Journal Club – CAD

Röth, A., Berentsen, S., Barcellini, W., et al. Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial. Blood. 2022;140(9):980-991.

Clinical Question

In patients with symptomatic cold agglutinin disease without recent transfusions, does treatment with the C1s complement inhibitor sutimlimab improve anemia and hemolysis compared to placebo?

Background

Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia characterized by chronic hemolysis mediated by IgM autoantibodies (cold agglutinins) that bind to the “I” antigen of erythrocytes at temperatures <37°C. The antigen-IgM antibody complex activates the classical complement pathway by binding to the C1 complement complex, resulting in activation of C1s (a C1 complex serine protease) that subsequently activates C2 and C4, generating C3 convertase, C3b deposition on erythrocytes, and extravascular hemolysis. Severe disease may lead to further terminal complement activation (C5 convertase and membrane attack complex production) and intravascular hemolysis (to a lesser degree thanks to intact CD55- and CD59-mediated regulation, in contrast to paroxysmal nocturnal hemoglobinuria [PNH]). These cold agglutinins result from a clonal, low-grade lymphoproliferative disorder that can be detected in blood or bone marrow (without clinical or radiologic evidence of a malignant condition). Cold agglutinin syndrome (CAS) differs by being transient and secondary to infections, overt malignant, or autoimmune conditions. Patients with CAD experience complement-mediated symptoms from chronic hemolysis (anemia, fatigue, and jaundice) as well as non-complement-mediated symptoms (acrocyanosis and Raynaud phenomenon), reduced quality of life, depression, and anxiety. Patients also have a higher risk of thromboembolism and early mortality.

Sutimlimab is a humanized monoclonal antibody that targets C1s, which was approved for the treatment of CAD after the pivotal, phase 3, open-label, single-arm CARDINAL study – sutimlimab for 26 weeks had a rapid and sustained response (increased mean Hgb, normalized mean bilirubin, reduced transfusions, and reductions in fatigue) in patients recently transfused. This first randomized, placebo-controlled phase 3 trial was done to investigate the efficacy and safety of sutimlimab vs placebo in patients with CAD who were not recently transfused.

Guidelines

There are no formal, dedicated disease-specific guidelines for CAD, but recommendations come from international consensus papers and broader autoimmune hemolytic anemia (AIHA) guidelines, such as the International Consensus on AIHA (2020). Prior to the approval of sutimlimab, there were no approved therapies for CAD. Treatment included supportive care with folic acid supplementation, warmed transfusions, and cold avoidance, but it did not address complement-mediated symptoms (level C: expert consensus). Rituximab, an anti-CD20 antibody, induced partial responses in ~50% of patients after a median of 1.5 months, with relapses within 12 months (level B: small, non-randomized studies). Adding cytotoxic agents like fludarabine or bendamustine to rituximab increases response rates but has more serious toxicities, including severe neutropenia (level B). Eculizumab, a C5 inhibitor, reduced LDH levels and needs for transfusions but only modestly increased hemoglobin (Hgb) due to ongoing extravascular hemolysis (level B). Other therapies include plasmapheresis, bortezomib-based therapies, and BTK-inhibitors (level C, the latter still investigational). Options with poor response rates and not routinely recommended include corticosteroids, azathioprine, cyclophosphamide, and splenectomy (level B).

Study Design

• Multicentered, randomized, placebo-controlled, double-blind Phase 3 study (with open-label extension period/part B to evaluate long term safety) 
• Setting: 53 sites across 14 countries (Australia, Austria, Belgium, Canada, France, Germany, Israel, Italy, Japan, Netherlands, Norway, Spain, United Kingdom, and United States) 
• N = 42: 
  • 22 patients randomized to receive sutimlimab 
  • 40 patients randomized to receive placebo  
• Follow-up period: at least 26 weeks (part A)  
• Primary efficacy outcome: composite of Hgb increase from baseline of >1.5g/dL at the treatment assessment timepoint (mean value from weeks 23, 25, and 26), absence of blood transfusions from week 5 to week 26, and avoidance of protocol-prohibited CAD medications from week 5 to week 26   
• Key secondary outcomes: 
  • Efficacy Outcomes 
    • Mean change from baseline in Hgb level and number of patients achieving mean increases of >1g/dL, >1.5g/dL, >2g/dL, and >3g/dL in Hgb levels 
    • Mean change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (scores range from 0 to 52, higher scores indicate less fatigue) 
    • Mean change from baseline in total bilirubin level, LDH, haptoglobin, and reticulocytes 
  • Pharmacodynamic Outcomes: 
    • Changes in classical complement pathway activity, complement component C4, C1q concentration, and hemolytic activity of the classical complement pathway (CH50) 
  • Safety Outcomes 
    • Treatment-emergent adverse events (TEAE) 
    • Treatment-emergent serious adverse events (TESAE) 
    • Clinical laboratory parameters and changes in autoimmune disease panel parameters 

Populations

• Key inclusion criteria
  • Patients > 18 years  
  • Body weight >39kg 
    • Confirmed diagnosis of primary CAD based on: 
    • Chronic hemolysis 
    • Polyspecific direct antiglobulin test positive 
    • Monospecific direct antiglobulin test strongly positive for C3d 
    • Cold agglutinin titer >64 at 4°C 
    • IgG direct antiglobulin test <1+, and 
    • No overt malignant disease 
  • Hemoglobin level <10g/dL 
  • Bilirubin level above the normal reference, including patients with Gilbert’s syndrome 
  • Normal ferritin levels (concurrent treatment with iron supplementation was permitted if the patient had been on a stable dose during the previous 4 weeks) 
  • Presence of one or more of the following CAD-related signs or symptoms within 3 months of screening: 
    • Symptomatic anemia (fatigue, weakness, shortness of breath, palpitations, lightheadedness, chest pain) 
    • Acrocyanosis 
    • Raynaud’s syndrome 
    • Hemoglobinuria 
    • Disabling circulatory symptoms, and/or 
    • Major adverse vascular event (including thrombosis)  
  • Bone marrow biopsy within 6 months of screening with no overt evidence of lymphoproliferative disease or other hematologic malignancy.  
  • Documented vaccinations against encapsulated bacterial pathogens (Neisseria meningitis, including serogroup B meningococcus, Haemophilus influenzae, where available, and Streptococcus pneumoniae) within 5 years of enrollment 
  • Willing to receive transfusions  
  • Adequate IV access 
  • If female in reproductive age, highly effective methods of birth control throughout the study and for 9 weeks following the last dose of the study drug 
  • If male, agree to use highly effective contraception from Day 0 until 9 weeks following administration of the last dose of the study drug 
• Key exclusion criteria:
  • Cold agglutinin syndrome secondary to infection, rheumatologic disease, or active hematologic malignancy
  • History of blood transfusion within 6 months of screening, or history of more than one blood transfusion within 12 months of screening
  • Clinically relevant infection of any kind within the month preceding enrollment, positive HIV or hepatitis panel, or any clinically significant comorbidity
  • Clinical diagnosis of systemic lupus erythematosus, or other autoimmune disorders with anti-nuclear antibodies at screening
  • Treatment with rituximab monotherapy within 3 months or rituximab combination therapies (e.g. with bendamustine, fludarabine, ibrutinib, or cytotoxic drugs) within 6 months prior to enrollment
  • Concurrent treatment with corticosteroids other than a stable daily dose equivalent to <10mg/day prednisone for the previous 3 months
  • Erythropoietin deficiency (concurrent treatment with erythropoietin was allowed)
  • Concurrent use of iron supplementation (unless being on a stable dose for at least 4 weeks)
  • Concurrent treatment with other experimental drugs
  • Females who are pregnant, lactating, or considered unreliable with respect to contraceptive practice
  • History of hypersensitivity to BIVV009 or any of its components
• Baseline characteristics:
  • 66 patients screened:
    • 42 patients enrolled to Part A (24 did not meet entry criteria). Randomized to Sutimlimab (n=22) and Placebo (n=20)
  • Most patients were female (79%) with median age of 66. No other demographic data described. Groups matched on age, sex, geographic location, prior therapies, baseline Hgb, total bilirubin, haptoglobin, and FACIT-Fatigue scores
  • Control patients:
    • Median baseline Hgb 9.3 g/dL, total bilirubin 34umol/L, LDH 294 U/L
  • Trial patients:
    • Median baseline Hgb 9.3 g/dL, total bilirubin 35umol/L, LDH 359 U/L, absolute reticulocytes 176×109/L, IgM 2.9g/L, cold agglutinin titer at 4°C 2560, and FACIT-Fatigue score 32.6
    • 14% of patients had disabling circulatory symptoms, 41% acrocyanosis, 23% Raynaud
    • 73% had received >1 CAD therapy in the last 5 years

Interventions

• Patients in treatment arm got sutimlimab 6.5g (if weight <75kg) or 7.5g (if weight >75kg) vs placebo with 500mL IV infusion over 60min on day 0, day 7, and every 14 days thereafter through week 25
• All trial patients received red blood cell transfusions if they were symptomatic with Hgb<9g/dL or asymptomatic with Hgb<7g/dL

Outcomes

• Primary outcome: Primary efficacy endpoint was a composite of Hgb increase from baseline of ≥1.5 g/dL at the treatment assessment timepoint (mean value from weeks 23, 25, and 26), absence of blood transfusions and prohibited CAD medications (from week 5 to week 26). 
  • Sixteen patients (72.7%) treated with sutimlimab vs 3 patients (15%) who received placebo met the prespecified criteria for the composite primary endpoint. Patients in the sutimlimab arm had significantly greater odds of achieving the response criteria than patients on placebo (OR 15.9, p<0.001)
    • Three patients in the sutimlimab arm did not meet the response criteria; two patients did not achieve ≥1.5 g/dL increase in Hgb and one received a blood transfusion
• Key secondary outcomes: Mean change from baseline in Hgb level and FACIT-Fatigue score, as well as total bilirubin, LDH, haptoglobin, and reticulocytes. Number of patients achieving mean increases of ≥1 g/dL, ≥1.5 g/dL, ≥2 g/dL, and ≥3 g/dL in Hgb levels.
  • Sutimlimab resulted in rapid (within 3 weeks) and sustained increase in Hgb and control of hemolysis. 16 (72.7%) sutimlimab-treated patients had increased Hgb levels ≥2.0 g/dL from baseline, compared with 2 (10.0%) patients on placebo. Fifteen (88.2%) patients in the sutimlimab arm and 4 (22.2%) patients in the placebo arm achieved normal total bilirubin levels (with similar results in additional markers of hemolysis).
  • Sutimlimab treatment led to rapid (by 1 week) and sustained improvements in FACIT-Fatigue scores: least squares (LS) mean change in FACIT-Fatigue score from baseline was 10.8 points in the sutimlimab arm and 1.9 points in the placebo arm.
• Pharmacodynamic endpoints included changes in classical complement pathway activity, complement component C4, C1q concentration, and hemolytic activity of the classical complement pathway (CH50) up to week 26.
  • Sutimlimab resulted in near-complete inhibition of classical complement pathway activity (22.4% to 2.3% compared to 32.8% to 35.6% in placebo arm). Complement inhibition was sustained throughout the treatment period
• Safety: Treatment-emergent adverse events (TEAE), treatment-emergent serious adverse events (TESAE), changes in autoimmune disease panel parameters, and other clinical laboratory evaluations were recorded up to week 26.
  • Total TEAEs were similar between groups
  • 3 patients in sutimlimab arm discontinued the study drug prematurely due to adverse events (1 was deemed related to sutimlimab; low back and bilateral leg pain after drug infusion)
  • The majority of TEAEs were considered unrelated to the study. Headache (22.7% vs 10.0%), hypertension (22.7% vs 0%), rhinitis (18.2% vs 0%), Raynaud phenomenon (18.2% vs 0%), and acrocyanosis (13.6% vs 0%) were reported more frequently in sutimlimab-treated patients compared with placebo
  • TESAEs were experienced by 3 patients (14%) in the sutimlimab arm compared to 1 patient (5%) in the placebo arm. In treatment arm, 1 experienced febrile infection and increased IgM (not attributed to sutimlimab and related to a low-grade B-cell lymphoma), 1 Raynaud phenomenon (not attributed to sutimlimab), and 1 cerebral venous thrombosis (possibly related to sutimlimab)
  • Two serious infections were reported (one fever of unknown origin in treatment arm that resolved on day 23 and one vascular device infection by Bacillus cereus in placebo arm). There was no development or worsening of autoimmune disease, no serious hypersensitivity reactions and/or anaphylaxis, and no deaths during the study

Commentary

Commentary: The CADENZA trial answers whether targeted classical complement inhibition with sutimlimab (C1s inhibitor) provides clinically meaningful improvement in anemia and hemolysis in adult patients with CAD (without recent transfusions) compared with placebo. The primary endpoint (a composite response defined as a Hgb increase ≥1.5 g/dL without transfusions or additional CAD-directed therapies between weeks 5 and 26) was met by a 73% in the sutimlimab arm compared with 15% in the placebo arm. Other findings included rapid improvements in hemoglobin, bilirubin, and patient-reported fatigue; fatigue improved within 1 week of treatment, while control of anemia and hemolysis within 3 weeks. These findings confirmed that classical complement activation plays a central role in CAD hemolysis and that targeted complement blockade can provide clinically meaningful hematologic and symptomatic benefit.

Despite these promising results, several limitations should be considered. The study population was relatively small, reflecting the rarity of CAD, and the trial duration was limited to 26 weeks in the randomized phase, restricting conclusions about long-term durability and safety. Nevertheless, part B of the study offers a longer-term efficacy and safety data that shows sustained improvement in these markers and no new safety signals. Additionally, sutimlimab targets complement-mediated hemolysis but does not address the underlying clonal B-cell disorder that produces the pathogenic IgM, meaning treatment likely needs to be continued indefinitely to maintain disease control. Furthermore, complement inhibition does not improve cold-induced circulatory symptoms such as acrocyanosis.

Overall, CADENZA provides high-level evidence that classical complement inhibition is an effective strategy for controlling hemolysis in CAD and establishes sutimlimab as an important therapeutic option, particularly for patients who require rapid control of anemia or who are not ideal candidates for B-cell–directed therapies.

References

Jäger U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, Jilma B, Kuter DJ, Michel M, Montillo M, Röth A, Zeerleder SS, Berentsen S. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Rev. 2020 May;41:100648. doi: 10.1016/j.blre.2019.100648. Epub 2019 Dec 5. PMID: 31839434.

Nico Ruiz Lopez MD completed medical school in Guatemala at Universidad Francisco Marroquin, followed by Internal Medicine residency at Boston University Medical Center and Hematology-focused fellowship at University of Washington/Fred Hutchinson Cancer Center. His clinical focus is in classical hematology, while his research focuses on outcomes in rare hematologic diseases such as immune cytopenias and thrombotic microangiopathies.