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

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.

Keywords: RBC; infection; iron; thalassaemia; transfusion.

Figure 1

Study design. The study design for 2 wash‐in transfusions (TXNS) followed by 4 efficacy evaluation transfusions (TXNS) is indicated.

Figure 2

Disposition of patients. The disposition of patients from eligibility screening (n = 86), to randomization (n = 86) and exclusion (n = 5) is indicated. The randomization sequence assigned (Test to Control or Control to Test) is indicated with the first period assigned. The safety population (n = 81), the intent to treat (ITT) population (n = 80), and the per‐protocol only (PPO) population (n = 71) are shown. One patient withdrew after a single study transfusion and was only assessed for safety. In the ITT population, 6 patients received off‐protocol red blood cell concentrates (RBCC), 2 patients received incorrectly assigned study RBCC for a single transfusion episode, and 1 patient received all of the assigned transfusions in the Control period and only 3 of 6 transfusions in the Test period, thus was included in the ITT analysis but not the PPO analysis.

Figure 3

Haemoglobin content of test and control RBCC. The proportional (%) distributions of total haemoglobin (Hb) content (g) for 1024 Test (dots) and 1008 Control (diagonal) red blood cell concentrates (RBCC) are shown.

Figure 4

Transfused haemoglobin dose, pre‐transfusion haemoglobin and patient mean corpuscular haemoglobin. (A–C) Test and Control Transfusion Episodes by Type of RBCC. (A) Mean haemoglobin (Hb) dose (g) transfused per episode; (B) Mean pre‐transfusion patient Hb (g/l) per episode; (C) Pre‐transfusion patient mean corpuscular haemoglobin (MCH, pg) are indicated for all Test (▲) and Control () red blood cell concentrate (RBCC) transfusion episodes. (D–F) Test and Control Transfusion Episodes by Sequence and Type of RBCC: For 41 patients, Test were transfused in Period 1 (▲) for episodes 1–6 followed by Control RBCC in Period 2 () for episodes 7–12. For 39 patients, Control RBCC () were transfused in Period 1 for episodes 1–6 followed by Test RBCC () in Period 2 for episodes 7–12. (D) Mean Hb dose (g) transfused per episode; (E) Mean pre‐transfusion patient Hb (g/l) per episode; (F) Pre‐transfusion patient MCH (pg) are indicated for Test and Control RBCC by randomized treatment sequence for all transfusion episodes.