Abstract Background: Cold agglutinin disease (CAD) is a rare clonal IgM disorder of haemolysis by antibodies that bind to I/i red cell antigens optimally at 4°C. CAD may lead to significant burden of disease and treatment directed at the underlying clone via chemoimmunotherapy or directed at the complement cascade. We evaluated the presenting features and outcomes of patients with CAD at our referral centre. Methods: Patients with CAD were retrospective analysed from 2016-2023 at our specialist referral centre. Details of baseline laboratory findings, clinical features, treatment and survival data were collected. Response was defined as a stable (2 consecutive measurements) increase in haemoglobin concentration of 20 g/L or to the normal range and no transfusion requirement. Overall survival (OS) was defined from the date of diagnosis of CAD to death or last follow-up. Analysis was performed using Stata v18.5 (StataCorp, Texas). Results: Fifty-four patients (23 male, 31 female) were included. Median age at CAD diagnosis was 67 (range 41-88) years, haemoglobin concentration was 88g/L (range 40-129), reticulocytes 120 x109/L (range 8-341), lactate dehydrogenase 373 U/L (range 153-1000) and total bilirubin 27 µmol/L (range 9-256). Median cold agglutinin titre at 4°C was 1024 (range 64-2048). DAT was positive for C3d in all and positive for IgM in 14 cases. Cryoglobulins were tested in 51 patients and co-existent in 51% (26/51): type I n=22, type II n=2, type III n=2. Median serum IgM monoclonal protein was 2.25g/L (range 0-53). Bone marrow histology results were available in 37 patients: 34 had an underlying MYD88L265 unmutated B-cell clone (median bone marrow infiltrate 5%, range 0-55%), 3 were MYD88L265P mutated and had infiltration by lymphoplasmacytic lymphoma without clinical features of overt lymphoma. The remaining did not have molecular testing performed. Cold-induced acrocyanosis was present in 66% (35/53) and thrombosis was observed in 22% of the entire cohort. At a median follow-up of 73 months (95% CI 53-103) after diagnosis of CAD, 11 patients died (1 CAD, 4 infection, 6 other). Estimated median overall survival was 14 years and 3-year and 5-year OS was 93% (95% CI: 81-98) and 86% (95% CI: 71-93), respectively. Fifteen patients (28%) were untreated and 17% (9/54) with erythropoietin stimulating agent as a part of supportive care. The median number of 1 (range 0-7) lines of therapy for CAD were administered. Rituximab monotherapy ± plasma exchange were most frequently employed (n=31) and, along with dexamethasone-rituximab-cyclophosphamide (n=7), achieved the highest response rates of 71% (22/31 and 5/7, respectively). Bortezomib combinations yielded a 67% response (2/3), as did R-CHOP-like combinations (4/6). Complement inhibitors were used in 13 patients with a 61% response rate (8/13). Bendamustine-rituximab, BTKi, and daratumumab each demonstrated response rates of 57% (4/7 each), while venetoclax produced a 50% response (1/2). Other combination therapies had a lower response rate of 33% (2/6), and mycophenolate mofetil or azathioprine showed no responses among 5 patients. Conclusion: Among 54 patients with CAD, many required multiple treatment regimens. Response rates exceeded 50% in the majority with best responses with traditional rituximab-based therapies and efficacy with clone and complement-directed therapy.
Japzon et al. (Mon,) studied this question.