Advice

Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in October 2014. See summaries of product characteristics (SPCs), British national formulary (BNF), BNF for children (BNFc) or the MHRA or NICE websites for up-to-date information.

Summary

Most of the evidence for using rituximab in adults with immune thrombocytopenic purpura comes from observational studies, with no comparator arm. The populations in the included studies varied, as did the platelet count considered to represent an overall response or complete response. The randomised controlled trials (RCTs) discussed in this evidence summary had a number of limitations, including small numbers of participants. All of these factors make it difficult to draw firm conclusions from the evidence.

The evidence for efficacy of rituximab in children and young people is weaker, drawn from case series and 1 cohort study with no comparator arm.

Regulatory status: off-label. This topic was prioritised because there was a high volume of requests from the NHS.

Effectiveness

  • A systematic review of mainly observational studies (n=368) suggests that rituximab can increase platelet levels in adults with immune thrombocytopenic purpura; although response rates varied significantly between individual studies. No comparisons with other treatments were made.

  • An RCT (n=137) suggests that rituximab plus dexamethasone may be better than dexamethasone alone for achieving a sustained response in terms of increased platelet levels in adults with newly diagnosed primary immune thrombocytopenic purpura.

  • Another RCT (n=60) shows that rituximab is no better than placebo for preventing treatment failure in adults with immune thrombocytopenic purpura once standard treatment was stopped.

  • A retrospective cohort study (n=105) suggests that there is no difference between rituximab and splenectomy for the composite outcome of death from, or hospitalisation for, bleeding or infection in adults with immune thrombocytopenic purpura.

  • In children and young people with immune thrombocytopenic purpura, a systematic review (n=352) suggests that rituximab can increase platelet levels. However included studies were all observational, limiting the conclusions that can be drawn.

Safety

  • The summary of product characteristics (SPC) for rituximab describes that infusion related reactions are very common 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 use of rituximab and people should be monitored at regular intervals for any new or worsening neurological symptoms or signs suggestive of this condition.

Patient factors

  • Rituximab is administered as an intravenous infusion over several hours.

  • Rituximab is usually given as a 4-week course of treatment aimed at inducing a long-term response, whereas some other treatments might need to be taken continuously.

  • Second-line treatment options include splenectomy, which some people may prefer to avoid.

Resource implications

  • Most of the studies in this evidence summary used 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 September 2014).

    • 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 September 2014).

  • Some studies 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 September 2014).

Introduction and current guidance

Immune (idiopathic) thrombocytopenic purpura is an autoimmune condition characterised by increased platelet destruction and, in many cases, inadequate platelet production. The condition can result in low platelet counts and bleeding (Eltrombopag for treating chronic immune [idiopathic] thrombocytopenic purpura [review of technology appraisal 205]; NICE technology appraisal guidance 293: final scope).

For adults that need treatment, first-line options include corticosteroids, intravenous immunoglobulin and intravenous anti-D immunoglobulin (although specialist opinion suggests this is rarely used in the UK). Second-line options include azathioprine, ciclosporin, cyclophosphamide, danazol, dapsone, mycophenolate, rituximab, vinca alkaloids, and splenectomy. Not all of these drug treatments are licensed for treating immune thrombocytopenic purpura in adults and most of the evidence for using these agents is from non-randomised or descriptive studies (International consensus report on the investigation and management of primary immune thrombocytopenia [2010]).

Newer therapies for immune thrombocytopenic purpura include the thrombopoietin receptor agonists eltrombopag and romiplostim. The NICE technology appraisal on eltrombopag for treating chronic immune (idiopathic) thrombocytopenic purpura recommends eltrombopag as an option for treating adults with chronic immune (idiopathic) thrombocytopenic purpura, within its marketing authorisation (that is, in adults who have had a splenectomy and whose condition is refractory to other treatments, or as a second-line treatment in adults who have not had a splenectomy because surgery is contraindicated), and only if:

  • their condition is refractory to standard active treatments and rescue therapies, or

  • they have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies, and

  • the manufacturer provides eltrombopag with the discount agreed in the patient access scheme.

Similarly, the NICE technology appraisal on romiplostim for the treatment of chronic immune (idiopathic) thrombocytopenic purpura recommends romiplostim as an option for treating adults with chronic immune (idiopathic) thrombocytopenic purpura, within its marketing authorisation (that is, in adults who have had a splenectomy and whose condition is refractory to other treatments, or as a second-line treatment in adults who have not had a splenectomy because surgery is contraindicated), and only if:

  • their condition is refractory to standard active treatments and rescue therapies, or

  • they have severe disease and a high risk of bleeding that needs frequent courses of rescue therapies, and

  • the manufacturer makes romiplostim available with the discount agreed in the patient access scheme.

For children that need treatment, first-line options include corticosteroids, intravenous immunoglobulin and intravenous anti-D immunoglobulin (although specialist opinion suggests this is rarely used in the UK). Second-line treatments include corticosteroids, rituximab, immunosuppressants, cytotoxic drugs and splenectomy, and are usually considered by specialist paediatricians on a case by case basis (International consensus report on the investigation and management of primary immune thrombocytopenia [2010]).

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, therefore only this formulation is reviewed in this evidence summary.

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 immune thrombocytopenic purpura and so use for this indication is off-label.

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 September 2014):

  • 2×10 ml=£349.25

  • 1×50 ml=£873.15

Full text of Product overview.

Evidence review

  • The evidence reported in this summary for adults includes a systematic review and meta-analysis (Auger et al. 2012), 2 RCTs (Arnold et al. 2012 and Gudbrandsdottir et al. 2013) that have been published since the systematic review, and a retrospective cohort study (Moulis et al. 2013) comparing rituximab with splenectomy. Also included in the evidence summary is a systematic review (Liang et al. 2012) of studies carried out in children and young people.

  • Auger et al. (2012) included 19 studies (n=368) in adults who had immune thrombocytopenic purpura and were receiving rituximab before splenectomy. Only 4 of the included studies were randomised. The remaining studies were prospective and retrospective observational studies with no comparator arm. Consequently, no comparisons of rituximab with other treatments were made in the review. Most studies used rituximab at a dosage of 375 mg/m2 body surface area weekly for 4 weeks. Pooled overall response rate (defined as a platelet count of greater than 50×109 per litre) was 57% (n=368, 95% confidence interval [CI] 48 to 65%) after rituximab treatment (time point 'after' not further defined), and 57% (n=157, 95% CI 35 to 76%) at 1 year after rituximab treatment. However, there was a large variation in the reported overall response rates in the individual studies (16−100% after rituximab, and 33−85% at 1 year after rituximab treatment). Pooled complete response rate (defined as either a platelet count of greater than 100×109 per litre, or greater than 150×109 per litre depending on the individual study) was 41.5% (n=346, 95% CI 33 to 50%) after rituximab treatment (time point 'after' not further defined), and 40% (n=108, 95% CI 31 to 49%) at 1 year after rituximab treatment. However, again there was a large variation in the reported complete response rates in the individual studies (0−86% after rituximab, and 0−48.4% at 1 year after rituximab treatment). Heterogeneity was moderate or high in most analyses.

  • Arnold et al. (2012) was a pilot double-blind, placebo-controlled randomised trial of adjuvant rituximab or placebo in 60 adults with newly diagnosed or relapsed primary immune thrombocytopenic purpura who had not received a splenectomy, and who had a platelet count of less than 30×109 per litre (median baseline platelet count 15×109 per litre). Participants received intravenous rituximab 375 mg/m2 body surface area (n=33) or saline placebo (n=27) once weekly, for 4 weeks. Participants also received standard treatment for up to 8 weeks with 1 or more of: corticosteroids; intravenous immunoglobulin; intravenous anti-D immunoglobulin; romiplostim; or platelet transfusions. For the primary outcome of treatment failure (defined as the composite of any of: platelet count below 50×109 per litre; significant bleeding or administration of rescue treatment because of severe thrombocytopenia; bleeding; or a planned invasive procedure) there was no statistically significant difference between the rituximab and placebo groups (treatment failure: 65.6% in the rituximab group compared with 80.8% in the placebo group; relative risk [RR] 0.81, 95% CI 0.59 to 1.11).

  • Gudbrandsdottir et al. (2013) was an open-label RCT of rituximab plus dexamethasone, compared with dexamethasone alone in 137 adults with newly diagnosed primary immune thrombocytopenic purpura who had not had a splenectomy, and who had a platelet count of 25×109 per litre or less, or 50×109 per litre or less and concomitant bleeding symptoms. Participants received a combination of rituximab 375 mg/m2 body surface area once weekly for 4 weeks plus dexamethasone 40 mg daily (n=63) for 4 days, or the same dosage of dexamethasone alone (n=74). In an intention-to-treat analysis, the primary outcome of sustained partial (defined as a platelet count of at least 50×109 per litre) or complete (defined as a platelet count of at least 100×109 per litre) response at 6 months' follow-up was achieved in 57% of people in the rituximab plus dexamethasone group, compared with 35% of people in the dexamethasone monotherapy group (p=0.01).

  • Moulis et al. (2013) was a retrospective cohort study comparing rituximab 375 mg/m2 body surface area weekly for 4 weeks with splenectomy for treating 105 adults with primary immune thrombocytopenic purpura. The primary outcome (a composite of death from bleeding or infection and hospitalisation for bleeding or infection) occurred in 14/43 (32.6%) people in the rituximab group, and 11/62 (17.7%) people in the splenectomy group. After adjusting for propensity score, there was no difference between the groups for the primary outcome (p=0.7).

  • Liang et al. (2012) included 18 studies (n=352) that contributed to efficacy analyses, including 17 case series, and 1 observational cohort study. The participants in the studies had an age range of 0.5 to 19 years. Most participants (84.5%) received intravenous rituximab at a dosage of 375 mg/m2 body surface area weekly for 1−6 doses (14 studies). When the results from 14 studies (n=312) were pooled, response to rituximab (defined as a platelet count of at least 30×109 per litre and at least double that of baseline) was achieved in 68% of participants (95% CI 58% to 77%). Complete response (defined as a platelet count of at least 100×109 per litre; 14 studies, n=243) was achieved in 39% of participants (95% CI 30% to 49%). There was statistically significant heterogeneity between the included studies for these outcomes (p<0.001 for response, and p=0.005 for complete response) and there was a large variation in the reported response and complete response rates in the individual studies (33−100% for response rate and 14−67% for complete response rate).

  • The SPC for rituximab (MabThera, Roche Products Limited) lists contraindications and adverse events separately for each licensed indication (see the SPC for more information).

  • The SPC for rituximab describes that infusion-related reactions are very common 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.

  • Most of the evidence for using rituximab in adults with immune thrombocytopenic purpura comes from observational studies, with no comparator arm. The populations in the included studies varied, as did the platelet count considered to represent an overall response or complete response. The RCTs discussed in this evidence summary included relatively small numbers of people and had other limitations. All of these factors make it difficult to draw firm conclusions from the evidence.

  • The evidence for efficacy of rituximab in children and young people is weaker, drawn from 17 case series and 1 cohort study; none of the studies included UK populations. The observational nature of the studies and lack of comparator arm make it difficult to draw any conclusions about using rituximab to treat immune thrombocytopenic purpura in children and young people.

  • Further evidence is needed to determine the efficacy and safety of rituximab for treating immune thrombocytopenic purpura, particularly in children and young people.

Full text of Evidence review.

Context and estimated impact for the NHS

Most of the studies in this evidence summary used rituximab at a dosage of 375 mg/m2 body surface area weekly for 4 weeks. 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, September 2014). 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 September 2014).

Two studies in adults in the systematic review by Auger et al. (2012), and 3 studies in children and young people in the systematic review by Liang et al. (2012) 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 September 2014).

Comparing the cost of rituximab with other second-line drug treatments is difficult because rituximab is usually given as only 1 course of treatment and is intended to induce long-term remission. Other second-line drug treatments usually need to be given continuously. Specialist opinion suggests that further treatment with rituximab may be given to people whose immune thrombocytopenic purpura initially responds to treatment with rituximab, but then relapses. Rescue treatment may also be needed in people whose condition relapses after receiving rituximab. Both of these factors may increase the costs associated with using rituximab for treating immune thrombocytopenic purpura.

The only other treatment for immune thrombocytopenic purpura that is a one-off treatment aimed at inducing long-term remission is splenectomy. By comparison, the cost to commissioners of an elective splenectomy is estimated to be in the range of £3252 to £4548, depending on the complexity of the procedure.

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 immune thrombocytopenic purpura 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.