The role of tocilizumab in the treatment of post‐transfusion hyperhaemolysis

Abstract Hyperhaemolysis syndrome (HHS) is a serious complication of transfusion mostly reported in patients with sickle cell disease. HHS is characterised by the destruction of both donor and autologous red blood cells. Tocilizumab is a recombinant humanised monoclonal antibody that inhibits the binding of interleukin‐6 and has been used in the treatment of severe/critical coronavirus disease 2019 infection but also some cases of HHS. We describe two further cases of HHS successfully treated with tocilizumab and propose a decision aid for when to consider this treatment.


INTRODUCTION
The pathogenesis of hyperhaemolysis syndrome (HHS) remains unclear; proposed mechanisms include complement-mediated 'bystander' haemolysis in the context of alloimmunisation and macrophage activation resulting in peripheral consumption of erythrocytes [1,2].
In England, eculizumab is recommended for both delayed haemolytic transfusion reaction (DHTR) and HHS where first-line treatment has failed with ongoing haemolysis [3,4].Based on the hypothesis of macrophage activation, tocilizumab, an interleukin (IL)-6 receptor blocker, has recently been used in a small number of cases of HHS [5,6].HHS can present with similar clinical features to a DHTR [7].

CASE 1
later he became acutely unwell with generalised bone pain, tachycardia, fever, haemoglobinuria and a haemoglobin of 47 g/L.He was treated with intravenous immunoglobulin (IVIg) 1 g/kg for 2 days and methylprednisolone 500 mg IV for 2 days.Haemoglobin continued to decline to a nadir 36 g/L over the subsequent 5 days and he was transfused a further 1-unit RBC.Within a few days, the haemoglobin level declined from 52 to 33 g/L with a relative reticulocytopenia (see Figure 1).HPLC results demonstrated persistence of HbA (32%).Red  given for ongoing severe haemolysis and the patient was transfused 1 unit RBC.Immediately following the transfusion, the patient developed frank haemoglobinuria, fever, and generalised bone pain.
Tocilizumab was administered at a dose of 8 mg/kg and resulted in an immediate clinical response including improvement in vital signs and resolution of frank haemoglobinuria.There was a marked reduction in serum ferritin from 47,000 µg/L (pre-dose) to 40,000 µg/L immediately post-dose and to 27,000 µg/L the following day.The repeat haemoglobin the following day remained critically low at 24 g/L (see Figure 3).Due to severe drowsiness and concern of cerebral hypoperfusion a further one-unit RBC was administered.The patient again experienced severe generalised bone pain, fever, and frank haemoglobinuria.The transfusion was immediately discontinued, and a second dose of tocilizumab was administered associated with a rapid clinical improvement in vital signs and pain, resolution of haemoglobinuria within hours and reduction in serum ferritin to 14,000 µg/L.She received 2 further doses of tocilizumab over the next 2 days with continuous improvement in haemolytic markers, reticulocyte count and serum ferritin.The patient continued to improve clinically over 7 days with an increase in haemoglobin to a peak of 97 g/L.There was also a marked improvement in neurological symptoms with no gross deficit and the patient was discharged home.

DISCUSSION
The use of tocilizumab in these two cases was associated with rapid improvement in clinical and biochemical features of inflamma-tion and recovery in haemoglobin and reticulocytes.Tocilizumab is widely used for the treatment of chimeric antigen receptor (CAR) T-cell-induced cytokine release syndrome and in other rheumatological and inflammatory conditions [8][9][10].It has also been associated with improved outcomes in coronavirus disease 2019 infection and appears to be well tolerated [11][12][13].IL-6 is the main proinflammatory cytokine resulting in C-reactive protein (CRP) generation and tocilizumab has been associated with lower CRP levels and therefore caution is recommended interpreting CRP values within the clinical context [14].
We propose that in cases of HHS with predominant features of systemic inflammation and without laboratory features of DHTR, tocilizumab should be considered (see Figure 4).HHS in SCD is associated with significant morbidity and has implications for future transfusion.Strategies to prevent alloimmunisation and haemolytic transfusion reactions are essential [15].
Further understanding of the underlying pathophysiology of HHS is required to aid diagnosis and classification as well as guide treatment.
National registries and haemovigilance schemes must capture all pertinent details of cases to facilitate further research in this at-risk patient group.

AUTHOR CONTRIBUTIONS
Naeem Desai and Joseph Sharif collected the data.Naeem Desai, Jayne Peters, Elizabeth Davies and Joseph Sharif wrote the manuscript.
cell immunohematology investigations did not identify a new alloantibody by indirect antiglobulin test (IAT) or enzyme and the direct antiglobulin test (DAT) was 1+ (IgG).The patient remained unwell with generalised pains, high fevers and persistent tachycardia.There were no signs of localised infection and therefore empirical antibiotics were discontinued.A decision was made to give tocilizumab at 8 mg/kg for 4 days in lieu of eculizumab.Within 12 h of the first dose there was an improvement in the clinical and laboratory parameters including resolution of pain, fever, and tachycardia (see Figure2).Over the subsequent days there was a steady rise in reticulocytes and haemoglobin, and he was discharged the following week, subsequent bloods tests demonstrating complete recovery to baseline haemoglobin.Ferritin improved to 4924 µg/L from a peak of 52,211 µg/L prior to IVIg and F I G U R E 1 X-axis: days from admission; composite y-axis representing haemoglobin (Hb), reticulocyte count (retics).Vertical arrows representing timing of blood transfusion (RBC), intravenous immunoglobulin (IVIg) and tocilizumab.F I G U R E 2 X-axis: days from admission; composite y-axis representing peak daily temperature and CRP (C-reactive protein).Vertical arrows representing timing of blood transfusion (RBC), intravenous immunoglobulin (IVIg) and tocilizumab.corticosteroid; the patient had a high baseline ferritin due to a history of multiple transfusions.

3 CASE 2 AF I G U R E 4
female in her 30s with HbSS underwent urgent red cell exchange due to a suspected stroke.Prior to transfusion, she received rituximab 375 mg/m 2 and prednisolone 1 mg/kg due to a history of recurrent HHS.During transfusion she became acutely unwell with all-over body pain, tachycardia and haemoglobinuria; transfusion was immediately stopped after approximately 2 units and the patient was treated for suspected HHS with eculizumab 900 mg.Six days post-transfusion the patient became acutely unwell with fever, generalised bone pain, haemoglobinuria with a drop in haemoglobin to 39 g/L.HPLC demonstrated the persistence of HbA at 31%.Red cell immunohaematology investigations did not identify a new alloantibody by IAT or enzyme and the DAT was 1+ (IgG).The patient was treated for HHS with IVIg 1 g/kg and methylprednisolone 500 mg IV.The following day, the haemoglobin concentration was 29 g/L.Eculizumab 900 mg was F I G U R E 3 X-axis: days from admission; composite y-axis representing haemoglobin (Hb) and serum ferritin levels.Vertical arrows representing timing of blood transfusion (RBC), intravenous immunoglobulin (IVIg) and MTP (methylprednisolone), eculizumab and tocilizumab.Management algorithm for the management of delayed haemolytic transfusion reaction/hyperhaemolysis syndrome (DHTR/HHS) as per NHS England with proposed amendments to include tocilizumab.