Autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 26 years and over

People with relapsed or refractory B-cell acute lymphoblastic leukaemia would welcome a new treatment

3.1 Outcomes for people with relapsed or refractory B‑cell acute lymphoblastic leukaemia are poor. The disease has low levels of response to treatment and is associated with limited survival. Common symptoms include fatigue, breathlessness, infections, bleeding, bruising, fever and sweating. The clinical and patient experts noted that people with relapsed or refractory B‑cell acute lymphoblastic leukaemia have limited treatment options. This is because the current treatments do not provide a cure and can only extend life for less than a year. This has a serious impact on the quality of life of people with the disease and this also could affect their families. The only potentially curative option is an allogeneic stem cell transplant (allo‑SCT), which not many people can have because of the eligibility requirements such as remission, age, fitness levels and donor availability. They further explained that stem cell transplants are associated with a slow and laborious recovery over around a year. The clinical expert explained that people from minority ethnic backgrounds are less likely to find a matching donor. Chimeric antigen receptor (CAR) T‑cell therapies are a new generation of personalised cancer immunotherapies in which the patients' own immune cells are collected and modified to treat their cancer. The clinical expert said that people having a CAR T‑cell therapy experienced less severe short-term and more manageable side effects than with allo‑SCT. Also, they said that the technology could potentially lead to a cure in some people. This type of technology is currently recommended for people under 25 years (see NICE technology appraisal guidance on tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years). So, there is an unmet need for people above that age. The clinical expert explained that clinicians in the UK are in a difficult position when treating B‑cell acute lymphoblastic leukaemia in people 26 years and over, because there are no CAR T‑cell therapy options for this population. The committee concluded that people with relapsed or refractory B‑cell acute lymphoblastic leukaemia, especially those 26 years and over, would welcome new treatment options such as CAR T‑cell therapies that improve the chance of survival.

The company's positioning of autologous anti-CD19-transduced CD3+ cells in the treatment pathway is appropriate

3.2 The company proposed 3 potential positions for autologous anti-CD19-transduced CD3+ cells in the treatment pathway. Specifically, for people 26 years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia:

The clinical experts stated that currently there are no curative treatment options for people 26 years and over whose disease has relapsed after having an allo‑SCT. CAR T‑cell therapy is not available for this group of people in the NHS. They also explained that in the UK, clinicians would not give a second allo‑SCT and that allo‑SCT use may decrease in favour of CAR T‑cell therapy. This is because allo‑SCT is a highly toxic treatment and can lead to graft-versus-host disease (an immune-mediated condition resulting from a complex interaction between donor and recipient adaptive immunity). The clinical experts also stressed the importance of having this treatment option for people who are ineligible for allo‑SCT. The committee noted that the treatment pathway proposed by the company included Philadelphia chromosome-negative and Philadelphia chromosome-positive relapsed or refractory B‑cell acute lymphoblastic leukaemia. It further noted that the anticipated marketing authorisation covered people both with and without the Philadelphia chromosome. The committee concluded that the company's positioning of autologous anti-CD19-transduced CD3+ cells in the treatment pathway is appropriate.

The relevant comparators are inotuzumab, blinatumomab and ponatinib

3.3 The company compared autologous anti‑CD19‑transduced CD3+ cells with all comparators in the NICE scope, that is, FLAG‑IDA, inotuzumab, blinatumomab and tyrosine kinase inhibitors (ponatinib). Based on clinical advice, the company refined the list of comparators and categorised them by treatment group: overall population (irrespective of Philadelphia chromosome), Philadelphia chromosome negative, and Philadelphia chromosome positive. The clinical experts explained that FLAG-IDA-based chemotherapy is rarely used in the UK because of its toxicity, poor tolerance and poor outcomes. They further explained that inotuzumab is given to both subgroups (Philadelphia chromosome negative and Philadelphia chromosome positive), whereas blinatumomab is restricted to Philadelphia chromosome-negative relapsed or refractory B-cell acute lymphoblastic leukaemia. Ponatinib is restricted to Philadelphia chromosome-positive relapsed or refractory B‑cell acute lymphoblastic leukaemia in people whose disease does not respond or who cannot tolerate a tyrosine kinase inhibitor before having an allo‑SCT. The committee discussed if FLAG‑IDA should be included as a comparator in light of the clinical experts' comments. It agreed that since FLAG‑IDA is rarely used in clinical practice, it should not be included as a comparator The committee concluded that inotuzumab, blinatumomab and ponatinib were the appropriate comparators for people 26 years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia.

Autologous anti-CD19-transduced CD3+ cells could be clinically effective, but a curative treatment effect is uncertain

3.4 The clinical-effectiveness evidence for autologous anti‑CD19‑transduced CD3+ cells came from ZUMA‑3, a single-arm open-label study of relapsed or refractory B‑cell acute lymphoblastic leukaemia. The trial recruited people from 32 centres across 5 countries, but there were no centres in the UK. A total of 78 people with relapsed or refractory B‑cell acute lymphoblastic leukaemia were included in the final analysis, which provided the clinical evidence for the company's base-case cost-effectiveness analysis. The trial population included people under 26 years, so restricting the analysis to people covered by the anticipated marketing authorisation reduced the number of people included. The exact number is confidential so cannot be shown here. The primary outcome of the trial was overall complete remission. Secondary outcomes included overall survival and relapse-free survival. The median overall survival and relapse-free survival results are considered confidential by the company, so they cannot be shown here. The results suggested that autologous anti‑CD19‑transduced CD3+ cells could be potentially curative. The ERG explained that results supporting an assumption of cure with autologous anti‑CD19‑transduced CD3+ cells were uncertain, because the analyses did not distinguish between people who had an allo‑SCT before treatment with autologous anti‑CD19‑transduced CD3+ cells and those who did not. Therefore, it was unclear if any survival benefit resulted from treatment with autologous anti‑CD19‑transduced CD3+ cells or from an allo‑SCT. The clinical experts expressed concerns about how to interpret the relapse-free survival curve given the uncertainties. They added that curative outcomes can be seen in real-world evidence from people with relapsed or refractory B‑cell acute lymphoblastic leukaemia who have had multiple different treatments before the CAR T‑cell therapy. One of the clinical experts stressed that relapses after 12 months are infrequent and that this should be considered. The committee concluded that treatment with autologous anti‑CD19‑transduced CD3+ cells could be clinically effective, but a curative treatment effect is uncertain.

Autologous anti-CD19-transduced CD3+ cells are expected to be clinically effective in both subgroups

3.5 The company had proposed autologous anti‑CD19‑transduced CD3+ cells for Philadelphia chromosome-positive and -negative relapsed or refractory B‑cell acute lymphoblastic leukaemia. The clinical experts stated that the treatment is expected to have similar efficacy in both populations. This is because the mechanism of action is not related to Philadelphia chromosome status. They noted that tisagenlecleucel is equally clinically effective in Philadelphia chromosome-negative and -positive. The committee concluded that autologous anti-CD19-transduced CD3+ cells are expected to be clinically effective in both Philadelphia chromosome-negative and Philadelphia chromosome-positive disease.

The inverse hazard ratio analysis is preferred over matching-adjusted indirect comparisons and naive comparisons

3.6 Because ZUMA‑3 is a single-arm trial, an indirect treatment comparison was needed to estimate the efficacy of autologous anti‑CD19‑transduced CD3+ cells compared with the comparators. The company did an unanchored analysis using naive indirect comparisons and matching-adjusted indirect comparisons (MAICs). ZUMA‑3 was used as the evidence source for autologous anti‑CD19‑transduced CD3+ cells. The evidence sources for the comparators were as follows: INO‑VATE (inotuzumab); TOWER and SCHOLAR‑3 (blinatumomab); pooled data from INO‑VATE and TOWER (FLAG‑IDA) and PACE (ponatinib). The company did 3 types of comparative analysis – a naive unadjusted comparison, a matched comparison via SCHOLAR‑3, and a MAIC:

The company's economic model is appropriate for decision making

3.7 The company used a partitioned survival model that included 3 mutually exclusive health states: event-free, progressed disease and death. The company modelled the cost effectiveness of treatment with autologous anti-CD19-transduced CD3+ cells using data from ZUMA‑3 and data from INO‑VATE, TOWER, PACE and SCHOLAR‑3 for the comparators. After technical engagement the company updated its economic model to include a recent data cut of ZUMA‑3, revised clinical-effectiveness data for people 26 years and over (the population in the anticipated marketing authorisation) and data from SCHOLAR‑3. The committee agreed that the model was appropriate for decision making.

People having autologous anti-CD19-transduced CD3+ cells are likely to be at a higher risk of mortality than the general population

3.8 The company's model assumed a standardised mortality ratio of 1.09 to model the mortality risk of people whose cancer was considered cured compared with that of the age- and sex-matched general population in the UK. The ERG considered this to be an underestimate. It noted that this value was from a study of people with diffuse large B‑cell lymphoma rather than B‑cell acute lymphoblastic leukaemia. The ERG proposed a standardised mortality ratio of 4, sourced from a study in relapsed or refractory B‑cell acute lymphoblastic leukaemia in which the mortality risk ranged between 4 and 9. It noted that it had chosen the lowest value in the study, which was a conservative approach. The company noted that the study used by the ERG was in people who had allo‑SCT, which is more burdensome and has longer-term treatment requirements than CAR T‑cell therapy. The clinical expert explained that there is no long-term survival data for people with relapsed or refractory B‑cell acute lymphoblastic leukaemia who have had autologous anti-CD19-transduced CD3+ cells. But he noted that he expected it to be similar to data for tisagenlecleucel, in which many people have been followed up for 5 to 10 years. The clinical expert highlighted that the main risk of the disease relapsing is during the first year after treatment and that after that, relapse is unlikely. He further explained that the risk of dying was associated with having an allo‑SCT. This is because of the risk of graft-versus-host disease. The clinical expert added that it is rare that people who have had a CAR T‑cell therapy develop graft-versus-host disease. The committee understood that the risk of dying was linked to allo‑SCT before the CAR T‑cell therapy. So, it considered that the true standardised mortality ratio for this population would be aligned to the value proposed by ERG (a standardised mortality ratio of 4). The committee concluded that people having autologous anti-CD19-transduced CD3+ cells are likely to be at a higher risk of mortality than the general population and the ERG approach should be used in decision making.

People who have had autologous anti-CD19-transduced CD3+ cells do not have the same quality of life as the general population

3.9 The company's model assumed that people who had autologous anti‑CD19‑transduced CD3+ cells and whose disease had not progressed after 3 years of treatment would have the same health-related quality of life as that of the same age- and sex-matched general population in the UK. The ERG had received clinical advice that there is cumulative toxicity from previous therapies, and that the disease itself reduced quality of life. Therefore, the ERG proposed a utility multiplier of 0.92 applied to the general population utility values to adjust for lower quality of life. This was a midpoint between the utility value after the infusion and before relapse, and the general population of a similar age. The clinical experts explained that there is not enough evidence in CAR T‑cell therapies to support either approach. But they explained that reduced quality of life in this population is likely to be related to previous treatments. People can live a near-normal life after treatment with the new technology and can return to daily activities soon after having a CAR T‑cell therapy. The clinical expert also explained that CAR T‑cell therapy can lead to better quality of life because the treatment is given in an outpatient setting and so people need less time in hospital. The patient expert stated that the condition had a huge emotional and financial impact on her and her family after she was diagnosed. She explained that she has a sustained risk from infections and so has to have regular follow-up appointments in the immunology department. The committee understood that people whose disease has not progressed will have a worse health-related quality of life than the general population because of the risks associated with CAR T‑cell treatments and the effect of previous therapies. Therefore, it concluded that people having autologous anti-CD19-transduced CD3+ cells do not have the same quality of life as the general population and the ERG approach should be used in decision making.

Allo-SCT costs and QALY loss should be included in the model for people having autologous anti-CD19-transduced CD3+ cells

3.10 In ZUMA‑3, 14 out of 78 people had an allo‑SCT. But, the company did not account for the costs or quality-adjusted life year (QALY) impact of allo‑SCT use in the autologous anti-CD19-transduced CD3+ cells arm in the economic model. The company stated that the technology is not planned to be used after an allo‑SCT in UK clinical practice. It had done a sensitivity analysis adjusting for overall survival, censoring for allo‑SCT, and no statistical difference was found. The ERG stated that the sensitivity analysis was not sufficiently powered to detect a difference. It also noted that an allo‑SCT could have provided a survival advantage to the people who had had one. The clinical experts stated that allo‑SCT would be considered for some people whose disease had relapsed after having a CAR T‑cell therapy and who were well enough to have this procedure. The committee concluded that allo‑SCT costs and a QALY loss should be included in the model for people having autologous anti-CD19-transduced CD3+ cells.

CAR T-cell delivery costs of about £60,000 are most appropriate for decision making

3.11 The company used a bottom-up costing approach to calculate the cost of administering autologous anti-CD19-transduced CD3+ cells. The ERG considered that the company's approach likely underestimated the true cost based on expert advice it had received. The committee was aware that the tariff was developed after NICE recommended tisagenlecleucel, the first CAR T‑cell therapy to be appraised, for use in the Cancer Drugs Fund in December 2018. NHS England stated that the tariff includes all costs of care from when a person is identified for CAR T‑cell therapy to 100 days after infusion. It does not include acquisition costs of autologous anti-CD19-transduced CD3+ cells. The original tariff was £96,016. The tariff is subject to ongoing review and will be updated periodically. For use in NICE appraisals, NHS England provided a revised estimate of £65,415. NHS England explained that it worked with 1 NHS trust to provide a reasonable distribution of the total tariff costs across the different phases of treatment. The revised tariff also had an adjusted length of stay and an adjusted proportion of people who have care in an outpatient setting and outside the hospital. It also removed overheads that are legitimate costs incurred in the NHS but are not in line with NICE methods. The NHS England estimate is subject to ongoing review and will be updated periodically. NHS England explained that there is not a Healthcare Resource Group (HRG) that captures CAR T‑cell therapies. It also commented that a key difference between its estimate of costs and the company's costs is the number of staff who look after people who have had CAR T‑cell therapy. The company commented that is it not appropriate to use the tariff in the modelling because it is a mechanism for NHS England to fund hospitals for providing CAR T‑cell therapy and is not designed for technology evaluation. It is concerned that the evidence underlying the estimated cost has not been transparently shared and that it may not reflect the true cost of treatment. The ERG stated that the NHS England costing exercise had been a rapid review and that micro-costing had not been implemented. So, it had been unable to critique the cost components robustly because of the lack of alternative data sources for some costs. The NHS England Cancer Drugs Fund Clinical Lead commented that the company's costs were underestimated because some people need high intensity care after treatment, and because there are additional costs related to monitoring (such as paying for people to stay in hotels near hospitals). The committee was concerned that the company's costs underestimated the true cost of delivering autologous anti-CD19-transduced CD3+ cells. It noted that the company's cost was significantly less than the figure provided by NHS England. It noted that it was difficult to compare the company's cost with the NHS England tariff because they were reported differently. In the absence of an HRG, the NHS England estimate was the best available source for the costs of delivering CAR T‑cell therapy. The committee considered that some costs included in the NHS estimate of £65,415 were already captured in the company's model. It concluded that a CAR T‑cell administration cost of £60,000 was more relevant for decision making, but this value should be reviewed if any new evidence is presented.

Autologous anti-CD19-transduced CD3+ cells meets the criteria to be considered a life-extending treatment at the end of life

3.12 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. The literature showed that median overall survival with the comparator treatments ranged from 5.3 to 8 months. The clinical experts stated that life expectancy is the same for people with Philadelphia chromosome-negative and -positive disease. The company's model predicted that mean overall survival with the comparator treatments was more than 24 months, but the percentage of people alive at 2 years ranged from 13% to 22%. So, the committee was reassured that people are unlikely to live for longer than 24 months and that the short life expectancy criterion was met. The clinical experts explained that it is likely that autologous anti-CD19-transduced CD3+ cells will extend life for more than 3 months. Also, the model estimated a mean overall survival gain for autologous anti-CD19-transduced CD3+ cells compared with the comparators of more than 3 months. The exact data is confidential and so cannot be shown here. The committee concluded that the end of life criteria were met for people 26 years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia.

The most plausible ICERs are higher than those normally considered a cost-effective use of NHS resources

3.13 NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, decisions 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. The committee noted that the ERG's base-case analysis was more closely aligned with several of its preferred assumptions for both Philadelphia chromosome subgroups, specifically:

Autologous anti-CD19-transduced CD3+ cells are not recommended for routine use in the NHS

3.14 The committee recalled the uncertainties in the evidence for this technology (see section 3.13). It agreed that its preferred ICERs were likely to be above what NICE considers to be a cost-effective use of NHS resources. So, it concluded that autologous anti-CD19-transduced CD3+ cells cannot be recommended for routine use within its anticipated marketing authorisation for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 26 years and over.

Autologous anti-CD19-transduced CD3+ cells cannot be recommended for use in the Cancer Drugs Fund

3.15 The committee considered if autologous anti-CD19-transduced CD3+ cells could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee discussed if the uncertainties identified in the company's cost-effectiveness evidence could be addressed by collecting more data in the Cancer Drugs Fund. The ongoing single-arm ZUMA‑3 trial will provide further data on the follow up of people after 15 years of autologous anti-CD19-transduced CD3+ cells. But the committee agreed that this would not address any of the substantial uncertainty in the comparative clinical-effectiveness evidence. Other issues, such as the uncertainties in the mortality rate value (see section 3.8) and the utility value (see section 3.9), could not be resolved through further data collection in the Cancer Drugs Fund. The committee noted that the technology does not have plausible potential to be cost effective because the ICERs were still higher than what NICE considers acceptable use of NHS resources (see section 3.13). It concluded that autologous anti-CD19-transduced CD3+ cells did not meet the criteria to be considered for inclusion in the Cancer Drugs Fund.