Real-world Prescription Pattern, Discontinuation and Costs of Ibrutinib-Naïve Patients with Chronic Lymphocytic Leukemia: An Italian Healthcare Administrative Database Analysis.

BACKGROUND AND OBJECTIVE: In order to integrate the existing and inconsistent information from clinical trials and real-world practice on chronic lymphocytic leukemia (CLL) treated with ibrutinib, this analysis aimed to describe the prescription pattern of new users of ibrutinib affected by CLL, focusing on discontinuation, severe adverse events (AEs) and change of treatment, and to assess the integrated healthcare expenditure from the Italian National Health System (INHS) perspective. METHODS: Starting from the ReS database, adults with at least a supply of ibrutinib (ATC code L01XE27) were selected from 01/01/2016 to 12/31/2017. Those without any ibrutinib supply in the year before the index prescription were considered new users. Out of them, only patients with at least a primary or secondary in-hospital diagnosis of CLL (ICD-9-CM code 204.1*) from 01/01/2013 to 12/31/2018 were further broken down according to the ibrutinib's line treatment (first line-FL; second or later line-SLL) and analysed. They were characterized by sex and age in the selection period. Mean annual consumption (defined daily doses [DDD]), treatment discontinuation, changes of therapy, interruptions and healthcare costs in charge of the INHS were assessed during two follow-up years. RESULTS: Out of more than 5 million inhabitants of the ReS database, 69 new ibrutinib users and diagnosed with CLL in 2016 (incidence: 1.6 × 100,000) and 41 in 2017 (incidence: 0.9 × 100,000) were selected. Of these, 21 (19.1%) were FL ibrutinib users and 89 (80.9%) were SLL ones, mostly males and with mean ages (±SD) of 65 ± 14 and 70 ± 10, respectively. The mean annual consumption among FL users decreased from 222.2 DDD per patient treated to 216.0 DDD, while increased among SLL patients from 238.6 DDD to 260.1 DDD, in the first and second follow-up year, respectively. The discontinuation rate was about 40% in the first year, similarly among FL and SLL users. SLL patients discontinued more frequently (52.8% vs 20.0%) in the second year. Very few AEs were recorded. The 62.5% of FL and 55.6% of SLL users discontinuing ibrutinib in 1-year follow-up, while one SLL patient (5.3%) in the second year changed therapy. The 20.0% and 15.9% of all new users in first and second year interrupted ibrutinib. The total integrated cost of FL patients was €55,732 reducing by about €15,000, while it was €58,716 for SLL ones decreasing by €6,000, respectively, in the first and in the second year. Pharmaceuticals were the key cost driver (ibrutinib accounted for more than 77%). CONCLUSIONS: This analysis on Italian administrative data provided results about prescription patterns of ibrutinib FL and SLL new users with CLL, focusing on discontinuation, treatment change and healthcare costs over 2-year follow-up, and contributed to improve the knowledge on this hard-to-treat disease.

Cost-effectiveness of first-line vs third-line ibrutinib in patients with untreated chronic lymphocytic leukemia.

The ALLIANCE A041202 trial found that continuously administered ibrutinib in the first-line setting significantly prolonged progression-free survival compared with a fixed-duration treatment of rituximab and bendamustine in older adults with chronic lymphocytic leukemia (CLL). In this study, we created a Markov model to assess the cost-effectiveness of ibrutinib in the first-line setting, compared with a strategy of using ibrutinib in the third-line after failure of time-limited bendamustine and venetoclax-based regimens. We estimated transition probabilities from randomized trials using parametric survival modeling. Lifetime direct health care costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated from a US payer perspective. First-line ibrutinib was associated with an improvement of 0.26 QALYs and 0.40 life-years compared with using ibrutinib in the third-line setting. However, using ibrutinib in the first-line led to significantly higher health care costs (incremental cost of $612 700), resulting in an ICER of $2 350 041 per QALY. The monthly cost of ibrutinib would need to be decreased by 72% for first-line ibrutinib therapy to be cost-effective at a willingness-to-pay threshold of $150 000 per QALY. In a scenario analysis where ibrutinib was used in the second-line in the delayed ibrutinib arm, first-line ibrutinib had an incremental cost of $478 823, an incremental effectiveness of 0.05 QALYs, and an ICER of $9 810 360 per QALY when compared with second-line use. These data suggest that first-line ibrutinib for unselected older adults with CLL is unlikely to be cost-effective under current pricing. Delaying ibrutinib for most patients with CLL until later lines of therapy may be a reasonable strategy to limit health care costs without compromising clinical outcomes.

Challenges in the Clinical Application of the American Society of Clinical Oncology Value Framework: A Medicare Cost-Benefit Analysis in Chronic Lymphocytic Leukemia.

PURPOSE: The ASCO Value Framework calculates the value of cancer therapies. Given costly novel therapeutics for chronic lymphocytic leukemia, we used the framework to compare net health benefit (NHB) and cost within Medicare of all regimens listed in the National Comprehensive Cancer Network (NCCN) guidelines. METHODS: The current NCCN guidelines for chronic lymphocytic leukemia were reviewed. All referenced studies were screened, and only randomized controlled prospective trials were included. The revised ASCO Value Framework was used to calculate NHB. Medicare drug pricing was used to calculate the cost of therapies. RESULTS: Forty-nine studies were screened. The following observations were made: only 10 studies (20%) could be evaluated; when comparing regimens studied against the same control arm, ranking NHB scores were comparable to their preference in guidelines; NHB scores varied depending on which variables were used, and there were no clinically validated thresholds for low or high values; treatment-related deaths were not weighted in the toxicity scores; and six of the 10 studies used less potent control arms, ranked as the least-preferred NCCN-recommended regimens. CONCLUSION: The ASCO Value Framework is an important initial step to quantify value of therapies. Essential limitations include the lack of clinically relevant validated thresholds for NHB scores and lack of incorporation of grade 5 toxicities/treatment-related mortality into its methodology. To optimize its application for clinical practice, we urge investigators/sponsors to incorporate and report the required variables to calculate the NHB of regimens and encourage trials with stronger comparator arms to properly quantify the relative value of therapies.

The use of inexpensive broad spectrum lower toxicity therapeutics in chronic lymphocytic leukemia.

The use of new and highly efficient targeted therapies for chronic lymphocytic leukemia (CLL) is costly and out of reach for many health care systems. On the other hand, in recent years, few inexpensive, broad-spectrum low-toxicity therapeutics have proven to be effective both in the preclinical and clinical settings. In early-stage CLL, the use of 2000 mg of epigallocatechin-3-gallate (EGCG) from the green tea extract twice a day was able to reduce the absolute leukocyte count. Supplementation of >2000 IU/day of Vitamin D in early low-risk CLL patients is able to delay disease progression and postpone the moment of initiation of the first treatment. The doses of both vitamin D and EGCG were shown to be safe in older patients. Vitamin D, EGCG and Curcumin, either as monotherapy or in combination, have additive and synergistic effects with conventional chemotherapy. Further observations have identified the improvement of response to rituximab-fludarabine-cyclophosphamide (R-FC) therapy with concomitant administration of statin and aspirin combination in relapsed/refractory CLL. Finally, high dose dexamethasone with 40mg/m2/day for 4 days, every 28 days, either alone or with monoclonal antibody, might be used as a salvage therapy or for debulking before transplantation in refractory/resistant cases. Dexamethasone therapy is followed by transient response and high rate of infections, but fluid retention and other toxicities are lower compared to high dose methylprednisolone schedules. The low cost therapeutics discussed in this review could not be a substitute for the more effective targeted therapies, but their use in every day practice might postpone the need for early implementation of new and costly medications.

Bendamustine versus chlorambucil for the first-line treatment of chronic lymphocytic leukemia in England and Wales: a cost-utility analysis.

OBJECTIVES: To evaluate the cost-effectiveness of bendamustine compared with chlorambucil as first-line treatment for patients with chronic lymphocytic leukemia who would be considered unsuitable for treatment with fludarabine combination chemotherapy regimens. METHODS: A semi-Markov approach was used to estimate time in each health state. The model was parameterized primarily by using data from a phase III randomized, open-label trial comparing bendamustine with chlorambucil. It captured the increased progression-free survival and improved response rates with bendamustine, and the cost and quality of life impacts of postprogression treatments. The analysis was conducted from the perspective of the National Health Service in England and Wales. A lifetime (35-year) time horizon was used. Deterministic sensitivity analyses, probabilistic sensitivity analyses, and subgroup analyses in older patients and patients with poor performance status were carried out. RESULTS: The estimated incremental cost-effectiveness ratio was £ 11,960 per quality-adjusted life-year. None of the deterministic sensitivity analyses increased the incremental cost-effectiveness ratio by more than £ 2000. Subgroup analyses showed that bendamustine remained cost-effective across different patient groups. Probabilistic sensitivity analysis showed that at the £ 20,000 threshold, bendamustine has a 90% probability of being cost-effective. CONCLUSIONS: Bendamustine represents good value for first-line treatment of patients with chronic lymphocytic leukemia who are unsuitable for treatment with fludarabine combination chemotherapy. The incremental cost-effectiveness ratio is below the thresholds commonly applied in England and Wales (£ 20,000-£ 30,000 per quality-adjusted life-year).