Cold Agglutinin Disease (CAD) Real-World Evidence (CADENCE) Registry: Design of the First International, Prospective CAD Registry

Introduction

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia in which hemolysis is mediated via the classical complement pathway. Its estimated incidence rate is 1 per 1 million persons per year, with a prevalence of 16 cases per 1 million persons. Patients with CAD can experience debilitating fatigue and poor quality of life (QoL), and they may have an increased risk of thromboembolism and early mortality. Owing to the rarity of the disease, information regarding the natural history of this condition and its long-term impact and complications is sparse (Jäger et al. Blood Rev. 2019). The rationale and design of a large, international database of patients with CAD is presented.

Methods

CADENCE is a multinational, multicenter, observational, prospective, longitudinal registry. Patients ≥18 years of age with primary CAD, secondary CAD/cold agglutinin syndrome, and mixed warm and cold autoimmune hemolytic anemia will be included. The main objective of this registry is to better understand various aspects of CAD, including patient and clinical characteristics, patterns of CAD treatment use, healthcare resource utilization (HRU), natural history of disease, long-term clinical outcomes, and impact on patient QoL. The enrollment period is expected to last ≥2 years, and patients will be followed for 3 years after enrollment. Data will be collected and analyzed at regional and global levels; sites will complete electronic case report forms, and patients will complete patient-reported outcome (PRO) questionnaires (36-Item Short Form Health Survey [version 2] and Functional Assessment of Chronic Illness Therapy-Fatigue scale) at enrollment and at intervals of about every 6 months during follow-up.

Results

The CADENCE Registry was launched in December 2019, with last patient last visit expected at the end of 2024. It is expected to enroll approximately 725 patients with CAD across 121 sites in multiple countries, including the United States, Canada, France, United Kingdom, Italy, Germany, Austria, Norway, Japan, Australia, and Spain (Figure). Data collected will include clinical characteristics, disease complications (eg, thromboembolism), comorbidities, mortality, treatment regimens, HRU, and PROs. Relevant biomarkers will be assessed. Interim analyses will be performed after 100 patients, 250 patients, and 500 patients are enrolled in the study. Final analyses will be performed at the end of the study both at regional and global levels.

Conclusions

As the first global registry for patients with CAD, CADENCE will help advance the understanding of the natural history and disease process of this ultra-rare disease for which the ability to conduct prospective trials with sufficient numbers of patients is challenging. This registry will provide clinicians with a data resource that may help improve treatment practices for patients with CAD.