Chronic myeloid leukaemia - dasatinib and nilotinib: appraisal consultation document

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal consultation document
Dasatinib and nilotinib for imatinib-resistant and/or imatinib-intolerant chronic myeloid leukaemia

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on the use of dasatinib and nilotinib for imatinib-resistant and/or intolerant for patients with chronic myeloid leukaemia in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

  • Has all of the relevant evidence been taken into account?
  • Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
  • Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
  • Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on these technologies. The recommendations in section 1 may change after consultation.

After consultation:

  • The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
  • At that meeting, the Committee will also consider comments made by people who are not consultees.
  • After considering these comments, the Committee will prepare the final appraisal determination (FAD).
  • Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using dasatinib and nilotinib for chronic myeloid leukaemia in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 7 December 2009

Second Appraisal Committee meeting: 13 January 2010

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document is not NICE's final guidance these technologies. The recommendations in section 1 may change after consultation.

1 Appraisal Committee’s preliminary recommendations

1.1 Dasatinib and nilotinib are not recommended for the treatment of chronic myeloid leukaemia in people for whom treatment with imatinib has failed because of imatinib resistance and/or intolerance.

1.2 People who are currently receiving dasatinib or nilotinib for the treatment of chronic myeloid leukaemia should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

2 Clinical need and practice

2.1 Chronic myeloid leukaemia (CML) is a cancer of myeloid blood cells characterised by a proliferation of granulocytes in blood and bone marrow. More than 90% of people with CML have an acquired chromosomal abnormality, the Philadelphia chromosome, which is caused by reciprocal translocations between chromosomes 9 and 22. These translocations result in a BCR-ABL fusion gene that codes an active tyrosine kinase protein. This protein leads to uncontrolled cell proliferation. People with Philadelphia-chromosome-negative CML have different translocations that result in the same BCR-ABL fusion gene and its tyrosine kinase protein.

2.2 CML has three phases. The initial chronic phase lasts between 3 and 5 years. In this phase the symptoms are usually mild and non−specific and can include fatigue, weight loss, night sweats, anaemia, a feeling of ‘fullness’ or a tender lump on the left side of the abdomen caused by enlargement of the spleen. Around 90% of people with CML are diagnosed during the chronic phase. Of these, CML is asymptomatic in approximately 40% and is diagnosed as a result of a routine blood test. The disease then progresses to an accelerated phase that lasts for about 6 months. During this phase disease progression is more rapid and immature blast cells in blood and bone marrow proliferate. Symptoms include bruising, bleeding and infections. In the final phase a blast cell crisis occurs. There is a rapid increase in immature forms of cells, which replace normal cells in bone marrow and affect other organs. Symptoms include fever, sweating, pain and enlargement of organs. When this phase is reached CML is usually fatal within 3–6 months.

2.3 CML is diagnosed by finding characteristic cells in blood and bone marrow. The Philadelphia chromosome is identified using cytogenetic techniques involving the examination of chromosomes under a microscope, fluorescence in situ hybridisation and reverse transcriptase polymerase chain reaction to detect products of the BCR-ABL gene. Various criteria, including the percentage of blast cells in blood or bone marrow, have been proposed to define the accelerated and blast crisis phases.

2.4 It is estimated that about 560 people are diagnosed with CML in the UK each year. Slightly more men than women are diagnosed (annual age-standardised rate 1.2 per 100,000 for men and 0.7 per 100,000 for women). The median age at diagnosis is 60 years.

2.5 A potential cure for CML is an allogeneic stem cell transplant, also known as bone marrow transplantation, but patient characteristics and the lack of availability of a matched donor preclude this option for many patients. However, imatinib can slow down the progression of CML, a first-generation tyrosine kinase inhibitor. Imatinib (400 mg daily) is currently the standard treatment for CML. It produces high rates of remission in the chronic phase but is less effective when the disease has progressed. Imatinib is associated with improved 5-year survival, especially in younger age groups (15–44 and 45–54 years). For all age groups combined, following the introduction of imatinib into routine clinical practice 5-year relative survival increased from 27.1% in 1990–1992 to 48.7% in 2002–2004 (p < 0.0001 for the trend).

2.6 Resistance to imatinib may be primary (if there is a poor initial response) or acquired (following a period of successful treatment). Imatinib intolerance is frequently defined as a grade 3 non−haematological or grade 4 haematological adverse events persisting for more than 7 days.

2.7 According to recommendations published by an expert panel on behalf of the European LeukemiaNet in 2006, the first choice of treatment in patients with imatinib resistance is allogeneic stem cell transplantation. If this is not possible dose escalation of imatinib to 600 or 800 mg daily is an option, provided that 400 mg daily is tolerated and that resistance to imatinib is not associated with a BCR-ABL mutation with a high level of insensitivity to imatinib. However, current NICE guidance only recommends dose escalation of imatinib in the context of clinical study (NICE technology appraisal guidance 70). Other treatment options include interferon alfa, busulfan and hydroxycarbamide.

2.8 Response to treatment is assessed haematologically by examining the peripheral blood and cytogenetically by searching for the Philadelphia chromosome in bone marrow aspirates. A molecular response can be assessed using polymerase chain reaction techniques.

2.9 A complete haematological response has been defined as maintaining all of the following for at least 4 weeks: white blood cell count no more than the upper limit of normal; absolute neutrophil count at least 1 x 109/l; platelet count less than 450 x 109/l and no more than the upper limit of normal; no blasts or promyelocytes in peripheral blood; less than 2% basophils in peripheral blood; and no extramedullary involvement.

2.10 A complete cytogenetic response is defined as absence of the Philadelphia chromosome among at least 20 cells in metaphase in a bone marrow aspirate. A major cytogenetic response has been defined as the number of participants experiencing either a complete or a partial cytogenetic response (that is, ≤35% Philadelphia-positive chromosomes in metaphase in a bone marrow aspirate).

3 The technologies

3.1 Dasatinib and nilotinib are second-generation tyrosine kinase inhibitors. Dasatinib is an orally active inhibitor of SRC and the Src family of kinases. These tyrosine kinases are involved in cell growth, differentiation, migration and survival, and many are involved in oncogenesis, tumour metastasis and angiogenesis. Dasatinib has been shown to directly inhibit 21 out of 22 mutant forms of BCR-ABL that are resistant to imatinib.

3.2 Dasatinib is licensed for the treatment of adults with chronic-, accelerated- or blast-phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate. The most common reported side effects in the trials are headache, pleural effusion, shortness of breath, cough, diarrhoea, nausea, vomiting, abdominal pain, skin rash, musculoskeletal pain, infections, haemorrhage, superficial oedema, fatigue, fever, neutropenia, thrombocytopenia and anaemia. For full details of side effects and contraindications, see the summary of product characteristics.

3.3 Nilotinib is an orally active phenylaminopyrimidine derivative of imatinib. Nilotinib does not inhibit the Src family of tyrosine kinases. Studies performed in vitro suggest that nilotinib inhibits 32 of 33 mutant BCR-ABL forms that are resistant to imatinib at physiologically relevant concentrations.

3.4 Nilotinib is licensed for the treatment of adults with chronic-phase and accelerated-phase Philadelphia-chromosome-positive chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib. Nilotinib is not licensed for use in the blast crisis. The most common side effects with nilotinib are thrombocytopenia, neutropenia, anaemia, headache, nausea, constipation, diarrhoea, rash, pruritus, fatigue and increased blood levels of lipase and bilirubin. Nilotinib prolongs the QT interval and is therefore contraindicated in patients with hypokalaemia, hypomagnesaemia or long QT syndrome.

3.5 The acquisition cost of dasatinib is £83.50 per 100-mg tablet (excluding VAT; British national formulary [BNF] edition 58). The cost of dasatinib treatment is £30,477.50 per year, assuming a treatment regimen of 100 mg daily. Costs may vary in different settings because of negotiated procurement discounts.

3.6 The acquisition cost of nilotinib is £21.72 per 200-mg tablet (excluding VAT; BNF edition 58). The cost of nilotinib treatment is £31,711.20 per year assuming a treatment regimen of 400 mg twice daily. Costs may vary in different settings because of negotiated procurement discounts.

4.1 Clinical effectiveness

Manufacturers’ analyses of clinical effectiveness

4.1.1 The manufacturer of dasatinib identified seven studies that were deemed relevant in patients with CML resistance or intolerance to prior therapy including imatinib. These were a randomised controlled trial (RCT) of dasatinib 70 mg twice daily versus imatinib 800 mg per day (N = 150); a comparative cohort study of dasatinib versus nilotinib (N = 120); two dasatinib dosage optimisation studies comparing once-daily with twice-daily dosage regimens (N = 862); two single-arm open-label studies of nilotinib (N = 458); and an imatinib dose escalation cohort study (N = 84).

4.1.2 The manufacturer of dasatinib stated that the lack of head-to-head RCTs prevented any robust direct or formal indirect comparisons of dasatinib (at the licensed starting dosage of 100 mg once per day) with either nilotinib or high-dose imatinib. Therefore cross-study comparisons were undertaken of data from single study arms for each drug by disease phase. Although this approach cannot control for differences between the patient populations in the respective studies and end points measured, it was regarded as an appropriate use of the limited evidence available.

4.1.3 The manufacturer of nilotinib presented a non-comparative phase II open-label study (N = 458) that was conducted to assess the efficacy, safety, tolerability, biological activity and pharmacokinetic profile of nilotinib in six disease-specific groups: relapsed/refractory Philadelphia-chromosome-positive acute lymphoid leukaemia; imatinib-resistant/intolerant CML in the blast phase; imatinib-resistant/intolerant CML in the accelerated phase; imatinib-resistant/intolerant CML in the chronic phase; hypereosinophilia/chronic eosinophilic leukaemia; and systemic mastocytosis.

4.1.4 The study population was defined as adult patients with Philadelphia-chromosome-positive CML in the chronic or accelerated phase with imatinib resistance and/or intolerance. Patients were treated with 400 mg nilotinib twice daily until adverse events were unacceptable, until there was disease progression or the patient was no longer benefiting from treatment. Dosage escalation to 600 mg nilotinib twice daily was permitted if the patient had signs of resistance or relapse.

Assessment Group’s analysis of clinical effectiveness

4.1.5 The Assessment Group conducted a systematic review for evidence of the comparative clinical efficacy of the two technologies. Additional comparators were high-dose imatinib for imatinib-resistant CML and interferon alfa for imatinib-intolerant CML. Of 15 identified studies, three were RCTs. One of the RCTs compared dasatinib with imatinib and the other two compared different doses of dasatinib. Twelve studies were observational (seven of dasatinib, four of nilotinib and one retrospective study with both technologies).

4.1.6 Dasatinib was used at the licensed dosage in only one arm of the dasatinib trials. The definitions of intolerance and resistance varied between trials of dasatinib and nilotinib. In the dasatinib trials, intolerance was assessed based on persistent adverse effects. In the nilotinib trials, in addition to persistent adverse events, a lack of cytogenetic response had to be demonstrated. Most dasatinib trials defined resistance as a lack of complete cytogenetic response within a specified treatment period and included patients with major cytogenetic responses. The trials of nilotinib excluded patients with major cytogenetic responses.

4.1.7 One RCT included a direct comparison of dasatinib and high-dose imatinib, but this was of limited usefulness because of the extent of premature crossover from the high-dose imatinib arm (80% of participants changed therapy after a median of 13 weeks). Neither this trial nor the trials comparing different dosages reported methods of allocation concealment. They were open-label trials and did not present power calculations.

4.1.8 There was also an absence of data comparing dasatinib with nilotinib. Significant sources of variation between studies included differences in eligibility criteria, baseline characteristics, definitions of haematological response and progression-free survival, and differences in the reporting of outcomes. Overall the definitions of cytogenetic response were consistent across the dasatinib studies. The definitions of haematological response differed across studies but were similar. Some trials appeared to include a small number of participants with the target response at study entry who were not equally distributed between trial arms.

4.1.9 For dasatinib in chronic-phase CML,  patients with imatinib intolerance had a percentage of 68.1% complete cytogenetic response (95% confidence interval [CI] 62.7 to 73.5), 75.5% major cytogenetic response (95% CI 70.5 to 80.5) and 93.7% complete haematological response (95% CI 89.5 to 97.9), which were higher compared with the patients who had imatinib resistance whose percentages were 37.4% (95% CI 34.2 to 40.5) for major cytogenetic response, 50.9% (95% CI 47.6 to 54.1) for complete cytogenetic response and 89.2% (95% CI 87.2 to 91.3), respectively. Such a difference in response was not noted in the patients in accelerated-phase CML. In chronic-phase CML no dose-related response was noted for any outcome measure.

4.1.10 For dasatinib, in chronic-phase CML the median progression-free survival was not reached in any trial, with the longest follow-up being 3 years. In accelerated-phase CML median progression-free survival was 25.2 and 26.1 months in two trials, and in blast-phase CML progression-free survival was 2.8–5.8 months. The median overall survival in chronic-phase CML was not reached in any trial at 36 months, and in accelerated-phase CML a median overall survival of 30.75 months was reached in one trial.

4.1.11 For dasatinib, the most common adverse events in all phases of CML were haematological events and cytopenias, although many trials used a higher dose than that licensed. The most frequent non-haematological grade 3–4 adverse events were dyspnoea and pleural effusion, fatigue and pyrexia. Other common adverse events include diarrhoea, vomiting, febrile neutropenia and fluid retention.

4.1.12 The trials of nilotinib used different entry criteria from the dasatinib trials. In particular, the definition of imatinib-resistant CML in the nilotinib trials included a lack or loss of cytogenetic response, and the definition of imatinib-intolerant CML excluded patients who had a major cytogenetic response. In addition, some patients in the trials had already achieved a target response.

4.1.13 The definitions of cytogenetic and haematological responses were largely consistent across the nilotinib studies that were included. There was no evidence of differing levels of complete or major cytogenetic response between patients with imatinib-intolerant and imatinib-resistant chronic-phase CML (34.9% [95% CI 24.9 to 45.9] for imatinib- intolerant versus 30.3% [95% CI 24.1 to 36.5] for imatinib-resistant complete cytogenetic response, respectively; 46.5% [95% CI 35.7 to 57.6] for imatinib- intolerant versus 46.5% [95% CI 37.3 to 55.7] for imatinib-resistant major cytogenetic response, respectively) and those with accelerated-stage CML (complete cytogenetic response: imatinib resistant 14.3% [95% CI 6.4 to 26.2] versus overall pooled 16.4% [95% CI 11.5 to 21.4]; major cytogenetic response: imatinib resistant 26.8% [95% CI 15.8 to 40.3] versus overall pooled 28.3% [95% CI 22.2 to 34.3]).

4.1.14 When assessing the evidence for the chronic phase submitted by the manufacturer of nilotinib, the Assessment Group noted that the entry criteria for the large, multicentre trial were such that patients were enrolled as having imatinib-resistant CML only if they had never had a major cytogenetic response to imatinib or there had been a loss of cytogenetic response during imatinib therapy. The imatinib-intolerant population excluded patients who had achieved a major cytogenetic response to imatinib before. Therefore, none of the patients in the trials had had a major cytogenetic response at study entry.

4.1.15 There was heterogeneity in the rates of complete haematological response for imatinib-intolerant and imatinib-resistant CML for nilotinib in the chronic phase (90.0% [95% CI 78.2 to 96.7] versus 78.9% [95% CI 55.9 to 100.0]) and in the accelerated phase (imatinib resistant 51.0% [95% CI 36.6 to 65.2] versus overall pooled 44.6% [95% CI 14.6 to 74.6]).

4.1.16 Progression-free survival was defined differently across the trials of nilotinib. In chronic-phase CML median progression-free survival was not reached at 36 months in any trial, and in accelerated-phase CML median progression-free survival was 16 months in one trial. Median overall survival in chronic-phase CML was not reached at 30 months in any trial and in accelerated-phase CML median overall survival was not reached at 30 months in one trial.

4.1.17 For nilotinib, grade 3–4 haematological adverse events were seen in frequencies of 15–30% and did not vary between the chronic and accelerated phases of CML. The most common non−haematological severe adverse event was rash. Other common adverse events included constipation, diarrhoea, vomiting and fatigue.

Summary of clinical effectiveness

4.1.18 The Assessment Group was unable to identify sufficient published evidence for the technologies being appraised, with only one included study assessing either of the technologies under review against a relevant comparator – a randomised controlled trial comparing dasatinib with high-dose imatinib. The studies investigating dasatinib and nilotinib were heterogeneous in design, population, implementation and analysis. Among the most notable sources of variation were differences in eligibility criteria, baseline characteristics, outcome definitions and outcome reporting. Dasatinib and nilotinib showed clinical benefit in patients resistant and/or intolerant to imatinib.

4.2 Cost effectiveness

Manufacturers’ analyses of cost effectiveness

Dasatinib

4.2.1 The manufacturer of dasatinib submitted a cost-effectiveness analysis of dasatinib for the treatment of CML in adults in whom prior therapy, including imatinib, had failed. The main comparators were nilotinib and high-dose (600 mg daily in chronic-stage CML only, and 800 mg per day in all phases of CML) imatinib. The manufacturer of dasatinib did not present any comparisons of dasatinib with best supportive care or other comparators.

4.2.2 A Markov model was developed to estimate long-term costs and outcomes (life years and quality-adjusted life years [QALYs]) for typical patients, from failure of prior therapy (imatinib) to death. The results of the cost-effectiveness analysis suggested that dasatinib is cost effective for adult patients with chronic-phase CML in whom prior therapy, including imatinib, has failed. Based on data for the licensed dosage of 100 mg once daily, dasatinib was estimated to be less expensive and more effective (dominant) than high-dose (800 mg per day) imatinib and cost effective compared with nilotinib. In the manufacturer of dasatinib submission, the costs for dasatinib were £280,619 and QALYs of 6.21, compared with £278,087 and QALYs of 5.91 for nilotinib. This represents an increase in costs of £2500 and in QALYs of 0.34, resulting in a final ICER of £8507 per QALY gained. In accelerated-phase CML dasatinib was estimated to be broadly cost effective compared with nilotinib and high-dose imatinib. In accelerated- and blast-phase CML, the manufacturer’s cost-effectiveness estimates were favourable, particularly in the blast phase, but were associated with more uncertainty because of a lack of comparative efficacy data. A comparison of costs suggested that dasatinib is less expensive than both nilotinib for patients in accelerated-phase CML and high-dose imatinib for patients in accelerated- and blast-phase CML, and more clinically effective than both treatment options (dominant). These results were suggested to be broadly robust under extensive one-way and probabilistic sensitivity analyses.

Nilotinib

4.2.3 Two Markov models were developed by the manufacturer of nilotinib to evaluate the cost effectiveness of nilotinib for the treatment of adult patients with CML resistant and/or intolerant to prior therapy in the chronic and accelerated phases of CML. For patients with resistance, nilotinib was compared with high-dose (800 mg per day) imatinib. For patients with intolerance nilotinib was compared with hydroxycarbamide. The manufacturer stated that nilotinib was not compared with interferon alfa or dasatinib because of a lack of suitable data.

4.2.4 The results for patients with chronic-phase CML suggested that nilotinib is less costly and more effective than high-dose imatinib. The results for patients with accelerated-phase CML suggested that nilotinib has a cost per QALY gained of £18,541 compared with high-dose imatinib. The cost of nilotinib is £57,571 with QALYs of 1.41 compared with a cost of high-dose imatinib of £53,144 and QALYs of 1.17, which represents an increase in costs of nearly £4500 and 0.24 in QALYs. Furthermore, the manufacturer’s analysis for imatinib-intolerant patients showed that the costs for nilotinib were £231,156 and QALYs of 6.72 compared to costs of £20,111 and QALYs of 3.12, which was an increase in costs of nearly £210,000 and in QALYs of 3.6, resulting in an ICER of £58,590 per QALY gained, when comparing nilotinib with hydroxycarbamide in patients with imatinib intolerance. For patients with accelerated-phase CML with imatinib intolerance as well as resistance the costs for nilotinib were £100,414 and QALYs of 2.13, while for hydroxycarbamide the costs were £9,448 and QALYs of 0.99. There is an increase in costs of nearly £91,000 and in QALYs of 2.14, resulting in an ICER of £79,914 per QALY gained.

Assessment Group’s analysis of cost effectiveness

4.2.5 The Assessment Group conducted a systematic review of available literature on the cost effectiveness of dasatinib and nilotinib for CML in people who have resistance or intolerance to imatinib. Nine abstracts and two reports were identified that met the specified inclusion criteria. Seven studies reported on dasatinib and four reported on nilotinib. All studies used high-dose imatinib as the comparator.

4.2.6 All 11 studies included patients with imatinib resistance or imatinib intolerance. In some studies, it was not clear whether the participants had imatinib resistance, imatinib intolerance or both. Most of the studies of dasatinib modelled cost effectiveness based on patients in the chronic, accelerated and blast crisis phases of CML separately. The studies of nilotinib modelled cost effectiveness based on patients starting in chronic-phase CML and progressing through the accelerated and blast phases. Four of the studies were based on a UK perspective. Not all studies stated the source of data on clinical effectiveness, but those that did cited the phase II trials of dasatinib and nilotinib, with two studies using data from a subgroup of the International Randomized Study of Interferon vs. STI571 (IRIS) trial (interferon versus imatinib) to predict long-term overall survival for dasatinib and nilotinib. The cost-effectiveness results for dasatinib and nilotinib showed that each was less costly and more effective than imatinib, with incremental cost-effectiveness ratios (ICERs) of £22,000 per QALY gained for nilotinib, and up to CAN $173,922 per QALY gained and US $205,405 per life year gained for dasatinib.

4.2.7 The Assessment Group produced a de novo model restricted to imatinib-resistant or imatinib-intolerant CML in the chronic phase because it was unable to identify suitable effectiveness data for the comparator treatments in these populations with which to populate the model in accelerated- and blast-phase CML.

4.2.8 Two separate models were implemented: one simulating a cohort of patients who showed (or developed) resistance to standard-dose imatinib (imatinib resistant) and one representing patients who had been unable to continue imatinib treatment because of adverse events (imatinib intolerant). The comparators were high-dose imatinib for people in chronic-phase CML who developed resistance to imatinib, and interferon alfa for people in chronic-phase CML who had intolerance of imatinib.

4.2.9 For imatinib-resistant CML three technologies were considered: dasatinib, nilotinib and high-dose imatinib. A clinical adviser to the Assessment Group noted that interferon alfa is not a realistic comparator because it is not used in clinical practice. The cost-effectiveness analysis carried by the Assessment Group showed that all three technologies resulted in relatively similar gains in survival, with median overall survival ranging from 9.11 years for nilotinib to 9.53 years for dasatinib. Gains in survival with high-dose imatinib were predicted to lie between those of the two new technologies.

4.2.10 The base-case incremental cost-effectiveness results for imatinib-resistant CML from the Assessment Group model showed that high-dose imatinib produced an ICER of £13,273 per QALY gained compared with nilotinib, and dasatinib produced an ICER of £3,206,512 per QALY gained compared with high-dose imatinib.

4.2.11 For imatinib-intolerant CML the Assessment Group’s economic analysis compared the technologies under review with interferon alfa plus cytarabine. The Assessment Group used interferon alfa as a comparator for this population on the assumption that it is the most effective technology available if imatinib cannot be tolerated and the technologies under review are assumed to be unavailable. The Assessment Group’s expert advisers were not unanimous on this point, with some arguing that hydroxycarbamide would be appropriate as a comparator. However, others stated that interferon alfa was the standard of care for this population before the development of tyrosine kinase inhibitors (as corroborated by its use as comparator in the landmark trial of effectiveness of first-line, standard-dose imatinib).

4.2.12 The Assessment Group’s deterministic base-case incremental cost–utility analysis for patients with chronic-phase imatinib-intolerant CML showed that nilotinib (cost of nilotinib £193,613; 7.09QALYs) was more expensive and less effective than interferon plus cytarabine (cost of interferon plus cytarabine £39,747; 5.88 QALYs) with an ICER of £128,000 per QALY gained for nilotinib. Dasatinib was slightly more cost-effective compared with nilotinib with a cost of £280,639 and QALYs of 8.19, but still not cost-effective when compared with interferon plus cytarabine with an ICER of £104,500 per QALY gained.  

4.2.13 The probabilistic sensitivity analysis demonstrated substantial uncertainty about the effectiveness of the new technologies. It showed that dasatinib generated most QALYs in 49% of the simulations, high-dose imatinib in 41% and nilotinib in 10%. The cost-effectiveness evaluation demonstrated that the most cost-effective treatment was likely to be high-dose imatinib at a threshold of up to £66,000 per QALY gained, when nilotinib became more likely to be cost effective. Dasatinib was only cost effective at an approximate threshold of more than £150,000 per QALY. At a threshold of £30,000 per QALY gained there was a 60% probability of high-dose imatinib being most cost effective and a 40% probability of nilotinib being cost effective.

4.2.14 For accelerated-phase CML the Assessment Group performed a review, a critical appraisal and an exploration of the cost-effectiveness analyses contained within the manufacturers’ submissions. The Assessment Group had concerns about the manufacturer’s model of dasatinib. The model predicted much shorter-tailed overall survival for high-dose imatinib and nilotinib than was seen in the trials and assumed that all treatments are always taken at the recommended dose. It also took the cost of dasatinib from MIMS (rather than the BNF). All these factors would have an impact on increasing the final ICER for dasatinib in accelerated-phase CML.

4.2.15 The Assessment Group also had important concerns about the manufacturer’s submission for nilotinib in accelerated-phase CML. The data used to estimate the effectiveness of high-dose imatinib in an imatinib-resistant population were questioned. When the parameters were remodelled by the Assessment Group, the model predicted that nilotinib would be less effective and less costly than high-dose imatinib, saving around £100,000 per QALY lost. The Assessment Group was also concerned about the manufacturer’s degree of extrapolation of progression-free survival, in particular for the imatinib-intolerant subgroup, which made all cost-effectiveness results highly uncertain; and again the manufacturer assumed that all treatments are always taken at the recommended dose.

4.2.16 For blast-phase CML, the Assessment Group found that the data used by the manufacturer of dasatinib to estimate the effectiveness of high-dose imatinib in an imatinib-resistant population were questioned, being based on an imatinib-naïve comparator population receiving standard-dose and low-dose imatinib. In addition, a much shorter-tailed overall survival for high-dose imatinib than was seen in the trial was assumed by the manufacturer of dasatinib.

4.3 Consideration of the evidence

4.3.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dasatinib and nilotinib for CML, having considered evidence on the nature of CML and the value placed on the benefits of dasatinib and nilotinib by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources.

4.3.2 The Committee considered current clinical practice in the treatment of CML following imatinib resistance or imatinib intolerance. In doing so, it considered both current NICE guidance and evidence from the clinical specialists and patient experts. The Committee heard from the clinical specialists that dasatinib and nilotinib are considered to be clinically effective. Their use is encouraged by cancer networks, but is not universal given their extremely high acquisition costs. High-dose imatinib was considered by the experts to be a poor option, given that these patients are resistant to or do not tolerate imatinib. The Committee heard from a patient expert that treatment with high-dose imatinib provided some improvements, although these were not durable. The Committee heard from all the clinical specialists that interferon alfa plus cytarabine was very rarely used and hydroxycarbamide was a last resort. For patients with imatinib resistance the options are dasatinib or nilotinib at the licensed doses. The clinical specialists stated that many patients take a lower dose than the licensed dose of dasatinib or nilotinib, but there is no evidence available clarifying the median dose for the drugs.

4.3.3 The Committee discussed current NICE guidance on the use of imatinib in patients with CML and imatinib resistance and/or intolerance. NICE technology appraisal guidance 70 recommends continued use of imatinib at a higher dose than 400 mg/day that has been initiated in the chronic phase of CML but has failed to stop disease progression to either the accelerated phase or blast crisis only in the context of clinical study (see ‘Guidance on the use of imatinib for chronic myeloid leukaemia’ [NICE technology appraisal guidance 70]). The Appraisal Committee for NICE technology appraisal guidance 70 noted at the time of the appraisal that there was no evidence available about dose escalation of imatinib to 600 mg per day or 800 mg daily and that it was ’fully aware of the implications regarding the significantly increased cost-effectiveness ratios where dosages of imatinib greater than 400mg daily were used. A review of NICE technology appraisal guidance 70 will start in November 2009 and might allow for more evidence to be gathered relating to the use of imatinib at high doses in patients whose disease progresses at the standard dosage of 400 mg daily. The Committee was mindful that high-dose imatinib was included as one of a number of comparators in the scope. However, it did not consider that this overrode NICE technology appraisal guidance 70, or that it was intended to instigate an appraisal in which other comparators were ignored.

4.3.4 Given existing NICE guidance recommending that high-dose imatinib be used only in clinical studies (see ‘Guidance on the use of imatinib for chronic myeloid leukaemia [NICE technology appraisal guidance 70]), the use of high-dose imatinib in populations who already have imatinib resistance and/or intolerance, and the clinical specialists’ views that it was a poor option, the Committee discussed what the correct comparator for the appraisal should be. It heard from the clinical specialists that bone marrow transplantation would probably be the best option but for many patients is unsuitable or not possible because of the lack of a suitable donor and higher risk of mortality. The Committee, noting the specialists’ views on the other alternatives, considered that it was more appropriate to regard best supportive care as the principal comparator for patients with imatinib intolerance or resistance. However, the Committee considered that the evidence available for patients who take hydroxycarbamide or interferon alfa could be considered to give some indication of how well patients might survive on best supportive care.

4.3.5 The Committee considered the clinical evidence for chronic-phase CML presented by the manufacturers and the Assessment Group. It noted the paucity of data available for dasatinib and nilotinib in this phase of CML. There was a very small amount of comparative evidence available for either dasatinib or nilotinib. The Committee noted that not only were there no trials comparing these technologies with best supportive care (or with interferon or hydroxycarbamide), there was only one study comparing dasatinib with high-dose imatinib, which the Committee could not regard as the appropriate comparator. Furthermore, the Committee had been advised by the Assessment Group that this study was of limited usefulness because of the extent of premature crossover from the high-dose imatinib arm (80% of patients changed therapy after a median of 13 weeks).

4.3.6 Nevertheless, the Committee heard from clinical specialists that both dasatinib and nilotinib could be considered effective based on evidence from both the single-arm studies and from increasing clinical experience. In the absence of these treatments life expectancy is likely to be around 3 years. With dasatinib and nilotinib this would be considerably extended for some patients and has the potential to do so with a good quality of life. The Committee also heard from a patient with CML who had first received treatment with interferon alfa, which was later discontinued and treatment with imatinib initiated. Treatment with imatinib at the standard dose (400 mg daily) eventually failed. With high-dose imatinib adverse events increased and there was a diminished quality of life. Treatment was changed to dasatinib and the patient had been taking dasatinib for 3 years and 8 months. The patient’s quality of life continued to be very good, although adverse events had occurred.

4.3.7 The Committee noted the response rates seen in the single-arm studies and the modelled gains in life years seen in the reports from the Assessment Group and the manufacturers. Both demonstrated evidence of efficacy of the technologies although their relative efficacies had to remain speculative. These uncertainties were emphasised by the considerable range in estimates of overall survival made available to the Committee.

4.3.8 Within the different models, the overall survival estimates were generally longer for patients with imatinib intolerance than those with imatinib resistance. The clinical specialists and the Committee agreed that this was a reasonable inference given that patients with imatinib intolerance are generally less heavily pre-treated than those who develop resistance over time.

4.3.9 The Committee discussed the differences in treatment with dasatinib and nilotinib. It noted not only the slightly fuller evidence base for dasatinib, but also the modelling by the manufacturer of dasatinib indicating a gain of 0.34 life years when using dasatinib rather than nilotinib, and a marginal advantage estimated in the Assessment Group’s modelling. However, the Committee noted that there was no comparative evidence, and the clinical specialists said that they regarded the two technologies as essentially comparable. The Committee concluded that it is important to have further evidence from head-to-head trials comparing the technologies, but that meanwhile for chronic-phase CML both drugs could be regarded as equivalent.

4.3.10 The Committee was made aware that for patients with CML with a specific mutation (T315I) there is currently no effective treatment. The clinical specialists considered that it might be possible to customise therapy in future, to enable the best treatment and the best outcome for each patient with CML.

4.3.11 For accelerated-phase CML, the Committee again noted that although the data are non-comparative and heterogeneous, both dasatinib and nilotinib can be considered clinically effective. In blast-phase (or blast-crisis) CML the Committee, noting that nilotinib is not licensed, considered that CML in this phase is very difficult to treat and that dasatinib can be considered clinically effective. It heard that dasatinib may prolong survival by a few months compared with intensive chemotherapy or best supportive care and may provide a better quality of life.

4.3.12 The Committee then discussed the cost effectiveness of the technologies in chronic-phase imatinib-intolerant/resistant CML. It acknowledged the great difficulties of undertaking an assessment of cost effectiveness in these circumstances: that is, in the absence of reasonable comparative evidence, with reliance on surrogate outcomes, and given the uncertainty of treatment durations (although expert opinion is that treatment would normally be offered indefinitely as long as response to treatment continued and treatment was tolerated). The widely ranging estimates consequent on these problems were exacerbated by the use of different comparators – comparison with the expensive but contentious high-dose imatinib can be expected to yield better incremental gains per unit cost than if high-dose imatinib is not taken as the proven comparator.

4.3.13 The Committee considered the results presented in the models from the Assessment Group and the manufacturers. The Committee noted the variation in modelling methods and the different estimates of overall survival and treatment duration, and therefore cost, in the models. The Committee considered that the Assessment Group’s report provided a good basis for discussion given the paucity of data, but that there were useful insights to be gained from the manufacturers’ calculations too. The clinical specialists criticised the Assessment Group’s model, arguing that it did not reflect disease progression and clinical practice, and that it was wrong to estimate much shorter treatment durations (and therefore costs) for nilotinib as opposed to dasatinib. In the Assessment Group analysis, dasatinib was considered to be more effective than nilotinib, which was reflected in higher costs because of longer treatment durations. The Committee heard from clinical specialists that both drugs are equally effective, and that this was not reflected in the Assessment Group model. They also pointed to the fact that the Assessment Group’s overall survival estimates for patients taking interferon alfa were much too high and lacked validity.

4.3.14 The Committee was made aware that the average costs of the technologies in patients with imatinib resistance and/or intolerance were around £200,000 or more, reflecting several years of treatment at more than £30,000 per year for dasatinib and nilotinib alone. The Committee noted that the only exceptions to this were from the optimistic treatment duration estimates for nilotinib from the Assessment Group and the manufacturer of nilotinib. The Committee heard from the clinical specialists that dasatinib and nilotinib are taken for the patient’s lifetime, with no stopping rule with current evidence. The clinical specialists considered that current evidence is very scarce and that an evidence-based stopping rule for dasatinib or nilotinib, which might improve cost effectiveness, is currently not possible.

4.3.15 The Committee noted that net costs could be argued to be much lower if the costs of high-dose imatinib could be subtracted from the total. But the Committee agreed that this was an artificial comparison. In order to get an estimate of cost effectiveness in which the net costs of high-dose imatinib were not used, the Committee took advantage of the calculations available (accepting their numerous uncertainties) where high-dose imatinib had not been modelled as the comparator. These calculations were available for some of the estimates made for the imatinib-intolerant case, in which high-dose imatinib could not be considered. An estimate was provided for the patient population with imatinib intolerance by the manufacturer of nilotinib, presenting an ICER of £58,600 per QALY gained for nilotinib compared with hydroxycarbamide. The Committee also noted that the Assessment Group provided an estimated ICER of £105,000 per QALY gained for dasatinib and an ICER of £128,000 per QALY gained for nilotinib in the population with imatinib intolerance when compared with interferon alfa. The Committee noted that all these estimates were still highly uncertain. Furthermore, the Committee was unable to make an informed judgement in the population with imatinib resistance because all the cost-effectiveness analyses presented had high-dose imatinib as a comparator, which was rejected by the Committee. It did note, however, that it was unlikely that cost effectiveness would equal that in the population with imatinib intolerance, given the apparently lower response in this group because of heavier pre-treatment.

4.3.16 For accelerated-phase CML, the Committee considered that there was an even weaker evidence base. It noted that the manufacturer of nilotinib provided an estimate for this patient population, with an ICER of approximately £80,000 per QALY gained. For blast-phase CML the Committee was unable to reach firm conclusions because of the paucity of the evidence presented.

4.3.17 The Committee was aware that for patients with CML in the accelerated and blast phases, both dasatinib and nilotinib might be considered against the criteria set by NICE in the supplementary advice for appraising life-extending, end-of-life treatments. For this advice to be applied, all the following criteria must be met.

  • The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
  • There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
  • The treatment is licensed or otherwise indicated for small patient populations.

In addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.

4.3.18 However, the Committee agreed that the criterion for the robustness of evidence for the accelerated and blast phase CML was not met. Therefore the Committee did not consider that dasatinib and/or nilotinib for the treatment of people with CML resistant and/or intolerant to imatinib fulfilled the criteria for consideration as a life-extending, end-of-life treatment; the available evidence on life extension was too weak.

4.3.19 In summary, the Committee was persuaded that even though the evidence was of extremely poor quality, taken together with expert opinion, dasatinib and nilotinib can be considered clinically effective for the treatment of CML in people with imatinib resistance and/or imatinib intolerance. However, the uncertainty in the estimates concerning the size of this gain taken together with the exceptionally high acquisition costs of these drugs means that, at their current acquisition costs, they cannot be regarded as an appropriate use of NHS resources.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

  • Slides highlighting key messages for local discussion.
  • Costing report and costing template to estimate the savings and costs associated with implementation.
  • Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
  • A costing statement explaining the resource impact of this guidance.
  • Audit support for monitoring local practice.

6 Related NICE guidance

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in November 2012 NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Andrew Stevens
Chair, Appraisal Committee
October 2009

Appendix A: Appraisal Committee members, guideline representatives and NICE project team

A Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Kathryn Abel
Reader and Consultant Psychiatrist/Director of Centre for Women's Mental Health, University of Manchester

Dr David Black
Director of Public Health, Derbyshire County Primary Care Trust

Professor Mike Campbell
Statistician, Institute of Primary Care and General Practice, University of Sheffield

Mr David Chandler
Lay member

Mary Cooke
Lecturer School of Nursing, Midwifery and Social Work, University of Manchester

Professor Rachel A Elliott
Lord Trent Professor of Medicines and Health, University of Nottingham

Stephen Greep
Chief Executive of Hull and East Yorkshire Hospitals NHS Trust 

Dr Wasim Hanif
Consultant Physician and Honorary Senior Lecturer University Hospital Birmingham

Dr Alan Haycox
Reader in Health Economics, University of Liverpool Management School

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Dr Catherine Jackson
Professor of Primary Care Medicine, University of St Andrews

Professor Gary McVeigh (Vice Chair)
Cardiovascular Medicine, Queens University Belfast and Consultant Physician Belfast City Hospital

Dr Eugene Milne
Deputy Medical Director, North East Strategic Health Authority

Dr Richard Nakielny
Consultant Radiologist, Sheffield Teaching Hospitals Foundation Trust

Mrs Ruth Oliver-Williams
Head of Nursing/Quality Improvement Lead Surgical Services, Royal Derby Hospital

Dr Katherine Payne
Health Economics Research Fellow, University of Manchester

Dr Danielle Preedy
Lay member

Dr Martin J Price
Head of Outcomes Research, Janssen-Cilag

Mr Miles Scott
Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust

John Stevens
Director, Centre for Bayesian Statistics in Health Economics University of Sheffield

Dr Surinder Sethi
Consultant in Public Health Medicine, North West Specialised Services Commissioning Team

Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Dr Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Dr Judith Wardle
Lay member

 NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

João Vieira
Technical Lead

Dr Bhash Naidoo
Technical Adviser

Laura Malone
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The assessment report for this appraisal was prepared by Peninsula Health Technology Assessment Group:

  • Thompson Coon J, Hoyle M, Pitt M, et al Dasatinib and nilotinib for imatinib-resistant or ‑intolerant chronic myeloid leukaemia: A systematic review and economic evaluation, August 2009

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I and II were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I Manufacturers/sponsors:

  • Bristol Myers Squibb
  • Novartis

II Professional/specialist and patient/carer groups:

  • British Committee for Standards in Haematology
  • British Society for Haematology
  • Cancer Research UK
  • Royal College of Nursing
  • Royal College of Pathologists
  • Royal College of Physicians, Intercollegiate Committee on HaematologyChronic Myeloid Leukaemia Support Group (CML Support)
  • Leukaemia CARE
  • Leukaemia Research Fund
  • Macmillan Cancer Support

III Other consultees:

  • Department of Health
  • Welsh Assembly Government
  • Wiltshire PCT

IV Commentator organisations (without the right of appeal):

  • Department of Health, Social Services and Public Safety for Northern Ireland
  • NHS Quality Improvement Scotland
  • Bristol-Myers Squibb (hydroxycarbamide)
  • Novartis (imatinib)
  • Peninsula Technology Assessment Group, University of Exeter (PenTAG)
  • National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA Programme)
  • National Collaborating Centre for Cancer
  • National Institute for Health and Clinical Excellence (NICE)

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on Dasatinib and Nilotinib for the treatment of chronic myeloid leukaemia by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

  • Dr Stephen O’Brien, Consultant Haematologist, nominated by Royal College of Pathologists – clinical specialist
  • Professor Jane Apperley, Chair of Haemato-oncology Imperial College – clinical expert
  • Tony Gavin, Director of Campaigning and Patient Advocacy, Leukaemia CARE, patient expert
  • Lynsey Wombwell, representing Leukaemia CARE, patient expert

 

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Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.