficacy of virus removal due to leukofiltration as for CMV. Some experimental studies indicate a significant reduction of HTLV I in a blood component but the prevention of HTLV I infections with leukofiltration in humans has not been proven 42. Thus, leukofiltration cannot currently be used as a substitute for HTLV I testing for this rare disease (the rate of infection in the United States blood donor population has been estimated to be between 0.009% and % 43.) However, leukofiltration could add more safety to transfusions of blood components since not all HTLV-I infected donors necessarily express HTLV I antibodies 44. Bacterial/protozoal infection Bacterial contamination of blood components can be a severe complication of blood transfusions. The risk of contaminated pooled platelet-transfusion is estimated to be up to 2% (asymptomatic cases) since platelet concentrates are stored at room temperature to preserve their viability and function 6,45. Asymptomatic infection of a donor, and the ability of Yersinia enterocolitica to grow at low temperatures in an iron-rich environment such as in blood components, makes Y. enterocolitica the most commonly encountered serious bacterial contaminant in red cell concentrates 22,46. Transfusion-associated Y. enterocolitica fatal sepsis cases related to red blood cell 47 and platelet transfusions 48 have been reported in the U.S. Several studies demonstrated that the bacterial overgrowth of blood components by Y. enterocolitica inoculated in blood components in experimental conditions is diminished or prevented by pre-storage leukofiltration after a roomtemperature holding period 46,47,49. However, these studies have been criticized because these experimental results might not be achieved with blood components of an infected donor 50. Taking this into consideration, and due to the unknown actual number of cases of Y. enterocolitica sepsis cases related to transfusion, it is speculative to estimate how many cases of Y. enterocolitica sepsis could be prevented by pre-storage filtration Canadian Coordinating Office for Health Technology Assessment

23 The transmission of Trypanosomaniasis, which is caused by Trypanosoma cruzi, is more common in South America but a rare disease in North America. Transmission was decreased by leukofiltration in an experimental study 51, but no observational studies in humans exist. Conclusion The risk of CMV transmission via transfusion of RBC and platelets is markedly decreased by leukofiltration. However, whether leukofiltration is an alternative to CMV-seronegative blood components remains controversial. For other viral or for bacterial/protozoal infections we found no evidence that leukofiltration is an alternative to existing screening programs. The impact of leukofiltration on the prevention of transfusion-transmitted infections beside CMV remains unknown. 3.3 Platelet-refractoriness During chemotherapy for leukemic or other patients who receive high dose chemotherapy, thrombocytopenic bleeding can be a severe clinical complication. Because of the thrombocytopenic side effect of drugs used in chemotherapy, in particular when applied in high doses, platelet counts can fall below the level necessary to prevent spontaneous bleeding. A common treatment to prevent thrombocytopenic bleeding, once the platelet count is below a certain value, is prophylactic transfusion of either pooled platelets or apheresis platelets. However, the efficacy of this approach has never been demonstrated in a randomized trial. The ability of these transfusions to increase the platelet count can be inhibited if the recipient has an immune response due to prior HLA-alloimmunization to donor blood components, mainly leukocytes. In such cases patients antibodies inactivate the donor platelets. In other words, the patient platelet count continues to be very low despite platelet transfusions, a potentially lifethreatening situation. Morbidity and mortality caused by bleeding is relatively rare, occurring in 2.3% of patients receiving induction chemotherapy for acute leukemia 52. Therefore, published studies use platelet refractoriness instead of bleeding as an outcome. However, the term refractoriness is not clearly defined. An inadequate platelet increment on two consecutive platelet transfusions in the absence of clinical factors known to the affect platelet response 52 is the usual definition of platelet refractoriness. Numerous clinical factors influence platelet response, and only in rare cases are they absent. They include: hereditary or disease-associated variations in immune responsiveness; the extent of therapy-induced immuno-suppression (due to chemotherapeuticals, cortisone, etc.) 15 ; non-immunologic factors such as fever; specific drug treatment (for example, antibiotics like Canadian Coordinating Office for Health Technology Assessment 11

24 Amphotericin B); splenomegaly, and bleeding 53. Doughty et al found in a small prospective study of 26 hematology patients who received 116 unsuccessful platelet transfusions (inadequate platelet increment after transfusions) that immune factors were present in only 25% of those transfusions. The most common non-immune factors were fever, infection, antibiotic treatment or a combination of these 54. In addition, patients suffering refractoriness can change their refractory state during different treatments 52. The authors conclude that leukofiltration may have thus a limited impact in reducing the incidence of refractoriness to platelet transfusions 29. Since donor leukocytes are not responsible for all cases of platelet refractoriness, leukocyte reduction can prevent some cases of refractoriness: those which have leukocyte-related immunologic causes 54. It has been hypothesized that pre-storage filtration may also prevent cases of refractoriness which are due to soluble antigens and white cell fragments set free from leukocytes during storage 55. The therapeutic strategies to overcome platelet refractoriness are costly and often not effective 16. Thus it is better to prevent alloimmunization rather to treat it 56. The extent to which refractoriness is avoided by leukofiltration differs among the clinical studies. Heddle et al performed a meta-analysis of five randomized controlled trials on this topic. The five studies were undertaken with patients with hematological malignancies in the years Compared with patients receiving unfiltered blood components, the common odds ratio was 0.27 (95% CI, ) for alloimmunization a, and for refractoriness 0.28 (95% CI, ) 52. The authors conclude that (1) leukodepletion of red blood cell and platelet concentrates to levels below 5x10 6 leukocytes per product will delay and in some patients possibly prevent alloimmunization; and (2) prevention of alloimmunization seems to improve the post-transfusion platelet increment in selected transfusions when concomitant clinical factors known to affect platelet response are absent 52. They also conclude that 63 patients would have to be administered leukodepleted blood products to prevent one clinically significant bleeding event. The largest randomized controlled trial regarding alloimmunization in leukemia patients is the TRAP study (Level II study). The study is currently not published and we rely on information kindly given by Dr. Slichter during the CBA ad hoc meeting in Winnipeg 57. The primary endpoint of the study was platelet refractoriness in AML patients and its prevention by leukofiltration and ultraviolet technology. Only non-alloimmunized patients (ie. those who tested negative in a lymphocytotoxicity assay) were considered eligible for inclusion in the study. All patients were randomly assigned either to a control arm in which patients received regular pooled platelets or to one of the three treatment arms in which patients received ultraviolet B radiated pooled platelets (not discussed in this report), WBC-reduced pooled platelets, or WBC-reduced apheresis platelets 58. The overall conclusions were that leukofiltration can prevent or delay alloimmunization in some patients, since not all patients benefited from leukofiltration. In particular, those with prior a The outcome measure of alloimmunization is the development of HLA-Antibodies. These are measured in the laboratory with a lymphocytotoxicity assay Canadian Coordinating Office for Health Technology Assessment

25 pregnancies or prior transfusions were at a higher risk for platelet-refractoriness. Some patients, about 40% of the study group, were non-reactive and remain non-immunized regardless of the amount and the type (filtered or unfiltered) of the received blood component. In contrast, 20% of all recipients became alloimmunized regardless of the use of leukofiltrated blood products. Similar to the meta-analysis of Heddle, the key threshold to prevent alloimmunization was 5x10 6 leukocytes per unit. Interestingly there was no difference in development of platelet-refractoriness due to HLA alloimmunization between those patients receiving post-storage filtered low-leukocytes apheresis platelets or post-storage filtered pooled platelets 59. Table 4 shows the rate of platelet refractoriness after the transfusion of blood components. We compared studies regarding this topic published after 1990, achieving a level of 5x10 6 leukocytes in the administered blood component by leukocyte filtration. Two of the studies 21,60 were part of the meta-analysis done by Heddle. The studies vary considerably in study design (prospective and retrospective; randomized and non-randomized etc.), their definition of refractoriness, and the study population. Furthermore, some leukocyte-reduced blood components were produced using the buffy coat technology b, and others were not. In all studies clinically important outcomes were not measured (eg. serious bleeding). The results show a reduction, but with the exception of two studies, not a total prevention of platelet refractoriness. Patients who were previously exposed (prior unfiltered transfusion, prior pregnancy), benefited less from receiving leukocyte-reduced components (filtered either pre- or post-storage) than unexposed patients. The extent to which the reduction in platelet refractoriness translates into reduced morbidity or mortality from bleeding is not established 52,59. Conclusion Leukofiltration of platelet and red blood cell components reduces the incidence of alloimmunization and thus platelet refractoriness, particularly in unsensitized patients. Despite several experimental and retrospective studies, no RCT exists to demonstrate the advantage of pre - over post-storage filtration. b Buffy coat technology: red cells and plasma are expressed from the primary collection pack leaving a platelet-rich, greyish-white buffy coat layer in the primary pack (Optipress-instrument). Approximately one log of leukocyte reduction in the red blood cells can be produced with the buffy coat technology with the residual buffy-coat subsequently processed to produce a platelet unit. 64 Canadian Coordinating Office for Health Technology Assessment 13