Monoclonal antibodies for treatment of cold agglutinin disease

ABSTRACT

Introduction

Cold agglutinin disease (CAD) is a difficult-to-treat autoimmune hemolytic anemia and B cell lymphoproliferative disorder associated with fatigue, acrocyanosis, and a risk of thromboembolic events. Cold-induced binding of autoantibody agglutinates red blood cells and triggers the classical complement pathway, leading to predominantly extravascular hemolysis.

Areas covered

This review summarizes clinical and experimental antibody-based treatments for CAD and analyzes the risks and benefits of B cell and complement directed therapies, and discusses potential future treatments for CAD.

Expert opinion

Conventional treatment of CAD includes a B cell targeted treatment approach with rituximab, yielding only limited treatment success. The addition of a cytotoxic agent (e.g. bendamustine) increases efficacy, but this is accompanied by an increased risk of neutropenia and infection. Novel complement directed therapies have emerged and were shown to have good efficacy against hemolysis and safety profiles but are expensive and unable to address circulatory symptoms. Complement inhibition with sutimlimab may be used as a bridging strategy until B cell directed therapy with rituximab takes effect or continued indefinitely if needed. Future antibody-based treatment approaches for CAD involve the further development of complement directed antibodies, a combination of rituximab and bortezomib, and daratumumab. Non-antibody based prospective treatments may include the use of Bruton tyrosine kinase inhibitors.

KEYWORDS:

• Cold agglutinin disease
• autoimmune hemolytic anemia
• AIHA
• hemolysis
• lymphoproliferative
• rituximab
• complement inhibition
• sutimlimab
• eculizumab

Article highlights

• Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, caused by autoantibody-induced classical complement pathway-mediated erythrocyte destruction

• Rituximab is the mostly used first-line therapy but shows considerable response variability

• Rituximab in combination with a cytotoxic agent (bendamustine or fludarabine) enhances efficacy but increases the risk for neutropenia and infection

• Complement inhibition with sutimlimab is a safe and effective treatment for CAD

• An individualized treatment approach (B cell directed versus complement directed) is needed for the ideal management of CAD

• Future treatment options for CAD involve the advancement of complement inhibition therapy, combination of rituximab and bortezomib, and the anti-CD38 antibody daratumumab

Declaration of interest

S Berentsen has received consulting and advisory board honoraria from Annexon, Momenta Pharmaceuticals, Sanofi and Sobi, and lecture honoraria from Apellis, BeiGene, Janssen-Cilag, Sanofi and Sobi. B Jilma has received reimbursement of travel costs and for scientific advice, and lectures from Sanofi and reimbursement of travel costs related scientific presentations from SOBI. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

G Gelbenegger is supported by a grant from the Austrian Science Funds SFB54-P04.