Rituximab For The Treatment Of Hepatitis C Associated IgM Mediated Cold Hemolytic Anemia – Case Report and Literature Review

In April 2007 a 48-year-old woman with a history of hepatitis C and anti-phospholipid antibody syndrome presented with a hemoglobin (Hb) of 5.3g/dL. Lactate dehydrogenase and bilirubin were elevated at 582U/L and 66µmol/L respectively. Severe autoimmune hemolytic anemia due to cold agglutinins was diagnosed based on a positive DAT (C3B and C3D positive, IgG negative) and detection of cold agglutinins. The patient was discharged 4 days later with a Hb of 8.3g/dL after plasma exchange and transfusion of 3 units of RBCs. Immunosuppressive therapy was initially avoided due to the risk of hepatitis C activation. Treatment over the next 12 months consisted of as needed RBC transfusions and IVIg infusions. Treatment with corticosteroids occurred only during 1 of 2 hospital admissions for severe anemia – the patient otherwise refused corticosteroid treatment. Although responses to IVIg were consistently favorable they were short lived. Rituximab was administered in an effort to achieve a more sustained treatment response. The dose of 375mg/m²weekly for 4 weeks was administered in August 2008. A dramatic but transient decrease in IVIg requirements was observed. Periodic treatment with IVIg was continued over the next 19 months until a second rituximab course was administered in June 2010. IVIg has been required on only 6 occasions in the almost three years since the second rituximab course (see Figure 1).

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To determine the efficacy of rituximab in this condition, we searched the MEDLINE and EMBASE databases. Articles citing the use of rituximab to treat mixed-type or cold autoimmune hemolytic anemia (CAIHA) were identified. Ten studies (summarized in Table 1) and 43 case reports/series (48 total cases) met our criteria for inclusion. A complete response (CR) required Hb>12g/dL and the sustained absence of hemolysis. Disappearance of cold agglutinins was not required for a CR. A partial response (PR) required an improvement of symptoms, transfusion independency, and either: Hb>10g/dL or at least 2.0g/dL above pre-treatment levels, or a decrease in serum IgM concentration by at least 50%. Non-responders met neither CR nor PR criteria. Ages of the 26 male and 22 female patients ranged from 1-85 years with a median of 62 years. Diagnoses of CAIHA were reported in 40 cases, and mixed-type in 8. On average, patients had received 3 modes of treatment prior to rituximab. CRs were observed in 34 patients (70.8%), PRs in 7 (14.6%), and NRs in 7 (14.6%). Three of the 7 non-responders experienced an improvement in condition despite not meeting response criteria. Adverse effects were reported in only 3 cases and included a post-infusion low-grade fever, transient lymphopenia, and agranulocytosis (possibly due to CMV reactivation and not rituximab therapy).

In summary, we report a case of CAIHA. A literature summary supported the efficacy of rituximab for this condition. Based on our observations we recommend the use of rituximab over alternative therapies for patients with CAIHA to reduce symptoms, need for transfusion and reduce exposure to immunosuppressive drugs (Grade 2C Recommendation).