Cold agglutinin disease revisited: a multinational, observational study of 232 patients
Berentsen, Sigbjørn; Barcellini, Wilma; D'Sa, Shirley; Randen, Ulla; Tvedt, Tor Henrik Anderson; Fattizzo, Bruno; Haukås, Einar; Kell, Megan; Brudevold, Robert; Dahm, Anders Erik Astrup; Dalgaard, Jakob; Frøen, Hege; Hallstensen, Randi; Jæger, Pernille Horgmo; Hjorth-Hansen, Henrik; Malecka, Agnieszka Maria; Oksman, Markku; Rolke, Jürgen; Sekhar, Mallika; Sørbø, Jon Hjalmar; Tjønnfjord, Eirik; Tsykunova, Galina; Tjønnfjord, Geir Erland
Peer reviewed, Journal article
MetadataShow full item record
Original versionBlood. 2020, 136 (4), 480-488. 10.1182/blood.2020005674
We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.