Röth, A., Barcellini, W., D’Sa, S., Miyakawa, Y., Broome, C.M., Michel, M., Kuter, D.J., Jilma, B., Tvedt, T.H., Fruebis, J. and Jiang, X., 2021. Sutimlimab in cold agglutinin disease. New England Journal of Medicine, 384(14), pp.1323-1334.
Clinical Question
In patients with cold agglutinin disease and a recent history of blood transfusion, does addition of sutimlimab result in normalization or increase of hemoglobin?
Background
Cold agglutinin disease is caused by IgM autoantibodies binding primarily to the I antigen on red blood cells at temperatures at or below 37°C1. IgM-antibody complexes bind to the C1 complex and activate the classical complement pathway, which triggers extravascular hemolysis in the liver and intravascular hemolysis mediated by C5b-C9.
Prior to the use of sutimlimab, therapies for cold agglutinin disease included rituximab, bendamustine or fludarabine, and eculizumab (C5 inhibitor). However, these treatment modalities were associated with only partial responses, severe neutropenia, and only small increases in hemoglobin, respectively.
Sutimlimab is a humanized monoclonal antibody targeting the enzymatically active C1s component of the C1 complex. In a phase 1b study, 7/10 (70%) patients with cold agglutinin disease experienced hemoglobin increase >2 g/dL after receipt of sutimlimab2. The CARDINAL study was conducted to study the efficacy and safety of sutimlimab among patients with cold agglutinin disease and recent transfusion3.
Study Design
- Multicenter, prospective, open-label, single-group clinical trial
- n = 24
- Setting: 16 study sites worldwide
- Timeline: Screening period (6 weeks), treatment period (26 weeks)
- Primary efficacy end point: Composite of a hemoglobin normalization (12 g/dL) or increase (2 g/dL) from baseline at assessment time point (mean at weeks 23, 25, 26).
- Key secondary end points:
- Mean change from baseline hemoglobin
- Hemolysis (per bilirubin and LDH)
- Quality of life (Functional Assessment of Chronic Illness Therapy [FACIT] Fatigue Scale)
- Number of transfusions (weeks 0-5)
- Pharmacodynamic end points:
- Total CH50 level
- Total C4 level
- C1q level
- Key safety end points:
- Adverse events
- Hemolytic breakthrough
- Grade 3+ infections
- Changes in antinuclear and anti–double-stranded DNA antibodies
- Laboratory studies
Populations
- Key inclusion criteria
- 18 years or older
- Confirmed cold agglutinin disease (chronic hemolysis, polyspecific direct antiglobulin test result positive, monospecific direct antiglobulin test strongly positive for C3d, direct antiglobulin tests with no greater than 1+ IgG positivity, cold agglutinin titer of 1:64 or higher, no known malignancy)
- Hemoglobin <10 g/dL
- Total bilirubin greater than normal range
- 1+ symptom (symptomatic anemia, acrocyanosis, Raynaud’s phenomenon, hemoglobinuria, disabling circulatory symptoms, major adverse vascular event)
- Key exclusion criteria:
- Cold agglutinin syndrome (secondary cold agglutinin-mediated hemolytic anemia complicating diseases such as Mycoplasma pneumoniae pneumonia, Epstein-Barr virus, or lymphoma4
- Systemic lupus erythematosus or other autoimmune disorder with antinuclear antibodies at screening
- Malignancy
- Treatment with rituximab monotherapy within 3 months of enrollment or rituximab+chemotherapy within 6 months of enrollment
- Clinically relevant infection (within 1 month before enrollment)
- Baseline characteristics:
- Median age (range): 72 (55-85)
- Female Sex: 62%
- Median (range) no. transfusions in past 6 months/1year: 2 (1-19), 2 (1-23)
- 62% of patients had ≥1 prior therapy for CAD within last 5 years, 33% with prior VTE, and 67% with prior CAD-related hospitalization
- Median (range) hemoglobin (g/dl), total bilirubin (micromole/liter), LDH (U/liter) were 8.7 (4.7-11.1), 46 (16-112), and 325 (160-1040)
Interventions
- Eligible patients received sutimlimab on days 0, 7, and every 2 weeks thereafter
- Red blood cell transfusions administered if (a) hemoglobin <7 g/dL or (b) symptoms and hemoglobin <9 g/Dl
Outcomes
- Primary outcome:
- 13/24 patients (54%, 95% CI 33-74) met primary end point (composite of hemoglobin normalization [12 g/dL] or increase [2 g/dL] from baseline at assessment time point [mean at weeks 23, 25, 26].
- 6/24 patients (25%) had evidence of treatment response (increase in the hemoglobin level at least by 0.8 g/dL)
- 3/24 patients (13%) had no evidence of treatment response
- Key secondary outcomes:
- Baseline hemoglobin: Mean change by +2.6 g/dL (95% CI 0.7-4.5), 17/24 (71%) transfusion-free during weeks 5-26
- Hemolysis: Mean change from baseline bilirubin by -2.2 mg/dL (95% CI 2-2.5), LDH decreased by at least 1.5 times the upper limit of normal range in 14/24 (58%) patients
- Quality of Life: Mean increase in score on FACIT Fatigue Scale +10.9 points (95% CI, 8-13.7)
- Pharmacokinetics: Mean classical complement activity decreased by approximately 15%
- Safety:
- Most frequent adverse events: Infections and infestations (54%), gastrointestinal disorders (33%), and general disorders or administration-site conditions (29%)
- Treatment-emergent adverse events (9/24, 38%)
- Treatment-emergent serious adverse events (7/24, 29%)
- 1 death attributed to newly diagnostic hepatic cancer diagnosed after enrollment.
Commentary
In the CARDINAL study, sutimlimab was found to increase mean hemoglobin level, normalize bilirubin level, reduce transfusion dependence, and decrease fatigue among patients with cold agglutinin disease, many of whom had experienced prior treatments. Pharmacokinetically, these changes corresponded to inhibition of the classical complement pathway.
Although cold agglutinin disease is associated with an increased risk of thromboembolic events, no patients developed new thromboembolism on study. Patients experienced treatment-emergent serious adverse events such as renal cell carcinoma and arthralgias. However, no obvious correlations between the study drug and these outcomes were appreciated, as most adverse events were unique to individual patients. Unlike eculizumab, sutimlimab was not found to predispose to meningococcal infection.
This study is limited by the single-group design and small sample size. Outcomes cannot necessarily be attributed to sutimlimab rather than natural disease trajectory in the absence of a comparator drug. However, sutimlimab does present a compelling alternative to rituximab, chemotherapy, and eculizumab by virtue of its majority response pattern and mild-moderate adverse event profile.
References
- Berentsen S. (2018). Complement Activation and Inhibition in Autoimmune Hemolytic Anemia: Focus on Cold Agglutinin Disease. Seminars in hematology, 55(3), 141–149. https://doi.org/10.1053/j.seminhematol.2018.04.002 ↩︎
- Jäger, U., D’Sa, S., Schörgenhofer, C., Bartko, J., Derhaschnig, U., Sillaber, C., Jilma-Stohlawetz, P., Fillitz, M., Schenk, T., Patou, G., Panicker, S., Parry, G. C., Gilbert, J. C., & Jilma, B. (2019). Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood, 133(9), 893–901. https://doi.org/10.1182/blood-2018-06-856930 ↩︎
- Röth, A., Barcellini, W., D’Sa, S., Miyakawa, Y., Broome, C.M., Michel, M., Kuter, D.J., Jilma, B., Tvedt, T.H., Fruebis, J. and Jiang, X., 2021. Sutimlimab in cold agglutinin disease. New England Journal of Medicine, 384(14), pp.1323-1334. ↩︎
- Berentsen, S., & Tjønnfjord, G. E. (2012). Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood reviews, 26(3), 107–115. https://doi.org/10.1016/j.blre.2012.01.002 ↩︎
Grace Ferri, MD completed medical school at Boston University School of Medicine followed by Internal Medicine residency at Boston Medical Center and hematology/oncology fellowship. She is a clinical fellow at Beth Israel Deaconess Medical Center in Boston, MA and interested in paraproteinemias.
