Ruxolitinib for treating polycythaemia vera

3.1 Polycythaemia vera is a bone marrow condition that leads to an increase in the number of cells in the blood. It mostly affects the number of red blood cells. As more red blood cells are made, the blood becomes thicker. This can lead to complications such as gout, bleeding problems and blood clots. These clots can cause strokes, heart attacks, or blockage of an artery in the lungs (pulmonary embolism) or in a vein deep in a muscle (deep vein thrombosis). There can also be severe itching, the cause of which is unknown. Polycythaemia vera can also cause an increase in white blood cells. In some cases, the extra white blood cells collect in the spleen, which may then become enlarged (splenomegaly). In addition, polycythaemia vera can lead to other problems such as scarring of the bone marrow (myelofibrosis) and acute myeloid leukaemia. The clinical experts noted that ruxolitinib is already in widespread use for treating myelofibrosis. Ruxolitinib is recommended in NICE's technology appraisal guidance on ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. The patient experts highlighted that polycythaemia vera is a debilitating illness that significantly affects people living with the condition, and their families and carers. They said that the symptoms that affect people the most are severe fatigue, bone pain, itching and having an enlarged spleen. They also noted how highly disruptive frequent venesections are (when blood is removed from a person to reduce excess red blood cells). The patient experts also highlighted the extra psychological burden of being diagnosed with a rare condition. People with polycythaemia vera explained how the condition can worsen very quickly because they can be feeling good, but the next day be in considerable pain and have to rest. They emphasised the significant disruption this has on their lives, and on families and carers. The patient experts also noted how 25% of people surveyed by MPN Voice and Leukaemia Care reported stopping first-line treatments because of side effects or declining treatment effectiveness. People with polycythaemia vera also explained how current treatment options can fail to have the desired effect and result in significant side effects. The clinical experts identified that current treatment options carry a high risk of developing leukaemia, which can be fatal within 3 to 6 months. They noted that, in people who cannot tolerate hydroxycarbamide or when their condition is resistant to it, there are few options other than busulfan. With busulfan treatment, there is a 20% risk of developing leukaemia. The clinical experts highlighted the unmet need for a treatment option that reduces symptoms and improves quality of life compared with current treatments. The committee concluded that polycythaemia vera is a debilitating condition. It also concluded that there is high unmet need for effective treatments that improve survival and quality of life, and have manageable side effects.

3.2 The clinical and patient experts, and the company, identified the British Society for Haematology 2018 guidelines on treating polycythaemia vera as the most appropriate for the NHS. The guidelines recommend venesection and low-dose aspirin for everyone with polycythaemia vera. Cytoreductive therapy is recommended for people who are at high risk (65 years and over or with a history of thrombosis), have an uncontrolled haematocrit (percentage of red blood cells in the blood) or whose tolerability of venesections is poor. First-line cytoreductive therapy is hydroxycarbamide or interferon alfa. Second-line cytoreductive therapy is interferon alfa if hydroxycarbamide is used first line, or hydroxycarbamide if interferon alfa is used first line. Third-line cytoreductive therapies include anagrelide plus hydroxycarbamide, busulfan and radioactive phosphorous. Pipobroman is recommended by the British Society for Haematology for people with a limited life expectancy, but was not included in the NICE scope for this evaluation. The company explained that the clinical experts it consulted said that radioactive phosphorus is rarely used, so it was not included in the company's submission. The comparator presented in the company's submission was called 'best available therapy'. It included hydroxycarbamide, interferon alfa, anagrelide and busulfan, with the use of each weighted by use in the MAJIC‑PV clinical trial (see section 3.6). The EAG noted that the clinical experts it consulted agreed with the exclusion of radioactive phosphorous, and highlighted the limited use (if at all) of anagrelide and busulfan. The clinical experts also explained during the committee meeting that anagrelide, busulfan, radioactive phosphorous and pibobroman are very rarely used in clinical practice. They explained that this is because they are not licensed for, and have not been shown to be effective for, treating polycythaemia vera. The EAG commented that the company's definition of best available therapy was appropriate, and that hydroxycarbamide and interferon alfa were the most used treatments. The committee concluded that hydroxycarbamide and interferon alfa were the most relevant treatment options for polycythaemia vera, and that the company had appropriately defined best available therapy.

3.3 The committee recalled the wording of the marketing authorisation for ruxolitinib. It noted that ruxolitinib is indicated for people with polycythaemia vera when there is resistance or intolerance to hydroxycarbamide. The company explained that this meant ruxolitinib would be used as second- or third-line cytoreductive therapy. It added that this would depend on which line hydroxycarbamide was used and whether there was resistance or intolerance to it (see section 3.2). The clinical experts highlighted that ruxolitinib does not have to be used immediately after hydroxycarbamide. They said that this is because ruxolitinib eligibility can be based on previous intolerance to hydroxycarbamide. They noted that the availability of ruxolitinib would give people another treatment option besides interferon alfa when there is resistance or intolerance to hydroxycarbamide. They explained that interferon alfa can exacerbate some of the symptoms of polycythaemia vera, such as itching. The patient experts described their experience of treatment with ruxolitinib. They noted that they had significant improvements in their condition and reduced side effects compared with hydroxycarbamide and interferon alfa. The patient and clinical experts highlighted that ruxolitinib can lead to improved control of blood cell counts and improve symptoms. For example, it can reduce fatigue, spleen size, pain and itchy skin. The clinical experts noted that there are potential risks with ruxolitinib, such as infections, skin cancer, weight gain, raised blood pressure and high cholesterol levels. But they noted that these side effects can be mitigated against. The committee concluded that the company's proposed positioning of ruxolitinib in the treatment pathway was appropriate. It concluded that best available therapy, as defined in the company's submission (see section 3.2), was an appropriate comparator at this point in the pathway.

3.4 The main clinical evidence provided by the company for ruxolitinib was from the phase 3 RESPONSE and RESPONSE‑2 trials. Both were multicentre open-label randomised trials funded by the company. They compared ruxolitinib with best available therapy and both trials lasted 5 years. Crossover from the best available therapy arm to the ruxolitinib arm was allowed (see section 3.5). Both trials included adults with polycythaemia vera who could not tolerate hydroxycarbamide or when the condition was resistant to it. RESPONSE included people with splenomegaly and RESPONSE‑2 included people without splenomegaly. Everyone in the trials had to have an Eastern Cooperative Oncology Group performance status of 0, 1 or 2. RESPONSE recruited 222 people from 18 countries including 3 UK sites. RESPONSE‑2 recruited 149 people from 12 countries not including the UK. The median age of people was about 61 years in RESPONSE and about 65 years in RESPONSE‑2. The median time since diagnosis was about 8.8 years in RESPONSE and about 6.6 years in RESPONSE‑2. The primary outcome of RESPONSE was primary response (controlled volume of red blood cells in the blood and a more than 35% reduction in spleen volume) at 32 weeks. This was statistically significantly improved for ruxolitinib compared with best available therapy (22.7% compared with 0.9%; p<0.001). The primary outcome of RESPONSE‑2 was controlled volume of red blood cells in the blood at 28 weeks. This was statistically significantly improved for ruxolitinib compared with best available therapy (62.2% compared with 18.7%; p<0.0001). Overall survival for ruxolitinib at 5 years was 92% in RESPONSE and 96% in RESPONSE‑2. Overall survival for best available therapy was not reported because crossover confounded results (see section 3.5). The committee concluded that RESPONSE and RESPONSE‑2 show clinical advantages with ruxolitinib over best available therapy in controlling the volume of red blood cells in the blood and reducing spleen volume.

3.5 Crossover was permitted in RESPONSE at 32 weeks and RESPONSE‑2 at 28 weeks. Crossover from best available therapy to ruxolitinib was 88% in RESPONSE and 77% in RESPONSE‑2. The company acknowledged the limitations of crossover in RESPONSE and RESPONSE‑2. It explained that adjusting for crossover was not feasible because of the low number of deaths in RESPONSE and RESPONSE‑2. So, it developed an indirect treatment comparison from overall survival data from RESPONSE for ruxolitinib and from real-world GEMFIN registry data for best available therapy. Propensity score matching was done using individual patient level data from the respective sources. RESPONSE‑2 data was not included because of considerable overlap with RESPONSE in the number of people in GEMFIN that could be matched. Using a combined population with RESPONSE and RESPONSE‑2 would have resulted in a poor fit when estimating propensity scores for matching because these people could not be double counted. The indirect treatment comparison was not used to inform the company's base case. The overall survival results are academic in confidence so cannot be reported here. But the company noted that they showed statistically significantly improved survival for ruxolitinib compared with best available therapy. The company did identify limitations associated with the results because of:

3.6 Additional clinical evidence for ruxolitinib was from the phase 2 MAJIC‑PV trial. This was a multicentre open-label randomised trial funded by Blood Cancer UK, with an unrestricted funding grant from the company. It investigated ruxolitinib compared with best available therapy over 5 years. MAJIC‑PV was a UK only trial, recruiting 190 people from 38 sites. Crossover was not specified in the trial protocol for MAJIC‑PV, but the clinical experts noted that 10 people did crossover to ruxolitinib. MAJIC‑PV recruited adults with high-risk polycythaemia vera who were intolerant of hydroxycarbamide or in whom the condition was resistant to it. High risk was defined as meeting at least 1 of these criteria:

3.7 The committee considered whether ruxolitinib improved overall survival compared with best available therapy. It noted that none of the 3 clinical trials showed an overall survival benefit with ruxolitinib compared with best available therapy. This was because of confounded data in RESPONSE and RESPONSE‑2 (see section 3.4 and section 3.5) and lack of statistical significance in MAJIC‑PV (section 3.6). The committee noted the small number of deaths in the clinical trials over their 5‑year follow-up durations:

3.8 The committee considered the generalisability of RESPONSE, RESPONSE‑2 and MAJIC‑PV to NHS clinical practice. MAJIC‑PV only included people from the UK. RESPONSE included people from 3 UK sites and RESPONSE‑2 did not include anyone from the UK. The EAG highlighted that the clinical experts it consulted agreed that all 3 trial populations were reflective of NHS clinical practice. But it considered that MAJIC‑PV was most generalisable to the NHS because of the age of those included (see section 3.4 and section 3.6). It also noted a concern expressed by the clinical experts that the definition of hydroxycarbamide intolerance in all 3 trials may not have reflected that used in NHS clinical practice. This was because there is no standard definition. The EAG also highlighted uncertainty on how much the MAJIC‑PV population represented a high-risk subgroup. This was because baseline characteristics seemed similar to the other trials, but mortality was substantially higher. The company considered that all 3 trial populations represented people who would benefit from ruxolitinib and were relevant to decision making. The clinical experts thought that all 3 trials were relevant to NHS clinical practice. One clinical expert expressed a preference for MAJIC‑PV because of the very specific entry criteria and crossover present in RESPONSE and RESPONSE‑2 (see section 3.4, section 3.5 and section 3.6). The clinical experts explained that this specific entry criteria likely meant people recruited to RESPONSE and RESPONSE‑2 were generally fitter than people in MAJIC‑PV and in the NHS. The clinical experts noted that most people they saw in NHS clinical practice would have been eligible for MAJIC‑PV. They also considered that most people in RESPONSE and RESPONSE‑2 would have been eligible for MAJIC‑PV. The committee noted that MAJIC‑PV was considered to enrol a broader range of people than RESPONSE and RESPONSE‑2. So, it considered that evidence from MAJIC‑PV was likely to be most appropriate for assessing the use of ruxolitinib within its marketing authorisation, rather than just within a high-risk subgroup. It also considered that the population recruited in MAJIC‑PV best represented the polycythaemia vera population in NHS clinical practice, compared with RESPONSE and RESPONSE‑2. The committee also recalled its previous conclusion that MAJIC‑PV was the best source of unconfounded evidence because it had limited treatment arm crossover (see section 3.6). So, it concluded that MAJIC‑PV was the most appropriate source of clinical-effectiveness evidence for its decision making.

3.9 RESPONSE included people with splenomegaly whereas RESPONSE‑2 included people without splenomegaly. The company's base-case economic model included separate cost-effectiveness estimates for people with and without splenomegaly (see section 3.10). The clinical experts explained that treatments offered do not vary by whether or not splenomegaly is present. But they said that identifying splenomegaly helps clinicians adopt more targeted disease monitoring. This is because splenomegaly may increase the chance of the condition being resistant to hydroxycarbamide or people being intolerant of it. Also, it may indicate that the condition is transforming into myelofibrosis. The clinical experts added that the presence of splenomegaly is not routinely checked or measured in clinical practice. Instead, splenomegaly investigations are prompted by people reporting symptoms, but the effect on quality of life can vary significantly. The clinical experts explained that, for some people, splenomegaly means difficulty in eating, which leads to weight loss, but others have very few symptoms. One clinical expert also highlighted that subgroup results from MAJIC‑PV showed no evidence of a differential benefit for ruxolitinib in people with and without splenomegaly. The committee concluded that the presence of splenomegaly was not a treatment- or outcome-altering factor, so was not a subgroup-defining characteristic for decision making.

3.10 The company initially developed a state-transition model to model the cost effectiveness of ruxolitinib compared with best available therapy. In its base case, the company presented cost-effectiveness results separately for people with and without splenomegaly. The baseline characteristics of people in the model were aligned with RESPONSE and RESPONSE‑2. The time to treatment discontinuation and overall survival in the ruxolitinib arm for each population was informed by individual patient data from RESPONSE and RESPONSE‑2 (section 3.4, section 3.5). The time to treatment discontinuation and overall survival in the best available therapy arm for each population was informed by data from MAJIC‑PV (see section 3.6). The company also developed a separate model based on MAJIC‑PV data for the high-risk subgroup (see section 3.11). In the RESPONSE and RESPONSE‑2 model, people were modelled to enter and have treatment in either a 'ruxolitinib' or 'best available therapy' state. People in the 'ruxolitinib' state could move to the 'best available therapy' state or 'death'. People in the 'best available therapy' state could move only to 'death'. In the 'best available therapy' state, people were also separated by treatment line (first, second and beyond, or no treatment). For each treatment state, the model captured:

3.11 The company also developed a partitioned survival model for the MAJIC‑PV high-risk subgroup population. A partitioned survival model was used because of the lack of individual patient data that is needed to estimate transition probabilities for a state-transition model. The MAJIC‑PV model used the same model structure and modelled treatment stages as the RESPONSE and RESPONSE‑2 model (see section 3.10). The EAG preferred the MAJIC‑PV model, based on generalisability to the NHS (see section 3.8). But it noted the same concerns with the treatment stage-based model structure as for the RESPONSE and RESPONSE‑2 model (see section 3.10). The committee recalled that it considered that MAJIC‑PV data was the most appropriate source of unconfounded clinical-effectiveness evidence for assessing the cost effectiveness of ruxolitinib for polycythaemia vera (see section 3.8). It concluded that the company's MAJIC‑PV model was also developed appropriately but subject to the same model structure concerns as with the RESPONSE and RESPONSE‑2 model.

3.12 During technical engagement, the company developed an updated model structure based on stages of disease progression. In the updated model structure, people entered the model in 'progression-free on ruxolitinib' or 'progression-free on best available therapy' health states. People in the 'progression-free on ruxolitinib' health state could then move to 'progression-free on best available therapy', 'progressed disease' or 'death' health states. People in the 'progression-free on best available therapy' health state could then move to 'progressed disease' or 'death' health states. The progressed disease state was further divided into:

3.13 For the second committee meeting, the company provided an updated progression-based model based on MAJIC‑PV data. This included the committee's preferred assumptions at the first committee meeting (see section 3.18). The company also provided:

3.14 At the first committee meeting, the committee also requested validation of the model results for the relative effects on overall survival compared with MAJIC‑PV results and longer-term registry data. The company provided a comparison of the model predictions using the progression-based model against MAJIC‑PV results. The company stated that the predictions for progression-free survival and overall survival were generally aligned with observed data from MAJIC‑PV at 5 years. This was despite the assumptions and the use of external data in the model. The EAG commented that overall survival and progression-free survival predictions had reasonable fit to the trial results, given the variation in the Kaplan–Meier curves. The EAG also noted that MAJIC‑PV was not powered for the progression-free survival and overall survival outcomes. It added that the number of deaths and incidence of myelofibrosis, acute myeloid leukaemia and myelodysplastic syndrome were low. The company also presented validation of the predicted overall survival for best available therapy against longer-term registry data. The company did targeted searches to identify studies reporting survival in people with polycythaemia vera that is resistant or intolerant to hydroxycarbamide. They identified 2 studies that were relevant, both of which reported results from the GEMFIN cohort. The company selected the larger cohort with longer follow-up for validation. The study included 272 people with polycythaemia vera resistant or intolerant to hydroxycarbamide treated with best available therapy. The company presented the model predictions for overall survival in the best available therapy arm alongside survival for best available therapy reported in MAJIC‑PV and in the GEMFIN cohort. The company considered that survival reported in the GEMFIN cohort was broadly aligned with the best available therapy arm of MAJIC‑PV and the model predictions. The committee noted that the company had not provided fit statistics for the data from the GEMFIN cohort compared with the model predictions. The company explained that this was because the model was not fitted to the data from the GEMFIN cohort, and this curve was presented for visual comparison only. The EAG had some concerns with the targeted searches done but noted the clinical experts did not identify any additional studies. So, the EAG thought it was likely that all relevant studies had been identified. The committee considered that the overall survival predictions from the progression-based model were broadly aligned with the MAJIC‑PV and GEMFIN registry data.

3.15 The committee preferred the company's updated progression-based model structure. This was because it captured the prognostic value of preventing progression on survival, rather than modelling overall survival directly (see section 3.12). The committee noted that the clinical trials did not show a statistically significant overall survival benefit with ruxolitinib compared with best available therapy. But it noted that ruxolitinib did statistically significantly improve event-free survival compared with best available therapy in MAJIC‑PV (see section 3.7). It also noted that it was plausible that ruxolitinib may improve overall survival by:

3.16 Overall survival for ruxolitinib in the MAJIC‑PV model with the original model structure was estimated by applying the overall survival hazard ratio for ruxolitinib compared with best available therapy from the MAJIC‑PV trial to the estimated overall survival for best available therapy from MAJIC‑PV. This was because of the lack of individual patient data for MAJIC‑PV (see section 3.11). At the second committee meeting, the company provided a scenario analysis that assumed there was no difference in overall survival between best available therapy and ruxolitinib using the original model structure. This was done by setting the hazard ratio for overall survival to 1. Although the committee preferred the progression-based model structure (see section 3.12), it considered that this scenario provided a reasonable bound to uncertainty.

3.17 The NICE reference case stipulates that EQ‑5D utility values should be used in company submissions unless there is empirical evidence to deviate from this measure. Data for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ‑C30) and Myeloproliferative Neoplasm Symptom Assessment Form (MPN‑SAF) measures were collected in RESPONSE. Data for EQ‑5D‑5L and MPN‑SAF measures were collected in RESPONSE‑2 and MAJIC‑PV. The EQ‑5D and EORTC measures are generic measures of quality of life, whereas MPN‑SAF is a disease-specific measure for myeloproliferative neoplasms. The company used Myelofibrosis 8 dimensions (MF‑8D; a myelofibrosis disease-specific measure) utility values in its economic model. It did this by incorporating 3 items from EORTC QLQ‑30 and 5 items from MPN‑SAF data from the RESPONSE trial in its base case. Only RESPONSE data was used because it was the only trial to collect EORTC QLQ‑30 data. The company explained the decision based on this evidence from RESPONSE‑2:

3.18 At the second committee meeting, the company's base case and the EAG's base case were the same. They were also aligned with the committee's preferred assumptions at the first committee meeting and included that:

3.19 NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjust life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. After the first committee meeting, the committee considered that there was substantial uncertainty in the cost-effectiveness estimates generated using its preferred assumptions because of uncertainty in the:

3.20 The cost-effectiveness results included confidential prices for ruxolitinib and other treatments. So, the exact results cannot be reported here. The company's and EAG's base-case ICER for ruxolitinib against best available therapy was below £20,000 per QALY gained. In the 'conservative scenario', in which ruxolitinib only affected deaths due to a reduction in myelofibrosis and acute myeloid leukaemia or myelodysplastic syndrome, the ICER was also below £20,000 per QALY gained. The original model structure, in which the overall survival hazard ratio was equal to 1, was not the committee's preferred modelling approach. But it noted that the scenario using the original model structure was also within the range of what NICE considers to be a cost-effective use of NHS resources. The committee considered the uncertainty and the range of the cost-effectiveness estimates. It agreed that the most plausible ICERs were below £20,000 per QALY gained, so considered that ruxolitinib represented a cost-effective use of NHS resources.

3.21 The committee did not identify any equality issues.

3.22 The committee recalled the substantial uncertainty associated with the long-term treatment effect of ruxolitinib on overall survival (see section 3.15). But it agreed that the most likely cost-effectiveness estimates for ruxolitinib were within what NICE considers a cost-effective use of NHS resources. So, ruxolitinib is recommended for treating polycythaemia vera in adults who cannot tolerate hydroxycarbamide or when the condition is resistant to it.