To our knowledge, these data represent the first randomized trial of washed platelet transfusions in any setting. The issues of the efficacy and safety of washed platelet transfusions are of importance because (1) some patients require plasma-reduced transfusions to treat allergic or febrile reactions, (2) new methods of viral and bacterial pathogen-inactivation for transfusions may require washing prior to transfusion, and (3) a growing body of evidence suggests that immunologically important molecules are present in the stored supernatant of blood transfusions that might, speculatively, affect clinical outcomes. Our study design was less likely to detect a benefit of platelet washing because, unlike many centers, we routinely use ABO identical platelet transfusions for patients with leukemia. There is evidence from two small randomized trials in leukemia that this reduces refractoriness [4, 5] and increases survival . Preliminary results exist that ABO matching may also reduce morbidity and mortality in surgical patients .
There was no apparent benefit to washed transfusions in terms of reduced platelet transfusion refractoriness, reduced bacterial infections, reduction in reported febrile or allergic transfusion reactions or reduced length of stay. Confirmed transfusion reactions were less frequent in the washed arm of the study, and 15% of the patients in the leukoreduced arm of the study had severe or repeated reactions that led to their receiving washed transfusions, which abrogated those reactions. Our data do provide evidence, for the first time, that washed platelet transfusions are probably as safe and efficacious as standard leukoreduced transfusions. The mean number of days with bleeding was marginally but not significantly reduced in the patients in the washed group, as were the number of platelet transfusions needed per day in younger patients, and the ratio of platelet transfusions to red cell transfusions. However, there was more minor bleeding in the washed group raising the possibility that washed platelets are slightly less effective. However, the prevalence of major bleeding requiring treatment was the same in each group and very low (<5%). The only life threatening hemorrhage in these 43 patients occurred in a patient in the leukoreduced arm.
This study is also the first attempt to investigate whether transfusion practices during initial induction therapy are associated with changes in overall survival in acute leukemia in adults. The underlying rationale for studying this issue are observations demonstrating that allogeneic transfusions alter host T cell and natural killer cell immune function in surgical patients and experimental animals . The major causes of death in adults with leukemia are failure to achieve complete remission, and relapse after achieving complete remission. There is some evidence from the allogeneic bone marrow transplant literature that host immune function may play a role in preventing relapse during the post-treatment period, but there are no data that demonstrate a role for the immune system in achieving complete initial remissions . Our study found no difference in complete remission induction success rates with differing transfusion protocols, but does support the possibility of an association between type of red cell and platelet preparation transfused and long term survival.
Large numbers of red cell and platelet transfusions are given to patients with acute leukemia during the period of recovery from aplasia that is caused by cytotoxic chemotherapy given during remission induction. Additional transfusions are given during consolidation and bone marrow or peripheral blood stem cell transplantation. Many of these transfusions occur during the period when at least the bone marrow and peripheral blood compartments of the immune system are reconstituting and might be susceptible to the immunomodulatory effects of transfusions. Both white cell and platelet-derived mediators are present in the transfused red cells as well as platelets. Prestorage leukoreduction (not employed in this study) removes the vast majority of the white cells and platelets from stored red cells, and red cell concentrates would be expected to have much lesser concentrations of biologic mediators, even without washing. Platelet derived mediators would, of course, still be present in prestorage leukoreduced platelet concentrates.
Transfusions are known to cause suppression of type 1 cellular immunity and upregulation of type 2 humoral immunity [20, 21]. Such immune deviation could, speculatively, impair host defenses provided by T cells, dendritic cells and natural killer cells that might be involved in the eradication or control of residual tumor. Potential mediators of down regulation of cellular immunity by transfusions include allogeneic white cells, red cells or platelets, ABO antigen-antibody complexes formed after repeated ABO non-identical platelet transfusions, and the stored supernatant of, in particular, platelet concentrates. Transfusion of stored platelet supernatant plasma might be hypothesized to mediate such effects by immunoregulatory and tumor growth promoting factors, such as sCD40L or angiogenic factors such as VEGF [16–18].
Leukoreduction filters remove white cells from the transfused blood components. In the case of pre-storage leukoreduction, filtration also removes some of the biologic response modifiers secreted by white cells during storage. Platelet concentrate supernatant contains large amounts of mediators such as soluble CD40L (CD154), VEGF, TGF-β1, histamine and other biologic response modifiers that might impair cellular immunity [16–18]. Washing immediately prior to transfusion removes most soluble materials from the transfused platelet and red cell transfusions, including those released during storage from the platelets, red cells and white cells. Our data provide initial support for the novel hypothesis that changing transfusion practices could play a role in long-term survival in acute leukemia, particularly in younger patients who can be potentially cured.
There are distinct limitations to what can be concluded from our data. The number of patients studied is very small and almost all of them had AML. The statistically significant improvement in survival in patients ≤50 years of age with AML who had unusually good survival represents a subset analysis, not a primary outcome group and thus may represent the play of chance. The survival of 75% of any cohort of adult patients with acute leukemia for 4–5 years is a distinctly unusual circumstance . This could be due to the benefits of receiving washed transfusions, but could also be a chance occurrence in a small cohort of patients. Our overall survival in all patients of 40% in the larger cohort of patients of all ages and risk factors in the washed arm is equivalent to the best survival that has been reported in low risk, younger patients in other trials from the period of the early 1990s . As shown in the figures, there was only one relapse and death that occurred at beyond five years in our cohorts, with a number of patients alive and in remission at 5–12 years after diagnosis. Thus it appears that if there was benefit from washing of transfusions, it probably involves an increased likelihood of durable remission, rather than purely delaying relapse.
These data, however promising, raise hypotheses for additional testing rather than proving a principle. If transfusion practice impacts anti-leukemic immunity, and/or survival as our data suggest, a moderate sized randomized clinical trial should be able to confirm this in relatively few years. This is a propitious time for such trials as the need for prophylactic platelet transfusion therapy is being revisited. The question is being raised as to whether platelet transfusions in non-bleeding patients are truly necessary or need be as frequent as currently employed in this disease . One strategy for randomized trials would be to randomize patients to only therapeutic platelet transfusions (transfusion only for bleeding manifestations) versus current standard practice of prophylactic transfusions at a set threshold such as 10 × 109/μl.
Platelet washing is time consuming, delaying transfusion by about 2.5–3 hours, may present an additional opportunity for bacterial contamination, and involves some loss of platelets (about 20%). Platelet washing may not be feasible in clinically urgent situations. Direct costs are modest, at less than $40 per transfusion. Washing adds about $500–2000 to the total cost of caring for patients with acute leukemia in our center from diagnosis to cure or death. This is less than 0.5–1% of the total costs of treating AML or ALL with curative intent. There are few or no proven side effects of platelet washing other than reduced dose of platelets transfused. There are some additional potential clinical benefits of washing including a reduced likelihood of transfusion complications such as febrile non-hemolytic transfusion reactions, transfusion-related acute lung injury, and allergic reactions. These preliminary data, albeit from a very small number of patients, raise the possibility that some patients with acute leukemia might benefit from washed transfusions. Larger studies are indicated to explore this possibility.