Folic acid supplementation is advisable in individuals with cold agglutinin disease to meet the increased requirements, as a result of hemolytic anemia, for RBC production.
Immunosuppressive and immunomodulating drugs are seldom necessary; however, in cases with underlying malignancies, these agents are required to treat the malignancy. Potent immunosuppression to reduce the production of monoclonal antibody and to reduce/eliminate the abnormal lymphocyte clone has been achieved with cyclophosphamide (1200 mg) and vincristine (2 mg) administered intravenously (IV) on day 1 and prednisone (80 mg/d) administered orally for 5 days, with some beneficial effect in an anecdotal case. 
The same patient was treated 10 months later with IV fludarabine (25 mg/m2) daily for 5 days and then every 28 days for 3 courses. Following a third course of treatment, the patient went into remission that lasted for at least 4 years. 
Corticosteroids alone may not be routinely useful in patients with cold agglutinin disease, although occasionally a patient may have a clinical response. Patients with mixed cold and warm immune hemolytic anemia are more likely to have a response because of the warm antibody component.
The corticosteroid-sparing agent chlorambucil has also been used to treat cold agglutinin disease. 
Rituximab and fludarabine
Rituximab has been widely recognized as being very effective for treating cold agglutinin disease. One study documented a high response rate and durable remissions following therapy using a combination of fludarabine and rituximab. While the results from this study appear positive, extreme caution should be exercised, because the immunosuppressive effects of rituximab superimpose on those of fludarabine. 
Bear in mind that one uncommon reported adverse effect of fludarabine is the appearance of a warm autoantibody–induced autoimmune hemolytic anemia. However, according to the authors' experience, persons with Coombs-positive hemolytic anemias have been treated effectively with fludarabine. Responses to interferon alfa therapy have been reported. This therapy may be useful for some B-cell neoplasms. 
The reader is advised to read the package insert approved by the US Food and Drug Administration (FDA) before using any of the agents listed.
In general, the use of chemotherapeutic agents—which have long-term consequences for the patient and are associated with secondary malignancies, such as leukemias, that are hard to treat—requires very careful decision making in collaboration with a well-informed patient. These agents should be used only for life-threatening, severely symptomatic disease. Therapy also may need to be administered intermittently or infrequently, as the case demands. Tailor therapy to individual needs.
Although alkylating agents have been used in the past and references to these treatments are part of standard texts, the authors suggest that these drugs not be used in patients with cold agglutinin disease, because of the potential for long-term adverse effects from such therapy.
Identifying the proper drug for use in a patient depends on patient characteristics and patient participation in the decision-making process. No guarantees of success can be given with any therapy in cold agglutinin disease.
The metabolites of immunosuppressive alkylating agents cross-link DNA, thereby interfering with cell proliferation. These agents are not needed in patients with idiopathic cold agglutinin disease. Immunosuppressant agents also include antibodies directed against the CD20 antigen found on the surface of B-lymphocytes.
This agent is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Cystitis can develop with long-term administration, and the leukemogenic potential should be kept in mind. The primary (idiopathic) form of cold agglutinin disease is unlikely to require use of this class of drugs.
These agents elicit anti-inflammatory and immunosuppressive properties, causing profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
This agent is an immunosuppressant used for the treatment of autoimmune or lymphoproliferative disorders. Prednisone modulates lymphocytes and decreases antibody production. It is frequently used with alkylating agents.
Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. It stabilizes lysosomal membranes and suppresses lymphocyte and antibody production. Prednisone may be beneficial in certain cases with low-titer cold agglutinin of high thermal amplitude.
Interferons have had variable success in cold agglutinin–induced hemolytic anemia. Expense and serious adverse effects are issues to consider up front before choosing this class of drug. Interferons are used in the treatment of lymphoproliferative disorders.
Interferon alfa is manufactured by recombinant DNA technology. Its mechanism of effect is not clearly understood. However, direct antiproliferative effects against many different kinds of malignant cells have been shown in clinical disease states (eg, lymphoma, melanoma, chronic granulocytic leukemia), and modulation of the host immune response may play an important role.
Vitamin, Water Soluble
Water-soluble vitamins are necessary for hematopoiesis.
Folic acid is an important cofactor for enzymes used in the production of RBCs. Chronic hemolytic process requires additional folate.
Immunosuppressive agents include antibodies that are directed against the CD20 antigen found on the surface of B-lymphocytes.
Effective lowering of IgM and IgG levels is achievable with this anti–B cell antibody. Hypersensitivity reactions can be severe; users of the drug should become completely familiar with the adverse reactions known to occur.
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