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EDITORIALS
Improving the safety of platelet transfusions by UV-C: let’s go back to the bench
Daniele Prati
Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy E-mail: DANIELE PRATI - daniele.prati@policlinico.mi.it
doi:10.3324/haematol.2020.275156
Technologies for pathogen reduction in blood compo- nents have been under development for more than 30 years, with the aim of mitigating the infectious risks of blood transfusion. They are based on the principle of inac- tivating all nucleic acids in the blood unit (including intra-cel- lular), to prevent the replication of any possible pathogen. This is particularly desirable to protect platelet transfusion recipients, who are at higher risk of septic reactions. In fact platelets - differently from other blood products which are kept refrigerated or frozen - are stored at room temperature, thus increasing the risk of bacterial growth.
As recently outlined, designing and conducting clinical tri- als on pathogen reduced platelets is not straightforward.1,2 In principle, studies should aim to demonstrate that pathogen- reduced platelets are more effective than standard platelets in preventing transfusion-transmitted infections. However, demonstrating such an advantage is considered unrealistic: given the unprecedented levels of blood safety, too many participants would need to be enrolled to achieve an ade- quate statistical power. Thus, the antimicrobial efficacy of these techniques is taken for granted from in vitro studies, and aims are set on the efficacy of platelet transfusion: i.e., whether or not pathogen-reduced products retain their abili- ty to increase platelet count, prevent bleeding and do not overly increase product need. Trials are generally based on a non-inferiority hypothesis, because pathogen-reduced platelets are not expected to provide better hemostatic effi- cacy than conventional platelets.3
Two pathogen-reduction techniques based on photochem- ical treatment of platelets, amotosalen plus UV-A light (Intercept, Cerus) and riboflavin plus UV light (Mirasol, TerumoBCT) – have already been tested in several random- ized studies of prophylactic transfusion in thrombocytopenic patients. As summarized in a Cochrane systematic review the treatment with either of these two methods does not seem to cause higher rates of bleeding, death, or serious adverse events in recipients.2 However, it is associated with approximately 20% lower post transfusion platelet count increments, shorter transfusion intervals and higher rates of refractoriness to platelet transfusions.2,4 This, together with concerns about the long-term safety profile of amotosalen or riboflavin and cost, have hampered the widespread introduc- tion of pathogen-reduction techniques in many countries.
Another pathogen reduction method, the Theraflex sys- tem (Macopharma S.A.S.), has more recently been devel- oped. In contrast with Mirasol and Intercept, it is based on simple UV-C irradiation of platelets, without the addition of photoactive substances. The article by Brixner and colleagues in the current issue of Haematologica5 reports the results of the first clinical study comparing the efficacy and safety of UV-C treated platelets to standard platelets (the CAPTURE trial). In a non-inferiority trial, the working group selected as primary endpoint the 1-hour corrected count increment (CCI), a measure of response to platelet transfusion that “corrects”
the post-transfusion increase of platelet count for blood vol- ume and number of platelets transfused, and set the accept- able inferiority margin at 30%.
From a methodological point of view, the trial was well designed and well conducted, and the authors should be commended for their effort. The main sponsor of the study was a non-commercial institution, the Research Foundation of the German Red Cross Blood Services. The working group successfully enrolled 175 patients (slightly more than the 166 planned), in 10 clinical centers. Patients were evaluated in up to eight per-protocol platelet transfusion episodes, and the percentage of off-protocol transfusions was kept low (about 5% in both arms). Both aphaeresis and buffy-coat derived platelet pools were used, reflecting the standard transfusion practice in Europe. Perhaps, the main limitation of the CAPTURE study was the choice of 1-hour CCI as pri- mary endpoint. CCI is commonly used as a surrogate out- come for platelet transfusion efficacy, but its correlation with clinical efficacy has not been documented.1 Theoretically, bleeding endpoints graded according to World Health Organisation system would have been more appropriate. However, reliable grading is not easy to standardise and apply, especially in a context of independent studies involv- ing multiple evaluation sites.1,3,6 However, CCI has been used in most previous trials on platelet concentrate pathogen- reduction,2 which makes it acceptable for this initial evalua- tion of the Theraflex system.
The results of the CAPTURE trial are of great interest. In an intent-to-treat analysis, the mean 1-hour CCI was 12.7 (95% CI: 11.42-13.97) in the patients receiving UV-C treated products, and 15.53 (95% CI: 14.88-16.88) in those receiving conventional platelets. This accounted for a mean difference of 18.24% (95% CI: 6.4-30.8) between the two groups. Similar results were obtained using a per-protocol analysis. Thus, non-inferiority of pathogen-reduced platelets com- pared to the standard of care cannot be claimed, despite a narrow margin well below the pre-trial defined limit of 30%. In other words UV-C-treated platelets were clearly less effec- tive than standard platelets in increasing post transfusion counts.7 In addition, patients in the experimental treatment arm received 25% more platelet transfusions, seriously affecting treatment costs, and patients receiving pathogen- treated platelets had a higher frequency of low-grade trans- fusion-related adverse events (probably related to the higher transfusion requirements). No differences between the two treatment arms were observed with regards to the incidence of platelet alloimmunization and serious adverse events (including severe bleeding episodes), but it should be empha- sized that the trial was not adequately powered for detecting them. Therefore, as correctly stated by the authors, no firm conclusions on safety could be drawn on the basis of the CAPTURE data.
Theraflex received the CE mark in 2009, but has not yet been commercialized. Certainly the evidence emerging from
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haematologica | 2021; 106(4)