New Therapy For Cold Autoimmune Hemolytic Anemia
Kakaiya, M.D., Medical Director
LifeSource Blood Center
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.
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.
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
Collectively, rituximab has been used in a total of 12 adult
patients with CAIHA1-2, 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
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.
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.
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Copyright © 2002,
Institute For Transfusion Medicine