Cold agglutinin disease (CAD) is a clonal B-cell lymphoproliferative disorder of the bone marrow that leads to the development of an autoimmune hemolytic anemia (AIHA). Autoantibodies designated as cold agglutinins, which function at an optimal temperature of 3°C to 4°C and frequently belong to the immunoglobulin M (IgM) class, cause red blood cells to agglutinate.1 The immune attack on the red blood cells results in hemolysis. The premature destruction of the red blood cells is not compensated by the production of new cells in the bone marrow, so that symptoms of anemia (the reduced number of red blood cells), such as fatigue, dizziness, palpitations, and dyspnea, develop.2
When patients who have CAD present with mild symptoms, nonpharmacological treatment can be implemented, such as thermal protection, in which exposure to cold temperatures is avoided. When an increase in red blood cell destruction is observed, however, pharmacological treatment is recommended.2 Recent studies suggest that treatment should be started in any of the following situations: clinical symptoms of anemia; hemoglobin level below 10 g/dL; transfusion requirement; disabling cold-induced circulatory symptoms.1
The use of nonspecific immunosuppressive therapies, such as azathioprine and cyclosporine, lacks supportive evidence.1,3 Erythropoietin (EPO) may be considered for selected patients. High doses of EPO have been associated with increases in the hemoglobin levels of patients with AIHA.4,5 Folic acid supplementation may also be used; however, this recommendation is based on theoretical considerations.3
Corticosteroids have previously been prescribed to patients with CAD; however, they are not currently recommended. Available data indicate that the rates of response to these drugs may be as low as 20%. In addition, high maintenance doses are needed, which are not considered safe.1,6
Therapies Directed at B-cells
Rituximab is considered a first-line therapy for patients with CAD, even though it is not approved by either the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for this indication.2,6 Rituximab is a monoclonal antibody with a specific affinity for CD20 antigen, a B-lymphocyte transmembrane protein that is expressed on many B cells, thereby preventing production of the autoantibodies that induce red blood cells lysis.2,7
In 2 prospective non-randomized trials, 4 weekly infusions of rituximab at 375 mg/m2 led to overall response rates of 45% to 54%, and to a duration of response of approximately 1 year.8,9 The median increase in hemoglobin levels reached 4.0 g/dL, with a median time to response of 1.5 months. Complete responses were rare.8 Treatment with rituximab is well tolerated, with few associated adverse events; however, relapses are common.2,3
Rituximab can be given in combination with a chemotherapy agent–either fludarabine or bendamustine.2 The use of fludarabine with rituximab has been studied in a prospective nonrandomized trial of 29 patients with a median age of 73 years; during 4 treatment cycles, each lasting 28 days, rituximab at 375 mg/m2 was administered on day 1 and fludarabine at 40 mg/m2 on days 1 to 4.10 The overall response rate was 76%, and the median duration of response was 66 months. Hematologic toxicity occurred in 41% of the patients, and infections developed in 59%. Because of the possibility of long-term toxic effects, fludarabine should be used with caution.
The efficacy of bendamustine added to rituximab therapy was studied in a nonrandomized multicenter trial of 45 patients with median age of 74 years.11 Rituximab at 375 mg/m2 was administered on day 1 and bendamustine at 90 mg/m2 on days 1 and 2 of 4 cycles, each lasting 28 days. In this study, 40% of the participants showed a complete response, and 31% had a partial response. The hemoglobin levels increased by a median of 4.4 g/dL in the participants with a complete response and by 3.9 g/dL in the participants with a partial response. Remission was observed in participants after 32 months of treatment. Adverse effects such as neutropenia developed; however, these were mild and correlated with the toxicity of bendamustine. Rituximab/bendamustine combination therapy should be the first treatment option to consider for patients who have severe CAD and no relevant comorbidities, and who can receive chemotherapy.1
Bortezomib as monotherapy has also been evaluated in a prospective trial of 19 patients.12 Of these participants, 6 responded to treatment; 3 had a complete response and 3 had a partial response. Additional studies are needed to support the further use of this drug, either as monotherapy or in combination therapy.
1. Berentsen S, Malecka A, Randen U, Tjønnfjord GE. Cold agglutinin disease: where do we stand, and where are we going? Clin Adv Hematol Oncol. 2020;18(1):35-44. PMID: 32511221.
2. Cold agglutinin disease. National Organization for Rare Disorders. Accessed September 7, 2021.
3. Berentsen S. How I manage patients with cold agglutinin disease. Br J Haematol. 2018;181(3):320-330. doi:10.1111/bjh.15109
4. Salama A, Hartnack D, Lindemann HW, Lange HJ, Rummel M, Loew A. The effect of erythropoiesis-stimulating agents in patients with therapy-refractory autoimmune hemolytic anemia. Transfus Med Hemother. 2014;41(6):462-468. doi:10.1159/000366244
5. Fattizzo B, Michel M, Zaninoni A, et al. Efficacy of recombinant erythropoietin in autoimmune hemolytic anemia: a multicenter international study. Haematologica. 2021;106(2):622-625. doi:10.3324/haematol.2020.250522
6. Berentsen S. New Insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590. doi:10.3389/fimmu.2020.00590
7. Salles G, Barrett M, Foà R, et al. Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience. Adv Ther. 2017;34(10):2232-2273. doi:10.1007/s12325-017-0612-x
8. Berentsen S, Ulvestad E, Gjertsen BT, et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004;103(8):2925-2928. doi:10.1182/blood-2003-10-3597
9. Schöllkopf C, Kjeldsen L, Bjerrum OW, et al. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma. 2006;47(2):253-260. doi:10.1080/10428190500286481
10. Berentsen S, Randen U, Vågan AM, et al. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010;116(17):3180-3184. doi:10.1182/blood-2010-06-288647
11. Berentsen S, Randen U, Oksman M, et al. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017;130(4):537-541. doi:10.1182/blood-2017-04-778175
12. Rossi G, Gramegna D, Paoloni F, et al. Short course of bortezomib in anemic patients with relapsed cold agglutinin disease: a phase 2 prospective GIMEMA study. Blood. 2018;132(5):547-550. doi:10.1182/blood-2018-03-835413
Reviewed by Harshi Dhingra, MD, on 9/7/2021.