The impact of individual clinical features in cold agglutinin disease: hemolytic versus non-hemolytic symptoms

ABSTRACT

Introduction

During the last decades, the pathogenesis of cold agglutinin disease (CAD) has been well elucidated and shown to be complex. Several documented or investigational therapies have been made available. This development has resulted in major therapeutic advances, but also in challenges in choice of therapy.

Areas covered

In this review, we address each step in pathogenesis: bone marrow clonal lymphoproliferation, composition and effects of monoclonal cold agglutinin, non-complement mediated erythrocyte agglutination, complement-dependent hemolysis, and other effects of complement activation. We also discuss the heterogeneous clinical features and their relation to specific steps in pathogenesis, in particular with respect to the impact of complement involvement. CAD can be classified into three clinical phenotypes with consequences for established treatments as well as development of new therapies. Some promising future treatment approaches – beyond chemoimmunotherapy and complement inhibition – are reviewed.

Expert opinion

The patient’s individual clinical profile regarding complement involvement and hemolytic versus non-hemolytic features is important for the choice of treatment. Further development of treatment approaches is encouraged, and some candidate drugs are promising irrespective of clinical phenotype. Patients with CAD requiring therapy should be considered for inclusion in clinical trials.

KEYWORDS:

• Cold agglutinin disease
• pathogenesis
• clinical phenotypes
• hemolytic anemia
• circulatory symptoms
• complement
• therapy

Article highlights

• CAD is an autoimmune hemolytic anemia and a specific clonal lymphoproliferative disorder.

• Pathogenesis is complex, comprising complement-mediated as well as non-complement mediated mechanisms resulting in the respective clinical features.

• Until now, treatments have aimed at targeting the clonal B-cells or the classical complement activation pathway.

• Treatment should be individualized based on clinical phenotypes, patient preferences, and availability.

• Several new therapeutic agents are being developed, including entirely new principles of therapy.

• Clinical phenotypes of CAD will also have impact on development of new therapies.

Declaration of interest

S Berentsen has received consultancy and advisory board honoraria from BeiGene, HillStar Bio, Hummingbird Bioscience, Sanofi, and Sobi, and has received lecture honoraria from BeiGene, Janssen-Cilag, Sanofi, and Sobi. JMI Vos has received consultancy and advisory board honoraria from Sanofi and Janssen, has received research support from Beigene and Abbvie/Genmab, and has participated in the speakers’ bureau for BMS, Sanofi, and Amgen, with all honoraria directed to their institution. GE Tjønnfjord has received research grants from Mundipharma and Alexion Pharmaceuticals, has received advisory board honoraria from Alexion Pharmaceuticals and Janssen-Cilag, and has received lecture honoraria from Novartis, Janssen-Cilag, Alexion Pharmaceuticals, and Mundipharma, with all honoraria directed to their institution. S D’sa has received consultancy and advisory board honoraria from Janssen, BeiGene, Sanofi, HillStar Bio and Kite Pharma, and has received research funding from BeiGene and Janssen. 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 on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.