-
1.
Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia
Aydinok Y, Piga A, Origa R, Mufti N, Erickson A, North A, Waldhaus K, Ernst C, Lin JS, Huang N, et al
British journal of haematology. 2019
Abstract
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.
-
2.
Red blood cell concentrates treated with the amustaline (S-303) pathogen reduction system and stored for 35 days retain post-transfusion viability: results of a two-centre study
Cancelas JA, Gottschall JL, Rugg N, Graminske S, Schott MA, North A, Huang N, Mufti N, Erickson A, Rico S, et al
Vox Sanguinis. 2017;112((3):):210-218
Abstract
BACKGROUND AND OBJECTIVES Pathogen reduction technology using amustaline (S-303) was developed to reduce the risk of transfusion-transmitted infection and adverse effects of residual leucocytes. In this study, the viability of red blood cells (RBCs) prepared with a second-generation process and stored for 35 days was evaluated in two different blood centres. MATERIALS AND METHODS In a single-blind, randomized, controlled, two-period crossover study (n = 42 healthy subjects), amustaline-treated (Test) or Control RBCs were prepared in random sequence and stored for 35 days. On day 35, an aliquot of 51 Cr/99m Tc radiolabeled RBCs was transfused. In a subgroup of 26 evaluable subjects, 24-h RBC post-transfusion recovery, mean life span, median life span (T50 ) and life span area under the curve (AUC) were analysed. RESULTS The mean 24-h post-transfusion recovery of Test and Control RBCs was comparable (83.2 +/- 5.2 and 84.9 +/- 5.9%, respectively; P = 0.06) and consistent with the US Food and Drug Administration (FDA) criteria for acceptable RBC viability. There were differences in the T50 between Test and Control RBCs (33.5 and 39.7 days, respectively; P < 0.001), however, these were within published reference ranges of 28-35 days. The AUC (per cent surviving x days) for Test and Control RBCs was similar (22.6 and 23.1 per cent surviving cells x days, respectively; P > 0.05). Following infusion of Test RBCs, there were no clinically relevant abnormal laboratory values or adverse events. CONCLUSION RBCs prepared using amustaline pathogen reduction meet the FDA criteria for post-transfusion recovery and are metabolically and physiologically appropriate for transfusion following 35 days of storage.
-
3.
A multi-centre study of therapeutic efficacy and safety of platelet components treated with amotosalen and ultraviolet A pathogen inactivation stored for 6 or 7 d prior to transfusion
Lozano M, Knutson F, Tardivel R, Cid J, Maymo RM, Lof H, Roddie H, Pelly J, Docherty A, Sherman C, et al
British Journal of Haematology. 2011;153((3):):393-401.
Abstract
Bacteria in platelet components (PC) may result in transfusion-related sepsis (TRS). Pathogen inactivation of PC with amotosalen (A-PC) can abrogate the risk of TRS and hence facilitate storage to 7 d. A randomized, controlled, double-blinded trial to evaluate the efficacy and safety of A-PC stored for 6-7 d was conducted. Patients were randomized to receive one transfusion of conventional PC (C-PC) or A-PC stored for 6-7 d. The primary endpoint was the 1 h corrected count increment (CCI) with an acceptable inferiority of 30%. Secondary endpoints included 1- and 24-h count increment (CI), 24-h CCI, time to next PC transfusion, red blood cell (RBC) use, bleeding and adverse events. 101 and 100 patients received A-PC or C-PC respectively. The ratio of 1-h CCI (A-PC:C-PC) was 0·87 (95% confidence interval: 0·73, 1·03) demonstrating non-inferiority (P = 0·007), with respective mean 1-h CCIs of 8163 and 9383; mean 1-h CI was not significantly different. Post-transfusion bleeding and RBC use were not significantly different (P = 0·44, P = 0·82 respectively). Median time to the next PC transfusion after study PC was not significantly different between groups: (2·2 vs. 2·3 d, P = 0·72). Storage of A-PCs for 6-7 d had no impact on platelet efficacy.
-
4.
Platelets photochemically treated with amotosalen HCl and ultraviolet A light correct prolonged bleeding times in patients with thrombocytopenia
Slichter SJ, Raife TJ, Davis K, Rheinschmidt M, Buchholz DH, Corash L, Conlan MG
Transfusion. 2006;46((5):):731-40.
Abstract
BACKGROUND Photochemical treatment (PCT) with amotosalen HCl with ultraviolet A illumination inactivates pathogens and white blood cells in platelet (PLT) concentrates. STUDY DESIGN AND METHODS In a Phase II crossover study, 32 patients with thrombocytopenia received one transfusion of PCT and/or one transfusion of untreated (reference) apheresis PLTs. Hemostatic efficacy was assessed with the cutaneous template bleeding time and clinical observations. RESULTS Paired bleeding time data for PCT and reference transfusions were available for 10 patients. Mean pretransfusion bleeding times were 29. 2 +/- 1. 6 minutes in the PCT group and 28. 7 +/- 2. 5 minutes in the reference group. After transfusion of a dose of PLTs of at least 6. 0 x 10(11), mean 1-hour posttransfusion template bleeding times corrected to 19. 3 +/- 9. 5 minutes in the PCT group and 14. 3 +/- 6. 5 minutes in the reference group (p = 0. 25). In 29 patients receiving paired PCT and reference transfusions, mean 1-hour posttransfusion PLT count increments were 41. 9 x 10(9) +/- 20. 8 x 10(9) and 52. 3 x 10(9) +/- 18. 3 x 10(9) per L for PCT and reference, respectively (p = 0. 007), and mean 1-hour posttransfusion PLT corrected count increments (CCIs) were 10. 4 x 10(3) +/- 4. 9 x 10(3) and 13. 6 x 10(3) +/- 4. 3 x 10(3) for PCT and reference, respectively (p < 0. 001). The time to next PLT transfusion was 2. 9 +/- 1. 2 days after PCT transfusions versus 3. 4 +/- 1. 3 days after reference transfusions (p = 0. 18). Clinical hemostasis was not significantly different after PCT and reference transfusions. CONCLUSION PCT PLTs provided correction of prolonged bleeding times and transfusion intervals not significantly different than reference PLTs despite significantly lower PLT count increments and CCIs.
-
5.
Photochemically treated fresh frozen plasma for transfusion of patients with acquired coagulopathy of liver disease
Mintz PD, Bass NM, Petz LD, Steadman R, Streiff M, McCullough J, Burks S, Wages D, Van Doren S, Corash L
Blood. 2006;107((9):):3753-60.
Abstract
An ex vivo photochemical treatment (PCT) process was developed to inactivate pathogens in fresh frozen plasma (PCT-FFP). A prospective, controlled, double-blinded, randomized study was conducted to evaluate the efficacy and safety of PCT-FFP compared with conventional FFP (C-FFP). Patients (n = 121) with acquired coagulopathy, largely due to liver disease, including hepatic transplantation, were transfused with either PCT-FFP or C-FFP for up to 7 days. Primary end points were changes in the prothrombin time (PT) and the partial thromboplastin time (PTT) in response to the first FFP transfusion. Secondary analyses compared changes in the PT and the PTT, factor VII levels, clinical hemostasis, blood component usage, and safety following FFP transfusions for up to 7 days. Following the first transfusion, correction in the PT and PTT adjusted for FFP dose and patient weight was not different. Changes in the PT were equivalent between treatment groups (P = . 002 by noninferiority). Equivalence was not demonstrated for changes in the PTT. Following multiple transfusions, correction of the PT and the PTT was similar between groups. No differences were observed in use of blood components, clinical hemostasis, or safety. These results suggest PCT-FFP supported hemostasis in the treatment of acquired coagulopathy similarly to conventional FFP.
-
6.
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
Mintz PD, Neff A, MacKenzie M, Goodnough LT, Hillyer C, Kessler C, McCrae K, Menitove JE, Skikne BS, Damon L, et al
Transfusion. 2006;46((10):):1693-704.
Abstract
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.
-
7.
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
Murphy S, Snyder E, Cable R, Slichter SJ, Strauss RG, McCullough J, Lin JS, Corash L, Conlan MG, SPRINT Study Group
Transfusion. 2006;46((1):):24-33.
Abstract
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.
-
8.
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
Benjamin RJ, McCullough J, Mintz PD, Snyder E, Spotnitz WD, Rizzo RJ, Wages D, Lin JS, Wood L, Corash L, et al
Transfusion. 2005;45((11):):1739-49.
Abstract
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.
-
9.
Clinical safety of platelets photochemically treated with amotosalen HCl and ultraviolet A light for pathogen inactivation: the SPRINT trial
Snyder E, McCullough J, Slichter SJ, Strauss RG, Lopez-Plaza I, Lin JS, Corash L, Conlan MG, SPRINT Study Group
Transfusion. 2005;45((12):):1864-75.
Abstract
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.
-
10.
Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial
McCullough J, Vesole DH, Benjamin RJ, Slichter SJ, Pineda A, Snyder E, Stadtmauer EA, Lopez-Plaza I, Coutre S, Strauss RG, et al
Blood. 2004;104((5):):1534-41.
Abstract
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.