New Therapy For Cold Autoimmune Hemolytic Anemia

Ram Kakaiya, M.D., Medical Director
LifeSource Blood Center

INTRODUCTION 

Clinical Presentation Of Cold Autoimmune Hemolytic Anemia (CAIHA)

CAIHA can be either acute or chronic. The acute type occurs after certain infections, such as, M. pneumoniae infection and infectious mononucleosis; and is always self-limited. The chronic variety is a rare autoimmune hemolytic disease characterized by a moderate degree of anemia and painful attacks of cyanosis of the extremities on exposure to cold (acrocyanosis). Many of the patients with chronic type are classified as having “secondary” CAIHA if they also suffer from a B-cell neoplasm, such as lymphoma, Waldenstrom macroglobulinemia, or chronic lymphocytic leukemia. In “primary” disease, no overt clinical neoplasm can be found, but the proliferation of CD20-positive clonal lymphocytes producing monoclonal cold agglutinins can be demonstrated in bone marrow of these patients. The cold agglutinin antibody is usually IgM with a titer >1:10⁵ that reacts with all adult red blood cells bearing carbohydrate antigen I. The antibodies react best at cold temperature (4C) and are generally inactive at 37C. They sensitize red blood cells with complement component C3b. Anemia results from clearance of the complement-sensitized cells in the liver.

Conventional Therapy

Prednisone is beneficial in patients with IgG cold agglutinins of low titer. However, it is not helpful in the vast majority of cases because cold agglutinins are usually IgM and high titered. Splenectomy is usually ineffective because sensitized red blood cells are generally cleared in the liver. Plasma exchange is helpful only as a temporizing measure in acute situations. B-cell neoplasms that respond to cytotoxic drugs may also have a salutary effect on CAIHA. However, the course of CAIHA waxes and wanes with the activity of the neoplasm.

Rituximab therapy

Because the response to previous therapies for CAIHA is poor and the fact that the cold hemagglutinins are produced by clonal proliferation of CD20⁺ B-lymphocytes, monoclonal anti-CD20 antibody (rituximab) therapy has been recently tried.

Rituximab is a genetically engineered hybrid murine/human monocloncal antibody directed against CD-20 antigens found on normal and malignant B-lymphocytes. It is currently approved for the treatment of non-Hodgkin’s lymphoma.

Collectively, rituximab has been used in a total of 12 adult patients with CAIHA^{1-2, 4-8}. Only three patients did not have any previous treatment. The remaining patients had failed previous treatments with one or more agents including corticosteroids, cyclophosphamide, chlorambucil, cyclosporine, and azathioprine. Plasma exchange or splenectomy had also been tried in some patients.

The average age of the patients was 65.4 years (range: 53 to 80 years). Seven of the 12 patients were males. Hemoglobin concentration averaged 8.0 gm/dl before the treatment. Because the patients were receiving red blood cell transfusions on as needed basis, the severity of anemia before the treatment with rituximab may have been underestimated. The cold hemagglutinin specificity of anti-I was reported in four patients.

Rituximab was given at a dose of 375 mg/M² by intravenous infusion once per week for four weeks. Rituximab was used in combination with other therapy in five patients.

Ten of 12 (83%) patients had a complete or partial response with rituximab. Six patients had a complete response and four had a partial response. The response to therapy was generally defined as an increase in hemoglobin concentration sufficient to obviate the need for further red blood cell transfusions and/or the resolution of symptoms. Cold agglutinin titers before and after the treatment were reported for seven patients. The average titer before treatment was 50,688 (range: 512 to 256,000) and decreased to 3078 after the treatment (range: 8 to 8196). In six instances, CD20⁺ B-lymphocytes were shown to decrease by 35% to 98% in bone marrow, as compared to the pre-treatment levels.  Hematologic parameters generally improved in 4 weeks from the start of the treatment. In responding patients, the hemoglobin level increased from an average of 8.0 gm/dl to 12.2 gm/dl. The mean duration of response was at least 11.9 months. Persistence of positive antiglobulin test (DAT) and continued elevation of LDH and/or haptoglobin levels despite improvement in patient’s hemoglobin concentration and symptoms suggest that these tests are not helpful in determining the clinical response to rituximab.

Rituximab treatment was well tolerated in all patients. Side effects consisted of transient leukopenia in two patients. Of particular interest, no infusion-related adverse events were seen (see below).

Limitations of the above observations include the fact that only a small number of patients with CAIHA have been treated with rituximab. Moreover, some of the patients were receiving other agents besides rituximab. In addition, the optimal number of infusions of rituximab needed to achieve a response is yet to be determined. The duration of follow up for most patients was short and therefore, delayed side effects of the therapy may not have been identified. Total duration of the response and the indications for re-therapy in relapsing patients also remain to be determined.

Despite the above limitations, the response to rituximab compares very favorably with the poor results observed with all other previous therapies for patients with CAIHA. Rituximab has been used with variable success in other B-lymphocyte disorders, such as, warm autoimmune hemolytic anemia and immune thrombocytopenia.  In fact, rituximab may be a more specific therapeutic agent compared to the others that have been used to treat the conditions in which CD20+ B-lymphocytes have a pathogenic role.

Side effects of Rituximab

As noted above, rituximab was well tolerated in patients with CAIHA. Specifically, no infusion-related side effects were seen. This is important because the product insert for rituximab contains a boxed warning indicating that deaths within 24 hours of rituximab infusions have been reported. The infusion reaction complex can include hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation or cardiogenic shock. Other serious reactions seen with rituximab therapy include tumor lysis syndrome, severe mucocutaneous reactions and prolonged impairment of humoral immune system leading to an increased risk of viral and bacterial infections. However, these serious reactions were not seen in patients described above.

Summary

Clinicians should be aware of the role of rituximab therapy in chronic cold autoimmune hemolytic anemia and should consider this treatment for selected patients after careful consideration of the risks and the benefits of such a therapy. Additional studies are clearly needed to more precisely define the optimal schedule of administration, duration of response, and indications for re-therapy with rituximab.

References

1. Bauduer F.  Rituximab: a very efficient therapy in  cold agglutinins and refractory autoimmune  haemolytic anaemia associated with CD20-positive, low-grade non-Hodgkin’s lymphoma.   Br J Haematol 112:1085-1086, 2001.
    

2. Berentsen S, Tjonnfjord GE, Brudevold R, et al. Favorable response to therapy with the anti-CD20 monoclonal antibody rituximab in primary chronic cold agglutinin disease. Br J Haematol 115:79-83, 2001.
    

3. Finazzi G.  Rituximab in autoimmune cytopenias: for which patients? Haematologica 87:113-114, 2002.
    

4. Gharib M and Poyton C.  Complete, long-term remission of refractory idiopathic cold hemagglutinin disease after abthera. Br J Haematol 117:248, 2002.
    

5. Layios N, van Den Neste E, Jost E et al. Remission of severe cold agglutinin disease after rituximab therapy. Leukemia 15:187-189, 2001.
    

6. Lee EJ and Kueck B. Rituxan in the treatment of cold agglutinin disease. Blood 92:3490-3491, 1998.
    

7. Sparling TG, Andricevic M and Wass H. Remission of cold hemagglutinin disease induced by rituximab therapy. CMAJ 164:1405, 2001.
    

8. Zala F, Russo D, Fuga G et al. Rituximab in a case of cold agglutinin disease. Br J Haematol 114:229-234, 2001.