Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare costs in patients receiving these regimens in a real-world setting. Aims: To describe all-cause and CAE-related healthcare costs in relapse/refractory (R/R) elderly patients with CLL treated with bendamustine-based regimens in a real-world setting. Methods: Adult patients with R/R CLL who received bendamustine-based regimens on/after January 2010 were selected from the Medicare Limited Data Set (LDS) 5% Standard Analytic Files. Selected patients were classified into cohorts based on the two most prevalent bendamustine-based regimens observed (index treatment): 1) bendamustine + rituximab (BR cohort) and 2) bendamustine monotherapy (B-mono cohort). For each cohort, all-cause and CAE-related healthcare costs, while on treatment, were reported per-patient-per-month (PPPM). Overall survival (OS) rates following initiation of the index treatment were described using age- and gender-adjusted Kaplan-Meier curves. Results: A total of 275 patients were included in the BR cohort and 100 patients in the B-mono cohort. Most patients were male and the mean age was approximately 75 years old. During treatment, total all-cause healthcare costs were $14,520 PPPM for the BR cohort and $13,125 PPPM for the B-mono cohort—outpatient costs (mainly driven by CLL-drug costs) represented 86.1% of the total all-cause healthcare costs for the BR cohort and 69.8% for the B-mono cohort. CAE costs accounted for 58.3% of the total all-cause healthcare costs for the BR cohort and 66.9% for the B-mono cohort. Median OS was 35 months in the BR cohort and 21 months in the B-mono cohort. Conclusion: In this population of elderly patients with R/R CLL treated with bendamustine-based regimens, CAEs were common and translated into important medical costs. Median OS was also relatively short suggesting an unmet medical need.
Chronic lymphocytic leukemia (CLL) is a type of lymphoproliferative neoplasm characterized by progressive accumulation of mature but functionally incompetent B-lymphocytes in the blood, bone marrow, and in later stages of the disease, lymph nodes, liver, and spleen [
Most patients with CLL typically experience an indolent course of their disease and remain asymptomatic for many years [
However, to date there is no point of reference for real-world outcomes of patients with CLL treated with bendamustine-based regimens. The aim of this study was to describe healthcare costs, including comorbidity- and/or adverse event (CAE)-related healthcare costs, and overall survival (OS) rates in an elderly population of patients with R/R CLL treated with a bendamustine-based regimen.
A retrospective cross-sectional study design was used. Given that the population of patients with CLL is primarily composed of elderly patients and that OS was an outcome of interest in this study, data were extracted from the Medicare Limited Data Set (LDS) 5% Standard Analytic Files (data availability: 1999-2014) [
Patients with CLL (International Classification of Diseases, Ninth Edition, Clinical Modification [ICD-9-CM] code 204.1x) who received a bendamustine-based regimen in a medical setting in second or later lines of therapy on/after January 2010 were identified. The index date was defined as the initiation date for the first bendamustine-based regimen. Selected patients were required to be continuously enrolled in their healthcare plan for ≥6 months before the index date and ≥3 months after the index date (unless the patients died during the first 3 months after the index date, in which case no minimum follow-up was required). Patients in this study were required to be ≥65 years of age as of the index date.
The sample of patients was limited to patients with an indicator of R/R CLL before the initiation of the bendamustine-based regimen. As laboratory test results and clinical information are not available in claims databases, an empirical algorithm based on treatment patterns was used to identify patients with R/R CLL. More specifically, R/R patients were identified based on the following treatment changes 1) a treatment add-on, 2) the initiation or re-initiation of a CLL treatment after a discontinuation (treatment interruption of ≥60 consecutive days), or 3) a treatment switch that was not preceded by claims for a medical service, in an inpatient or emergency room setting, with a diagnosis for a CAE.
Patient cohorts were determined based on the treatment initiated on the index date (index treatment). The two most common bendamustine-based regimens were selected for analysis: 1) combination of bendamustine and rituximab (BR cohort) and 2) bendamustine in monotherapy (B-mono cohort) [
Healthcare costs
All-cause healthcare costs, including inpatient, emergency department, and outpatient costs were measured during the line of therapy for the index treatment, i.e., between the index date and the date of the first treatment change (switch, drop, add-on, or discontinuation), the end of continuous healthcare
plan enrollment, the end of data availability, or the date of a patient’s death, whichever occurred first.
Total CLL-drug cost and total CAE-related cost were also reported. The total CLL-drug cost was defined as the sum of the costs associated with CLL drug and administration in a medical setting (including inpatient, outpatient, or emergency department). The total CAE-related cost was defined as the sum of the costs for claims with inpatient, emergency department, and outpatient services including an ICD-9-CM diagnosis code for one of the studied CAEs―the list of studied CAEs was created based on a review of the adverse events reported in product labels and clinical trials. As patients could have both a procedure for CLL treatment administration and a diagnosis code for one of the selected CAEs in the same claim, and there is no information in claims data to distinguish the portion of the costs associated with treatment administration versus services related to CAEs, CLL drug cost and CAE-related cost were reported as non-mutually exclusive cost categories.
Healthcare costs were adjusted for inflation using the consumer price index for medical components (2016 US Dollars) and reflected the costs reimbursed by Medicare.
Healthcare costs were described for each cohort using mean, median, and standard deviation and reported per-patient-per-month (PPPM) as the duration of the line of therapy for the index treatment varied across patients. This study was descriptive; no statistical comparison was conducted.
Overall survival
OS rates were measured between the index date and the date of death, end of healthcare plan enrollment or end of data availability, whichever occurred first. OS rates were presented graphically as age- and gender-adjusted Kaplan-Meier curves. OS rates were reported separately for the two study cohorts. No statistical comparison was conducted.
A total of 275 patients were included in the BR cohort and 100 patients in the B-mono cohort. Mean age was approximately 75 years in both cohorts, 61.8% of patients in the BR cohort and 65.0% of the patients in the B-mono cohort were men. During the 6 months prior to the index date, patients in both cohorts presented a high comorbidity burden. The mean Charlson Comorbidity Index (CCI) was 3.5 in the BR cohort and 3.7 in the B-mono cohort. Over half of the patients in both cohorts had a diagnosis for hypertension (BR cohort = 57.1%; B-mono cohort = 54.0%), approximately 30% of patients had a diagnosis of diabetes (BR cohort = 29.5%; B-mono cohort = 27.0%) and coagulopathy (BR cohort = 28.7%; B-mono cohort = 26.0%), and over 20% of patients had a diagnosis for cardiac arrhythmias (BR cohort = 24.7%; B-mono cohort = 21.0%) and solid tumor (BR cohort = 20.7%; B-mono cohort = 20.0%) (
The mean follow-up period after the index date was 24 months for the BR cohort and 22 months for the B-mono cohort. The average duration of the line of therapy for the index treatment was 121 days (median = 116 days) in the BR cohort and 75 days (median = 56 days) in the B-mono cohort.
The total all-cause healthcare cost during the line of therapy for the index treatment was high in both cohorts: mean of $14,520 PPPM in the BR cohort and $13,125 PPPM in the B-mono cohort. Outpatient cost, mainly driven by CLL-drug cost, represented 86.1% of the cost in the BR cohort and 69.8% of the cost in the B-mono cohort. Total CAE-related cost (any CAE events) accounted for over half of the total all-cause healthcare cost; 58.3% for the BR cohort and 66.9% for the B-mono cohort (
The median OS following the index date was 35 months in the BR cohort and 21 months in the B-mono cohort (
Since 2014, new oral targeted therapies have been approved for treatment of patients with R/R CLL. These new agents are currently evaluated in clinical trials with or compared to bendamustine-based regimens. However, real-world data on outcomes in patients with R/R CLL receiving bendamustine-based regimens are lacking. This study provided evidence on all-cause and CAE-related costs and OS in an elderly population of patients with R/R CLL treated with bendamustine-based regimens in a real-world setting.
Results from the current study showed that the total healthcare costs during therapy were $14,520 PPPM for the BR cohort and $13,125 PPPM for the B-mono cohort. Outpatient cost, mainly driven by CLL-drug cost, represented the largest cost component. Results also showed that CAE-related healthcare costs accounted for 58% of total healthcare costs in the BR cohort and 67% in the B-mono cohort. This finding is not surprising given the profile of this patient population, i.e., R/R CLL patients in their late seventies with the presence of a relatively high comorbidity burden at the time of the initiation of the studied bendamustine-based regimens.
| BR | B-mono | |
|---|---|---|
| n = 275 | n = 100 | |
| Age, mean ± SD [median] | 75.6 ± 6.5 [75.0] | 75.4 ± 7.0 [74.0] |
| 65 - 69 years, n (%) | 42 (15.3) | 18 (18.0) |
| 70 - 74 years, n (%) | 70 (25.5) | 25 (25.0) |
| 75 - 79 years, n (%) | 73 (26.5) | 27 (27.0) |
| ≥80 years, n (%) | 90 (32.7) | 30 (30.0) |
| Male, n (%) | 170 (61.8) | 65 (65.0) |
| Region of residence, n (%) | ||
| South | 89 (32.4) | 40 (40.0) |
| North central | 46 (16.7) | 22 (22.0) |
| West | 35 (12.7) | 9 (9.0) |
| North east | 69 (25.1) | 23 (23.0) |
| Unknown | 36 (13.1) | 6 (6.0) |
| Year of index date, n (%) | ||
| 2010 | 69 (25.1) | 53 (53.0) |
| 2011 | 63 (22.9) | 20 (20.0) |
| 2012 | 60 (21.8) | 15 (15.0) |
| 2013 | 56 (20.4) | 10 (10.0) |
| 2014 | 27 (9.8) | 2 (2.0) |
| Months from first CLL diagnosis to index date, mean ± SD [median] | 61.31 ± 42.02 [54.64] | 61.78 ± 42.44 [60.58] |
| Charlson comorbidity index (CCI), mean ± SD [median] | 3.53 ± 1.82 [3.00] | 3.66 ± 1.87 [3.00] |
| Six most common physical and mental comorbidities | ||
| Hypertension | 157 (57.1) | 54 (54.0) |
| Lymphoma | 134 (48.7) | 53 (53.0) |
| Diabetes | 81 (29.5) | 27 (27.0) |
| Coagulopathy | 79 (28.7) | 26 (26.0) |
| Cardiac arrhythmias | 68 (24.7) | 21 (21.0) |
| Solid tumor | 57 (20.7) | 20 (20.0) |
Abbreviations: B-mono: bendamustine in monotherapy; BR: bendamustine and rituximab; CCI: Charlson comorbidity index; CLL: chronic lymphocytic leukemia; SD: standard deviation.
| Patients with CAE, n (%) | BR | B-mono |
|---|---|---|
| n = 275 | n = 100 | |
| Duration of the line of therapy (days), mean [median] | 121 [ | 75 [ |
| Blood and lymphatic system disorders | 201 (73.1) | 67 (67.0) |
| Anemia (deficiency and hemolytic) | 73 (26.5) | 35 (35.0) |
| Neutropenia and febrile neutropenia | 112 (40.7) | 37 (37.0) |
| Lymphadenopathy | 62 (22.5) | 18 (18.0) |
| Thrombocytopenia (including autoimmune) | 78 (28.4) | 25 (25.0) |
| Cardiac disorders | 75 (27.3) | 21 (21.0) |
| Arrhythmia (including atrial fibrillation and flutter) | 58 (21.1) | 12 (12.0) |
| Cardiac failure congestive | 35 (12.7) | 11 (11.0) |
| Endocrine disorders, i.e., hypothyroidism | 47 (17.1) | 6 (6.0) |
| Gastrointestinal disorders | 162 (58.9) | 48 (48.0) |
| Nausea/vomiting | 97 (35.3) | 34 (34.0) |
| General disorders | 139 (50.5) | 47 (47.0) |
| Chills/pyrexia (with and without fever) | 50 (18.2) | 21 (21.0) |
| Malaise and fatigue | 78 (28.4) | 25 (25.0) |
| Hepatobiliary disorders | 1 (0.4) | 0 (0.0) |
| Injury, poisoning and procedural complications | 34 (12.4) | 21 (21.0) |
| Allergic reaction + application/administration site reaction | 30 (10.9) | 20 (20.0) |
| Metabolism and nutrition disorders | 114 (41.5) | 28 (28.0) |
| Dehydration | 54 (19.6) | 18 (18.0) |
| Hypokalaemia | 25 (9.1) | 4 (4.0) |
| Musculoskeletal and connective tissue disorders | 69 (25.1) | 17 (17.0) |
| Neoplasms | 97 (35.3) | 24 (24.0) |
| Nervous system disorder | 50 (18.2) | 10 (10.0) |
| Renal and urinary disorders | 71 (25.8) | 15 (15.0) |
| Psychiatric disorders | 35 (12.7) | 12 (12.0) |
| Respiratory, thoracic and mediastinal disorders | 136 (49.5) | 43 (43.0) |
| Cough | 60 (21.8) | 19 (19.0) |
| Dyspnea | 69 (25.1) | 20 (20.0) |
| Skin and subcutaneous tissue disorders | 26 (9.5) | 5 (5.0) |
| Vascular disorders | 156 (56.7) | 39 (39.0) |
| Hypertension | 134 (48.7) | 31 (31.0) |
| Infections | 141 (51.3) | 39 (39.0) |
Abbreviations: B-mono: bendamustine in monotherapy; BR: bendamustine and rituximab; CAE: comorbidity and/or adverse event.
| Healthcare cost PPPM, mean ± SD [median] | BR | B-mono |
|---|---|---|
| n = 275 | n = 100 | |
| Total all-cause healthcare costs | 14,520 ± 5760 [13,755] | 13,125 ± 9439 [10,607] |
| Inpatient | 1922 ± 4789 [ | 3720 ± 7745 [ |
| Emergency department | 96 ± 331 [ | 243 ± 836 [ |
| Other outpatient | 12,501 ± 3741 [12,310] | 9163 ± 4788 [ |
| Total CLL drug costsa | 10,568 ± 3506 [10,447] | 7055 ± 3672 [ |
| Total CAE-related healthcare costsa | 8462 ± 6691 [ | 8783 ± 9641 [ |
| Inpatient | 1922 ± 4789 [ | 3703 ± 7751 [ |
| Emergency department | 91 ± 321 [ | 120 ± 411 [ |
| Other outpatient | 6449 ± 5293 [ | 4961 ± 5288 [ |
Abbreviations: B-mono: bendamustine in monotherapy; BR: bendamustine and rituximab; CAE: comorbidity and/or adverse event; CLL: chronic lymphocytic leukemia; PPPM: per-patient-per-month; SD: standard deviation. aCLL drug cost and CAE-related healthcare cost categories are not mutually exclusive.
To the best of our knowledge, this is the first study to assess all-cause and CAE-related healthcare costs in a sample of R/R CLL patients treated with bendamustine-based regimens. One prior study has assessed healthcare costs in patients with R/R CLL in the US (not specific to BR or B-mono therapy) and estimated mean total healthcare costs of $14,920 PPPM during the first month following R/R CLL, mean costs above $7000 PPPM for the next 3 months, and costs ranging between $4231 and $5992 PPPM over the subsequent months [
In the current study, the median OS was relatively short, with 35 months in the BR cohort and 21 months in the B-mono cohort, suggesting an unmet medical need. Comparisons of these results with existing literature are limited. To the best of our knowledge, this study is the first to assess OS in patients who were treated with bendamustine-based regimens in a real-world setting. In addition, although OS has been reported in clinical trials, results from the current study cannot be directly compared with those from clinical trials given the fundamental differences in study design and patient population. For example, elderly patients with a high comorbidity burden and poor performance status are often underrepresented in clinical trials, although they represent the bulk of the CLL population treated in real-world settings [
The management of patients with R/R CLL can be particularly challenging. Treatments need to consider multiple aspects of a patient’s profile, including the age of the patient, presence of significant comorbidities, and genetic/mutation status. In this population of elderly patients, results suggest that the management of CLL can be complicated by the presence of comorbidities and the risk of developing CAEs, which can limit the treatment options and translate into important medical costs. These results suggest a need for a multidisciplinary approach in the management of CLL.
The current study is subject to limitations inherent in the use of claims databases. First, the claims databases only record diagnostic and procedural codes and do not include information on disease severity which may impact the choice of treatment regimens and outcomes. Second, due to the unavailability of laboratory test results and clinical information in claims databases, an empirical algorithm based on treatment patterns was used to identify patients with R/R CLL. Third, in 2014, novel oral agents were approved by the Food and Drug Administration for the treatment of patients with CLL. However, since the Medicare databases do not include Part D claims (i.e., information on prescription drugs), it was not possible to identify and exclude these patients from the analysis. Additional studies would be needed to assess the healthcare costs in patients with R/R CLL treated with novel oral agents in a real-world setting. Fourth, claims databases do not include information on the cause of concomitant comorbid conditions. Accordingly, this study assessed the association of costs and CAE rather than the causation between the CAE and treatments. Fifth, in some cases, CLL drug costs and CAE-related costs could not be distinguished, as both a procedure for CLL treatment administration and a diagnosis code for one of the selected CAEs could be observed in the same claim. Costs for these specific components should be interpreted in light of this limitation. Finally, healthcare costs reported in this study reflect the medical costs reimbursed by Medicare. Therefore, the generalizability of the findings is limited to a population of elderly adult patients with CLL insured by Medicare, and may not be representative of the costs reimbursed for CLL patients insured by private payers.
In this population of elderly patients with R/R CLL treated with bendamustine-based regimens, CAEs were common and translated into important medical costs. Median OS was also relatively short suggesting an unmet medical need. Management of patients with R/R CLL can be particularly challenging and must consider multiple aspects of a patient’s profile including age, presence of comorbidities, and genetic/mutation profile. These complexities point to a need for a multidisciplinary approach in the management of patients with R/R CLL. However, the treatment outlook of CLL remains dynamic and rapidly developing with combination regimens using targeted novel agents holding considerable promise.
Carolina Reyes is an employee of Genentech Inc. and may own stocks/stock options. Genevieve Gauthier, Sherry Shi, and Annie Guerin are employees of Analysis Group Inc., which has received consultancy fees from Genentech Inc.
Venetoclax is being developed in collaboration between Genentech and AbbVie. Genentech and AbbVie provided financial support for the study. Genentech participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the manuscript. Abbvie participated in the review and approval of the manuscript.
Medical writing assistance was provided by Sara Kaffashian, an employee of Analysis Group Inc.
Reyes, C., Gautheir, G., Shi, S. and Guerin, A. (2018) Overall Survival and Health Care Costs of Medicare Patients with Previously Treated Chronic Lymphocytic Leukemia. Journal of Cancer Therapy, 9, 576-587. https://doi.org/10.4236/jct.2018.97049