- Email: [email protected]
Comparative clinical studies of platelet concentrates: Effects on clinical outcome and the use of healthcare resources
Pergamon
Transfus. Sci. Vol. 17, No. 3, pp. 343~46, 1996 Copyright © 1996 Published by Elsevier Science Ltd. All rights reserved Printed in Great Britain PII: S0955-3886(96}00041.0 0955-3886/96 $15.00 + 0.00
Comparative Clinical Studies of Platelet Concentrates: Effects on Clinical Outcome and the Use of Healthcare Resources D. H. P a m p h i l o n (on b e h a l f of t h e NBS P l a t e l e t S t u d y G r o u p ) *
• The Platelet Study Group are developing proposals to conduct a prospective randomised trial of different platelet products in the transfusion support of patients with haematological malignancy. All patients will receive prestorage leucodepleted red cells and will be randomised to receive either multiple donor non-apheresis buffy coat platelets which are non-leucodepleted (BCP), single donor apheresis platelets non-leucocyte depleted (SDP) or single donor apheresis platelets leucocyte depleted (LD-SDP). All leucocyte depleted products will contain fewer than 5 x 106 WBC/transfusion. The primary objective of the study is to compare clinical efficacy, the incidence of adverse reactions treatment outcome and the use of healthcare resources. Copyright © 1996 Published by Elsevier Science Ltd •
BACKGROUND AND
INTRODUCTION Patients with acute myeloid and lymphoblastic leukaemia (AML, ALL), high-grade non-Hodgkins lymphoma and multiple myeloma require transfusions of platelet concentrates (PCs} during and after intensive chemotherapy and stem cell transplantation to prevent bleeding during periods of thrombocytopenia. The leucocytes present in red cell and platelet products may be associated with adverse effects after transfusion. These include nonhaemolytic febrile transfusion reactions (NHFTR) alloimmunisation to leucocyte antigens such as HLA and transmission of viruses, e.g. cytomegalovirus (CMV). In addition, it has been suggested that the presence of leucocytes might be detrimental to product quality. Recent studies indicate that third generation leucocyte filters consistently achieve >3 log depletion: they are currently the method of choice and it has been shown that leucodepletion of red cells improves their storage characteristics. Laboratory leucodepletion of PCs prevents leucocyte {and platelet) fragmentation which occurs early in storage and results in the accumulation of lysosomal contents, acid phosphatase and proteolytic enzymes which naight be deleterious to platelet storage. Leucodepletion reduces the incidence of alloimmunisation to HLA and more recent studies indicate that this depends on the efficiency of leucocyte removal. It is probable that
Bristol Institute of Transfusion Sciences, "Dr Savitri, Abeyasekera, Senior Statistician, Statistical Services Centre, University of Reading, U.K. Ms Eleanor Allen, Deputy Director, Statistical Services Centre, University of Reading, U.K. Dr Mary Brennan, Consultant Haematologist, North London Blood Transfusion Centre, U.K. Ms Linda Davies, Health Economist, Centre for Health Economics, University of York, U.K. Dr Alison Goodall, Senior Lecturer, Royal Free Hospital School of Medicine, London, U.K. Dr Moji Gesinde,Consultant Haematologist, National Blood Service Leeds, Leeds, U.K. Mr R. Hawker, Principal Clinical Scientist, National Blood Service West Midlands Centre, U.K. Dr D. Norfolk, Consultant Haematologist, Leeds General Infirmary, Leeds, U.K. Dr D. Pamphilnn, Consultant Haematologist, National Blond Service South West, U.K. Dr I. Seghatchian, Principal Clinical Scientist, North London Blood Transfusion Centre, London, U.K. Dr Alison Seymour-Mead, Senior Clinical Medical Officer, National Blood Service West Midlands Centre, U.K. 343
344
Transfus. Sci. Vol. 17, No. 3
depletion of leucocytes to <5 x 106 is required to prevent primary sensitisation, and recently published guidelines in the U.K. require that leucocyte depleted red cells or platelets contain <5 x 10 6 leucocytes. Recent reports have cast doubt on the efficacy of bedside filtration, whereas the quality of filtration in Transfusion Centres and Hospital Blood Banks can be more readily monitored and leucocyte fragmentation is minimised (see above). Finally, there is evidence that levels of leucocyte-derived cytokines such as interleukin (IL)-I, IL6, IL-8 and tumour necrosis factor (TNF} increase during storage and removal of leucocytes prevents accumulation of IL-1 and IL-8 in stored platelet concentrates. These cytokines may be involved in the pathogenesis of NHFTR. Several previous studies have compared leucocyte-depleted vs non-leucocyte depleted blood products with the objective of assessing whether alloimmunisation and/or refractoriness were reduced. These studies were either cohort or randomised studies. In general, the number of patients enrolled in these studies was relatively small and three of the five randomised studies did not demonstrate a significant risk reduction for either alloimmunisation or refractoriness. In previously reported studies, the mean percent refractoriness was 30% (range 6.7 - 50%). The use of leucocyte depletion reduced this to 12%. Reviewing the clinical importance of these studies, Heddle pointed out that alloimmunisation is a laboratory outcome measure. Despite that there is evidence in the literature to suggest that alloimmunised patients have lower post-transfusion increments. The use of refractoriness as a surrogate outcome measure for bleeding is problematic for a variety of reasons; for example, bleeding is probably the most clinically relevant outcome measure but it is not used due to the difficulty in defining significant vs insignificant bleeding and the fact that morbidity/mortality resulting from bleeding is u n c o m m o n (<3%). Currently no prospective ran-
domised clinical trials have evaluated the implications of interventions such as leucodepletion on the use of healthcare resource. Finally non-immunological factors may be associated with a poor response to transfused platelets and refractoriness is often assessed in the absence of these important parameters. Newer methods such as calculation of the percentage of days at risk for each patient may be more meaningful. With these thoughts in mind, we propose to conduct a detailed in vitro and in vivo comparison of three currently available and relevant platelet products prepared from either single or multiple donors, and either leucorepleted or leucodepleted, to assess how they correlate with transfusion success, clinical outcome and whether the choice of a specific product impacts on the utilisation of healthcare resource.
HYPOTHESIS
Previously reported studies (vide supra) have demonstrated reduction in alloimmunisation and refractoriness but have not shown clinical benefit or improvement in treatment outcome. These studies employ new interventions which have major implications for the use of healthcare resources, for example, provision of apheresis platelets is expensive. If these products can be shown in a large prospective comparative study to have significant clinical benefits, then the expenditure is justified. The objectives defined above are designed to address this point. If, however, there is no proven benefit (the Null hypothesis) then there is scope for providing transfusion support to patients with haematological malignancy more cheaply, thus saving considerable sums of money.
PATIENTS
Patients of any age will be included if they are eligible to receive a standard
Platelet Concentrates: Effects on Clinical Outcome and the Use of Healthcare
adult therapeutic dose (ATD) of platelets. For the purposes of this study the specification of an ATD will be volume 150-350 mL, platelet count 2.24.0 x 10 H (mean 2.5-3.0 x 10~). Patients with the following diagnoses will be eligible: acute myeloid leukaemia, acute lymphoblastic leukaemia; high-grade non-Hodgkins lymphoma, multiple myeloma and Hodgkin's disease where it is expected that these patients will receive high dose chemotherapy and ± stem cell transplantation. In addition, patients with chronic myeloid leukaemia or myelodysplasia who undergo stem cell transplantation will be eligible. It is the intention that patients will be included if they are receiving parenteral amphotericin, although additional stratified analysis of patients falling into this category may be required. Patients will also be recruited if they present with other factors known to be associated with increased noni m m u n e platelet consumption, such as DIG and splenomegaly. Previously pregnant women will also be included. Patients will be enrolled to the study for 6 months but will stay on the study for a period of 9 months. Patients will be excluded from the trial if they are known to be refractory to platelet transfusions or where an intervention such as institution of HLA-matched platelet therapy excludes them from randomisation. They will also be excluded if they have been transfused within the preceding 28 days, have a diagnosis of severe aplastic anaemia or are known to have autoimmune thrombocytopenia.
OUTCOME MEASUREMENTS
The following information will be collected. Alloimmunisation: defined as >20% panel reactive antibody against a typed lymphocyte panel. Samples will be collected throughout the period of study and, in addition, will be analysed for platelet-specific antibodies if patients develop platelet refractoriness.
345
Refractoriness: the CCI will be measured at 1-6 and 18-24 h after each platelet transfusion. Refractoriness will be defined as two successive transfusion failures, where the CCI is <7.5 x 109/L at 1 h or <4.0 x 109/L at 24 h. Refractory patients will not be censored from further analysis since the refractory state is often transient. The incidence and site of haemorrhage will be documented. The presence of factors associated with non-immune platelet destruction will be recorded. NHFTR and other allergic/anaphylactic reactions defined by conventional criteria will be recorded for each transfusion episode. Patients will not ordinarily be pre-medicated unless they experience one or more clinically significant NHFTR. Documentation of a change in planned therapy which will impact on the use of Health Service resource. This will include a change from trial products to HLA-matched platelets in the event of alloimmunisation/refractoriness or a change from non-leucodepleted to leucodepleted platelets in the event of persistent NHFTR. Number of days of thrombocytopenia, neutropenia, antibiotic use and hospitalisation. Per cent of days at risk calculated from the formula: Number of days at risk for bleeding Number of days in the thrombocytopenic period
× 100
Total number of transfusions and intervals between transfusions of both red cell concentrates and PCs. Using these data, an overall assessment of treatment outcome will be made. This will take into account symptom-free days {when NHFTR, other reactions, haemorrhage and transfusion failure do not occur), the changes in planned therapy, additional transfusion therapy and treatment of adverse events. This will allow the calculation of total resource use and costs. From these data, a mean cost per patient for each group will be determined.
346
Trans[us. Sci. Vol. 17, No. 3
I N V I T R O STUDIES
It is of particular importance that Transfusion Centres supplying trial products to hospitals involved in the study adhere to very strict quality assurance procedures. This will include involvement in NEQAS schemes and in addition a platelet internal/external national quality assurance scheme (PIEQAS), which will be repeated at monthly intervals throughout the study after an initial validation period. This will ensure that all laboratories in the study testing PC aliquots in specially prepared containers from a range of different platelet products, each with inherently different levels of white cell contamination, are able to accurately determine the platelet and leucocyte content, volume and pH on days 2 and 5 after collection. A pilot
evaluation will be conducted to see if good results are obtained without changes to the laboratory methodologies currently in use at individual Transfusion Centres. In addition, the different types of platelet concentrate will be analysed by flow cytometry using monoclonal antibodies to GPIb, GPIIb/IIIa, CD62 and Annexin V to study changes in activation of platelet membrane during preparation and storage. In one or two Centres, an attempt will be made to assess whether activation or alteration of platelets during preparation and storage measured using the markers described above is associated with the poor clinical outcome, as measured by the 1-6 h CCI. It may also be possible to determine whether poor platelet concentrates can be identified prior to transfusion.
Transfus. Sci. Vol. 17, No. 3, pp. 343~46, 1996 Copyright © 1996 Published by Elsevier Science Ltd. All rights reserved Printed in Great Britain PII: S0955-3886(96}00041.0 0955-3886/96 $15.00 + 0.00
Comparative Clinical Studies of Platelet Concentrates: Effects on Clinical Outcome and the Use of Healthcare Resources D. H. P a m p h i l o n (on b e h a l f of t h e NBS P l a t e l e t S t u d y G r o u p ) *
• The Platelet Study Group are developing proposals to conduct a prospective randomised trial of different platelet products in the transfusion support of patients with haematological malignancy. All patients will receive prestorage leucodepleted red cells and will be randomised to receive either multiple donor non-apheresis buffy coat platelets which are non-leucodepleted (BCP), single donor apheresis platelets non-leucocyte depleted (SDP) or single donor apheresis platelets leucocyte depleted (LD-SDP). All leucocyte depleted products will contain fewer than 5 x 106 WBC/transfusion. The primary objective of the study is to compare clinical efficacy, the incidence of adverse reactions treatment outcome and the use of healthcare resources. Copyright © 1996 Published by Elsevier Science Ltd •
BACKGROUND AND
INTRODUCTION Patients with acute myeloid and lymphoblastic leukaemia (AML, ALL), high-grade non-Hodgkins lymphoma and multiple myeloma require transfusions of platelet concentrates (PCs} during and after intensive chemotherapy and stem cell transplantation to prevent bleeding during periods of thrombocytopenia. The leucocytes present in red cell and platelet products may be associated with adverse effects after transfusion. These include nonhaemolytic febrile transfusion reactions (NHFTR) alloimmunisation to leucocyte antigens such as HLA and transmission of viruses, e.g. cytomegalovirus (CMV). In addition, it has been suggested that the presence of leucocytes might be detrimental to product quality. Recent studies indicate that third generation leucocyte filters consistently achieve >3 log depletion: they are currently the method of choice and it has been shown that leucodepletion of red cells improves their storage characteristics. Laboratory leucodepletion of PCs prevents leucocyte {and platelet) fragmentation which occurs early in storage and results in the accumulation of lysosomal contents, acid phosphatase and proteolytic enzymes which naight be deleterious to platelet storage. Leucodepletion reduces the incidence of alloimmunisation to HLA and more recent studies indicate that this depends on the efficiency of leucocyte removal. It is probable that
Bristol Institute of Transfusion Sciences, "Dr Savitri, Abeyasekera, Senior Statistician, Statistical Services Centre, University of Reading, U.K. Ms Eleanor Allen, Deputy Director, Statistical Services Centre, University of Reading, U.K. Dr Mary Brennan, Consultant Haematologist, North London Blood Transfusion Centre, U.K. Ms Linda Davies, Health Economist, Centre for Health Economics, University of York, U.K. Dr Alison Goodall, Senior Lecturer, Royal Free Hospital School of Medicine, London, U.K. Dr Moji Gesinde,Consultant Haematologist, National Blood Service Leeds, Leeds, U.K. Mr R. Hawker, Principal Clinical Scientist, National Blood Service West Midlands Centre, U.K. Dr D. Norfolk, Consultant Haematologist, Leeds General Infirmary, Leeds, U.K. Dr D. Pamphilnn, Consultant Haematologist, National Blond Service South West, U.K. Dr I. Seghatchian, Principal Clinical Scientist, North London Blood Transfusion Centre, London, U.K. Dr Alison Seymour-Mead, Senior Clinical Medical Officer, National Blood Service West Midlands Centre, U.K. 343
344
Transfus. Sci. Vol. 17, No. 3
depletion of leucocytes to <5 x 106 is required to prevent primary sensitisation, and recently published guidelines in the U.K. require that leucocyte depleted red cells or platelets contain <5 x 10 6 leucocytes. Recent reports have cast doubt on the efficacy of bedside filtration, whereas the quality of filtration in Transfusion Centres and Hospital Blood Banks can be more readily monitored and leucocyte fragmentation is minimised (see above). Finally, there is evidence that levels of leucocyte-derived cytokines such as interleukin (IL)-I, IL6, IL-8 and tumour necrosis factor (TNF} increase during storage and removal of leucocytes prevents accumulation of IL-1 and IL-8 in stored platelet concentrates. These cytokines may be involved in the pathogenesis of NHFTR. Several previous studies have compared leucocyte-depleted vs non-leucocyte depleted blood products with the objective of assessing whether alloimmunisation and/or refractoriness were reduced. These studies were either cohort or randomised studies. In general, the number of patients enrolled in these studies was relatively small and three of the five randomised studies did not demonstrate a significant risk reduction for either alloimmunisation or refractoriness. In previously reported studies, the mean percent refractoriness was 30% (range 6.7 - 50%). The use of leucocyte depletion reduced this to 12%. Reviewing the clinical importance of these studies, Heddle pointed out that alloimmunisation is a laboratory outcome measure. Despite that there is evidence in the literature to suggest that alloimmunised patients have lower post-transfusion increments. The use of refractoriness as a surrogate outcome measure for bleeding is problematic for a variety of reasons; for example, bleeding is probably the most clinically relevant outcome measure but it is not used due to the difficulty in defining significant vs insignificant bleeding and the fact that morbidity/mortality resulting from bleeding is u n c o m m o n (<3%). Currently no prospective ran-
domised clinical trials have evaluated the implications of interventions such as leucodepletion on the use of healthcare resource. Finally non-immunological factors may be associated with a poor response to transfused platelets and refractoriness is often assessed in the absence of these important parameters. Newer methods such as calculation of the percentage of days at risk for each patient may be more meaningful. With these thoughts in mind, we propose to conduct a detailed in vitro and in vivo comparison of three currently available and relevant platelet products prepared from either single or multiple donors, and either leucorepleted or leucodepleted, to assess how they correlate with transfusion success, clinical outcome and whether the choice of a specific product impacts on the utilisation of healthcare resource.
HYPOTHESIS
Previously reported studies (vide supra) have demonstrated reduction in alloimmunisation and refractoriness but have not shown clinical benefit or improvement in treatment outcome. These studies employ new interventions which have major implications for the use of healthcare resources, for example, provision of apheresis platelets is expensive. If these products can be shown in a large prospective comparative study to have significant clinical benefits, then the expenditure is justified. The objectives defined above are designed to address this point. If, however, there is no proven benefit (the Null hypothesis) then there is scope for providing transfusion support to patients with haematological malignancy more cheaply, thus saving considerable sums of money.
PATIENTS
Patients of any age will be included if they are eligible to receive a standard
Platelet Concentrates: Effects on Clinical Outcome and the Use of Healthcare
adult therapeutic dose (ATD) of platelets. For the purposes of this study the specification of an ATD will be volume 150-350 mL, platelet count 2.24.0 x 10 H (mean 2.5-3.0 x 10~). Patients with the following diagnoses will be eligible: acute myeloid leukaemia, acute lymphoblastic leukaemia; high-grade non-Hodgkins lymphoma, multiple myeloma and Hodgkin's disease where it is expected that these patients will receive high dose chemotherapy and ± stem cell transplantation. In addition, patients with chronic myeloid leukaemia or myelodysplasia who undergo stem cell transplantation will be eligible. It is the intention that patients will be included if they are receiving parenteral amphotericin, although additional stratified analysis of patients falling into this category may be required. Patients will also be recruited if they present with other factors known to be associated with increased noni m m u n e platelet consumption, such as DIG and splenomegaly. Previously pregnant women will also be included. Patients will be enrolled to the study for 6 months but will stay on the study for a period of 9 months. Patients will be excluded from the trial if they are known to be refractory to platelet transfusions or where an intervention such as institution of HLA-matched platelet therapy excludes them from randomisation. They will also be excluded if they have been transfused within the preceding 28 days, have a diagnosis of severe aplastic anaemia or are known to have autoimmune thrombocytopenia.
OUTCOME MEASUREMENTS
The following information will be collected. Alloimmunisation: defined as >20% panel reactive antibody against a typed lymphocyte panel. Samples will be collected throughout the period of study and, in addition, will be analysed for platelet-specific antibodies if patients develop platelet refractoriness.
345
Refractoriness: the CCI will be measured at 1-6 and 18-24 h after each platelet transfusion. Refractoriness will be defined as two successive transfusion failures, where the CCI is <7.5 x 109/L at 1 h or <4.0 x 109/L at 24 h. Refractory patients will not be censored from further analysis since the refractory state is often transient. The incidence and site of haemorrhage will be documented. The presence of factors associated with non-immune platelet destruction will be recorded. NHFTR and other allergic/anaphylactic reactions defined by conventional criteria will be recorded for each transfusion episode. Patients will not ordinarily be pre-medicated unless they experience one or more clinically significant NHFTR. Documentation of a change in planned therapy which will impact on the use of Health Service resource. This will include a change from trial products to HLA-matched platelets in the event of alloimmunisation/refractoriness or a change from non-leucodepleted to leucodepleted platelets in the event of persistent NHFTR. Number of days of thrombocytopenia, neutropenia, antibiotic use and hospitalisation. Per cent of days at risk calculated from the formula: Number of days at risk for bleeding Number of days in the thrombocytopenic period
× 100
Total number of transfusions and intervals between transfusions of both red cell concentrates and PCs. Using these data, an overall assessment of treatment outcome will be made. This will take into account symptom-free days {when NHFTR, other reactions, haemorrhage and transfusion failure do not occur), the changes in planned therapy, additional transfusion therapy and treatment of adverse events. This will allow the calculation of total resource use and costs. From these data, a mean cost per patient for each group will be determined.
346
Trans[us. Sci. Vol. 17, No. 3
I N V I T R O STUDIES
It is of particular importance that Transfusion Centres supplying trial products to hospitals involved in the study adhere to very strict quality assurance procedures. This will include involvement in NEQAS schemes and in addition a platelet internal/external national quality assurance scheme (PIEQAS), which will be repeated at monthly intervals throughout the study after an initial validation period. This will ensure that all laboratories in the study testing PC aliquots in specially prepared containers from a range of different platelet products, each with inherently different levels of white cell contamination, are able to accurately determine the platelet and leucocyte content, volume and pH on days 2 and 5 after collection. A pilot
evaluation will be conducted to see if good results are obtained without changes to the laboratory methodologies currently in use at individual Transfusion Centres. In addition, the different types of platelet concentrate will be analysed by flow cytometry using monoclonal antibodies to GPIb, GPIIb/IIIa, CD62 and Annexin V to study changes in activation of platelet membrane during preparation and storage. In one or two Centres, an attempt will be made to assess whether activation or alteration of platelets during preparation and storage measured using the markers described above is associated with the poor clinical outcome, as measured by the 1-6 h CCI. It may also be possible to determine whether poor platelet concentrates can be identified prior to transfusion.