Brentuximab vedotin in adult patients with HL CD30⁺ at high risk of relapse or progression following ASCT: a cost-analysis in Italy

Introduction

Classic Hodgkin lymphoma (HL) is a relatively rare hematological malignancy and one of the lymphoproliferative disorders characterized by strong histological expression of the CD30 antigen on the pathognomonic Reed-Sternberg cells (CD30⁺) (1). In Italy, in the period 2000-2010, the observed incidence for men and women was 3.84 (95% confidence interval [CI], 3.73-3.96) and 3.18 (95% CI, 3.08-3.29) cases every 100,000 residents per year, respectively (2). The observed overall survival (OS) 5 years after the diagnosis is over 90% in the 15-44 years range, but for patients older than 65 years, HL still represents a relatively aggressive malignancy, with an overall survival of 34% and 52%, for men and women, respectively (3). Recent therapeutic advances in HL are expected to lead to an enduring remission in 70% to 90% of the patients treated with standard chemotherapy with or without consolidation radiotherapy (4); still, 10% to 15% of patients with early HL and up to 30% with advanced HL fail to respond or relapse after primary therapy (5). Second-line regimens suggested by guidelines (6), consisting of salvage chemotherapy followed by autologous stem cell transplantation (ASCT), have even lower responses, with OS probability of 47% (95% CI, 37%-57%) (7) at 10 years, with overall survival (OS) probability of reaching 61% (95% CI, 52-72%) (7) at 4 years, and a dismal median post-progression survival of about 1-2 years (7,8). Before brentuximab vedotin (BV) becomes available, third-line options for HL treatment were: palliation with single drug chemotherapy or radiotherapy for patients ineligible for transplant; intensive chemotherapy regimens to induce complete response (CR) or good partial response (PR) for patients eligible for transplant (6). BV is an antibody-drug conjugate combining an anti-CD-30⁺ antibody with the microtubule-dissolving agent, monomethyl auristatin E (9). Recently the European Medicines Agency issued an additional approval for BV for the treatment of adult CD30⁺ HL patients at increased risk of relapse or progression following ASCT based on results of the global, phase III, randomized controlled trial AETHERA (10). The early post-transplant administration of BV provided a consistent improvement in the median progression-free survival (mPFS) vs. Placebo, which was subsequently confirmed by long-term results (11), with the median PFS not yet reached in the experimental study arm after 5 years. The extended follow-up demonstrated sustained benefit and long-term tolerability and safety (11). In Italy, BV is not yet reimbursed for this indication. The present simulation aims to calculate the impact of BV consolidation therapy, thus introducing a novel paradigm not yet codified on a national level. The analysis estimates treatment and management costs for patients at high risk of lymphoma relapse (HL CD30⁺ HR). To this objective, a cost model was developed to compare the expenditure between two possible arms, BV in consolidation vs. no consolidation therapy (NCT) after ASCT, from the Italian National Health System’s perspective. The model’s input parameters were obtained from the AETHERA (12) trial and other published sources.

Material and methods

Cost inputs

The cost-analysis for both arms included drug acquisition, drug administration, and health care resource utilization (HCRU). The treatment costs were estimated according to the dosage reported for each regimen in the respective SPC and applied for the ToT reported in Fig. 1. The ex-factory price published in the Official Journals was used for BV and nivolumab (17,18), and the mandatory discounts (5%+5%) (23,24) were applied. Similarly, for drugs used in the fourth segment of Fig. 1, the prices were collected from codifa.it (Tabs. I, II; Supplementary Tables A and B). The dosage was based on the average body weight of the intent to treat (ITT) population in the AETHERA study (76.3 ± 20.6 kg) (12), assuming this was valid for the three or more risk factors population as well. Wherever required, the body surface area (BSA; 1.91 ± 0.10) was estimated by applying the mean body weight and height (171.9 ± 0.10 cm) (12) of the AETHERA trial ITT population to the Mosteller equation (25). Tables I and II have summarized the total costs associated with the two arms compared in the present analysis.

With regard to “Other” (Tab. II):

– the chemotherapies included represent multiagent salvage regimens recommended in different guidelines or reported in the literature for the management of patients relapsing after ASCT (6,21,22,26). These consisted of the following regimens administered to different percentages of patients: gemcitabine, cisplatin, methylprednisolone (GEM-P, 15%) (27); gemcitabine, oxaliplatin (GEM-Ox, 15%) (28); chlorambucil, vinblastine, procarbazine, prednisolone (ChlVPP, 25%) (29); bendamustine monotherapy 20% (30); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone (BEACOPP, 10%) (31), and dexamethasone, cisplatin, cytarabine (DHAP, 10%) (32). We also considered that 5% of the patients could have been enrolled in a clinical trial without additional costs.

– the PC includes the most common (>15%) concomitant therapies reported for all patients in the AETHERA study (12,33): pantoprazole, Bactrim^®, acyclovir, paracetamol, lorazepam, and psychological support (Tab. II and Supplementary table B).

– for ASCT and Allo-SCT, the costs (Tab. II) were obtained from Diagnosis Related Group (DRG) 481, considering specific codes (code 41.01, 41.04, 41.07, and 41.09 for ASCT; code 41.02, 41.03, 41.05, 41.06, and 41.08 for Allo-SCT) based on a document issued by the Region of Emilia Romagna (34). The costs include the whole procedure package (consultation fees, bone marrow transplant, stem cell apheresis, pharmacological treatment). The unit cost for ASCT was €37,197.79 and for Allo-SCT was €85,761.58.

	Mg per unit	Posology	Dose/administration	Unit/administration	Adm/month	Cost per unit (€)	Cost month (€)	ToT (months)	Cost per ToT (€)
Arm A
BV	50	1.8 mg/kg/21 days	137.34 mg	2.7468	1.4494	3,008.03	11,975.61	10.4	124,546
Total									124,546
Arm B
BV	50	1.8 mg/kg/21 days	137.34 mg	2.7468	1.4494	3,008.03	11,975.61	6.2	74,249
Nivolumab	240	3 mg/kg/14 days	228.90 mg	0.95375	2.1741	3,226.01	6,689.31	14.7	98,333
“Other”	(see Tab. II)						5,644.66	5.7	32,174
Total									204,756

BV = brentuximab vedotin; ToT = time on treatment.

Alternatives included in “Other”	% use	Cost per ToT per patient (€)
Chemotherapy*	47.50	5.7 months of chemotherapy = 1,390.62 Total per patient = 1,390.62
Chemotherapy* + Allo-SCT	35.00	5.7 months of chemotherapy = 1,390.62 Allo-SCT = 85,761.58 Total per patient = 87,152.20
Chemotherapy* + ASCT	2.50	5.7 months of chemotherapy = 1,390.62 ASCT = 37,197.79 Total per patient = 38,588.41
Palliative Care**	15.00	5.7 months of PC = 306.95
Weighted cost per ToT per patient		32,174.57

(*) For the details about how the monthly costs were calculated, refer to Tabs. A and (**) B in Supplementary materials.
Allo-SCT = allogenic stem cell transplantation; ASCT = autologous stem cell transplantation; ToT = time on treatment.

The administration cost of €45.34 was considered for all intravenous medicines based on the average outpatient tariffs applied in different Italian regions to assess the variability in how this is reimbursed (34-38; Tab. III). For the other drugs, the administration costs were not included.

For each resource considered in the model (Tab. IV), the frequency of use was collected 1) from the AETHERA trial (12) for arm A (Fig. 1); 2) from the AETHERA trial and various published sources for arm B (39,40). The annual frequencies reported in Table IV were applied according to each segment of the two arms’ duration compared (Fig. 1). The resource consumption in the off-treatment period was assumed to equal the one considered for the previous treatment period. In line with clinical reports (6,41-43), the health care resources included routine monitoring (computed tomography [CT] scans, physician counseling fees, laboratory test costs), emergency room (ER) visits, and hospitalizations. All the DRGs and outpatient service tariffs reported in the article were obtained from the Official Journal (44) if not stated differently. When two or more relevant DRGs were available, the number of hospitalizations was used to calculate a weighted average (45).

Results

The early administration of BV consolidation therapy has demonstrated a significant and long-lasting improvement in the PFS vs. no consolidation for patients at high risk of relapse or progression after ASCT (10,11). Indeed, after 3 years: 1) in arm A, the median PFS was not reached, so the cost evaluated was the one of BV for consolidation, only; 2) in arm B, further relapses occurred, so the estimated treatment cost resulted in the sum of all therapies considered to treat them. The median pharmaceutical cost per patient in 3 years was higher in patients without consolidation therapy as shown in Table V: €204,756 per patient not receiving consolidation therapy and treated only at the time of the relapse (arm B) compared to €124,546 per patient treated with BV consolidation therapy (arm A). Considering the drug acquisition cost alone, the savings due to the administration of BV consolidation therapy is around 40% (€80,210) in 3 years. Moreover, if other direct costs were considered (administration and resource consumption), the total expenditure would be €225,418 in arm B and €137,059 in arm A. Considering all the direct costs, the use of BV consolidation therapy allowed to save around €88,359, in 3 years (about 40%).

The NHS savings calculated with this model could be potentially underestimated because all the other direct costs associated with relapses were not considered (i.e., possible multiple transplants). Moreover, as reported in the SPC, the adoption of the BV consolidation therapy is associated not only with a reduction in the rate of hospitalizations and outpatient visits but also with a lower number of missed working days for both patients (5.62 for BV vs. 11.70 for no consolidation) (12) and their caregivers (0.11 for BV vs. 1.80 for no consolidation) (12). For this reason, when also considering indirect costs, the saving associated with the adoption of BV in consolidation would be even more significant than the one estimated in the present analysis focused on direct costs only. If we adopted a time horizon of 5 years, the results would still remain in favor of BV: 1) in arm A, the expenditure would remain stable due to a 5-year median PFS still not reached (11); 2) in arm B, the spending could be ≥€225,418 per patient, due to the possibility of further relapses and the eventual need of subsequent therapies and/or transplant procedures.

Discussion

BV is an anti-CD-30⁺-based antibody-drug conjugate recently approved by the European Medicines Agency to treat adult CD30⁺ HL patients at increased risk of relapse or progression following ASCT. This indication is not yet reimbursed in Italy, as the post-ASCT consolidation is a strategy that remains unrecognized in the lymphoma space. The objective of this analysis was to evaluate the advantages of introducing BV as consolidation therapy (arm A) vs. no-consolidation strategy and the administration of subsequent treatments at the time of relapse (arm B). The prescription of brentuximab as consolidative monotherapy demonstrated enhanced clinical outcomes vs. the choice of observation (10,11,14,15,47). Moskowitz and colleagues (11) confirmed that the median PFS for patients at high risk of HL relapse or progression receiving BV consolidation was not reached after 5 years compared to the progression rate for placebo (41%) through the long-term follow-up analysis (hazard ratio [HR] 0.52; 95% CI, 0.379-0.7171). Moreover, the risk associated with only one treatment (BV consolidation), which guarantees a long period free from relapses, is presumed to be lower than the one resulting from the sum of the risks associated with all the therapies needed to treat further relapses.

The modeling of the present analysis is based on median PFS values. As confirmed in the recent article from Sureda and colleagues (48), PFS is considered a clinically relevant endpoint in evaluating HL (12,49). The direct comparison of the two arms modeled highlighted a saving of about 40% generated from the administration of BV as consolidation therapy vs. the current paradigm, which consists of treating HL patients at the time of relapses. This saving could be even more significant if: 1) other direct costs would be considered; 2) indirect costs would be accounted for; 3) pembrolizumab (recently reimbursed for the same indication as nivolumab) (50) would be considered as an alternative to pre/post-nivolumab (its treatment cost is higher than the one estimated for nivolumab). Yasenchak and collaborators, in their work, assessed the burden of the disease after the first relapse and found that second and third lines of therapy were 2.7-3.5 times more expensive than the first-line therapy (51). Evidence from another study suggested that relapsed patients accrued $401,529 compared to $89,709 in non-relapsed patients (52). In line with observations reported in articles published in the pre-BV era, we also observed an increase in the year total costs after the first relapse (€79,449) to the second relapse (€106,281) in arm B (no consolidation). While the impact of the BV consolidation is estimated with appreciable precision, it appears clear that the economic burden for subsequent therapies is variable. This burden depends on many factors such as the number of relapses, the drugs administered at each relapse, the treatment durations, and the need for a transplant. All this highlights the importance to prevent relapses not only from the patients’ point of view but also from an economic perspective. The present analysis has clearly pointed out a preeminence of one arm concerning the other, despite several limitations like the duration of therapies in the real practice, the mix of therapies/transplants adopted, and the uncertainty on the PFS duration after the third relapse. Hence, real-world evidence would be opportune to validate the outcomes of the present analysis.

Acknowledgments

All authors have materially participated in the research and article preparation. Maria De Francesco designed the research project and supervised data collection. Gian Luca Breschi collected, edited, and analyzed data and performed statistical analyses, and also produced the manuscript. Paolo Morelli, Maria De Francesco, Federica Demma contributed to data interpretation and revising of the document. All authors have approved the final article.

Disclosures

Conflict of interest: Breschi GL and De Francesco M declare that they have no conflicts of interest in this research. Demma F and Morelli P are full-time employees of Takeda Italia S.p.A.

Financial support: Takeda sponsored the research.