Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in adults, accounting for 30% of adult leukaemia cases in Western countries1. The mean age at diagnosis is 71.7 years2.

In Spain, the incidence rate in 2010 was an estimated 13.6/100,0003. According to the Institut National de la Santé et de la Recherche Médicale (INSERM), in 2016, the prevalence of CLL in Europe was an estimated 27/100,0001.

Chronic lymphocytic leukaemia has a considerable impact on the survival and health-related quality of life (HRQoL) of CLL patients. In addition to the impact on patients’ health, CLL places a considerable economic burden on the Spanish National Health System (NHS)1.

In recent years, great progress has been made in understanding the biology of CLL, leading to significant advances in the treatment of this disease. In particular, oral targeted therapies have demonstrated remarkable results in CLL patients, improving both progression-free survival (PFS) after treatment and overall survival (OS). As stated in the latest clinical practice guideline of the European Society for Medical Oncology (ESMO), the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently approved various combinations of oral drugs for the treatment of CLL in both first-line and relapse settings4. Other therapies are expected to become available in the near future1,5,6.

New treatments pose a major challenge, mainly due to their economic burden1. A specific concern is their long treatment duration, an aspect that is expected to improve with the development of CLL therapies with a defined fixed treatment duration. The aim of this study was to perform a cost minimisation analysis of CLL for the Spanish NHS under two scenarios: the first, without oral targeted therapies; and the second, with the introduction of fixed time duration (FTD) oral therapies. The specific FTDs included in the model were the combinations venetoclax and obinutuzumab and venetoclax and rituximab.

We conducted the CLL cost minimisation analysis from the perspective of the Spanish NHS by adapting a model previously used in the United States5 and Canada7,8. This model was developed to analyse the economic burden of CLL before and after the introduction of FTDs and was subsequently adapted to the Spanish healthcare setting. Thus, on 19 November 2019, we conducted a literature search on the OVID platform, combining terms relating to the pathology of interest with terms relating to the inputs needed to adapt the model and terms to identify references in the Spanish population. The search was limited to references published in the last 5 years in English or Spanish. It was completed with a review of the grey literature. Subsequently, an expert group (the authors of this article) validated the scenarios, assumptions, and inputs by consensus and completed the information needed to perform the analysis.

Treatment strategies

The CLL treatment pattern was defined according to patient type by disease status, age, presence or absence of del(17p) determined by fluorescence in situ hybridisation (FISH), IGHV mutation status, and year of treatment. Table 1 shows the different parameters included in the model, as well as each of their values.

Table 1.

Parameters included in the model

Parameter		Value	Source
Probability of watchful waiting at the time of diagnosis		85.0%	5
Prevalence of del(17)p		7.0%	1
Probable age at diagnosis	< 65 years	35.0%
	65-70 years	15.0%	1
	> 70 years	50.0%
Probability of the patient being fit	< 65 years	87.5%
	65-70 years	50.0%	Expert opinion
	> 70 years	25.0%
IGHV mutation rate		60.0%	Expert opinion
IGHV nonmutation rate		40.0%	Expert opinion
	Oral	5.0%
Administration route	IV	95.0%	Expert opinion
Probability of discontinuation of oral targeted therapy for each 4-week cycle in 1st-line treatment		0.7%	19
Probability of discontinuing oral targeted therapy for each 4-week cycle in relapsed patients		1.4%	19

del(17p): deletions in the short arm of chromosome 17; IGHV: immunoglobulin heavy-chain; IV: intravenous.

The treatment algorithm was simulated from 2011 to 2025, dividing this time interval into five periods (2011-2015, 2016-2017, 2018-2019, 2020-2021, and 2022-2025), representing the evolution of standard care, as well as changes in actual clinical practice due to the entry of oral targeted therapies, all of which was validated by the clinical expert group. The second model was of a parallel clinical scenario which included the introduction of the FTD regimen.

The proposed scenarios were defined taking into account the therapies available in Spain and funded by the Spanish NHS in each time period. To simplify the model, a single treatment option was assumed for each type of patient and time period, such that 100% of the patients were on treatment with the most widely used option at each time point. In this respect, both scenarios were identical in terms of treatments and CLL management in the period from 2011 to 2019, inclusive, because FTD treatments only started to be marketed in Spain at the end of 2019 in Spain. Thus, for the purposes of the analysis, it was assumed that FTDs were marketed at the beginning of 2020 (Figure 1).

Figure 1.

Management strategies for patients with chronic lymphocytic leukaemia.

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In the scenario without FTDs, the total number of people diagnosed with CLL was estimated to increase from 13,726 in 2011 to 19,357 (41.0% increase) in 2025. With the introduction of FTDs, the total number of people with CLL in 2025 would be 19,196 (39.9% increase) by 2025. The average annual prevalence of CLL from 2011 to 2025 was estimated to be 16,436 patients in the scenario without FTDs and 16,413 patients in the scenario with FTDs.

Table 3 shows the different costs for each of the treatments included in the model. From the perspective of the Spanish NHS, the total costs from 2011 to 2025 would be €4,676.7 million in the scenario without FTDs and €4,111.8 million in the scenario with FTDs (Figure 2): thus, the introduction of FTDs would result in savings of €564.9 million. These savings would imply a 12.1% reduction in the cost of caring for CLL patients over the period assessed. As shown in figure 2, the differences between the alternatives assessed begin to be seen from 2020 onward, which is the year in which FTDs become available for use in clinical practice in Spain. After a slight increase in total costs during 2020, from 2022 until the end of the study period, there would be a decrease in total costs of care for LLC patients, which is related to the fixed duration of some of the treatments used.

Figure 2.

Total costs from 2011 to 2025.

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The total savings would amount to €475.1 million (84.1%) in first-line treatments after watchful waiting and €90.8 million (15.9%) in treatments after relapse or the discontinuation of first-line treatment (see Figure 2).

The total cost per patient from 2011 to 2025 would rise from €266,019 in the scenario without FTDs to €236,852 in the scenario with FTDs, saving the Spanish NHS €29,167 per patient.

The introduction of oral targeted therapies for the treatment of CLL led to improved OS in CLL patients compared to OS under standard therapies. This improvement was a relevant advance for CLL patients19, although there was an increase in their cost of treatment. Thus, the introduction of FTDs represents a significant advance in CLL treatment, allowing health care systems to predict treatment duration and the cost of care of CLL patients. Our study projected an annual increase in the number of CLL patients and in the total direct costs of managing these patients. Specifically, the total costs from 2011 to 2025 would be €4,676.7 million in the scenario without FTDs, representing an increase of 1,222.35% over this period, and €4,111.8 million in the scenario with FTDs, representing an increase of 808.64% over the same period (Figure 2). Thus, the introduction of FTDs would generate considerable resource savings of €564.9 million (12.1% of the total cost of care for CLL patients) for the Spanish NHS over the entire period under assessment. If these results are confirmed in further studies, FTDs would be a treatment alternative offering good efficacy results for CLL patients, while optimising the use of health care resources in health systems.

An analysis of the total direct costs shows that, for all treatments, the highest costs are pharmacological ones. The highest pharmacological cost was that of ibrutinib as monotherapy (€41,289.36), which is one of the most recommended treatments in both first-line and relapse settings6.

The highest administration cost was that of IV fludarabine, cyclophosphamide, and rituximab in combination (€5,619.42) because it was the treatment included in the model with the most IV administra- tions13.

Monitoring costs ranged from €2,730.64 for the chlorambucil combinations to €5,58733 for the venetoclax and rituximab combination, In the latter case, more resources were used, mainly in the form of routine visits.

Few studies have investigated CLL disease burden or its cost minimisation and of these, none have been conducted in Spain. A study conducted in Germany in 2008 estimated a CLL prevalence of 4.9/10,000 inhabitants, with an estimated CLL disease burden of €4,946 per patient and an average total annual cost of €201 million within the setting of the German NHS20. The mean cost per patient in our study was much higher in the scenarios without and with FTDs (€266,019 and €236,852 per patient and a total cost of €311.8 million and €274.1 million, respectively). However, the studies are not comparable because the German study was conducted before the introduction oral targeted therapies which, as we have highlighted, brought about a radical change in the management of the disease. Therefore, the pharmacological cost was much lower in that study than in ours.

This study has some limitations, the first of which stems from the fact that the model represents a simplification of reality which, although based on the best possible evidence, can never be an accurate representation of real clinical practice. In this sense, one of the limitations is the assumption of a single treatment option for each type of patient and time period, which means that the costs associated with other treatments were not taken into account. This simplification of reality implies that the savings estimated in our analysis would be the maximum achievable, since all patients would follow the therapeutic strategies presented in the analysis. Although the choice of treatment was made on a case-bycase basis, the clinical experts agreed that the typical patient in each of the categories described in the model used the treatment alternatives most widely used in each of the time periods considered. On the other hand, the lack of data was completed and validated by the expert panel based on the literature review, thus reducing the model's uncertainty. Another limitation is that the analysis was conducted using the public prices of medicines: thus, the results could be affected by differences between these prices and the prices of the same drugs, which are reimbursed by the health care service. This aspect could impact the magnitude of the difference between the strategies assessed. However, any such difference is unlikely to affect the direction of the results obtained in favour of strategies that include FTDs, and thus, the conclusion of the study. Another potential limitation is that some of the patient subtypes included in the model did not differentiate between patients with or without the IGHV mutation status or did not include TP53 mutation status. After assessing this aspect, we assumed that the treatment and management differences in these patient subtypes between the two scenarios would be minimal and the model was simplified. Although these limitations could lead to underestimations or overestimations of the costs included in the model, the analysis is considered to be reflecting real clinical practice. The model included a population with a range of health states, treatments, and stratifications, for which we do not have data on specific prevalence. This implies that this prevalence had to be estimated from the incidence rates of previous years, and so the results of this study should be interpreted taking this nuance into account. On the other hand, the PFS and OS data included in the model were taken from clinical trials, which may lead to overestimations compared to these aspects in clinical practice (e.g. exclusion of comorbidities, better stratification, or age of patients). Finally, in the absence of a sensitivity analysis, it was not possible to assess the effect of uncertainty in variations in the model parameters on the results. Although this effect cannot be ignored, it was minimised by the expert panel, who provided their expertise and realworld knowledge of the disease, such that the model would be as close as possible to real clinical practice.

This economic analysis shows how the direct cost of CLL varies in the era of oral targeted therapies with the introduction of FTDs. From the perspective of the Spanish NHS, this introduction would result in savings of €564.9 million (12.1% of the total health costs for CLL patients during the period assessed). Although further studies are needed to assess the full effects and costs associated with CLL treatment, the present study may help to define future costsaving therapeutic strategies.

The study was designed, conducted, and funded by AbbVie.

The authors would like to acknowledge the support of María del Carmen Barrull Santamaría and Daniel Callejo Velasco de IQVIA in study design, data analysis, and medical writing. This support was funded by AbbVie.

Dr. Montañés: Advisory board of AbbVie. Dr. Casado: Advisory board of AbbVie. Dr. Medina: Advisory board of AbbVie. Dr. Nieto: Consultancies for AbbVie and Boehringer, as well as training activities for Roche, Janssen, and Astellas. Dr. Ramírez: Advisory boards and presentations for Novartis, AbbVie, BMS, Gilead, Takeda, Janssen, Roche, Pfizer, Amgen, EUSA Pharma.

The results of this work were previously presented at the LXII National Congress of the SEHH and XXXVI National Congress of the SETH.