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interventions for acute lymphocytic leukaemia

Methods

No previously published studies on the potential cost-effectiveness of CAR T-cell therapy for ALL were identified in our searches (seeAppendix 7). To inform the conceptualisation and development of the economic model, a separate review of published studies evaluating the cost-effectiveness of other treatments for ALL was conducted. The primary aim of the review was to inform key structural

assumptions and potential parameter sources required for the model. Hence, the review focused on the main methodological approaches taken in the studies identified, rather than the specific results reported. A two-part approach was taken, consisting of a systematic review and a more pragmatic search. Details of the search strategy employed to inform the systematic review are provided inAppendix 8(seeTable 47). The pragmatic search searched for any publicly available reports considering the cost-effectiveness of any intervention in ALL using Google and Google Scholar; in addition, the relevant websites for NICE and AWMSG were searched to identify previous appraisals for ALL.

Results

The systematic search identified 489 records, 11 of which were deemed potentially relevant after a review of their titles and abstracts. However, after obtaining the full articles, none of these studies was found to be a full economic evaluation and hence these studies were not subsequently considered within the model conceptualisation stage. The pragmatic search using Google and Google Scholar found two papers deemed relevant to the primary aim of the review.182,183

Costaet al.182_{conducted a cost-effectiveness evaluation of unrelated stem cell transplantation for adults}

with acute leukaemia (ALL and acute myeloid leukaemia) structured around a 20-year Markov model. The study concluded that the two forms of transplantation considered (cord blood and bone marrow/peripheral blood stem cells) were cost-effective compared with no transplantation. The study found that, despite the high initial cost and short-term mortality associated with the transplantation procedures, the resulting life-year gains achieved by surviving patients were significant.

Liset al.183_{considered the cost-effectiveness of clofarabine combined with chemotherapy in children and}

adolescents with ALL who have failed at least two previous therapies compared with nelarabine (Atriance®_,

GlaxoSmithKline, Brentford, UK) and FLAG-IDA, through the use of a lifetime Markov model. After the initial treatments, a proportion of patients was assumed to subsequently receive HSCT; this proportion varied given the response to initial treatment (complete, partial, complete without platelet recovery or no response) and the treatment arm. A patient who survived for 2 years post HSCT was assumed to be cured of ALL; no cure was possible without HSCT. The authors found clofarabine to be cost-effective compared with both comparators. The result was driven by the success of a therapy in achieving a bridge to HSCT and thus a potential cure. As clofarabine was associated with a greater proportion of patients experiencing an initial CR, it had the greatest proportion of patients undergoing HSCT and thus cured patients.

The search of NICE and AWMSG appraisals found that the only appraisal by NICE for ALL (dasatinib, ID386)184_{was discontinued in 2008 because of the low number of patients anticipated to be treated.}

By contrast, the AWMSG provided details of four separate appraisals in ALL, although one of these (imatinib, no. 2014) did not receive a formal submission by the manufacturer.171,185–187_{Of the remaining}

AWMSG appraisals, only the final appraisal recommendations (FARs) are made publicly available, limiting the detail available on the evaluative approaches. Only two of the appraisals (clofarabine171_and

nelarabine185_{) provided sufficient detail to review.}

Clofarabine171_{was recommended by the AWMSG for children and adolescents with ALL who are relapsed}

or refractory after at least two previous regimens and for whom no other treatment is anticipated. Within the FAR, an important restriction was placed on the recommendation such that clofarabine should be given only to patients in whom there is an intention to proceed to HSCT. This recommendation was based on the findings that clofarabine did not appear to be cost-effective for patients who did not subsequently receive HSCT. In the submission, clofarabine was compared with palliative care alone. Palliative care was assumed to be associated with a very short median survival time (9–10 weeks) based on historical control data.

Although limited details of the modelling approach are reported, it is evident that the primary structural driver within the model is the bridging role of clofarabine to HSCT, with potentially significant gains in life-years assumed for patients who subsequently receive HSCT. The manufacturer assumed that the success of HSCT in achieving long-term remission (and cure) was driven by the achievement of remission (complete, with platelet involvement or partial) at the time of transplantation. Hence, improved rates of remission achieved with clofarabine compared with palliative care directly equate to long-term survival. The model submitted assumed that patients who received HSCT and survived for 1 year were cured, returning to the mortality risks and utilities of the general population.

Nelarabine185_{was recommended by the AWMSG for the treatment of patients with T-ALL and T-cell}

lymphoblastic leukaemia whose disease has not responded to, or has relapsed, following treatment with at least two chemotherapy regimens. Best supportive care was used as the main comparator and clofarabine was considered in a separate scenario based on indirect comparisons. In common with the restriction

previously applied within its recommendations for clofarabine in ALL, the AWMSG also restricted treatment to patients for whom there is an intention to proceed to HSCT. This restriction was based on a similar finding that the cost-effectiveness of nelarabine was closely related to the assumed increase in the proportion of patients subsequently receiving HSCT (and their related long-term health gains). The base-case analysis presented survival based on within-trial estimates with no extrapolation conducted. This was considered to be an extremely conservative estimate. Separate scenarios were presented considering the long-term survival of post-HSCT patients and were found to have a major impact on the results. The base-case ICER of £102,281 per QALY gained was subsequently reduced to £51,169 if post-HSCT survival was assumed to be 2 years and to £25,523 if normal life expectancy was assumed in patients who survived for>1 year (i.e. cure at 1 year).

Implications for model conceptualisation

The systematic and pragmatic searches highlighted a number of potential implications for our evaluation. Within existing studies, it is clear that the main benefit of existing treatments has been related to their ability to provide a_‘bridge_’to HSCT. The primary factor determining cost-effectiveness in the reviewed literature was the increased likelihood of receiving HSCT with a new treatment and the associated assumptions made regarding subsequent health gains associated with transplantation. Only a limited survival gain was attributed to patients who did not subsequently receive HSCT, such that none of the treatments reviewed appeared to be cost-effective as a palliative option.

The key structural assumptions employed within these studies were the potentially curative effect of HSCT and the short life expectancy assumed for the comparator treatments (best supportive care/palliative treatment alone) derived from historical controls. The majority of studies assumed a‘cure point’associated with HSCT, although the timing was different across studies. The‘cure point’was assumed to represent the time at which patients are assumed to no longer be at risk of disease relapse. The study by Costa et al.182_{assumed that at 5 years post transplantation the patient will be free of any procedural mortality}

risk or any risk of disease recurrence. In Liset al.183_{and the AWMSG appraisal of nelarabine}185_{this cure}

point was assumed to be 2 years after HSCT, whereas in the AWMSG appraisal of clofarabine171_the

cure point was assumed to be 1 year after HSCT.

The studies also differed in the assumptions made concerning subsequent survival after the‘cure point’. Costaet al.182_{acknowledged that long-term ALL survivors are likely to be subject to significant}

comorbidities over their remaining lifetime despite being leukaemia free. To account for the impact of comorbidities, an assumption was made that the long-term survival of ALL patients would be 50% less than that in the general population. The authors acknowledge that this was an arbitrary adjustment because of the lack of data on the long-term mortality rate in long-term survivors of ALL reported at the time. In contrast, the study reported by Liset al.183_{and the clofarabine submission}171_{effectively assumed}

no additional comorbidities (i.e. beyond those experienced by the general population) beyond the_‘cure point’. Hence, patients were subsequently assumed to return to the age-adjusted mortality risk and utility of the general population. The AWMSG raised concerns that, not only was this assumption insufficiently justified but, also, the model was very sensitive to changes in the long-term survival probability.

In the absence of RCT data, each model incorporated historical control data as the basis to inform outcomes associated with the comparator (best supportive care, palliative care and clofarabine within a scenario for the submission for nelarabine).171,185–187_{However, insufficient details were reported regarding}

the source of the historical control data used and whether attempts were made to identify possible biases or to formally account for potential confounding.

The existing cost-effectiveness literature is limited in ALL. No completed NICE appraisals of licensed treatments for ALL were identified. Furthermore, of the studies published, none was reported in sufficient detail to provide a suitable basis for informing the exemplar application. In the absence of previous NICE appraisals or sufficient reporting within existing publications, the development of a de novo model to inform the exemplar application was considered necessary. Full details of this are reported in the next chapter.