Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program

Abstract

Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. We aimed to evaluate the safety and efficacy of long-term maintenance treatment with sutimlimab in patients with CAD. Seven CAD patients treated with sutimlimab as part of a phase 1B study were transitioned to a named patient program. After a loading dose, patients received biweekly (once every 2 weeks) infusions of sutimlimab at various doses. When a patient's laboratory data showed signs of breakthrough hemolysis, the dose of sutimlimab was increased. Three patients started with a dose of 45 mg/kg, another 3 with 60 mg/kg, and 1 with a fixed dose of 5.5 g every other week. All CAD patients responded to re-treatment, and sutimlimab increased hemoglobin from a median initial level of 7.7 g/dL to a median peak of 12.5 g/dL (P = .016). Patients maintained near normal hemoglobin levels except for a few breakthrough events that were related to underdosing and which resolved after the appropriate dose increase. Four of the patients included were eventually treated with a biweekly 5.5 g fixed-dose regimen of sutimlimab. None of them had any breakthrough hemolysis. All patients remained transfusion free while receiving sutimlimab. There were no treatment-related serious adverse events. Overlapping treatment with erythropoietin, rituximab, or ibrutinib in individual patients was safe and did not cause untoward drug interactions. Long-term maintenance treatment with sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels in re-exposed, previously transfusion-dependent CAD patients.

Graphical abstract

Figure 1.

Response to sutimlimab. Start and peak/nadir levels of hemoglobin, bilirubin, LDH and haptoglobin. Box plots depict min-max (whiskers), quartiles (boxes), and median (horizontal lines).

Figure 2.

Laboratory course of patient 006. Patient 006 initially received 45 mg/kg (3.4 g once per week, then once every other week) of sutimlimab, and hemoglobin levels increased from 7.1 g/dL to 11.2 g/dL after 6 doses, when she experienced laboratory evidence of biochemical breakthrough. This prompted a subsequent dose increase to 60 mg/kg (4.3 g), which stopped hemolysis and stabilized hemoglobin levels. However, after 8 additional doses, breakthrough hemolysis re-occurred (increased bilirubin and LDH and decreased haptoglobin and C4), which led to a slight dose increase to 65 mg/kg preventing additional breakthrough events. Hemoglobin levels decreased significantly during repeated long washout periods (lengthy holiday and health treatment vacation). She was eventually assigned to a 5.5-g fixed-dose regimen, and after re-commencement of regular infusion therapy, the patient’s hemoglobin improved to a peak level of 11.4 g/dL. In week 75, her hemoglobin dropped to 6.1 g/dL which was a result of gastrointestinal bleeding after the re-operation of a diaphragmatic hernia. At that time, laboratory results revealed a sufficiently inhibited complement system (CH50, 30.8%; C4, 36 mg/dL) but no signs of hemolysis (bilirubin, 0.46 mg/dL; LDH, 213 U/L; and haptoglobin, 80 mg/dL). After transfusion of 4 erythrocyte concentrates, her hemoglobin rose to 10.2 g/dL and remained stable throughout her hospital stay. She continued with regular biweekly infusions of sutimlimab 5.5 g and her hemoglobin levels remained stable (blue arrows denote sutimlimab infusions).

Figure 3.

Laboratory course of patient 002. Because of renal insufficiency, patient 002 was treated with erythropoietin 5000 IU 3 times per week in addition to sutimlimab. This increased the speed with which her hemoglobin rose when compared with the phase 1 trial. She received 10 infusions of sutimlimab 60 mg/kg (4.5 g) over the course of 5 months. Her hemoglobin increased from 7.9 to 9.0 g/dL within 1 week and reached 13.4 g/dL after 9 weeks. Her participation in the NPP was terminated because of the diagnosis of a massive inoperable uterine cancer with unilateral hydronephrosis which required radiotherapy. After exclusion from the NPP, the patient received regular transfusions every 1 to 2 weeks. As part of a different study, the patient began treatment with rituximab 2 weeks before the last administered dose of sutimlimab. Although CD20⁺ cells decreased immediately and remained low over the course of treatment, she was not able to achieve an adequate clinical response. Approximately 1 year later, the patient developed sepsis after a stroke and subsequently died.

Figure 4.

Laboratory course of patient 004. At treatment initiation, patient 004 had a hemoglobin level of 7.4 g/dL. She was started on 45 mg/kg (3.4 g) sutimlimab which rapidly abrogated hemolysis and increased her hemoglobin level by 5.8 g/dL over the course of 4 weeks. Patient 004 experienced laboratory evidence of breakthrough hemolysis after the sixth and seventh doses of sutimlimab. However, when blood sampling was performed 1 week after the seventh dose of sutimlimab, the hemoglobin level was slightly increased and the bilirubin level normalized, suggesting that the treatment effect of sutimlimab was sufficient for at least 7 days but not sufficient for an interval of 14 days. This indicates that either the dose needed to be increased or the dosing interval needed to be decreased to achieve a sustained treatment effect. Despite underdosing, patient 004 was deliberately continued on 45 mg/kg of sutimlimab to allow for the detection of a putative beneficial effect of concomitantly started treatment with rituximab. The patient was eventually switched to a 5.5-g fixed-dose regimen, resulting in a rapid increase of hemoglobin and a decrease of bilirubin. Patient 004 experienced a washout of sutimlimab after the second fixed dose and her hemoglobin dropped to 9.2 g/dL. However, after 2 infusion cycles of sutimlimab, her hemoglobin promptly increased again to a level of 11.5 g/dL. During a scheduled checkup 2 weeks later, her hemoglobin level had further increased by 2.2 g/dL to a peak level of 13.7 g/dL, concluding the NPP. The investigator decided to discontinue treating this patient because she had repeated falls as a result of unrelated hydrocephalus, which required a shunt operation. In spite of a fifth dose of rituximab administered after the NPP, patient 004 could not maintain normal hemoglobin levels. Her hemoglobin levels decreased by more than 4 g/dL within 3 weeks to a level of 9.5 g/dL and then ranged from 7.7 to 10.2 g/dL over the following months, eventually reaching a nadir of 7.3 g/dL 8 months later.

Figure 5.

Laboratory course of patient 001. To target the underlying lymphoplasmacytic lymphoma, patient 001 had been treated with ibrutinib since her participation in the phase 1B trial. Her initial hemoglobin level was 7.7 g/dL accompanied by distinct laboratory markers of hemolysis. After initiation of ibrutinib, her IgM levels started to decrease, and her bilirubin levels steadily increased. Hemoglobin levels continued to improve until the patient suffered a urinary tract infection, which triggered a hemolytic crisis and caused a sudden drop in hemoglobin level and a peak in bilirubin level. She was subsequently re-treated with sutimlimab 60 mg/kg (3.4 g) on top of antibiotic therapy and responded with normalization of bilirubin within 3 days, a 1.6 g/dL increase in hemoglobin within 6 days, and a complete normalization of anemia within 5 weeks. The patient’s haptoglobin levels remained below measurable limits, indicating fully compensated residual hemolysis. *In week 9, the patient presented with increased levels of bilirubin (1.49 mg/dL) and LDH (566 U/L), while still retaining a normal level of hemoglobin, which we therefore classified as early breakthrough hemolysis.