Some Patients With CAD Experience Sustained Remission After Sutimlimab Discontinuation

Sutimlimab has been shown to reduce the need for blood transfusions in patients with cold agglutinin disease (CAD), but a recent research letter details the first reported clinical evidence of sustained hematologic remission post treatment.

CAD, a rare form of autoimmune hemolytic anemia (AIHA), is caused by classic complement pathway activation and is characterized by hemolysis and anemia and a risk of thromboembolic events. Sutimlimab, a humanized monoclonal antibody, blocks classic complement pathway activation by binding to the C1s protein. The first-in-class agent was shown to halt hemolysis and relieve CAD symptoms, leading to its February 2022 FDA approval for the treatment of CAD.

“In vitro, C1s inhibition with sutimlimab significantly inhibited complement-mediated activation and proliferation of primary human B cells,” the authors wrote. “Treatment with sutimlimab may therefore alter the pathogenic humoral immune response in patients with CAD.”

The observational posttrial study included 3 patients who responded to sutimlimab during the initial trial and an open-label extension. Patients received biweekly sutimlimab for approximately 3 years in the trial extension, and the posttreatment study took place from February 2021 to March 2022. The 3 patients included in the study were female and aged between 72 and 78 years.

Relapse was expected to occur immediately once sutimlimab concentrations dropped below threshold levels of roughly 20 mcg/mL. Therefore, follow-up visits were performed at increasing intervals after treatment completion. Follow-up visit measures included hemoglobin, bilirubin, lactate dehydrogenase (LDH), and complement component 4. Sustained hematologic remission was defined as hemoglobin levels nearly the same as on-treatment levels with no overt signs of hemolysis, while a drop in hemoglobin and reactive rise in bilirubin was considered hematologic relapse.

In patients 1 and 2, hemolysis ceased and hemoglobin increased to approximately normal levels on sutimlimab treatment. Posttreatment hematologic remission lasted up to 12 months, and both patients had stable hemoglobin levels without signs of hemolysis. These patients also tested negative for immunoglobulin M (IgM) and immunoglobulin G (IgG) autoantibodies in the direct antiglobulin (Coombs) test.

Patient 1 had normal hemoglobin and bilirubin levels during the observation period. Patient 2 had slightly increased bilirubin and LDH at 6 months after treatment ended, but hemoglobin remained within the normal range. LDH levels eventually rose to an above-normal level, and at 12 months, haptoglobin levels fell below normal. However, the patient did not report any CAD-related symptoms and their hemoglobin levels stayed consistent.

Patient 3 showed improvement but had residual hemolysis and continued to test positive for IgM autoantibodies while on treatment. During posttreatment follow-up, patient 3 showed a positive direct Coombs test for IgM autoantibodies and sometimes IgG autoantibodies—indicating mixed-type AIHA. This patient relapsed 7 weeks after treatment discontinuation and developed severe transfusion-dependent hemolysis.

These findings are the first clinical evidence of sustained remission in patients who have CAD after sutimlimab treatment, but the mechanisms behind this outcome are not yet clear.

“Considering the discrepancy between previous relapses during short washout periods and now sustained response, several aspects may contribute to sustained hematologic response following discontinuation of sutimlimab treatment,” the authors wrote. “Identifying factors that may be able to predict immunomodulation and long-term response following sutimlimab discontinuation will help to guide future treatment.”

Potential contributing factors to sustained hematologic remission are autoantibody status and titer, considering patients 1 and 2 in the study both tested negative for IgM and IgG autoantibodies in the Coombs test and had sustained remissions. Treatment duration and sutimlimab dose may also affect the likelihood of sustained hematologic responses after treatment. Patient 3 showed signs of mixed-type AIHA, which may have contributed to the lower efficacy and faster relapse she experienced, the authors noted.

Overall, the authors conclude that complement inhibition may be a viable alternative to rituximab, which has a limited response duration and comes with significant toxicity when given with cytotoxic agents. Sutimlimab is generally well tolerated and could potentially lead to sustained responses based on these initial findings.

“While further studies with larger sample sizes are needed to confirm our results, these interesting findings may potentially have implications for the extended use of complement inhibitors even in other diseases,” the authors wrote.

Reference

Gelbenegger G, Jaeger U, Fillitz M, Schoergenhofer C, Sillaber C, Jilma B. Sustained hematologic remission after discontinuation of sutimlimab treatment in patients with cold agglutinin disease. Blood Adv. Published online November 2, 2022. doi:10.1182/bloodadvances.2022008574