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Efficacy of UVC-treated platelets
Introduction
Improvements in donor screening, Good Manufacturing Practice (GMP) and viral marker testing have significantly reduced the incidence of transfusion- transmitted infections. However, the blood supply remains under threat from various disease-causing agents, including known pathogens which are often not assayed in conventional blood screening protocols, i.e., bacteria and human cytomegalovirus, low-titer viruses that escape detection early after infection, and novel emerging trans- fusion-transmissible pathogens such as Zika virus and hepatitis E virus.1,2 While techniques reducing the biolog- ical activities of pathogens in red blood cells are still under development, techniques for platelet and plasma products have been introduced or are under consideration as additional safety measure in an increasing number of countries.3,4 Current methods for platelets use chemical reagents (amotosalen or riboflavin) in combination with ultraviolet (UV) light.5 However, chemical additives and/or their photoproducts potentially increase the risk of adverse effects, such as immune reactions or toxicity, especially in polytransfused patients.
The THERAFLEX UV-Platelets (Macopharma, Mouvaux, France) method for pathogen reduction (PR) of platelet products is based on treatment with UVC light alone, without any photoactive substances.6 UVC is absorbed by nucleic acids, resulting in the formation of pyrimidine dimers, which block the elongation of nucleic acid transcripts. It was shown that UVC treatment signif- icantly reduces the infectivity of platelet concentrates (PC) contaminated by pathogenic viruses, bacteria and parasites.7-12 Moreover, this technique was shown in a mouse model to achieve sufficient white cell inactivation to prevent transfusion-associated graft-versus-host disease (TA-GvHD).13 Several studies have shown that UVC- treated platelets meet the quality requirements for PC.14-16 This randomized controlled non-inferiority trial evaluat- ed the clinical efficacy and safety of pathogen-reduced PC produced using UVC illumination technology compared to that of conventional untreated PCs in thrombocy- topenic hematology-oncology patients.
Methods
Study design
CAPTURE (Clinical Assessment of Platelets Treated with UVC in Relation to Established Preparations) was designed as a randomized, double-blind, parallel controlled, non-inferiority trial. The trial protocol was approved by a the central ethic com- mittee. Ten hematology/oncology centers in Germany partici- pated in the study. The treatment period started on the day of the first study platelet transfusion and continued for a maximum of 28 days. A safety follow-up period began after the treatment period and continued for 30 days or until the day of early with- drawal, loss to follow-up, or death of the subject, depending on which occurred first (Online Supplementray Figure S1 in the Online Supplementary Appendix).
Adult patients with hematologic or oncologic diseases and with thrombocytopenia or who were expected to become thrombocytopenic after chemotherapy or due to underlying active disease were eligible to participate in the study if they were expected to receive at least one platelet transfusion. All individuals involved in the clinical care, assessment and trial management of the patients were blinded.
Treatment
Reference and UVC-treated platelet products were either col- lected by apheresis or prepared from five buffy coats and resus- pended in platelet additive solution (PAS). PR of PC was per- formed within 6 hours after apheresis platelet collection or 6 hours after preparation of the pooled platelet unit using the THERAFLEX UV-Platelets system.6 Reference platelets were left untreated or were Ξ³-irradiated if indicated. UVC-treated products generally were not Ξ³-irradiated. Patients in both treatment arms received platelet transfusions prophylactically (trigger 10,000/mL) or for treatment of bleeding.
Study endpoints
The primary efficacy endpoint, the 1-hour CCI, was measured 30-90 minutes post-transfusion for each of a maximum of eight per-protocol platelet transfusion episodes per patient administered within the treatment period. The patient’s pre-transfusion platelet count, which was used for this calculation, had to be measured within 12 hours before the start of transfusion. CCI was calculated using the formula:
𝐢𝐢𝐼=π‘ƒπ‘œπ‘ π‘‘βˆ’π‘π‘Ÿπ‘’π‘π‘œπ‘’π‘›π‘‘ π‘₯ 109𝐿 π‘ƒπ‘™π‘Žπ‘‘π‘’π‘™π‘’π‘‘ π‘‘π‘œπ‘ π‘’ π‘‘π‘Ÿπ‘Žπ‘›π‘“π‘’π‘ π‘’π‘‘ π‘₯ 1011 π‘₯ 𝐡𝑆𝐴
𝐡𝑆𝐴 (π΅π‘œπ‘‘π‘¦ π‘†π‘’π‘Ÿfπ‘Žπ‘π‘’ π΄π‘Ÿπ‘’π‘Ž) =0.20247 π‘₯ 𝐻𝑒𝑖𝑔h𝑑 π‘š 0.725 π‘₯ π‘Šπ‘’π‘–π‘”h𝑑 π‘˜π‘” 0.425
Secondary efficacy endpoints included the variables 24-hour CCI, 1-hour count increment (CI), 24-hour CI (specimens collect- ed 18-30 hours post-transfusion were considered time compliant), number of platelet transfusions per patient, number of red blood cell (RBC) transfusions per patient, and interval between study platelet transfusions. Secondary safety endpoints included adverse events, clinical and immunological refractoriness, severe bleeding events (World Health Organization [WHO] grade 3 and 4), and alloimmunization to UVC-induced neoantigens on platelets.
Statistical analyses
The study was designed as a one-sided non-inferiority trial comparing the 1-hour CCI of UVC-treated PC transfusions with those of untreated PC transfusions to test the null-hypothesis and demonstrate that pathogen-reduced platelets are non-inferior to control platelets. The non-inferiority criterion was met if the upper limit of the 95% Confidence Interval (CI) of the mean dif- ference in 1-hour CCI between the control and UVC groups was below the lower limit of the zone of non-inferiority (based on the results of previous studies with alternative PR methods17-25 an up to 30% reduction of 1-hour CCI was considered non-inferior). A total of 166 patients were required (83 per arm).
Results
Patients
Out of a total of 177 patients screened at 10 study sites between October 2016 and January 2019, 175 were enrolled in the study and randomized to the UVC arm (n=89) or control arm (n=86) (Figure 1). Two patients in each arm did not receive the first platelet transfusion with- in the specified time period of 6 weeks after randomiza- tion and were excluded from the study. The intention-to- treat (ITT) analyses were thus performed on 171 patients. After excluding patients who received off-protocol trans- fusions and/or study platelet transfusions from the wrong treatment arm or who met exclusion criteria, the data set
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