29/10. Treatment (brand name, manufacturer): For the treatment of: Background: Rituximab (MabThera, Roche) SLE in adults (unlicensed)

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1 GENERAL POLICY Policy Ref: 29/10 Treatment (brand name, manufacturer): For the treatment of: Background: Commissioning position: Rituximab (MabThera, Roche) SLE in adults (unlicensed) There are frequent individual funding requests (IFRs) made by providers in the SHA for rituximab in systemic lupus erythematosus (SLE) patients. The majority of individual funding requests are supported by Yorkshire and Humber PCTs. The policy for use of rituximab in SLE has been developed as a clinical consensus by Rheumatologists and Pharmacists across Yorkshire and the Humber; and subsequent discussions with PCT representatives. It has been developed because there are frequent IFRs and as it is an unlicensed use of rituximab, it will not be subject to a NICE review. It is estimated that approximately 1 to 2 per 100,000 population will require rituximab for SLE in one year. Cost of 2 infusions (one cycle) is approximately 4300 (in addition 814, tariff for day case admission, HD23c). 50% of patients will require subsequent doses as defined above between 6 and 18 months (median 12 months) post initial infusions, i.e. 50% of patients gain >18 months response from 1 cycle of rituximab RTX (1g intravenously given on days 1 and 15) will be routinely funded in patients with SLE who meet all of the following criteria may receive rituximab without an individual funding request approval: Diagnosed with severe SLE, defined as 1 system with BILAG score A or 2 systems with score B, with progressive organ involvement (brain, heart, lungs, kidneys, musculoskeletal, haematological); AND \\gordon\home\amyb\desktop\ebc Policies October 2010\ Rituzimab.doc1

2 Patients who have failed or have a contraindication to other standard immunosuppressive including cyclophosphamide, and steroids. (Patients who have received mycofenolate for lupus nephritis may receive rituximab without an individual funding request approval; mycofenolate is now regarded as an equivalent therapy to cyclophosphamide and evidence is available that most patients who failed MMF will also/or already have failed cyclophosphamide) Definition of failure is defined as a single system BILAG score A or 2 or more systems with BILAG B despite a course of pulsed cyclophosphamide therapy or side effects of bone marrow suppression beyond acceptable limits or hepatitis, or other drug associated toxicity>grade 3 by CTC criteria for Adverse Events (CTCAE)*, which require stopping cyclophosphamide).(ctcae defined by NIH National Cancer Institute). Contraindications to cyclophosphamide are defined as presence of concurrent sepsis, strong suspicion of concurrent sepsis and serious risk of sepsis with cyclophosphamide. Monitoring of treatment and assessment of treatment failure Effectiveness of response of rituximab will be evaluated at 3 months post infusions. BILAG score of C denotes complete response, BILAG score of B denotes partial response, BILAG score of A denotes non response Re-treatment with two 1g rituximab doses would be suitable for patients who meet the criteria set out above (3), respond to BILAG B or C but have flare of disease, at least 6 months after initial rituximab with BILAG score of either A or B again. 12 months is the observed median time for retreatment for rituximab in SLE. IFRs will not be expected for patients previously given rituximab under this policy, and who meet the treatment criteria if their disease flares Effective from: 24 th September 2010 Summary of In selected patients with sever disease who meet \\gordon\home\amyb\desktop\ebc Policies October 2010\ Rituzimab.doc2

3 evidence: specific criteria in terms of disease severity and response to standard therapies, rituximab is believed to be a clinically and cost-effective option. Equality Impact: No formal EIA required. Date approved by 24 th September 2010 SCG Board: Policy to be 24 th September 2012 reviewed by: Version: 1 Supersedes: N/A Date approved by CSSG: 9 th September 2010 CSSG/RPSG: Responsible NHS Bradford & Airedale Officer/Contact: Distribution/Target Audience: IFR Managers Directors of Commissioning Directors of Public Health Contracting Leads PCT Nominated Officers SHA (Chris Welsh, Michelle Cossey) cc: Cancer Networks NOTES 1. Most patients being considered for rituximab will have failed cyclophosphamide and a standard DMARD (usually mycofenolate or azathioprine) and will have aggressive multi-system disease. The few therapeutic options that remain for these patients are often more expensive than rituximab. The costs of rituximab should also be considered against the costs of organ damage, eg renal replacement therapy. 2. Benefits of rituximab in this cohort of patients have been derived from case series data. The largest series from the UK are from Leeds and UCH, London. These demonstrate response rates of 70-80% in patients who have mostly failed cyclophosphamide or mycofenolate; these studies have used objective markers of response with BILAG and other validated outcome measures. 3. The randomised controlled trials EXPLORER and LUNAR did not meet primary end points and suggested that rituximab was not effective in SLE. 4. However, results from local and international experience in the cohort defined on this commissioning position are better than those seen in these studies. This is thought to be because the patient population in the trials was not representative of those in the open label series- the trial patients had less severe disease, had not generally failed cyclophosphamide and had received higher doses of steroids. \\gordon\home\amyb\desktop\ebc Policies October 2010\ Rituzimab.doc3

4 5. Leeds and Yorkshire Rheumatology (1 of 10 European Centres of Excellence) operates a hub & spoke system for research and clinical practice. There is close observation of use of rituximab and outcomes. Clinical practice is based on a shared regional model. Use of rituximab in this patient group will be with concurrent clinical audit (in addition to the monitoring of use by commissioners, as per all tariff excluded drugs). There will also be comparison with retrospective cohorts to confirm that the pattern of rituximab usage has not significantly changed after agreement of a routine commissioning policy. 6. Contra-indications to cyclophosphamide are active infection, suspected active infection or serious risk of infection due to other underlying diseases such as bronchiectasis. 7. Infection: these are usually patients with severe lupus, with multi-organ involvement, often in HDU/ITU and the clinical concern is that sepsis can often present in this way; furthermore, sepsis can often trigger a flare of SLE. The clinicians dilemma is that it is impossible to use cyclophsophamide safely in this situation but also impossible to delay treatment of SLE. This is the clinical situation in which RTX use is envisaged (not in someone who has a mild cold / URTI etc delaying use of cyclophosphamide for a few days). In this emergency situation, the choice would be between rituximab, intravenous immunoglobulin or plasma exchange. The latter two are significantly more expensive and have no better efficacy data than rituximab. 8. Use of rituximab after mycofenolate: mycofenolate and cyclophosphamide are now considered by many experts both in this region and nationally/internationally) to be at least equivalent in terms of efficacy; demonstrated in ALMS clinical trial (abstract ACR 2008) and in metaanalysis of 10 RCTs with 847 patients (Mak et al, Rheumatology 2009). First randomised trial (Ginzler, 2005) showed mycofenolate to be significantly better than cyclophosphamide at inducing complete remission at 6 months. Studies also show at least comparable side effect profile (ALMS study) and meta-analysis (Mak 2009) showed significantly fewer patients developed amenorrhoea (relative risk of developing amenorrhoea MMF:CYC 0.212) and leucopenia (RR 0.473) 9. Mycofenolate has therefore become first line choice of therapy in many patients with lupus nephritis. Many patients will already have been exposed to cyclophosphamide. However, of those who have not received cyclophosphamide, mycofenolate will have been chosen as a superior therapy. In these circumstances, if there is failure (due to inefficacy or toxicity) of MMF, clinical consensus is to choose rituximab as next line therapy. 10. Evidence for rituximab post mycofenolate (pooled data from 7 studies, 2009): patients with lupus nephritis; 61% previous CYC, 48% previous MMF i.e large numbers of patients had both therapies 12. Rituximab response rate (partial & complete renal remission) 61% 13. Three months is the earliest time point to assess efficacy. Some improvements can still sometimes be seen between 3-6 months. There is \\gordon\home\amyb\desktop\ebc Policies October 2010\ Rituzimab.doc4

5 a very small minority of patients who definitely respond but then flare before 6 months 14. BILAG is the most sensitive symptom severity score in this group of patients. In terms of use of assessments other than BILAG: this applies to skin manifestations of the disease, where patients would be reviewed jointly with a Dermatologist experienced in SLE and use skin biopsy where appropriate; to musculoskeletal we would use a Disease Activity Score, the validated universal measure for inflammatory arthritis and we have access to expert musculoskeletal ultrasound in our clinics to more sensitively assess response. Using these measures has allowed a higher rate of response and hence more efficient use of drug. 15. Prevalence. SLE is a diverse disease with a very heterogeneous patient group and some uncertainties about the natural history and epidemiology. Based on rapid analysis of the patients attending the Leeds clinic, it is estimated there are approximately 500 prevalent patients in Leeds from which 10 per year will require rituximab. The estimated incidence of 1 to 2 /100,000 needing rituximab per year is based on local consensus which may be a slight over estimate as Leeds takes referrals from other centres. There is considerable ethnic variation with SLE being more common among South Asian populations. 16. Responses: high response rates are observed in open label series, with objective validated endpoints; the largest UK series are from Leeds (Vital 2008, 2009) and UCH, London (Ng, 2008). 50% of patients have responses of 18 months or longer the median time for retreatment of these pts is 24 months. The other 50% require retreatment at 6-18 months, with a median time of 12 months. The response duration is bimodal. 17. Locally clinicians have put forward a number of issues to take into account when considering the applicability of the EXPLORER and LUNAR trials. (a) different patients population locally ours have mostly failed cyclophosphamide already; have more severe disease, therefore less likely to respond to cyclophosphamide; (b) comparator arm in trials use very high doses of steroid, higher than standard European clinical practice; (c) the outcome measure is less good when not used by specialists who have regular experience of it; it is intrinsically flawed in that it is insensitive to change in skin and musculoskeletal which were the 2 main types of disease entered into the study; (d) we have used rituximab mostly in patients with renal, cerebral, haematological SLE, all manisfestations either underrepresented or excluded from EXPLORER. (e) LUNAR rituximab was similar to mycofenolate for lupus nephritis only, with higher doses of intravenous and oral steroids than in general use(f) Also secondary endpoints were met in favour of rituximab (normalization of immunological features of disease) Locally, clinicians have operated a hub & spoke approach as a clinical & research centre for a decade (1 of 10 European Centres of Excellence in Rheumatology) so are ideally set up to do this audit. Basic audit would be to review disease status and previous treatments of pts receiving RTX, clinical outcome measurement and time to retreatment. Audit data will be collected to check use of rituximab in accordance with agreed criteria; to assess numbers of individual funding requests; and also to compare \\gordon\home\amyb\desktop\ebc Policies October 2010\ Rituzimab.doc5

6 patterns of use and clinical outcome with retrospective cohorts of cyclophosphamide and previously treated rituximab patients. Data will be collected by an already agreed standardized method across the regional centres and analysed as a whole and centrally. 19. In addition, there is an economic argument in favour of using rituximab in place of cyclophosphamide. Assuming that cyclophosphamide is given IV as a day case the tariff for day case admissions is 407 (HD23c planned same day tariff for inflammatory spine, joint or connective tissue). 1 cycle of 6 pulses would therefore cost Many patients (locally, clinicians state most) will be given a minimum of 2 cycles; this is especially the case in cases presenting with aggressive multi organ involvement. This is compared to a course of rituximab day case admissions total cost of Thus if 2 cycles are used, a strategy of using cyclophosphamide is slightly cheaper than RTX. In addition, there will be the cost of treating side effects, these are not factored into this calculation, nor are any long term complications following either treatment strategy. Neither rituximab or cyclophosphamide will cure, it is expected that retreatment will be required in patients treated with both (but see below re sustained responses following rituximab). Further economic modelling might be undertaken in this area, comparing the costs and outcomes of each treatment option. \\gordon\home\amyb\desktop\ebc Policies October 2010\ Rituzimab.doc6