Cold agglutinin disease (CAD) is a clonal, low-grade B-cell lymphoproliferative disorder in which cold agglutinins can lead to complement-mediated hemolysis. Cold agglutinins are antibodies (typically IgM) that cause agglutination of red cells at a particular thermal amplitude by activating C1s, which ultimately initiates the classical complement pathway, leading to extravascular hemolysis.1 Consequently, patients with symptomatic CAD may experience chronic anemia, acute hemolytic exacerbations, and cold-induced acrocyanosis. The current paradigm for treatment of CAD includes therapies directed at reducing B-cell clone size such as rituximab monotherapy (overall response rate [ORR], 50%; median time to response, 1.5 months)2 or rituximab with fludarabine (ORR, 75%; median time to response, 4.0 months).3 Meanwhile, eculizumab (C5 inhibitor) may reduce hemolytic parameters and transfusion requirement but is only modestly effective as it does not inhibit extravascular hemolysis.4
Sutimlimab is a novel complement-directed therapy — a monoclonal antibody that targets C1s. In this study, the authors presented data from a phase Ib study in patients with CAD treated with this novel agent. This was a prospective, open-label, single-group study in patients with clinically significant CAD and included patients with primary CAD (direct antiglobulin test positive for C3d; hemoglobin < 10 g/dL; at least one red cell transfusion within 6 months). Sixty percent of these patients had previously received therapy for CAD within five years; of this group, half had received single-agent rituximab, 42 percent had received steroids, and 17 percent had received bendamustine-rituximab.
Sutimlimab was administered every two weeks for a total treatment period of 26 weeks. After the initial treatment period, patients could also continue into the second extension phase of this study (this study only reported outcomes from the initial phase). The primary efficacy endpoint was normalization of hemoglobin level to 12 g/dL, or an increase in hemoglobin concentration by 2 g/dL from baseline, without need for red cell transfusion after week 5 or treatment for CAD. An increase by 1 g/dL was also considered to be clinically meaningful. Patients were vaccinated for Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae.
Forty-two patients were screened and 24 were eligible. In the six months preceding enrolment, mean transfusions were 3.2 units and mean baseline hemoglobin was 8.6 g/dL. Of the 24 patients, 13 (54%) met the primary endpoint, and a further six had evidence of treatment response. Twenty-two patients (92%) did not require CAD-directed therapy after week 5, and 17 patients (71%) were transfusion-free from week 5 onward. The mean increase in hemoglobin was 2.6 g/dL (95% CI, 0.7 to 4.5), and the improvements were mean +1.2 +/– 1.3 g/dL by week 1 and mean +2.3 +/–1.5 g/dL by week 3. By the end of this study, 15 patients (62%) had a mean increase of 2 g/dL or more, and eight patients (33%) had an increase of 3 g/dL or more. Seven patients (29%) experienced serious adverse events, with the most frequent including infections and infestations (54%) and gastrointestinal side effects (33%); however, none of these serious adverse events were attributed to sutimlimab. Infections from Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pyogenes did occur (but no meningococcal infections), and none were attributed to sutimlimab.
There are limitations in the data available — the numbers are small, and this is a nonrandomized study. Moreover, outcomes were only reported up to 26 weeks thus far, and it remains unclear whether this C1s inhibitor will have long-term efficacy of toxicity. It will be particularly important to establish the safety of sutimlimab in terms of infectious risks, though theoretically, given that this drug targets the classical pathway only, the lectin and alternative pathways remain intact to combat infection.
Overall, however, sutimlimab is a compelling agent for the treatment of CAD by attempting to target the classical complement pathway. There is a need for novel agents for this disease, as chemoimmunotherapies are unsuccessful in approximately 25 percent of cases due to treatment failure or toxicity.1 Moreover, this drug seems to act more quickly than rituximab-containing regimens, which suggests it may be helpful in acute exacerbations of CAD due to infection or other triggers. It is also compelling that there was disease activity in those who had previously received chemoimmunotherapy. Therefore, while this drug cannot yet be recommended for routine use, it is a promising therapy that merits further investigation. Here's to hoping that it represents a new therapeutic avenue while being “complementary” to existing clone-directed therapies.
Dr. Tseng indicated no relevant conflicts of interest.