Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder characterized by the expansion of mature-appearing CD5+ B cells in the peripheral blood, secondary lymphoid tissues, and bone marrow1. CLL is the most common form of leukaemia in adults in Western countries, with an estimated incidence of 4 to 5 cases per 100,000 population-years and a particularly significant prevalence in areas in which the population is older2. More than half of these patients have age-related comorbidities, such as hypertension, diabetes, osteoarthritis, or cardiorespiratory involvement3. The treatment decision is based on the presence or absence of adverse prognostic factors (deletion [17p], deletion [11q], TP53 mutation, IGHV mutational status) and on the functional status of the patient2.

In recent years, significant advances have been made in understanding the pathophysiology of CLL, and substantial progress has been made in the clinical management of the disease due to the identification of poor prognostic genetic variables, particularly those associated with chemoresistance and progression to highly aggressive forms of CLL4,5. Currently, chemoimmunotherapy is being displaced by biologic therapies, such as B-lymphocyte receptor inhibitors and BCL-2 inhibitors6,7.

Overexpression of BCL-2 contributes to the evasion of apoptosis, making tumour cells highly dependent on BCL-2 for their survival8. High expression of BCL-2 is observed uniformly across all CLL subtypes9. Venetoclax, the first selective BCL-2 inhibitor, restores the ability of tumour cells to initiate the process of apoptosis and, administered together with obinutuzumab, has a complementary and synergistic mechanism of action that provides high efficacy rates and profound responses, with a fixed duration of 1 year of treatment5,10. In the CLL14 trial, 2-year progression-free survival (PFS) was 88.2% (95% confidence interval [CI]: 83.7%-92.6%) in patients treated with venetoclax in combination with obinutuzumab (VenO) vs 64.1% (95% CI: 83.7%-92.6%) in the control group treated with chlorambucil in combination with obinutuzumab (ClbO)5. After a median follow-up of 28.1 months, these results showed a slow-down in the risk of progression or death with VenO (hazard ratio [HR] = 0.35; 95% CI: 0.23-0.53; P < 0.001). At data cutoff, the results of overall survival (OS) were immature, with the median not having been reached in either group (less than 10% of events in each arm)5. These results were confirmed at the subsequent cutoff time, after a median follow-up of 39.6 months, where PFS was 81.9% in the VenO arm and 49.5% in the ClbO arm. These results showed a slow-down in the risk of progression or death with VenO (HR = 0.31; 95% CI: 0.22-0.44; P < 0.001)11.

The aim of this study was to conduct a cost-utility analysis to determine whether VenO, which is a therapy indicated for previously untreated patients with CLL, would be an efficient intervention within the Spanish National Health System (NHS) compared to the therapeutic alternatives available in Spain.

The base case results showed that the costs per patient were lower and the gains in QALYs were greater with VenO than with other treatment alternatives (Table 2). In terms of economic assessment, VenO was the dominant alternative.

The lower cost of VenO vs ClbO, FCR, and BR was mainly due to a lower pharmacological cost of the subsequent treatments administered after progression. The lower cost of VenO vs ibrutinib as a comparator was mainly due to the shorter duration of time on treatment with VenO.

The sensitivity analyses supported these results. Table 3 shows the results of the deterministic sensitivity analyses. The probabilistic sensitivity analysis showed that 68% to 85% of the simulations performed identified VenO as the dominant alternative, with lower costs and more QALYs gained (Figure 3).

Figure 3.

Probabilistic sensitivity analysis.

(0,31MB).

This study assessed the efficiency of VenO in the Spanish setting as a treatment for CLL in previously untreated patients against comparators that are commonly used in clinical practice and are indicated for such pathology. The results of this analysis were presented at the LXII National Congress of the Spanish Society of Haematology and Chemotherapy (SEHH) and at the XXXVI National Congress of the Spanish Society of Thrombosis and Haemostasis (SETH)37.

The modelled population was based on the CLL14 trial population, which included patients with unfavourable cytogenetic prognosis (including patients with 17p deletion and TP53 mutation). It is noteworthy that these patients were not excluded from the baseline study population, what can make the study population more representative of the real clinical practice. The pivotal ibrutinib trial, RESONATE-24, excluded patients with 17p deletion, which was thus a methodological limitation of the study design.

In the present study, VenO was considered to be the dominant alternative to all comparators because of the increased number of QALYs obtained and lower cost per patient. These results are mainly due to VenO achieving greater PFS due to its increased effectiveness and its lower pharmacological costs. The cost of using VenO was substantially lower than that of ibrutinib because VenO has a fixed treatment duration of 1 year, whereas ibrutinib has an indefinite treatment duration until disease progression or unacceptable toxicity (a median treatment duration of 60 months was assumed based on the RESONATE-24 study, in which the median PFS was not reached). This is also particularly relevant from a budgetary point of view because, in addition to being efficient, the VenO combination can generate savings in pharmaceutical expenditures (the pharmacological cost of treatment per patient is €101,975 with VenO compared to €400,473 with ibrutinib)38, while providing budgetary predictability due to the fixed duration of treatment. Compared to the other comparators, VenO has lower treatment costs after disease progression. This lower cost is due to the high rates of deep response achieved with VenO. Deep response is understood as the achievement of complete remission and undetectable minimal residual disease, which avoids or delays the initiation of a second line of treatment11. Costs related to patient follow-up are also lower with VenO than with the other alternatives because the patient remains longer in progression-free and treatment-free states.

Several cost-effectiveness studies on CLL in previously untreated patients have been conducted in other countries, but most of these studies were conducted prior to the approval of VenO and none have used this therapy as a comparator.

Soini et al. (2016) studied the cost-effectiveness of first-line treatments for CLL in patients ineligible for full-dose fludarabine39. The most cost-effective treatment was ClbO vs the other alternatives studied, such as chlorambucil in combination with ofatumumab, chlorambucil in combination with rituximab, and BR.

Furthermore, after the approval of ibrutinib, several studies conducted in other countries conducted economic analyses on its efficiency as first-line treatment for CLL40-42. Although the results of these studies are not directly applicable to Spain, all of them seem to agree that ibrutinib offers reasonable results in terms of PFS and QALYs, but it is not considered to be cost-effective.

Due to the type of analysis, the present study is limited by the need to extrapolate survival data to a longer-term horizon than the trial follow-up period. However, the extrapolation was based on the distributions with the best goodness-of-fit to the KM curves in the CLL study14. It would be relevant to perform additional analyses when longer-term CLL14 study follow-up data are obtained or to conduct real-world evidence studies.

On the other hand, in the absence of direct evidence related to the other comparators, except for ClbO5, an indirect comparison was performed by means of a network meta-analysis. This type of analysis is not free of limitations, which are mainly at the level of methodological similarity (i.e. heterogeneity between studies). Nevertheless, it is the only possible alternative in order to be able to compare treatments that have not been directly compared in clinical trials. Other limitations are the differences in methodology and the patient selection procedure between the clinical trials chosen for each treatment. To increase the external validity of this type of analysis, all pivotal clinical trials for CLL treatments should include the same type of patients (not excluding those with unfavourable prognosis) and demonstrate efficacy and safety data over the same time horizon. At the time the CLL14 study was designed, ClbO was the standard treatment for this type of patient, although currently ibrutinib is considered to be the standard treatment for previously untreated CLL patients with the 17p deletion or TP53 mutation.

In conclusion, this study shows that VenO is emerging as an efficient and dominant alternative for the treatment of CLL in previously untreated patients in Spain. According to our analysis, the introduction of VenO in the Spanish NHS could reduce treatment costs, costs associated with patient follow-up, and the costs of subsequent treatments after progression, as well as improve the life expectancy and quality of life of Spanish patients with CLL.

The study was conducted with funding from AbbVie Spain. No honoraria or authorship payments were made.

The authors would like to thank Ferrán Pérez Alcántara and Irene Ambatlle Jiménez of Oblikue Consulting for their support in study design, data analysis, and drafting the manuscript. These services were funded by AbbVie.

Estela Moreno Martínez has received honoraria for her participation in training activities, lectures, and expert panels from AbbVie, Amgen, Astellas, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Fresenius Kabi, Incyte Biosciences Iberia, Ipsen, Janssen, Merck SL, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and Tesaro.

Javier de la Serna Torroba has received honoraria for his participation in training activities, lectures, and expert panels from AbbVie, AstraZeneca, Beigene Gilead, Janssen and Roche.

Vicente Escudero Vilaplana has conducted training support activities or received fees for lectures or consulting services from AbbVie, Astellas, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis and Pfizer.

José Ángel Hernández Rivas has been a consultant and lecturer for Janssen, AbbVie, Gilead, Roche, BMS-Celgene, Takeda, AstraZeneca and Beigene.

Marina Sánchez Cuervo has participated in consultancies for AbbVie. Raquel Sánchez Hernández is an employee of AbbVie and may own AbbVie stock.

LXII Congreso Nacional de la Sociedad Española de Hematología y Hemoterapia and XXXVI Congreso Nacional de la Sociedad Española de Trombosis y Hemostasia. Virtual; October 26-30, 2020.