NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE. Single Technology Appraisal (STA) Ruxolitinib for the treatment of myelofibrosis

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1 Thank you for agreeing to give us a statement on your organisation s view of the technology and the way it should be used in the NHS. Healthcare professionals can provide a unique perspective on the technology within the context of current clinical practice which is not typically available from the published literature. To help you in making your statement, we have provided a template. The questions are there as prompts to guide you. It is not essential that you answer all of them. Please do not exceed the 8-page limit. About you Your name: Comments submitted by xxxxxxxxxxxxxxxxxxxxxxxxxx on behalf of: Name of your organisation: NCRI haematological clinical studies group, RCP, RCR, ACP, JCCO Are you (tick all that apply): - a specialist in the treatment of people with the condition for which NICE is considering this technology? - a specialist in the clinical evidence base that is to support the technology (e.g. involved in clinical trials for the technology)? - an employee of a healthcare professional organisation that represents clinicians treating the condition for which NICE is considering the technology? If so, what is your position in the organisation where appropriate (e.g. policy officer, trustee, member etc)? 1

2 What is the expected place of the technology in current practice? How is the condition currently treated in the NHS? The only curative treatment for myelofibrosis is bone marrow transplantation which is restricted to younger patients high higher risk disease (a minority, approximately 10-20%). Other patients are managed according to their clinical need: Anaemia Blood transfusions, erythropoietin, thalidomide, danazol Spleen pain hydroxycarbamide, radiotherapy, splenectomy Constitutional symptoms no effective treatment, corticosteroids can be tried Myeloproliferation hytdroxycarbamide, interferon, busulfan Life expectancy no medical treatment has been shown to improve survival in myelofibrosis. Allogeneic transplantation is the only curative treatment option. Is there significant geographical variation in current practice? Yes, between specialist centres and district hospitals Are there differences of opinion between professionals as to what current practice should be? Yes, due to a major lack of good trials in patients with myelofibrosis e.g. which patients are eligible for allogeneic transplantation. What are the current alternatives (if any) to the technology, and what are their respective advantages and disadvantages? Ruxolitinib clearly improves symptoms relating to the enlarged spleen which occurs in patients with myelofibrosis. Ruxolitinib also markedly improves systemic symptoms in patients with myelofibrosis. There is a consequent improvement in QoL as objectively measured in RCTs through EORTC QLQc30; FACT Lym scores and specific MF scores. The impact of ruxolitinib on life expectancy is unclear, there is some data suggesting a possible improvement in overall survival in patients receiving ruxolitinib based on matched historical cohorts with conflicting data from another study which did not demonstrate any survival benefit (the latter with significant methodological limitations, in particular the choice of non-matched historical controls). Also one placebo randomised trial suggested a possible survival benefit although only borderline statistical significance. This study were confounded by crossover design which is clearly problematic when trying to collect survival data from patients with an indolent condition. An initial analysis of the second randomised trial comparing ruxolitinib versus best available therapy (COMFORT-II) did not demonstrate a survival advantage for ruxolitinib, however, a further update of these data, including a survival analysis, is expected at ASH Current evidence suggests that the natural history of myelofibrosis (leukaemia development) is not impacted by ruxolitinib. Thus, the reported survival benefit, if real, is likely related to improved QoL and performance status rather than a real disease modifying effect. 2

3 Are there any subgroups of patients with the condition who have a different prognosis from the typical patient? Yes. Prognosis can be predicted on the basis of: Age >65 Presence of constitutional symptoms Circulating blasts > 1% WBC >25 Hb<10 Plts <100 Cytogenetics Are there differences in the capacity of different subgroups to benefit from or to be put at risk by the technology? This is not yet clear on the basis of available evidence. The large, randomised trials included only patients with higher risk disease. In what setting should/could the technology be used for example, primary or secondary care, specialist clinics? The treatment should be under the care of a haemato-oncologist. Would there be any requirements for additional professional input (for example, community care, specialist nursing, other healthcare professionals)? No If the technology is already available, is there variation in how it is being used in the NHS? Yes, highly dependent on local funding arrangements through the cancer drug fund and also local experience of using the agent. Is it always used within its licensed indications? Probably not. If not, under what circumstances does this occur? May be used in patients with advanced polycythaemia vera or essential thrombocythaemia with marked symptoms or in patients with myelofibrosis associated with cytopenias. Please tell us about any relevant clinical guidelines and comment on the appropriateness of the methodology used in developing the guideline and the specific evidence that underpinned the various recommendations. 3

4 Recently published BCSH guidelines developed using standard algorithms. The advantages and disadvantages of the technology NICE is particularly interested in your views on how the technology, when it becomes available, will compare with current alternatives used in the UK. Will the technology be easier or more difficult to use, and are there any practical implications (for example, concomitant treatments, other additional clinical requirements, patient acceptability/ease of use or the need for additional tests) surrounding its future use? The treatment is extremely easy to use (orally administered agent with minimal side effects aside from myelosuppression). Ruxolitinib markedly improves constitutional symptoms in many patients, there was previously no effective therapy for such patients. Similarly, patients with myelofibrosis often have marked symptoms relating to the spleen. Hydroxycarbamide only has limited efficacy in this regard. Splenic radiotherapy and splenectomy are associated with considerable morbidity and mortality. Thus, ruxolitinib represents a major advance for the control of these symptoms. If appropriate, please give your view on the nature of any rules, informal or formal, for starting and stopping the use of the technology; this might include any requirements for additional testing to identify appropriate subgroups for treatment or to assess response and the potential for discontinuation. In my view, due to the lack of robust data supporting a survival benefit in patients receiving ruxolitinib, the agent should be restricted to patients with significant symptoms relating to the spleen or constitutional symptoms. Due to myelosuppression, use of ruxolitinib is restricted to patients with adequate blood counts (plts >50 and neutrophils >1). My view is that the agent should be discontinued if there is no clinically meaningful benefit after 6 months treatment. If you are familiar with the evidence base for the technology, please comment on whether the use of the technology under clinical trial conditions reflects that observed in clinical practice. Do the circumstances in which the trials were conducted reflect current UK practice, and if not, how could the results be extrapolated to a UK setting? There are 3 key clinical trials, all published in NEJM. One phase 2 study and 2 phase 3 studies with a randomised crossover design; one was placebo controlled, the other used best available therapy as a control arm. The clinical trial conditions reasonably accurately reflects that observed in clinical practice. Some lower risk patients were excluded from the trials but nevertheless are likely to benefit from the agent if they are symptomatic this is supported by the low number of patients with intermediate 1 risk disease included in the original phase 2 study published in the NEJM. What, in your view, are the most important outcomes, and were they measured in the trials? Spleen size, QoL and symptom scores. Highly statistically significantly, all clearly improved with ruxolitinib treatment. As discussed above, survival data is less clear, 4

5 perhaps not surprising as myelofibrosis is an indolent condition and follow up was relatively short in the published trials with a crossover design. Thus, the impact of ruxolitinib on survival is unlikely to be ever known now that the agent is in routine clinical use. If surrogate measures of outcome were used, do they adequately predict long-term outcomes? No. What is the relative significance of any side effects or adverse reactions? In what ways do these affect the management of the condition and the patient s quality of life? Are there any adverse effects that were not apparent in clinical trials but have come to light subsequently during routine clinical practice? The treatment is well tolerated. The most problematic side effect is myelosuppression with a significant number of patients developing new onset anaemia, thrombocytopenia and neutropenia. Importantly, however, these side effects are in general easily managed with dose reduction as appropriate without a major impact on QoL. Very few patients have to permanently discontinue the treatment due to cytopenias in phase 3 studies. The myelosuppression caused by ruxolitinib is also of relevance as this restricts the use of the agent to patients with adequate bone marrow reserve myelofibrosis patients in the greatest clinical need often have low blood counts and thus will not be eligible for ruxolitinib treatment according to the licence. The only other adverse event worthy of note is that some patients experience a rapid deterioration in symptoms on drug discontinuation. Large clinical trials suggests that this represents a return of symptoms to pre-drug levels (and not worse) however case reports suggest that rarely severe reactions can occur on drug withdrawal. Any additional sources of evidence Can you provide information about any relevant evidence that might not be found by a technology-focused systematic review of the available trial evidence? This could be information on recent and informal unpublished evidence, or information from registries and other nationally coordinated clinical audits. Any such information must include sufficient detail to allow a judgement to be made as to the quality of the evidence and to allow potential sources of bias to be determined. No relevant additional evidence of sufficient quality to be relevant. Implementation issues The NHS is required by the Department of Health and the Welsh Assembly Government to provide funding and resources for medicines and treatments that 5

6 have been recommended by NICE technology appraisal guidance. This provision has to be made within 3 months from the date of publication of the guidance. If the technology is unlikely to be available in sufficient quantity, or the staff and facilities to fulfil the general nature of the guidance cannot be put in place within 3 months, NICE may advise the Department of Health and the Welsh Assembly Government to vary this direction. Please note that NICE cannot suggest such a variation on the basis of budgetary constraints alone. How would possible NICE guidance on this technology affect the delivery of care for patients with this condition? Would NHS staff need extra education and training? Would any additional resources be required (for example, facilities or equipment)? No additional educational requirements or facilities would be required. Equality NICE is committed to promoting equality of opportunity, eliminating unlawful discrimination and fostering good relations between people with particular protected characteristics and others. Please let us know if you think that this appraisal: - could exclude from full consideration any people protected by the equality legislation who fall within the patient population for which [the treatment(s)] is/are/will be licensed; - could lead to recommendations that have a different impact on people protected by the equality legislation than on the wider population, e.g. by making it more difficult in practice for a specific group to access the technology; - could lead to recommendations that have any adverse impact on people with a particular disability or disabilities. Please tell us what evidence should be obtained to enable the Committee to identify and consider such impacts. We have no concerns in this regard. It should be noted that myelofibrosis is a disease of the elderly (median age 65 years) this is the only potential group of relevance to equality legislation. 6