Sutimlimab, an investigational C1s inhibitor, effectively prevents exacerbation of hemolytic anemia in a patient with cold agglutinin disease undergoing major surgery
Authors: Tor Henrik A. Tvedt, Egil Steien, Bente Øvrebø, Rune Haaverstad, William Hobbs, Marek Wardęcki, Geir Erland Tjønnfjord, Sigbjørn Andreas Berentsen
Journal: American Journal of Hematology (2021)

Cold agglutinins (CAs) are autoantibodies, usually of the IgM class, directed against surface proteins expressed on red blood cells (RBCs). Most CAs are of low clinical significance since their thermal amplitudes (i.e., the optimal temperature of reactivity with RBC antigens) are at temperatures that are not physiologically relevant.1 However, CAs with thermal amplitudes greater than 28–30°C are often associated with clinically relevant effects.2, 3 CAs can cause complications through two mechanisms. First, agglutination of RBCs in acral body parts can result in reduced microcirculation, vasospasm, and acrocyanosis.1 Second, bound to antigens on the RBC surface, the IgM is an avid activator of the classical complement pathway via binding of the C1 complex, resulting in hemolytic anemia by extravascular RBC destruction and modest intravascular hemolysis.2 The low levels of complement proteins limit the rate of RBC destruction.3 Hence, many patients with CAD are only mildly anemic, but approximately half of all patients with CAD require transfusions at some time point.4 However, after an infection or trauma, the 100 to 1000-fold increase in complement activity exacerbates hemolysis and may cause a significant drop in hemoglobin levels.1, 4 Coronary heart surgery poses particular challenges to patients with CAD; the intraoperative agglutination in the heart or other vital organs caused by the hypothermia induced by the extracorporeal cardiopulmonary bypass, and a significant increase in hemolysis caused by an increase in complement factors. Only a limited number of case reports and one case series describe management of patients with CAD undergoing cardiac surgery with warm heart surgery with cardioplegia and extracorporeal circulation at 37°C, or measures to reduce IgM levels as the main described strategies to prevent complications.5 However, since several of these series include patients with incidentally identified CAs in patients without hemolytic anemia, it is difficult two evaluate these measures. Furthermore, only a few case reports describe patients treated with measures to efficiently reduce IgM levels (mainly plasma exchange),6 while most patients have received ineffective therapies such as corticosteroids, low dose chemotherapy, or splenectomy. In the most recent case series by Barbara et al., warm heart surgery was described as a measure to avoid complications; however, most of the patients described had in incidentally discovered CAs, not CAD.5 Effective measures to prevent exacerbation of hemolysis have only been described in one case report.7 We describe a Caucasian male in his late 60s diagnosed with CAD. He had a 10-year history of coronary heart disease (CHD), presenting with myocardial infarction treated with three stents in the right coronary artery (RCA). Reoccurrence of symptoms led to an additional stent in the left anterior descending artery (LAD) 1 year later and, subsequently, also two LAD stents. At CAD diagnosis 1 year after his last cardiac surgery, he was severely anemic and required regular RBC transfusions. He was enrolled in the Phase 3 Cardinal trial, an open-label, single-arm study of sutimlimab, a selective inhibitor of complement C1s in recently transfused patients with CAD.8 His hemoglobin levels increased from below 10 g/dL with regular RBC transfusions to above 12.0 g/dL without transfusion requirements, but 9 months later, he developed progressive dyspnea with the demonstration of three-vessel disease with proximal and distal stenosis in the LAD and the circumflex artery (CX), indicating the need of open cardiac surgery. Currently, treatment for CAD involves one of two options: plasma exchange to remove IgM or chemo-immune therapy agents to reduce antibody production. Although plasmapheresis is highly effective in removing CA, the effect is short-lived since IgM production continues.6 Chemoimmunotherapy may lead to long-term remission, but time to response is delayed up to several months, and there is a risk of severe neutropenia and infection.9 As the patient required immediate cardiac surgery and had experienced a drop in hemoglobin level during acute phase reactions, we considered the risk of exacerbating hemolysis as significant during the postoperative phase. Thus, we did not consider any of these options as suitable. Sutimlimab is an inhibitor of complement C1s that selectively blocks classical complement activation, but leaves the alternative and lectin pathways intact. Phase 1 and 3 trials demonstrate rapid and complete blockade of hemolysis in CAD.8, 10 However, non-complement-mediated symptoms of RBC agglutination may not be relieved. Cold-induced, IgM-mediated agglutination can be prevented by keeping the body temperature and circulating fluids at 37°C throughout the surgery. We speculated that maintaining an optimal effect of sutimlimab might sufficiently block exacerbation of hemolysis via the classical complement pathway during surgery as well as the postoperative period. Significant dilution of circulating sutimlimab was expected during open cardiac surgery as the patient would have to be connected to extracorporeal circulation, that is, the heart–lung machine, which would be primed with 1300 mL of solution (Mannitol, electrolyte, and buffer solution). We further anticipated a blood loss of approximately 500 mL and infusion of 100–2000 mL of fluid. Using these data together with the patient's previous PK/PK profile (Figure 1A,B), we expected the intraoperative concentration of sutimlimab (Figure 1B) to be 4 times higher than what is needed to sufficiently suppress hemolysis if the surgery was done 2 days after a routine sutimlimab administration. The patient was admitted for cardiac surgery on day -2 and given a routine infusion of sutimlimab, at a 6.5 g dose as appropriate for the patient's weight. He then underwent coronary artery bypass grafting (CABG) on day 0. Precautions were taken to keep the operating room temperature high to avoid cooling of the patient. The fluids in the heart–lung machine were kept at 37°C. CABG was performed through median sternotomy with extracorporeal circulation through standard cannulation (at 37°C). Myocardial protection was delivered with antegrade warm (37°C) blood cardioplegia. The patient received two coronary grafts: the left anterior mammary artery (LIMA) to LAD and a vein graft to CX. To avoid replacement of C1q, no plasma products were given during surgery. Blood samples were collected at admission, prior to surgery, immediately prior to and after extracorporeal circulation, and 24 h after surgery. As expected, a slight decrease in hemoglobin level was observed as an initial dilution effect. Hemoglobin levels remained stable throughout the surgery with no signs of hemolysis, that is, stable lactate dehydrogenase levels and no hematuria or discoloration of plasma (Figure 1C). The early postoperative course was uneventful, and the patient was discharged to a local hospital after 5 days, well mobilized and in a good condition. As expected, a significant inflammatory response was observed, with increased C-reactive protein (CRP) levels that peaked 2 days after surgery (CRP 225 mg/L, but with no signs of infection. Despite this inflammatory response, no breakthrough hemolysis was observed and levels for LDH, bilirubin, and hemoglobin remained stable. At routine follow-up on day 14, he was fully mobilized, with a stable hemoglobin level and no signs of hemolysis (Figure 1C). Total complement activity (CH50), monitored to assess any activity of the classical complement pathway, was completely suppressed prior to surgery after sutimlimab infusion. CH50 remained suppressed during surgery, during the early post-operative period, and at follow-up 2 weeks later, indicating a continuous and complete inhibition of the classical pathway. The mean age at diagnosis for patient with CAD is 67 years, and even higher median ages are observed in studies exploring therapy for CAD.4 A retrospective study observed that a high proportion of CAD patients require treatment, with approximately 40% experiencing hemolytic exacerbations.4 Due to the chronic nature of CAD and age of these patients, the risk of comorbidities requiring medical treatment is significant. The current case demonstrates that even with a significant tissue trauma, acute phase reaction, and simultaneous shift in volume status, sutimlimab efficiently prevented complement activation. Furthermore, despite a marked and prolonged acute phase reaction, C1s inhibition was maintained postoperatively and blocked hemolysis sufficiently. As sutimlimab leaves the alternative and terminal pathways unaffected, an increase in infectious complications is unlikely. Hence, sutimlimab is potentially a new and safe tool for patients with CAD undergoing major surgery. Another significant observation is that the patient achieved a higher sutimlimab serum level after more than 52 weeks with sutimlimab infusions as compared to only a single infusion (Figure 1A). Hence, sutimlimab-naïve patients might require a higher dose than used in our patient. The current case report is from a patient included in the Cardinal study. The cardinal study was approved by the Institutional Review Board/ Regional Ethics Committee (REK vest 2017/2090). ClinicalTrials.gov Identifier: NCT03347396. Written informed consent has been obtained from the patient for publication of this case report. Sigbjørn Andreas Berentsen and Tor Henrik A. Tvedt have received honoraria from Bioverativ (a Sanofi company). Tor Henrik A. Tvedt have received honoraria from Sanofi. William Hobbs was an employee of Sanofi at study initiation. Marek Wardęcki is currently an employee of Sanofi. Egil Steien, Bente Øvrebø, Rune Haaverstad, and Geir Erland Tjønnfjord have no conflict of interests. Tor Henrik A. Tvedt collected data and wrote the initial manuscript, all authors contributed to the revision of the manuscript. All authors read and approved the final manuscript. Data available on request due to privacy/ethical restrictions.