Cost-effectiveness Analysis of Rituximab Associated With Fludarabine and Cyclophosphamide (R-FC) for the First-line Treatment of Chronic Lymphocytic Leukemia Under the Brazilian Public Health System (SUS).

<jats:title>Abstract</jats:title>         <jats:p><jats:bold>BACKGROUND</jats:bold>Chronic Lymphocytic leukemia is the most common leukemia in the western world. In the last decade, treatment options expanded with an expressive rise in treatment costs. In Brazil the overall cancer treatment costs are rising mainly due to the judicialization law suits. The efficacy and safety of associating rituximab to fludarabine and cyclophosphamide (R-FC) for the treatment of chronic lymphocytic leukemia has been demonstrated by the CLL8 trial, which was conducted in previously untreated patients positioning the immunochemotherapy regimen as the standard choice for physically fit patients. Considering this scenario, the current study has as objective to evaluate the cost-effectiveness of the addition of rituximab to the FC protocol considering the Brazilian public health system perspective. <jats:bold>METHODS</jats:bold>We developed a Markov model with three health states to extrapolate the CLL8 trial results. The transition probabilities and adverse events incidence were obtained from the trial published data. The costs were assessed from Brazil’s ministry of health pricing database (public available). A simplified treatment algorithm was developed according to the current available treatment options in the Brazilian public health system and assuming the availability of rituximab. <jats:bold>RESULTS</jats:bold>The addition of rituximab to the FC regimen results in an incremental cost-effectiveness ratio (ICER) of 8389 USD (45003,86 BRL) per year life free of progression. The sensititvity analysis conducted shows a From the Brazilian public health system perspective, the combination of rituximab with the FC chemotherapy represents a cost-effective strategic approach for first-line treatment of patients with CLL.<jats:bold>CONCLUSIONS</jats:bold>considering the data described in this study, we cqn conclude that the addition of rituximab to the first-line treatment of CLL is cost-effective strategy for the Brazil public health system. With the advent of new drugs and new treatment regimens that presents positive clinical outcomes in patients refratary to the R-FC regimen (del17p, p53 mutations), new studies must be conducted to evaluate their cost-effectiveness considering this population of patients.</jats:p>

section_content: According to the World Health Organization (WHO) classi cation of hematopoietic and lymphoid tissues, chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder characterized by the aberrant proliferation of clonal CD5 + /CD23 + B cells in the blood, bone marrow and lymphonodes (1). With an estimated incidence of 4. 7 new cases per 100. 000 individuals, CLL is the most common hematopoietic malignancy in the western world (2). The estimated number of new cases in 2020 is 21,040, making CLL accountable for 1,2% of all cancer cases and 40% of all leukemia cases in man and 34% in woman in USA (3). In Brazil, according with the National Cancer Institute (INCA) data, the estimated number of new cases of leukemia (all types, including CLL) between 2020 and 2023 will be of approximately 11. 000 cases (55% in males and 45% and females) per year (4). 

Compared with more common diseases such as cardiovascular or diabetes, the economic burden of CLL is signi cantly lower. However, the treatment cost per CLL-case is about twice as high as the common disease patient treatment (5). 

Since the publication of the CLL8 trial, the combination of rituximab, udarabine and cyclophosphamide (R-FC) is the recommend treatment for rst-line, t, CLL patients without comorbidities and normal renal function(6). After this publication, the CLL, and B-cell lymphomas in general, experienced a huge expansion on their therapeutic arsenal. New drugs, including second generation anti-CD20 monoclonal antibodies (ofatumumab and Obinutuzumab), PI3K inhibitors (Idelalisib), Bruton Tyrosine Kinase inhibitors (Ibrutinib) and BCL2 inhibitors (ABT199). These drugs have reduced toxicity in the short term and induce treatment responses, especially in relapse and refractory patients including those with molecular markers associated with poor prognosis such as del17p and p53 mutations. 

However, the cost of this target therapies is high, and their utilization must consider the patient physical tness, del17p deletion, p53 gene mutations, and IGVH mutational status (7). The utilization of this new regimens can potentially bring a signi cant economic impact for payors and patients. In a populational health economic evaluation, Shanafelt(8) estimates that the utilization of Ibrutininb in the rst-line treatment can enhance the CLL treatment costs in approximately 350%. In another report, Chen (9) demonstrates that the cost of CLL treatments overtake that of other cancers. 

As the annual cost of cancer care in the USA increased approximately 30% from 2010 to 2020, the annual cost of CLL treatment is expected to increase by 500% jumping from 0,7 billion USD in 2011 to 4. 2 billion USD in 2020. 

Brazil is one of the countries that recognizes a constitutional right to health, and an important part of this right is the access to pharmaceutical drugs. With the approval of new and expensive cancer treatments, the number of lawsuits to secure access to these new drugs increases. According to a report from developed by the Brazilian National Justice Council, the number of lawsuits related to health issues grew 198% after 2009 to 2017. From these cases, 69% were related to the access to new drugs (10) Moreover, a study conducted by Vidal (11) analyzed 158 lawsuits related to antineoplastic drugs, they found that rituximab was present in 23,2% of the claims analyzed, ranking rst in a list that includes antineoplastic drugs for the treatment of all cancer types. 

Currently, the Brazilian public health system offers the FC protocol as the only option for CLL rst-line treatment for physically t patients. It is critical for the cost management to have de nitions regarding the new available treatments and their indications. Furthermore, to provide health economic evaluation data about the cost-effectiveness of the R-FC can provide bene cial outcomes for both patients and public payors in Brazil. 

The objective of this study is to evaluate the cost-effectiveness of the rituximab addition to the FC protocol for rst line CLL treatment in the Brazilian public health system. 

2 Methods The model used a cycle length of 3 months and 10 years as time horizon. The Brazilian public healt system willingness to pay is considered as perspective. Future costs and utilities had an annual discount rate of 5%. The Markov Model was developed and calculated with the Tree Age Pro Healthcare ® software (Treeage, Williamstown, MA, USA). 

All patients started in the "On treatment" state. They could either remain on this state or change to the states "Progression" or "Death". The state "Progression" included all events from rst relapse or disease progression after the treatment. 

The Cost-effectiveness of R-FC over FC was assessed using an incremental cost-effectiveness ratio (ICER). The transition probabilities were obtained from the CLL8 trial progression-free survival (PFS) and overall survival (OS) curves, up to a follow up period of 3 years. Survival beyond the trial follow up period was projected according to the previous described methodology. The data reported in this publication was used to estimate the long-terms costs relative to the adding of rituximab in the rst-line treatment of CLL. 

A total of 817 patients diagnosed with CLL and treatment naïve were enrolled and in the trial. The study population had a mean age of 61 years, and 74% were male. Patients enrolled were in Binet stage C (31%) or with con rmed active disease in stages A or B (68%). 

With a median observation time of 3 years after the randomisation, CLL8 trial results demonstrated a signi cant bene t in R-FC treatment arm related with the progession free-survival (PFS) and overall survival (OS). Table 1 summarizes the clinical data extracted from CLL8.
section_name: Introduction

section_content: CLL8 study design randomly assigned participants to receive either R-FC or FC treatment regimens as described in the trial protocol. Patients were scheduled to receive 6 cycles of the regimen to which they were randomized. Treatment consisted of six 28-day intravenous administration of 25mg/m 2 /day of udarabine and 250 mg/m 2 /day of cyclophosphamide on the rst 3 days of each cycle. For the R-FC protocol, rituximab was administered intravenously in addition to FC as 375 mg/m 2 before the FC infusion on day 1 of the rst cycle and 500 mg/m 2 on day 1 of cycles 2-6.
section_name: Treatment

section_content: Although several therapeutic options are currently available for the treatment of rst line, treatment naïve CLL patients, there is no formal treatment consensus on the Brazil public health system. An algorithm for the treatment of CLL was developed on the basis of information available in the following guidelines: the International Workshop on CLL (iWCLL) 2018 (7), the European Society for Medical Oncology (ESMO) (13), US National Comprehensive Cancer Network (NCCN), clinical guidelines in Oncology: CLL/Small Lymphocytic Lymphoma (14), Brazilian Group of CLL (15). 

Using these sources, a preliminary treatment algorithm was developed, this process was them submitted to the review of hematologists with extensive practice in treating CLL in Brazil. The nal algorithm that closely re ects the treatment of CLL considering the Brazilian public health experience and the predicted use of rituximab is shown in Fig 2.
section_name: Treatment algorithm

section_content: The incremental costs were calculated considering only costs driven by the difference in the treatment arms, the association of rituximab to the FC protocol. The direct costs include drug costs from both protocols, adverse event costs, drug administration costs, and costs with follow-up visits, and laboratory tests (clinical examinations, blood exams. Other costs like administrative costs were not included in the model because available study data for these parameters is scarce and they have low representativity. 

The assessment of drug prices and costs was obtained from the Brazilian Health Ministry website (SIGTAP -Health procedures and drugs management system), which provides information related to the value paid by the Brazilian Public Health system (SUS) for procedures and medications. Speci cally, for CLL there are 2 procedures available for rst and second line treatment (nominated APAC's). They were used as main reference for the comparison of incremental costs and the current value allocated for rst line CLL treatment.
section_name: Costs

section_content: The model followed the protocol described on CLL8 trial and summarized brie y in the treatment section. 

The body surface (m 2 ) considered was 1. 8 according to the Brazilian populational average of height and weight, according with the Brazilian Institute of Demographics and Statistics (IBGE). 

The costs associated with salvage treatment were calculated based on the available guidelines and literature. The treatment costs associated with the R-FC protocol and FC were obtained in Brazilian Reais (BRL) and converted to US Dolars (USD), using a currency exchange rate of 5,39 BRL to 1 USD (currency exchange rates from November 9 th 2020).
section_name: Treatment

section_content: To ne the costs of adverse events associated with the R-FC protocol, we considered the incidence of adverse events published in the CLL8 trial. The incidence of events reported was signi cant higher on patients treated with R-FC compared with FC. Among the events reported, grade 3 or 4 adverse events were signi cant higher in patients treated with rituximab. According to the study protocol, granulocytestimulating factor (G-CSF), was administered to patients that presented this adverse event. 

Hospitalizations costs related to adverse events were disregarded as the treatment of neutropenia usually does not require hospital admission.
section_name: Adverse events costs

section_content: Probabilistic sensitivity analysis were performed to determine the magnitude of change in the ICER associated with a range of variations in four most critical parameters. We carried out tornado diagrams to test the model uncertainty when applying variations on the overall survival hazard ratio, the rituximab cost per milligram, the progression-free survival hazard ratio, and 3-month toxicity costs.
section_name: Sensitivity analysis

section_content: Con rming the clinical ndings published on the CLL8 trial and CLL8-follow up(6, 16), the main bene t of adding rituximab in the economic model is the lower rate of transitioning between the Markov states. 

Patients treated with the R-FC protocol spend longer in the unprogressed health state, in a clinical remission with non-detected or minimum detectable disease and a relatively good quality of life. The comparison between R-FC and FC resulted in an incremental cost of 6911 USD (37076,14 BRL) with an incremental cost-effectiveness ratio (ICER) of 8389 USD (45003,86 BRL) per year life free of progression. 

Rituximab was associated with additional costs including adverse events incidence. The cost related to acquisition of the monoclonal antibody alone accounts for 93% of the total cost difference between the regimens (see table 2 ). Values are displayed in USD (5,39 BRL to 1 USD exchange rate)

Salvage therapy accounted for signi cant costs in each treatment arm. Costs associated with salvage therapy were similar in both arms (table 3 ). Nevertheless, these costs incurred at an earlier time point in FC arm when compared with R-FC treatment, yielding an incremental cost in the FC arm. The analysis considers 1,7m 2 as an average value for Brazilian patients. 

Values are displayed in USD (5,39 BRL to 1 USD exchange rate) VCP protocol according with Marcus et al (17).
section_name: Results

section_content: In general, the results were shown to be robust in the sensitivity analyses. Toxicity costs, PFS HR, overall survival HR, and rituximab cost were the drivers for cost-effectiveness of the monoclonal antibody. The analysis outcomes points to a model sensitivity related to the overall survival hazard ratio alterations. 

The tornado diagram ( g 3) displays the results found.
section_name: Sensitivity analysis

section_content: This study evaluates the cost-effectiveness of the R-FC regimen for the rst line treatment of CLL patients versus the FC protocol, currently available for this segment of patients in the Brazilian public health system. The modeled population was based on the patients enrolled in the CLL8 trial. The analysis con rmed that the addition of rituximab results in a signi cant improvement in health gains with moderate additional costs. 

Despite the structural differences between distinct country's health systems, the results of this study endorse other published economic analysis from Australia(18), Spain (19), and two other health economic evaluations (5, 20) with the same objective. In these health evaluation studies, adding rituximab has been shown to be cost-effective with ICERs between 19000 USD -28500 USD. With an ICER of 8388,73 USD, the present analysis shows a considerable decrease in the incremental cost-effectiveness ratio. Assuming the decrease in rituximab prices since the publication of the studies and, also, by the fact that we used the biosimilar anti-CD20 prices, it is possible to justify the scenario, which is very favorable to a potential adoption of the immunochemotherapy regimen for this segment of patients. Because the drug costs for rituximab represents a major proportion (>90%) of the incremental costs for the R-FC regimen, the unity cost of the drug have a signi cant impact on the cost-effectiveness analysis, thus, governmental initiatives that could potentially reduce the price, will yield a positive economic outcome. 

According with the WHO Commission on Macroeconomics and Health, in developing countries with no de nition on the cost-effectiveness threshold, health interventions can be considered as cost-effective when the ICER value is between 1 to 3 times the country's per capita GDP (gross domestic product). 

According with the IBGE, Brazil's per capita GDP was 5667 USD (30407 BRL) in 2016. 

In conclusion, considering the data described in this study, we cqn conclude that the addition of rituximab to the rst-line treatment of CLL is cost-effective strategy for the Brazil public health system. With the advent of new drugs and new treatment regimens that presents positive clinical outcomes in patients

Simpli ed CLL treatment algorithm assuming rituximab availability
section_name: Discussion

section_name: Declarations 1 ETHICS APPROVAL

section_content: refratary to the R-FC regimen (del17p, p53 mutations), new studies must be conducted to evaluate their cost-effectiveness considering this population of patients.

section_content: The current study does not demand ethics approval.
section_name: Declarations 1 ETHICS APPROVAL

section_content: The datasets generated during and/or analysed during the current study are available in the following weblinks:

-Costs analysis: SIGTAP table: www. sigtap. datasus. gov. br -CLL8 Trial: Lancet 2010 Oct 2;376(9747):1164-74. doi: 10. 1016/S0140-6736(10)61381-5.
section_name: CONSENT FOR PUBLICATION Not applicable 3 AVAILABILITY OF DATA AND MATERIAL

section_content: The authors declare that they have no competing interests 5 FUNDING Not applicable. This research has not received any nancial support. 6 ACKNOWLEDGEMENTS Not applicable.
section_name: COMPETING INTERESTS

section_content: This is a list of supplementary les associated with this preprint. Click to download. 

CHEERSChecklist. pdf
section_name: Supplementary Files