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ASH 2023: Nonmalignant Hematology

CE / CME

Key Studies in Nonmalignant Hematology Disorders: Independent Conference Coverage of ASH 2023

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Pharmacists: 1.00 contact hour (0.1 CEUs)

Released: February 22, 2024

Expiration: February 21, 2025

Catherine M. Broome
Catherine M. Broome, MD
CME/CE Information

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Cold Agglutinin Disease: Background

The last presentation that I wish to highlight from ASH 2023 is for CAD. CAD Is a relatively rare subtype of autoimmune hemolytic anemia in which chronic hemolysis is caused by activation of the classical complement pathway.21 We are constantly learning more about CAD and have recently published new clinical data informing how we manage this disease.22,23

The complement pathway inhibitor sutimlimab is a humanized IgG4 monoclonal antibody directed against C1s.24  Sutimlimab acts by preventing complement pathway activation and complement-mediated hemolysis.22,23 It is FDA approved for treatment of hemolysis in adults with CAD, later receiving an expanded indication to encompass patients with or without previous history of transfusions.24   

The efficacy and safety of sutimlimab was evaluated in the single-arm phase III CARDINAL and the randomized, placebo-controlled phase III CADENZA trial.22,23 Based on these trials we learned that long-term treatment with sutimlimab (CARDINAL) is associated with improvements in efficacy, QoL, and safety is sustained for over 2 years.25

At ASH 2023, I presented a post-hoc analysis of the combined safety data from patients with CAD treated with sutimlimab through the phase III CARDINAL and CADENZA clinical trials.26

Pooled Safety Analysis of Sutimlimab in CAD: Study Design and Baseline Characteristics

The data pooled in this safety analysis of sutimlimab was from the phase III CARDINAL and phase III CADENZA trials. The difference between these 2 studies is that patients in CARDINAL had to have a recent history of RBC transfusion and those in CADENZA did not, which provides a window into how severely impacted by the disease patients in each of these trials were. Another key difference between the 2 trials is that CADENZA was a placebo‑controlled clinical trial. In total, this analysis included 66 patients, which is not that many for a phase III study, but I would like to remind you that this is a relatively rare disease in the general population.

The main objective of the analysis was to capture additional data on the long-term safety of sutimlimab including treatment-emergent AEs, treatment-emergent serious AEs, and AEs of special interest (chosen based on important identified and potential risks with sutimlimab).  

The median age was approximately 70 years (range: 46-88), 72% were women, and the median duration of CAD diagnosis to study entry was approximately 6 years. The median follow up was 129 weeks (range 5-175).

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Pooled Safety Analysis of Sutimlimab in CAD: TEAEs and TESAEs

The median treatment duration in the CARDINAL and CADENZA trial was 144 and 125 weeks, respectively.

The total number of treatment‑emergent AEs was 385 and 425 of patients enrolled in the CARDINAL and CADENZA trials, respectively. However, the number of treatment-related AEs possibly related to therapy were only 15 and 70, respectively― which I think overall was relatively low. Treatment-emergent serious AEs were reported in a total of 53 patients. Overall, the number of patients with ≥1 treatment-emergent serious AEs was 22 (33%). Here again, the number of possibly related treatment-emergent serious AEs was much lower at a total of 3 (4.6%).

Possibly related treatment-emergent AEs observed in >1 patient included headache, acrocyanosis, fatigue, hypertension, injection site erythema, nausea, and pyrexia. Possibly related serious AEs occurring in 3 (4.6%) patients included vitreous hemorrhage, a viral infection, and a case of cerebral vein thrombosis.

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Pooled Safety Analysis of Sutimlimab in CAD: AESIs

Looking at AEs of special interest, the most common were serious infection events, hypertension, acrocyanosis, and thromboembolic events.

Of importance, there were no treatment‑emergent AEs for hypersensitivity reaction or anaphylaxis. There also were no meningococcal infections or systemic lupus erythematosus. The latter is important because in patients genetically lacking C1, there is an increased rate of development of systemic lupus erythematosus, but fortunately exogenous blockade of C1 with a monoclonal antibody does not appear to have the same effect. In addition, and because all of these patients were monitored very carefully, there was no development of lupus in any of these patients.

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Pooled Safety Analysis of Sutimlimab in CAD: Conclusions and Takeaways

There were relatively few discontinuations (n = 7) related to ≥1 treatment emergent AE (eg, 3 in CARDINAL; and 4 in CADENZA). Two patients discontinued sutimlimab for possibly related treatment-emergent AEs in CARDINAL (1 due to vitreous hemorrhage in a patient with recurrent uveitis and latent tuberculosis; and 1 due to acrocyanosis and gastrointestinal symptoms [erosive gastritis]).

One patient in CADENZA discontinued treatment for a possibly related treatment-emergent AE of infusion‑related reaction which presented with pain in lumbar spine and both legs.

There were 4 deaths on study, but none were deemed related to the study drug. One patient had sutimlimab discontinued due to development of a squamous cell lung carcinoma, and another patient acquired a fatal infection with Klebsiella pneumoniae and acrocyanosis following premature discontinuation of the study drug. One patient had a new diagnosis of hepatic cancer in the first month of the trial, and the fourth patient had a CAD exacerbation approximately 1.5 months after the last dose during the 9‑week washout period.

Pooled Safety Analysis of Sutimlimab in CAD: Conclusions and Takeaways

In this post-hoc analysis of combined safety data from the phase III CARDINAL and CADENZA trials evaluating sutimlimab, 45.5% of patients with CAD developed ≥1 treatment-emergent AE possibly related to sutimlimab, and 1.0% to 25.8% of patients experienced an AE of special interest (eg, serious infections, hypertension, acrocyanosis and/or Raynaud phenomenon, thromboembolic events). This combined safety analysis demonstrated that sutimlimab has a tolerable safety profile.

Overall, we show that sutimlimab long-term administration was safe. Approximately 45% of patients developed 1 treatment‑emergent AE possibly related to sutimlimab use. There were 4 deaths in the study, but none was deemed related to sutimlimab use.

This combined safety analysis shows that sutimlimab has a tolerable safety profile and some of the AEs seen might be expected in this older, medically complex patient population. Together, these results give us additional comfort and reassurance when considering using sutimlimab drug in an older patient population.

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