Anti‐CD20 monoclonal antibody (rituximab) therapy in a child with refractory chronic autoimmune haemolytic anaemia

We report a case of a child with refractory, chronic autoimmune haemolytic anaemia in whom rapid remission was achieved with rituximab. A 9-month-old Kuwaiti girl first presented in 1993, with: (i) severe anaemia, (ii) haemoglobin (Hb) 34 g/L, (iii) reticulocytosis 480 × 109/L (50–150 × 109/L), (iv) spherocytosis, (v) unconjugated hyperbilirubinaemia 210 mmol/L and (vi) a direct antiglobulin test (DAT) strongly positive for IgG but negative for C3. A diagnosis of warm antibody-mediated idiopathic autoimmune haemolytic anaemia (AIHA) was made. Treatment consisted of transfusion, i.v. immunoglobulin (IVIG) 400 mg/kg per day for 3 days and prednisolone 2 mg/kg. Over the ensuing 6 years she had continuing haemolysis and remained steroid-dependent. She underwent splenectomy in 1999, but continued to haemolyse and to require steroids, despite the addition of cyclosporin A 1.5 mg/kg b.i. d. and mycophenolate 250 mg b.i. d. Steroid-dependency caused recurrent infections and cushingoid features with growth failure, skeletal osteopenia and truncal obesity. In early October 2001, four doses of rituximab (Mabthera; Roche Products Limited, London) were administered (375 mg/m2 per week). Her haemolysis improved within a week of commencing therapy and within 3 weeks her Hb had risen to 142 g/L. DAT became negative 5 weeks after commencing treatment. Prednisolone was tapered and discontinued over 3 months. The patient remains disease-free 10 months after treatment. Rituximab is a genetically engineered chimeric human/murine anti-CD20 monoclonal antibody. Following binding to the CD20 antigen expressed by the majority of cells of B-cell lineage it causes cell lysis via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and induction of apoptosis.1 Rituximab has been approved for the treatment of relapsed CD20-positive low-grade follicular non-Hodgkin lymphoma.2 It has also been used, with varying efficacy, in the treatment of other B-cell haematological malignancies expressing CD20. More recently, rituximab has proved to be effective in the treatment of immune cytopenias and IgM-related polyneuropathies and, as a immunosuppressant (via B-cell depletion), in autoimmune conditions including rheumatoid arthritis. The most convincing evidence of benefit in refractory haemolytic anaemia has been reported in cold haemoglutinin disease, where up to 85% of patients refractory to standard therapy may achieve a remission.3 Refractory AIHA case reports and small uncontrolled studies have demonstrated partial or complete haematological remission in approximately 50% of patients.4 The efficacy and sustained benefit of rituximab in AIHA are likely to result from its capacity to rapidly deplete pre-Band B-lymphocytes, thereby preventing generation and expansion of antibody-secreting autoreactive cells. However, the rapid clinical response seen in our patient, and in others4 suggests an alternative mechanism, such as inhibition of macrophage Fc-receptor function or clearance of IgG-coated red cells. There are limited reports of rituximab in refractory childhood AIHA.5,6 This is unsurprising because AIHA in children is usually responsive to treatment and is generally self-limited. Where it becomes recurrent or chronic it is frequently refractory to all therapy and the morbidity and mortality of further treatment are considerable. Our case adds to the literature suggesting that rituximab may be of value in relapsing/refractory AIHA. Further trials are needed to investigate the mechanism of action, remission rates, dosing schedules, re-treatment protocols, long-term safety and the need for prophylactic IVIG.