Advice

Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in February 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

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/m2 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 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 (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.

Evidence review

  • Only 1 RCT was identified that investigated using rituximab for autoimmune haemolytic anaemia. This evidence summary therefore also includes the largest uncontrolled studies that provide the best available evidence for using rituximab for treating autoimmune haemolytic anaemia. A meta analysis (Reynaud et al. 2014) of the 1 RCT and 20 uncontrolled studies of rituximab in autoimmune haemolytic anaemia has recently been published. However, it has a number of limitations.

  • Most studies used rituximab at a dosage of 375 mg/m2 body surface area weekly, usually for 4 doses. One study used the same dose of rituximab but at an interval of every 28 days for 4 doses, and another study used a lower fixed dosage of 100 mg weekly for 4 weeks.

  • The RCT by Birgens et al. 2013 compared prednisolone monotherapy with prednisolone plus rituximab therapy in 64 adults aged 18 years and over (median age 65−67 years) with newly diagnosed and previously untreated warm autoimmune haemolytic anaemia. At 3 and 6 months after treatment, there was no statistically significant difference in complete response (defined as normalised haemoglobin concentration without any ongoing immunosuppressive treatment) or any response (complete or partial [defined as normalised haemoglobin concentration but requiring ongoing treatment with less than 10 mg daily prednisolone]) between the prednisolone monotherapy and the prednisolone plus rituximab groups. After 12 months, participants reported only a complete response or persistent disease. The complete response rate was 36% (95% confidence interval [CI] 19 to 56%) in the prednisolone monotherapy group compared with 75% (95% CI 55 to 89%) in the prednisolone plus rituximab group. The difference between the groups was statistically significant (p=0.003). Relapse‑free survival in people whose condition had shown any response to treatment (complete or partial) was statistically significantly lower in the prednisolone monotherapy group compared with the prednisolone plus rituximab group (hazard ratio [HR] 0.33, 95% CI 0.12 to 0.88, p=0.02).

  • The uncontrolled studies in warm autoimmune haemolytic anaemia reported in this evidence summary (Dierickx et al. 2009; Maung et al. 2013; Barcellini et al. 2013 and Zecca et al. 2003) included a total of 101 children, young people and adults. The overall response rate (complete and partial) to rituximab reported in these studies ranged from 71% to 94%. Complete response rate ranged from 27% to 67%.

  • The results from the recently published meta‑analysis (Reynaud et al. 2014) were that the overall response rate to rituximab in warm autoimmune haemolytic anaemia was (despite methodological limitations) in line with the larger individual studies at 79% (95% CI 60 to 90%; 11 studies, n=154). The complete response rate was 42% (95% CI 27 to 58%; 11 studies, n=154).

  • The uncontrolled studies in cold antibody types of autoimmune haemolytic anaemia reported in this evidence summary (Berentsen et al. 2004; Berentsen et al. 2006; Berentsen et al. 2010; Schollkopf et al. 2006 and Barcellini et al. 2013) included a total of 142 adults. The overall response rate (complete and partial) to rituximab reported in these studies ranged from 45% to 85%. Complete response rate ranged from 4% to 54%.

  • In the recently published meta‑analysis (Reynaud et al. 2014), the overall response rate to rituximab in cold antibody types of autoimmune haemolytic anaemia was 57% (95% CI 47 to 66%; 6 studies, n=109). The complete response rate was 21% (95% CI 6 to 51%; 7 studies, n=118).

  • The uncontrolled studies included small numbers of participants and did not compare rituximab with any other treatment for autoimmune haemolytic anaemia. The studies are difficult to compare because the populations differed and included participants with primary, secondary, newly diagnosed, and relapsed autoimmune haemolytic anaemia. Some studies included people taking concomitant treatment with corticosteroids and some included people with lymphoproliferative diseases. Most studies reported outcomes such as complete, partial and overall response rates to treatment. However, there was no standardised definitions of these and they varied in the individual studies.

  • In the RCT by Birgens et al. (2013) there was no statistically significant difference between the prednisolone monotherapy and prednisolone plus rituximab groups in any adverse event in adults with warm autoimmune haemolytic anaemia. There were 8 non‑fatal serious adverse events in 5 people in the prednisolone plus rituximab group: pneumonia (3 events), fever (2 events), urinary tract infection (2 events) and Clostridium difficile enteritis (1 event). In the prednisolone monotherapy group there were 4 non‑fatal serious adverse events in 4 people: pneumonia (2 events), urinary tract infection (1 event) and pulmonary embolism (1 event). There was 1 fatal serious adverse event (pneumonia) in the prednisolone plus rituximab group that was possibly treatment‑related.

  • In the uncontrolled studies in warm and cold autoimmune haemolytic anaemia that discussed safety, treatment with rituximab was generally reported as being well tolerated. Adverse events that were described included haematological toxicity and infections.

  • The SPC for rituximab describes that infusion‑related reactions are very common (more than 1 in 10) in people treated with intravenous rituximab for any licensed indication. 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 (for example, tuberculosis, sepsis and opportunistic infections), and in people who are severely immunocompromised. Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in people receiving rituximab. Hepatitis B virus screening should be performed in all people before starting treatment with rituximab and people with active hepatitis B infection should not be treated with the drug. Very rare cases of fatal progressive multifocal leukoencephalopathy have been reported after use of rituximab and people should be monitored at regular intervals for any new or worsening neurological symptoms or signs suggestive of this condition. See the SPC for rituximab for full details of warnings, contraindications and adverse events.

Full text of evidence review.

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.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non‑technical language and may be especially helpful for people with autoimmune haemolytic anaemia who are thinking about trying rituximab.

About this evidence summary

'Evidence summaries: unlicensed or off‑label medicines' summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision‑making on the use of an unlicensed or off‑label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.