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

Abstract

Summary 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.

Prevalence of natural and acquired antibodies to amustaline/glutathione pathogen reduced red blood cells

“…In STARS, − a randomized controlled trial of amustaline/ GSH RBC in complex cardiac surgery (Table 3), 87 patients were screened 6 and in SPARC-a randomized, controlled trial of amustaline/GSH RBC in thalassemia patients, 86 thalassemia patients were screened. 5 All patient sera were found to be non-reactive for S-303 antibodies. Nine of the 87 thalassemia subjects had pre-existing RBC alloantibodies.…”

“…All results were non-reactive for treatment-emergent S-303-specific or RBC alloantibodies. 5,6 To assess how the S-303 epitope densities of the transfused RBCs in the SPARC and STARS studies compared to each other and to the S-303H and S-303L RRC, quantitative flow cytometry was performed. Freshly treated amustaline/GSH RBC from both the DRK Frankfurt and Izmir, Turkey clinical trial sites were different, but both had lower S-303 epitope densities (mean 9064 and 13,151 epitopes/RBC, respectively) than S-303L RRC (mean 15,643 epitopes/RBC: Figure 2B), and adduct density on RBC from both clinical trial sites decreased by~45% by Day 35 of storage (Table 3).…”

“…In the SPARC and STARS clinical studies, screening for S-303 antibodies was performed as previously described. 5,6…”

“…[1][2][3][4] Amustaline/ GSH RBCs have been shown to be safe and effective in cardiac surgery and repeatedly transfused thalassemia patients and are undergoing further clinical study. 5,6 RBCs prepared with a prior version of the process were evaluated in two Phase III clinical trials that were halted following discovery of low titer S-303 antibodies in two transfused subjects, but without evidence of hemolysis. The antibodies were low-titer, transient, and had characteristics unlikely to cause hemolysis in vivo based on evaluation of phagocytosis in a monocyte monolayer assay (MMA).…”

The long and winding road to pathogen reduction of platelets, red blood cells and whole blood

“…Paediatric and adult patients were transfused in two periods with a total of 1024 Intercept and 1008 control RBC stored for approximately 9 days before transfusion. No antibodies to S‐303 RBC were detected (Aydinok et al , ).…”