Background Cold Agglutinin Disease (CAD) is a rare autoimmune hemolytic anemia, caused by cold agglutinins (IgM autoantibodies) that bind to erythrocytes at temperatures at or below 37℃, resulting in activation of the classical complement pathway. This ultimately leads to extravascular hemolysis in the liver. There is a minimal component of intravascular hemolysis via terminal complement activation.

Sutimlimab is a first-in-class monoclonal antibody that selectively inhibits C1s, a key activator of the classical complement pathway central to CAD pathophysiology. Sutimlimab selectively blocks the classical pathway without impacting the alternative or lectin pathways, preventing hemolysis.

Sutimlimab has demonstrated clinical efficacy in clinical trials however, real-world data regarding long-term hematologic response, treatment durability, and survival remains sparse. This study utilized the TriNetX Research Network to evaluate clinical outcomes in CAD patients treated with sutimlimab.

Methods This multicenter retrospective cohort study included patients with a diagnosis of CAD in the TriNetX Network, a database of deidentified electronic medical record data from 104 large healthcare organizations with over 140 million patient records. Patients included had a diagnosis of CAD, received sutimlimab treatment within one year of diagnosis, and had laboratory values of hemoglobin (HgB) recorded in the TriNetX database prior to starting treatment and within 6-18 months of treatment with sutlimimab. Outcomes included difference in mean HgB from baseline (prior to treatment) to within 6-18 months of treatment, incidence of infusion reactions, infections, sepsis, and Raynaud's phenomenon, and median duration of sutimlimab treatment at one year.

Results and Discussion Of the 45 eligible CAD patients treated with sutimlimab, the cohort predominantly comprised older adults with a mean age of 71 years old. There was a female predominance (69%) and the majority of patients identified as white (71%). Approximately 38% of patients had concomitant lymphoid or hematopoietic malignancies, consistent with secondary CAD etiologies. Baseline mean HgB was 8.99 (SD: 2.16), consistent with moderate anemia, with elevated LDH and bilirubin suggestive of active hemolysis. Following treatment, on 6-18 month HgB follow up, the average mean HgB was 11.269 (SD: 2.049). Haptoglobin was reported for 18 patients on 6-18 month follow up and 16 patients (89%) had a haptoglobin level > 16 mg/dL. Following treatment with sutimlimab, on 6-18 month follow up 91% (41 patients) had HgB >10, 87% (39 patients) had HgB >11, and 78% (35 patients) displayed normalization of HgB with HgB >12. By the one year time mark 38% (17 patients) had experienced infection. The median duration patients received sutimlimab was 211 days.

The total number of patients who developed sepsis, transfusion reactions, or Raynaud's phenomenon by the one year time mark was less than 10. Due to TriNetX privacy safeguards, exact patient counts less than 10 are not reported to protect patient confidentiality, in accordance with federal and state data-sharing guidelines.

The CARDINAL trial was a multicenter, single-group phase 3 trial which evaluated sutimlimab in adults with CAD and a recent history of transfusion, using weight-based intravenous dosing over 26 weeks. Of 24 enrolled patients, 54% met the primary endpoint, a composite of hemoglobin normalization (≥12 g/dL) or an increase of ≥2 g/dL from baseline, without transfusion or protocol-prohibited medications. Our study demonstrates a mean increase of >2 g/dL from baseline in hemoglobin at 6-18 month follow up with 78% of patients displaying normalization of hemoglobin.

Conclusions

Prior to the development of sutimlimab, there were no approved treatments for cold agglutinin disease (CAD); traditional therapies such as rituximab and cytotoxic agents offered only partial or delayed responses and were limited by frequent relapse and significant toxicity. This large-scale, real-world analysis confirms that sutimlimab confers durable hematologic response and favorable outcomes in patients with CAD. This data supports the integration of sutimlimab into standard CAD management. Prospective studies are warranted to evaluate predictors of treatment durability, long term complications, and effect of discontinuation.

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2025
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