Key points from the evidence

Summary Limited high‑quality evidence was identified that investigated how well rituximab works for treating autoimmune haemolytic anaemia. One randomised controlled trial suggested that after 12 months, prednisolone plus rituximab was more effective than prednisolone monotherapy for inducing a complete response to treatment in adults with newly diagnosed and previously untreated warm autoimmune haemolytic anaemia. Other uncontrolled studies suggested some effectiveness of rituximab in warm and cold autoimmune haemolytic anaemia, but limitations of these studies make it difficult to draw any firm conclusions. Regulatory status: off‑label. This topic was prioritised because there was a high volume of requests from the NHS. Effectiveness A randomised controlled trial (RCT) in 64 adults with newly diagnosed and previously untreated warm autoimmune haemolytic anaemia suggested that after 12 months, prednisolone plus rituximab was statistically significantly more effective than prednisolone monotherapy for inducing a complete response to treatment (complete response rate 75% compared with 36% respectively; p=0.003).

Uncontrolled studies in people with warm autoimmune haemolytic anaemia (4 studies; n=101 in total) reported complete response rates ranging from 27% to 67%.

Uncontrolled studies in people with cold haemagglutinin disease (5 studies; n=142 in total) reported complete response rates ranging from 4% to 54%.

The non‑randomised nature of the uncontrolled studies, differing populations, and lack of standard definitions for response to treatment make it difficult to draw any firm conclusions from this evidence. Safety The summary of product characteristics (SPC) for rituximab describes that infusion‑related reactions are very common (more than 1 in 10) in people treated with intravenous rituximab. Severe infusion‑related reactions with a fatal outcome have been reported in post‑marketing use.

Serious infections, including fatalities, can occur during rituximab therapy, and rituximab is contraindicated in people with an active, severe infection, and in people who are severely immunocompromised.

Very rare cases of fatal progressive multifocal leukoencephalopathy have been reported after using rituximab and people should be monitored at regular intervals for any new or worsening neurological symptoms or signs suggestive of this condition.

In the RCT, the most commonly reported adverse events in people in the prednisolone monotherapy and prednisolone plus rituximab groups were dyspnoea (16.7% compared with 13.3% respectively), fatigue (13.3% in both groups), headache (13.3% compared with 6.7% respectively), dyspepsia (13.3% compared with 3.3% respectively) and insomnia (10% in both groups). Patient factors Rituximab is administered as an intravenous infusion over several hours, or subcutaneously.

All the studies in this evidence summary used intravenous rituximab. Resource implications Most studies in this evidence summary used intravenous rituximab at a dosage of 375 mg/m 2 body surface area weekly for 4 weeks: The cost for a 4‑week course based on an adult with a body surface area of 1.86 m 2 is estimated to be £4889.60 (assuming wastage and excluding VAT; MIMS January 2015). The cost for a 4‑week course based on a child with a body surface area of 0.89 m 2 is estimated to be £2794 (assuming wastage and excluding VAT; MIMS January 2015).

One study used a lower fixed dose of rituximab 100 mg weekly for 4 weeks. The cost for a 4‑week course using this lower fixed dose is £698.50 (excluding VAT; MIMS January 2015).

Introduction and current guidance Autoimmune haemolytic anaemia is a relatively rare condition caused by autoantibodies directed against a person's own red blood cells. The condition has warm and cold antibody types. Warm antibody type can be idiopathic or secondary to other conditions such as systemic lupus erythematosus, lymphoma, chronic lymphocytic leukaemia or Evans syndrome. Cold antibody types include cold haemagglutinin disease and paroxysmal cold haemoglobinuria (Zanella and Barcellini 2014; and haemolytic anaemia; patient.co.uk). There are currently (January 2015) no evidence based guidelines for treating autoimmune haemolytic anaemia. The British Committee for Standards in Haematology is in the process of producing a guideline on autoimmune haemolytic anaemia (see guidelines in progress for more information). For warm autoimmune haemolytic anaemia, first‑line treatment is normally with corticosteroids which are effective in 70−85% of people. Splenectomy and off‑label conventional immunosuppressive drugs have been traditionally used as second‑line treatments, and recently rituximab has also been used as a second‑line treatment option. If treatment is required in cold haemagglutinin disease, corticosteroids, splenectomy and conventional immunosuppressants are much less effective, and over the last 10−15 years, on the basis of limited published data, rituximab has become first‑line treatment (Zanella and Barcellini 2014). Rituximab is available as a solution for intravenous infusion, and as a subcutaneous injection. Studies included in this evidence review used the intravenous formulation of rituximab, and so the evidence summary focuses on the intravenous formulation only. Full text of introduction and current guidance.

Product overview Rituximab concentrate for solution for intravenous infusion (MabThera, Roche Products Limited) is licensed in adults for treating non‑Hodgkin's lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis. It is administered as an intravenous infusion, which can take several hours, depending on the dose and rate of infusion. Rituximab is not licensed for treating autoimmune haemolytic anaemia and so use for this indication is off‑label. NICE has published an evidence summary on another off‑label use of rituximab: Immune (idiopathic) thrombocytopenic purpura: rituximab (ESUOM 35). In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using rituximab outside its authorised indications. Rituximab 10 mg/ml concentrate for solution for intravenous infusion (MabThera, Roche Products Limited) costs (excluding VAT, MIMS January 2015): 2×10 ml=£349.25

1×50 ml=£873.15 Full text of product overview.

Context and estimated impact for the NHS Comparing the cost of rituximab with other therapies for autoimmune haemolytic anaemia is difficult because there is a lack of evidence to confirm the optimal dose, guide the use of recurrent courses in refractory cases, and confirm the advice on other aspects of the clinical pathway such as combination with other treatments. Most of the studies in this evidence summary used rituximab at a dosage of 375 mg/m2 body surface area weekly for 4 weeks. Costs would vary depending on the height and weight of a person. As an approximate guide, the cost for a 4‑week course based on an adult with a body surface area of 1.86 m2 is estimated to be £4889.60 (assuming wastage and excluding VAT; MIMS January 2015). The cost for a 4‑week course based on a child with a body surface area of 0.89 m2 is estimated to be £2794.00 (assuming wastage and excluding VAT; MIMS January 2015). One study investigated using a lower fixed dose of rituximab of 100 mg weekly for 4 weeks. The cost for a 4‑week course using this lower fixed dose is £698.50 (excluding VAT; MIMS January 2015). Full text of context and estimated impact for the NHS.