Venetoclax with low dose cytarabine for untreated acute myeloid leukaemia when intensive chemotherapy is unsuitable

Evidence-based recommendations on venetoclax (Venclyxto) with low dose cytarabine for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable.

# Recommendations
Venetoclax with low dose cytarabine is recommended as an option for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable, only if:
they have over 30% bone marrow blasts
the company provides venetoclax according to the commercial arrangement.
This is not intended to affect treatment with venetoclax with low dose cytarabine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
When intensive chemotherapy is unsuitable, treatment for untreated acute myeloid leukaemia is usually azacitidine or low dose cytarabine. The clinical trial evidence shows that people with untreated acute myeloid leukaemia with over 30% bone marrow blasts (from here, blasts) having venetoclax plus low dose cytarabine live longer than people having low dose cytarabine alone. The company did not submit any evidence for the 20% to 30% blast group.
Venetoclax plus low dose cytarabine meets NICE's criteria for a life-extending treatment at the end of life. The likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Therefore, for people with untreated acute myeloid leukaemia with over 30% blasts, venetoclax plus low dose cytarabine is recommended.# Information about venetoclax

# Marketing authorisation indication
Venetoclax (Venclyxto, AbbVie) in combination with low dose cytarabine is indicated for 'the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy'.

# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for venetoclax.

# Price
The cost of venetoclax is 299.34 for 7100mg tablets (excluding VAT; BNF online accessed September 2021). The cost of cytarabine is 6.29 per 1g/10ml vial (excluding VAT; electronic market information tool online, accessed November 2021). Costs may vary in different settings because of negotiated procurement discounts.
The company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The general population mortality adjustment should be removed from the transition to the progression/relapse health state in the model (issue 2, see ERG report, section 4.2.6).
The company's updated approach to modelling time to treatment discontinuation is acceptable (issue 3, see ERG report, section 4.2.6).
It is acceptable in this case for adverse event data in the model to be sourced from a separate study to the VIALE trials, because it is unlikely to have a big impact on the cost-effectiveness results (issue 4, see ERG report, section 4.2.7).
It is acceptable in this case for treatment-independent utility values in the model to be derived from pooled data from both VIALEA and VIALEC, because it is unlikely to have a big impact on the cost-effectiveness results (issue 4, see ERG report, section 4.2.7).
Seven days' wastage for venetoclax should be included in the model to account for tablets that are prescribed but not used because of treatment discontinuation or death during a cycle (issue 6, see ERG report, section 4.2.8).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed issues 1, 5 and an additional issue identified at technical engagement, issue 7, which were outstanding after the technical engagement stage.

# New treatment option

## People with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option
Intensive chemotherapy is unsuitable for about 40% of people with untreated acute myeloid leukaemia. This may be because of fitness status, age or presence of comorbidities. The patient expert explained that patients in this group feel that treatment options for them are very limited. They value increased survival as much as increased quality of life, and the possibility of long-term remission with venetoclax plus low dose cytarabine is appealing. Clinical experts also stated that there is a significant unmet need for new treatments for this population because outcomes with currently available treatments are poor. Venetoclax is an oral treatment that can be taken at home, so the time patients need to be in hospital might be significantly reduced. Patients would also appreciate being able to manage side effects at home when possible. The committee concluded that people with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option.

## Venetoclax plus low dose cytarabine would be a valuable option
Venetoclax is also available with azacitidine for people with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable. The company stated that for people with acute myeloid leukaemia, whether to have venetoclax plus azacitidine or venetoclax plus low dose cytarabine would be an individual choice for patients and clinicians. The clinical experts stated that venetoclax plus low dose cytarabine may be preferrable for some people, such as those with NPM1 mutations or people who are older and more frail. They stated that low dose cytarabine was less toxic than azacitidine and could be administered at home. The committee concluded that venetoclax plus low dose cytarabine would be a valuable option for some people with acute myeloid leukaemia when intensive chemotherapy is unsuitable.

# Comparators

## Splitting the trial population by blast cell count is necessary to compare venetoclax plus low dose cytarabine with the relevant comparator but increases uncertainty
The evidence for venetoclax plus low dose cytarabine came from a randomised controlled trial, VIALEC (n=211), which compared venetoclax plus low dose cytarabine with low dose cytarabine alone in people with untreated acute myeloid leukaemia who could not have intensive chemotherapy because of age or comorbidities. The clinical experts considered that the population in the trial would be generalisable to people who would be eligible for venetoclax plus low dose cytarabine in England. In the NHS in England, when intensive chemotherapy is unsuitable, acute myeloid leukaemia is treated with either azacitidine or low dose cytarabine. NICE's technology appraisal guidance on azacitidine recommends azacitidine only for acute myeloid leukaemia with 20% to 30% bone marrow blasts (from here, blasts). In practice, this means that low dose cytarabine is used for acute myeloid leukaemia with over 30% blasts. Therefore, the company did a post-hoc subgroup analysis to split the trial population by blast count. It used the data from the subgroup with over 30% blasts to compare venetoclax plus low dose cytarabine with low dose cytarabine alone. The company did not submit any analyses of venetoclax plus low dose cytarabine for acute myeloid leukaemia with 20% to 30% blasts. The committee concluded that it was necessary to use the subgroup data to compare venetoclax plus low dose cytarabine with the relevant comparator in clinical practice in England, but that the subgroup analysis increased uncertainty in the results.

# Clinical efficacy

## Venetoclax plus low dose cytarabine increases overall survival compared with low dose cytarabine alone
The post-hoc subgroup analysis splitting the trial population by blast count showed that venetoclax plus low dose cytarabine statistically significantly increased overall survival compared with low dose cytarabine alone in the subgroup with over 30% blasts. The company considers the exact results to be academic in confidence, so they cannot be reported here. The committee concluded that venetoclax plus low dose cytarabine increases overall survival compared with low dose cytarabine alone.

# Economic model

## The company's economic model included a cure health state
The company presented a cohort-level state transition model to assess the cost effectiveness of venetoclax plus low dose cytarabine. The model included 5 health states: remission, non-remission, cure, progressive disease or relapse, and death. In the company's original model, patients having venetoclax who were alive after 2 years of being in the remission health state moved into the cure state. Patients having low dose cytarabine alone could not transition to the cure state.

## The evidence for including a cure state in the model is uncertain
The company stated that the results from VIALEA (a separate trial comparing venetoclax plus azacitidine with azacitidine alone) showed that complete remission rates with venetoclax plus azacitidine were similar to those seen in patients over 60 receiving intensive chemotherapy, and that rates of sustained deep remission were higher with venetoclax plus azacitidine than with azacitidine alone. It argued that there was an established relationship between complete remission and long-term survival, and that it was therefore plausible to assume that some patients having venetoclax plus azacitidine, and venetoclax plus low dose cytarabine, could be considered cured. It cited clinical advice that the rate of relapse after 2 years in remission is low and commented that there was a plateau in the KaplanMeier curve for venetoclax plus azacitidine at 2 years. The ERG noted that there was a lack of long-term data to validate a cure assumption because the maximum follow up in VIALEA was 2.56 years. It highlighted that, historically, non-intensive treatments such as low dose cytarabine have not been considered curative in this population, and that the KaplanMeier curve was based on very few patients by 2 years. The clinical experts stated that it was plausible that there could be a proportion of patients who are cured after having venetoclax, but that it was difficult to specify a time frame and there was a lack of evidence to inform this. At technical engagement, a professional organisation highlighted a small study by Chyn Chua et al. (2021) comparing stopping venetoclax treatment while in remission with continuing it until relapse. It considered that the results suggested that venetoclax could be stopped after 2 years in remission without a negative impact on outcomes. However, the committee noted that in this study, a number of relapses occurred after 2 years. During the consultation on the appraisal consultation document for venetoclax plus azacitidine, the authors of the study commented that most of the late relapses were associated with new molecular or cytogenetic abnormalities, suggesting they were not relapses of the original disease. The company highlighted that a cure assumption had been included in NICE's technology appraisal guidance on gilteritinib for treating relapsed or refractory acute myeloid leukaemia. However, the committee noted that this appraisal was in a different population and that although the committee had accepted a cure assumption applied to all patients alive at between 2 and 3 years in the gilteritinib model, a substantial proportion of people in the trial had received a stem cell transplant. The committee also noted that the cure assumption in the gilteritinib model applied to both the gilteritinib and salvage chemotherapy arms, whereas in the venetoclax model it only applied to the venetoclax arm. The committee agreed that any cure state in the venetoclax model should have been applied to both arms. However, the ERG presented scenario analyses applying the cure state to the low dose cytarabine arm, and this only had a small impact on the cost-effectiveness results. After the first committee meeting, the company updated its base-case model so that people moved into the cure state after 3 years of being in remission, instead of 2 years. It also presented scenario analyses in which only a proportion of people in remission transitioned to the cure state. The rest remained in the remission state with a continuing disease-related risk of relapse and death. The ERG presented further scenario analyses with alternative proportions and noted that the cost-effectiveness results were not sensitive to the different proportions explored in these scenarios. The clinical experts explained that around 30% of people in this population have acute myeloid leukaemia with an NPM1, IDH1 or IDH2 mutation, and that these patients may be more likely to be cured. At the first committee meeting, the committee noted that cure fractions estimated from a mixture cure model may have been helpful to provide some basis for validating the proportion of patients remaining in the remission health state over time. After the first committee meeting, the company presented the proportion of people remaining in remission at various time points, based on removing the cure state and applying mixture cure models to separate transitions (from remission to relapse and from remission to death) to validate the proportion of the overall cohort who were in remission at different time points. The committee noted that it would have preferred to see the cure fraction reported from a mixture cure model fitted to the overall population. The committee noted that the company's evidence for a cure assumption related to venetoclax plus azacitidine and that it had not presented any evidence for a cure with venetoclax plus low dose cytarabine. The committee concluded that the evidence for including a cure state in the model was uncertain.

## Using the remission state utility value in the cure state does not affect the cost-effectiveness results
In the cure health state, patients were assumed to have the same utility value as that of the general population. The clinical experts stated that most people would return to the same level of quality of life after treatment as could be expected in the general population, but that a small number would not. The committee did not consider it plausible that patients in the cure state would experience the same level of quality of life as the general population. However, after the first committee meeting, the company stated that because of the age of patients in the model at the point of cure, the age-adjusted general population utility was always lower than the remission health state utility. Therefore, using the remission utility value in the cure state, capped by general population utility, had no effect on the cost-effectiveness results. The committee accepted that using the remission state utility value in the cure state did not affect the cost-effectiveness results.

## The company's updated assumptions about the proportions of people having subsequent gilteritinib are acceptable
In the company's original model, 3% of people in the venetoclax plus low dose cytarabine arm had gilteritinib after venetoclax plus low dose cytarabine, and all others who had subsequent treatment had hydroxycarbamide. The ERG suggested this proportion should be higher, based on clinical advice. At technical engagement, clinical experts and professional groups agreed that around 10% of people may have FLT3mutation-positive disease and be eligible for gilteritinib after venetoclax plus low dose cytarabine or low dose cytarabine alone. The company cited clinical advice that suggested more people who had venetoclax with low dose cytarabine would be able to have subsequent treatment with gilteritinib than people who had low dose cytarabine alone, because it was more likely their disease would go into complete remission. The company updated its base case to include 5% of people having gilteritinib after venetoclax plus low dose cytarabine and 3% having gilteritinib after low dose cytarabine. It also presented a scenario analysis showing that increasing the proportions to 15% after venetoclax plus low dose cytarabine and 10% after low dose cytarabine had a small impact on the cost-effectiveness results. The ERG's clinical expert considered that the company's updated base-case assumptions were plausible. The committee agreed that the company's updated base-case assumptions were acceptable to use in the model.

## The company's updated modelling of dose intensity reflects clinical practice
The dose of venetoclax in the summary of product characteristics in VIALEC and in the company's model was 600 mg daily, after treatment initiation. The company applied a lower dose intensity to venetoclax in its model, which was the dose intensity seen in VIALEC. The company considers the exact dose intensity to be academic in confidence so it cannot be reported here. At technical engagement, clinical experts stated that in clinical practice in England, almost all patients with acute myeloid leukaemia would have concomitant treatment with azoles such as posaconazole as antifungal prophylaxis. Azoles are strong CYP3A inhibitors, which affect the metabolism of venetoclax and increase its plasma level. Therefore, in line with the summary of product characteristics advice on managing potential venetoclax interactions with CYP3A inhibitors, the dose of venetoclax used in clinical practice would be much lower than in the trial, usually 100 mg a day rather than 600 mg. The clinical experts also stated that they would often only give venetoclax for 14 days from the second cycle onwards, rather than 28 days, to limit toxicity. The company highlighted the summary of product characteristics for venetoclax, which notes that in most cases this should be considered once the person's disease is in remission. The committee agreed that the dose intensity in the NHS in England would likely be 16.7% of the full licensed dose for the first cycle, and 8.3% from cycle 2 onwards. After the first committee meeting, the company updated its model to use a dose intensity for venetoclax of 16.7% for the first cycle and 8.3% from cycle 2 onwards. It also presented a pharmacokinetic study that showed that a 100 mg dose of venetoclax given with a strong CYP3A inhibitor led to drug exposure between that of a 400 mg dose and the safe maximum dose of 1,200 mg per day. The company also presented a post-hoc analysis of VIALEA data showing that complete remission rates were similar when an adjusted dose was given with a CYP3A inhibitor, compared with the licensed dose and no CYP3A inhibitor. The committee concluded that the company's updated modelling was appropriate and reflected clinical practice.

# End of life

## Venetoclax meets the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in VIALEC for people having low dose cytarabine in the over 30% blast count group was under 24 months. The company considers the exact figure to be academic in confidence so it cannot be reported here. The mean undiscounted life years in the model were 0.84 years for the low dose cytarabine (over 30% blast count) arm. The committee agreed that the short life expectancy criterion was met. The increase in median overall survival from VIALEC for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blast count group was over 3 months. The company considers the exact figure to be academic in confidence so it cannot be reported here. The mean incremental undiscounted life years in the model were more than 3 months across all scenarios for venetoclax plus low dose cytarabine compared with low dose cytarabine alone (over 30% blast count). The committee agreed that the extension to life criterion was met. It therefore concluded that venetoclax plus low dose cytarabine met the criteria to be considered a life-extending treatment at the end of life.

# Cost-effectiveness results

## All the plausible ICERs presented are below 50,000 per QALY gained
All analyses included the patient access scheme for venetoclax. After technical engagement, the company's base-case incremental cost-effectiveness ratio (ICER) was 36,995 per quality-adjusted life year (QALY) gained for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blasts population. This included a cure point at 2 years. In its exploratory analyses, the ERG preferred to use alternative costs for adverse events in the model, to account for long-stay admissions. It also corrected an error in the cost of subsequent treatment. After the first committee meeting, the company presented a revised base case for venetoclax plus low dose cytarabine, which included:
the ERG's correction and alternative costs for adverse events
a cure state at 3 years instead of 2 (see section 3.6)
the dose intensity of venetoclax that reflects clinical practice (see section 3.9).This resulted in an updated base-case ICER of 10,948 per QALY gained for venetoclax plus low dose cytarabine compared with low dose cytarabine alone in the over 30% blasts population. The company and ERG presented scenario analyses in which only a proportion of people who were in remission at 3 years were assumed to be cured. The committee noted that the ICER remained below 50,000 per QALY gained even when no patients in remission at 3 years were considered cured. When the ERG included the confidential discount for gilteritinib subsequent treatment in its analyses, the ICERs decreased slightly. Because of the confidentiality of this discount, the exact ICERs cannot be reported here. The committee concluded that all the plausible ICERs presented were below 50,000 per QALY gained.

## Venetoclax with low dose cytarabine is recommended for routine use in the NHS
Because all of the plausible ICERs were within the range that NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life, the committee recommended venetoclax plus low dose cytarabine as an option for untreated acute myeloid leukaemia with over 30% blasts in adults when intensive chemotherapy is unsuitable. Because the company did not submit any analyses for the 20% to 30% blast group (see section 3.3) the committee could not make any recommendations for this group.

# Equality and innovation

## There are no equality issues relevant to the recommendations
A committee member highlighted that venetoclax could provide an effective treatment option for older people who have not benefitted from other recent advances in treatment, and that anyone who cannot easily travel to a major hospital may particularly benefit from being able to take venetoclax at home. The committee considered these potential issues but noted that recommendations would apply to all patients, regardless of age or location. It concluded that no equality issues relevant to the recommendations had been identified.

## The benefits of venetoclax are captured in the cost-effectiveness analysis
The company, professional organisations and clinical experts considered that venetoclax was innovative because it was a targeted therapy, was different to currently available therapies, led to increased overall survival and rates of complete and deep remissions, and decreased the need for blood transfusions. The committee agreed that these were important benefits of venetoclax, but concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY calculation.