Pathogen inactivation treatment of triple-dose apheresis platelets with amotosalen and ultraviolet a light.

BACKGROUND: A triple storage (TS) set allows for pathogen inactivation (PI) treatment of triple-dose apheresis platelet products with amotosalen + UVA. We evaluated the quality and metabolic parameters of platelet concentrates (PCs) pathogen inactivated and stored for 7 days. MATERIALS AND METHODS: Twelve triple-dose products collected with two different apheresis platforms were treated with amotosalen+UVA. Products were split into three single-dose units. Testing was made pretreatment, after splitting, at days 5 and 7 of storage. RESULTS: Single-dose PI PCs had a mean platelet content of 2.89 ± 0.35 x 1011 . From baseline to day 7, pH remained stable (7.1 ± 0.1 vs. 7.0 ± 0.1), pO2 increased (11.3 ± 2.4 vs. 18.3 ± 3.5 kPa) as did LDH (201 ± 119 vs. 324 ± 203 U/L) and lactate (3.6 ± 1.7 vs. 12.1 ± 1.5 mmol/L) (all p < 0.01); pCO2 decreased (4.1 ± 0.8 vs. 1.5 ± 0.7 mmHg; p < 0.01) and so did bicarbonate (6.6 ± 1.1 vs. 2.5 ± 1.4 mmol/L), glucose (5.6 ± 1.2 vs. 0.4 ± 0.4 mmol/L) and ATP (3.4 ± 0.9 vs. 2.5 ± 1.4 nmol/108 platelets) (all p < 0.05). CONCLUSION: Triple-dose PCs processed with the TS sets fulfilled the quality requirements and displayed metabolic changes of expected extent during 7-day storage.

Comparative risk of pulmonary adverse events with transfusion of pathogen reduced and conventional platelet components.

BACKGROUND: Platelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion. STUDY DESIGN: An open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality. RESULTS: By modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio = 0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p = .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p = .151; odds ratio = 0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p = .256); and allergic TR were significantly less with PRPC (p = .006). PC and RBC use were not increased with PRPC. DISCUSSION: PRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.

Amotosalen-inactivated fresh frozen plasma is comparable to solvent-detergent inactivated plasma to treat thrombotic thrombocytopenic purpura.

BACKGROUND: Therapeutic Plasma Exchange (TPE) is the primary therapy of immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP). Efficacy and safety data for TPE of iTTP have been assessed with Quarantine and Solvent-Detergent inactivated (SD) plasma. Here, amotosalen-UVA pathogen inactivated (AI) plasma, also in routine use, was evaluated in iTTP. METHODS: We conducted a retrospective review of iTTP cases prospectively reported to the French national registry (2010-2013). Cases reviewed underwent TPE with ≥70% of either AI or SD plasma. The primary endpoint was time to platelet count recovery; secondary endpoints were related to follow-up (sustained remission, relapses, flare-ups and refractoriness). RESULTS: 30 Test patients were identified in the AI group which could be timely matched to 40 Control patients in the SD group. The groups were fairly comparable for clinical presentation. Major findings were: (i) iTTP patients were exposed to lower plasma volumes in the AI group than in the SD group; (ii) Recovery rates were comparable between the groups. Median time to platelet count recovery (>150 × 109/L) trended to be shorter in the AI group though non significantly. Tolerance of AI vs SD plasma was of comparable frequency and severity in either group. CONCLUSION: TPE with Amotosalen-inactivated plasma demonstrated therapeutic efficacy and tolerability for iTTP patients. In view of the retrospective design, confirmation of these results is required in larger prospective studies.

Clinical impact of amotosalen-ultraviolet A pathogen-inactivated platelets stored for up to 7 days.

BACKGROUND: Universal pathogen inactivation of platelet concentrates (PCs) using amotosalen/ultraviolet A with 7-day storage was implemented in Switzerland in 2011. Routine-use data were analyzed at the University Hospital Basel, Switzerland. STUDY DESIGN: A retrospective two-cohort study of patient and PC characteristics, component usage, patient outcomes, count increments (CIs), and adverse events were analyzed for two consecutive 5-year periods with either 0- to 5-day-old conventional PC (C-PC) (n = 14,181) or 0- to 7-day-old pathogen-inactivated PC (PI-PC) (n = 22,579). RESULTS: In both periods, PCs were issued for transfusion on a "first in, first out" basis. With 7-day PI-PC, wastage was reduced from 8.7% to 1.5%; 16.6% of transfused PI-PCs were more than 5 days old. Transfusion of PI-PC more than 5 days old compared with 5 days old or less did not increase platelet and RBC use on the same or next day as an indirect measure of hemostasis and did not increase transfusion reactions. Mean corrected count increments (CCIs) for PI-PC stored for 5 days or less were 22.6% lower than for C-PC (p < 0.001), and declined with increasing storage duration for both, although the correlation was weak (r2 = 0.005-0.014). Mean number of PCs used per patient and duration of PC support were not different for hematology/oncology, allogeneic and autologous hematopoietic stem cell transplant (HSCT), and general medical/surgical patients, who used the majority (~92.0%) of PI-PCs. Five-year treatment-related mortality in allogeneic HSCT was unchanged in the PI-PC period. CONCLUSIONS: PI-PCs with 7-day storage reduced wastage and did not increase PC or red blood cell utilization or adverse reactions compared with fresh PI-PC or a historical control group, demonstrating preserved efficacy and safety.

Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia.

Transfusion-dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen-reduced (PR) Amustaline-Glutathione (A-GSH) RBCC for TDT. Patients were randomized to a blinded 2-period crossover treatment sequence for six transfusions over 8-10 months with Control and A-GSH-RBCC. The efficacy outcome utilized non-inferiority analysis with 90% power to detect a 15% difference in transfused haemoglobin (Hb), and the safety outcome was the incidence of antibodies to A-GSH-PR-RBCC. By intent to treat (80 patients), 12·5 ± 1·9 RBCC were transfused in each period. Storage durations of A-GSH and C-RBCC were similar (8·9 days). Mean A-GSH-RBCC transfused Hb (g/kg/day) was not inferior to Control (0·113 ± 0·04 vs. 0·111 ± 0·04, P = 0·373, paired t-test). The upper bound of the one-sided 95% confidence interval for the treatment difference from the mixed effects model was 0·005 g/kg/day, within a non-inferiority margin of 0·017 g/kg/day. A-GSH-RBCC mean pre-transfusion Hb levels declined by 6·0 g/l. No antibodies to A-GSH-RBCC were detected, and there were no differences in adverse events. A-GSH-RBCCs offer potential to reduce infectious risk in TDT with a tolerable safety profile.

Amotosalen/UVA treatment inactivates T cells more effectively than the recommended gamma dose for prevention of transfusion-associated graft-versus-host disease.

INTRODUCTION: Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication after transfusion of components containing viable donor T cells. Gamma irradiation with doses that stop T-cell proliferation is the predominant method to prevent TA-GVHD. Treatment with pathogen inactivation methodologies has been found to also be effective against proliferating white blood cells, including T cells. In this study, T-cell inactivation was compared, between amotosalen/ultraviolet A (UVA) treatment and gamma-irradiation (2500 cGy), using a sensitive limiting dilution assay (LDA) with an enhanced dynamic range. METHODS AND MATERIALS: Matched plasma units (N = 8), contaminated with 1 × 106 peripheral blood mononuclear cells (PBMCs) per mL, were either treated with amotosalen/UVA or gamma irradiation, or retained as untreated control. Posttreatment, cells were cultured under standardized conditions. T-cell proliferation was determined by the incorporation of 3 H-thymidine and correlated with microscopic detection. RESULTS: Range-finding experiments showed that after gamma irradiation (2500 cGy), significant T-cell proliferation could be observed at a 1 × 107 cell culture density, some proliferation at 1 × 106 , and none at 1 × 105 cells/well. Based on these facts, a quantitative comparison was carried out between amotosalen/UVA at the highest challenge of 1 × 107 PBMCs/well, and gamma irradiation at 1 × 106 and 1 × 105 PBMCs/well. Complete inactivation of the T cells after amotosalen/UVA treatment was observed, equivalent to greater than 6.2 log inactivation. Complete inactivation of the T cells was also observed after gamma irradiation when 1 × 105 PBMCs/well were cultured (>4.2 log inactivation). Proliferation was observed when 1 × 106 PBMCs/well were cultured (≤5.2 log inactivation) after gamma irradiation. CONCLUSION: Amotosalen/UVA treatment more effectively inactivates T cells than the current standard of gamma irradiation (2500 cGy) for the prevention of TA-GVHD.

Determination of acute lung injury after repeated platelet transfusions.

Acute lung injury (ALI) during hematopoietic stem cell transplant (HSCT) is associated with substantial morbidity; however, the frequency of ALI in HSCT patients is poorly characterized. Platelets are postulated to play a critical role in the pathogenesis of ALI. Using a transfusion trial of pathogen inactivated platelet components (PC-Test) compared with conventional PC (Reference) populated with HSCT patients, data were reviewed by an adjudication panel to determine the frequency of ALI overall, by treatment groups, and key outcomes: PC exposure, ventilator-free days, and mortality. The diagnosis of ALI was based on American European Consensus Criteria. Of 645 patients who received PC over 28 days, 100 (15.5%) had clinically serious pulmonary adverse events, and 35 (5.4%) met criteria for ALI. Days of platelet support and number of platelet transfusions for patients with ALI were not significantly different from patients without ALI (P > .05). Mortality was greater for patients with ALI (57%) than those without (17%, P < .001) but not significantly different between treatment groups. For patients with ALI, the distributions of time to onset of mechanical ventilation were significantly different (P = .04). Patients supported with Reference PC were more likely to be ventilated sooner than patients receiving Test PC.

Universal adoption of pathogen inactivation of platelet components: impact on platelet and red blood cell component use.

BACKGROUND: Pathogen inactivation of platelet (PLT) components (INTERCEPT Blood System, Cerus Europe) was implemented into routine practice at a blood center supporting a tertiary care hospital. Utilization of platelet components (PCs) and red blood cell (RBC) components was analyzed for 3 years before and 3 years after introduction of pathogen inactivation to assess the impact of pathogen inactivation on component use. STUDY DESIGN AND METHODS: This was a retrospective analysis of prospectively collected data. An electronic database used in routine blood bank hemovigilance to monitor production and use of blood components was analyzed to assess clinical outcomes. RESULTS: Transfusion records were analyzed for 688 patients supported with conventional PCs and 795 patients supported with pathogen inactivation PCs. Additional analyses were conducted for intensively transfused hematology patients. Patient demographics (age category, sex, and diagnostic category) were not different in the two observation periods. For all patients, mean numbers of PC per patient were not different for conventional PCs and pathogen inactivation PCs (9.9 +/- 19.5 vs. 10.1 +/- 20.9, p = 0.88). Data for hematology patients (272 conventional PCs and 276 pathogen inactivation PCs) confirmed that days of PLT support were not different (31.6 +/- 42.6 vs. 33.1 +/- 47.9, p = 0.70) nor was total PLT dose (10(11)) per patient (87.3 +/- 115.4 vs. 88.1 +/- 111.6, p = 0.93). RBC use, for all patients and hematology patients, was not different in the two observation periods, either during periods of PLT support or outside periods of PLT transfusion support. CONCLUSION: Pathogen inactivation of PCs had no adverse impact on component use during a 3-year observation period of routine practice.

A randomized, controlled Phase III trial of therapeutic plasma exchange with fresh-frozen plasma (FFP) prepared with amotosalen and ultraviolet A light compared to untreated FFP in thrombotic thrombocytopenic purpura.

BACKGROUND: Photochemical treatment of fresh-frozen plasma (FFP) with amotosalen and ultraviolet (UV) A light (PCT FFP) results in inactivation of a broad spectrum of pathogens while retaining coagulation factor activity, antithrombotic proteins, and von Willebrand factor-cleaving protease (VWF-CP) activity. STUDY DESIGN AND METHODS: A randomized, controlled, double-blind Phase III trial was conducted with PCT FFP or control FFP for therapeutic plasma exchange (TPE) in patients with thrombotic thrombocytopenic purpura (TTP). Owing to the rarity of this diagnosis, the trial was not powered to demonstrate small differences between treatment groups. Patients were treated with study FFP for a maximum of 35 days until remission was achieved (for a maximum of 30 daily study TPEs with no remission) plus an additional 5 days after remission. RESULTS: Among the 35 patients treated, the primary endpoint, remission within 30 days, was achieved by 14 of 17 (82%) PCT patients and 16 of 18 (89%) control patients (p = 0.658) The 90 percent confidence interval for treatment difference in remission rate for test - control was (-0.291 to 0.163). Time to remission, relapse rates, time to relapse, total volume and number of FFP units exchanged, and number of study TPEs were not significantly different between groups. Improvement in VWF-CP and inhibitors was similar for both groups. The overall safety profile of PCT FFP was similar to control FFP. No antibodies to amotosalen neoantigens were detected. CONCLUSION: The comparable results between treatment groups observed from this small trial suggest that TPE with PCT FFP was safe and effective for treatment of TTP.

Transfusion of 7-day-old amotosalen photochemically treated buffy-coat platelets to patients with thrombocytopenia: a pilot study.

BACKGROUND: Photochemical treatment (PCT) of platelets (PLTs) with amotosalen and ultraviolet A light to inactivate bacteria may facilitate extension of storage from 5 to 7 days. STUDY DESIGN AND METHODS: A randomized, double-blinded, crossover, noninferiority, single-site pilot study utilizing pooled buffy-coat PLTs was conducted. The primary endpoint was the 1-hour corrected count increment (CCI) after one transfusion each of 7-day-old PCT and reference (R) PLT components. Secondary endpoints included 1-hour count increment, time to next transfusion, hemostasis, transfusion reactions, and serious adverse events. RESULTS: Twenty patients with thrombocytopenia were randomly assigned: 9 to the PCT-R sequence and 11 to the R-PCT sequence. A significant treatment-by-period interaction was observed. Therefore, the first period only was also analyzed for the primary endpoint. Including both treatment periods, mean 1-hour CCI was 6587 +/- 4531 for PCT versus 8935 +/- 5478 for R-PLTs. For the first period only, mean 1-hour CCI was 8739 +/- 3785 for PCT versus 7433 +/- 5408 for R-PLTs. The upper bound of the one-sided 95 percent confidence interval of 2400 for the mean difference was higher than the specified noninferiority margin of 2200 for both analyses. Overall median time to next transfusion was 22 hours for PCT versus 27 hours for R-PLTs. Hemostasis was adequate and no transfusion reactions or serious adverse events were reported. CONCLUSIONS: Although this pilot study of a limited number of patients failed to show noninferiority within the specified noninferiority margin, 7-day-old PCT PLTs showed acceptable efficacy and safety for support of thrombocytopenia. The results, however, warrant evaluation in a larger trial of 7-day-old PCT PLTs.

Platelet dose consistency and its effect on the number of platelet transfusions for support of thrombocytopenia: an analysis of the SPRINT trial of platelets photochemically treated with amotosalen HCl and ultraviolet A light.

BACKGROUND: The SPRINT trial examined efficacy and safety of photochemically treated (PCT) platelets (PLTs). PCT PLTs were equivalent to untreated (control) PLTs for prevention of bleeding. Transfused PLT dose and corrected count increments (CIs), however, were lower and transfusion intervals were shorter for PCT PLTs, resulting in more PCT than control transfusions. PLT dose was analyzed to determine the impact of the number of PLTs transfused on transfusion requirements. STUDY DESIGN AND METHODS: Transfusion response was compared for patients with all doses of >or=3.0 x 10(11) and the complementary subset of patients with any dose of fewer than 3.0 x 10(11). Analyses included comparison of bleeding, number of PLT and red blood cell (RBC) transfusions, transfusion intervals, and CIs between PCT and control groups within each PLT dose subset. RESULTS: Mean PLT dose per transfusion in the PCT group was lower than in the control group (3.7 x 10(11) vs. 4.0 x 10(11); p<0.001). More PCT patients received PLT doses of fewer than 3.0 x 10(11) (n=190) than control patients (n=118; p<0.01). Comparisons of patients receiving comparable PLT doses showed no significant differences between PCT and control groups for bleeding or number of PLT or RBC transfusions; however, transfusion intervals and CIs were significantly better for the control group. CONCLUSIONS: When patients were supported with comparable doses of PCT or conventional PLTs, the mean number of PLT transfusions was similar. Lower CIs and shorter transfusion intervals for PCT PLTs suggest that some PLT injury may occur during PCT. This injury does not result in a detectable increase in bleeding, however.

Clinical safety of platelets photochemically treated with amotosalen HCl and ultraviolet A light for pathogen inactivation: the SPRINT trial.

BACKGROUND: A photochemical treatment (PCT) method utilizing a novel psoralen, amotosalen HCl, with ultraviolet A illumination has been developed to inactivate viruses, bacteria, protozoa, and white blood cells in platelet (PLT) concentrates. A randomized, controlled, double-blind, Phase III trial (SPRINT) evaluated hemostatic efficacy and safety of PCT apheresis PLTs compared to untreated conventional (control) apheresis PLTs in 645 thrombocytopenic oncology patients requiring PLT transfusion support. Hemostatic equivalency was demonstrated. The proportion of patients with Grade 2 bleeding was not inferior for PCT PLTs. STUDY DESIGN AND METHODS: To further assess the safety of PCT PLTs, the adverse event (AE) profile of PCT PLTs transfused in the SPRINT trial is reported. Safety assessments included transfusion reactions, AEs, and deaths in patients treated with PCT or control PLTs in the SPRINT trial. RESULTS: A total of 4719 study PLT transfusions were given (2678 PCT and 2041 control). Transfusion reactions were significantly fewer following transfusion of PCT than control PLTs (3.0% vs. 4.1%; p = 0.02). Overall AEs (99.7% PCT vs. 98.2% control), Grade 3 or 4 AEs (79% PCT vs. 79% control), thrombotic AEs (3.8% PCT vs. 3.7% control), and deaths (3.5% PCT vs. 5.2% control) were comparable between treatment groups. Minor hemorrhagic AEs (petechiae [39% PCT vs. 29% control; p < 0.01] and fecal occult blood [33% PCT vs. 25% control; p = 0.03]) and skin rashes (56% PCT vs. 42% control; p < 0.001) were significantly more frequent in the PCT group. CONCLUSION: The overall safety profile of PCT PLTs was comparable to untreated PLTs.

Therapeutic efficacy and safety of red blood cells treated with a chemical process (S-303) for pathogen inactivation: a Phase III clinical trial in cardiac surgery patients.

BACKGROUND: A randomized, double-blind trial is reported of the clinical efficacy of red blood cells (RBCs) treated for pathogen inactivation with S-303, a synthetic labile alkylating agent. STUDY DESIGN AND METHODS: Patients undergoing complex cardiac surgeries were randomly assigned to receive either S-303-treated (test) or conventional (control) RBC transfusion during surgery and for 6 days thereafter. Efficacy was evaluated by comparing the occurrence of a composite primary endpoint of treatment-related morbidity (myocardial infarction and renal failure) and mortality. RESULTS: Two-hundred twenty-three patients were randomly assigned and 148 patients who received transfusions (74 with S-303-treated RBCs and 74 with control RBCs) were evaluable. The incidence of the primary endpoint was equivalent between the two groups (22 and 21% in the S-303-treated and control RBC groups, respectively). Secondary endpoints, including hemoglobin increment (mean, 1.4 vs. 1.5 g/dL), number of RBC transfusions (mean, 4.4 vs. 3.8 units), and other blood product support, were also comparable. The adverse event profile was similar between groups; however, patients who received S-303 RBCs were significantly more likely to develop constipation and less likely to suffer supraventricular extrasystoles. Four patients (2 test and 2 control) demonstrated positive indirect antiglobulin tests with reactivity for S-303 RBCs at one or more time points before or after transfusion, without evidence of hemolysis. CONCLUSION: S-303-treated and conventional RBCs were equivalent with respect to clinical efficacy and safety in supporting the transfusion needs of cardiac surgery patients. Investigations are under way to ascertain the significance of S-303 RBC antibodies and to prevent their occurrence.

Therapeutic efficacy and safety of photochemically treated apheresis platelets processed with an optimized integrated set.

BACKGROUND: This multicenter, randomized, controlled, double-blind Phase III clinical study evaluated the therapeutic efficacy and safety of apheresis platelets (PLTs) photochemically treated (PCT) with amotosalen and ultraviolet A light (INTERCEPT Blood System, Baxter Healthcare Corp.) compared with conventional apheresis PLTs (reference). STUDY DESIGN AND METHODS: Forty-three patients with transfusion-dependent thrombocytopenia were randomly assigned to receive either PCT or reference PLT transfusions for up to 28 days. RESULTS: The mean 1- and 24-hour corrected count increments were lower in response to PCT PLTs (not significant). When analyzed by longitudinal regression analysis, the estimated effect of treatment on 1-hour PLT count was a decrease of 7.2 x 10(9) per L (p = 0.05) and on 24-hour PLT count a decrease of 7.4 x 10(9) per L (p = 0.04). Number, frequency, and dose of PLT transfusions; acute transfusion reactions; and adverse events were similar between the two groups. There was no transfusion-associated bacteremia. Four PCT patients experienced clinical refractoriness; however, only one exhibited lymphocytotoxicity assay seroconversion. Antibodies against potential amotosalen-related neoantigens were not detected. CONCLUSION: PCT PLTs provide effective and safe transfusion support for thrombocytopenic patients.

Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial.

We report a transfusion trial of platelets photochemically treated for pathogen inactivation using the synthetic psoralen amotosalen HCl. Patients with thrombocytopenia were randomly assigned to receive either photochemically treated (PCT) or conventional (control) platelets for up to 28 days. The primary end point was the proportion of patients with World Health Organization (WHO) grade 2 bleeding during the period of platelet support. A total of 645 patients (318 PCT and 327 control) were evaluated. The primary end point, the incidence of grade 2 bleeding (58.5% PCT versus 57.5% control), and the secondary end point, the incidence of grade 3 or 4 bleeding (4.1% PCT versus 6.1% control), were equivalent between the 2 groups (P =.001 by noninferiority). The mean 1-hour posttransfusion platelet corrected count increment (CCI) (11.1 x 10(3) PCT versus 16.0 x 10(3) control), average number of days to next platelet transfusion (1.9 PCT versus 2.4 control), and number of platelet transfusions (8.4 PCT versus 6.2 control) were different (P <.001). Transfusion reactions were fewer following PCT platelets (3.0% PCT versus 4.4% control; P =.02). The incidence of grade 2 bleeding was equivalent for PCT and conventional platelets, although posttransfusion platelet count increments and days to next transfusion were decreased for PCT compared with conventional platelets.