Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma in the Western Hemisphere, comprising approximately 20% to 35% of newly diagnosed cases.1,2 The prognosis of patients with FL is closely related to the extent of the disease at diagnosis and additional factors such as early progression of disease within 24 months of starting first-line therapy (typically with chemoimmunotherapy); specific gene mutations may also have an impact.3-7 Hence, even though FL has a 5-year relative survival rate of approximately 90%, this rate is drastically reduced to only 50% in patients with early progression of disease.4,8
Current options for first-line therapy for patients with nonlocalized disease who require therapy include bendamustine plus anti-CD20 antibody rituximab or obinutuzumab; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab or obinutuzumab; cyclophosphamide, vincristine, and prednisone (CVP) plus rituximab or obinutuzumab; lenalidomide plus rituximab; and rituximab monotherapy.2,9 These regimens have demonstrated robust responses and comparable survival outcomes in patients with FL.10,11 Despite the efficacy of first-line treatment, most patients with FL eventually relapse.1 In these cases, second-line treatment options may include alternate chemoimmunotherapy regimens or novel therapies such as lenalidomide.2,9,12 In addition, the past few years have seen the approval of several other novel therapies for relapsed or refractory FL, including the phosphatidylinositol 3-kinase (PI3K) inhibitor copanlisib12,13 (idelalisib and duvelisib withdrawn due to inability to conduct confirmatory studies and toxicity concerns); the enhancer of zeste homolog 2 (EZH2) inhibitor tazemetostat12,14; and the CD19-directed chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel12,15 (the PI3K-delta and casein kinase 1 [CK1]-epsilon inhibitor umbralisib was also withdrawn because of toxicity concerns). Additional treatments under investigation for relapsed or refractory FL include the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (eg, phase 3 SELENE study),16-19 the B-cell lymphoma-2 inhibitor venetoclax,20 and bispecific T-cell engagers, among others.21 Despite these advances, the optimal second- or later-line therapies for patients with early progression of disease remain undetermined,1,18 stressing the importance of additional research to identify therapeutic treatments that may improve outcomes for these patients.
The clinical burden associated with FL may also translate into a substantial economic burden. In 2 claims-based studies of commercially insured patients with FL in the United States, total healthcare costs ranged from $10,192 to $10,460 per-patient per-month (PPPM).22,23 However, recent evidence regarding the economic burden of patients with FL with early progression of disease remains limited. Because aggressive lymphomas tend to be associated with higher costs than indolent lymphomas,24 it is likely that early treatment failure would be associated with a larger economic burden given its more aggressive progression rate and need for earlier second-line treatment. Accordingly, the present study aimed to evaluate treatment patterns, healthcare resource utilization, and direct healthcare costs among patients with FL with early treatment failure of first-line chemoimmunotherapy in a US commercially insured population.
Participants and Methods
Merative MarketScan Research Databases (formerly IBM MarketScan Research Databases) between January 1, 2005, and February 29, 2020 (representing the start and end of data availability, respectively), were used. The databases contain actual payer costs (paid amount and coordination of benefits) from both the Commercial Claims and Encounters database and the Medicare Supplemental and Coordination of Benefits database. The Commercial database represents approximately 30 million covered lives consisting of employees and dependents from birth through age 65 years across all US census regions. It includes enrollment history and claims for medical and pharmacy services. The Medicare Supplemental database focuses on patients with Medicare coverage plus employer-paid commercial plans; it includes both employer-paid and Medicare-paid components of healthcare. Data are deidentified and comply with the patient requirements HIPAA (Health Insurance Portability and Accountability Act).
A retrospective longitudinal study design was used to evaluate treatment patterns, healthcare resource utilization, and costs among patients with FL with early treatment failure of first-line chemoimmunotherapy. Early treatment failure was defined as the initiation of second-line therapy within 24 months following initiation of first-line chemoimmunotherapy. The index date was defined as the date of initiation of second-line therapy. Patients were required to have a washout period of ≥24 months of continuous insurance eligibility without any use of antineoplastic agents before the initiation of first-line chemoimmunotherapy. All antineoplastic agents (including guideline- and non–guideline-recommended agents for the treatment of FL) received within 30 days after the initiation of a given line of therapy were included in the therapy regimen. The end of a line of therapy was defined as the day before the initiation of a new antineoplastic agent that was not part of the regimen or at the resumption of the same treatment regimen after a gap in treatment of ≥90 days (retreatment). Because it is possible to have maintenance therapy with rituximab up to every 6 months, a 180-day gap was specifically used for rituximab (instead of a 90-day gap). Therefore, based on the above requirements, patients could initiate second-line therapy on February 1, 2007, or later (given the 24-month washout period prior to first-line initiation and the 30-day period needed to adequately identify the first-line regimen).
Demographic and clinical characteristics were described during the 12-month baseline period prior to initiation of first-line chemoimmunotherapy. Treatment patterns were evaluated until the end of the observation period, defined as the end of continuous insurance eligibility or data availability, whichever occurred first. To account for the potential impact of the approval of novel therapies in later years, treatment patterns were evaluated separately among patients who initiated first-line therapy before 2015 and those who initiated first-line therapy in 2015 or later (a period that followed the US Food and Drug Administration approval of one of the first novel therapies for FL, idelalisib, on July 23, 2014). Healthcare resource utilization and healthcare costs were evaluated over 2 periods: (1) during each line of therapy, defined as the period spanning from line of therapy start to the earliest of initiation of the next line of therapy, or the end of eligibility or lack of available follow-up data (if no additional lines of therapy are observed), and (2) during each Oncology Care Model (OCM) episode for each line of therapy, defined as the period spanning from the date of initiation of the line of therapy up to the earliest of 6 months post-initiation, end of eligibility, or lack of available follow-up data. The OCM model offers a framework to evaluate healthcare costs as it monitors coordinated oncology care and financial performance over a 6-month period (ie, OCM episode) after initiating treatment.25 The latter observation period was also chosen to reflect a time frame where patients in each line of therapy were likely to be continuously treated.
As shown in Figure 1, patients were included if they met the following criteria: (1) ≥2 FL diagnoses at any time between the start and end of their continuous insurance eligibility period, including ≥1 diagnoses pre–first-line therapy initiation; (2) initiation of chemoimmunotherapy in first-line; (3) ≥24 months of continuous eligibility prior to initiation of first-line chemoimmunotherapy (ie, washout period), with no claim for antineoplastic agents during this period; (4) initiation of second-line therapy within 24 months of initiation of first-line chemoimmunotherapy; (5) ≥18 years of age at initiation of first-line therapy; and (6) ≥30 days of continuous eligibility post–second-line therapy initiation (to identify the second-line regimen adequately). Patients were excluded if they met ≥1 of the following criteria: (1) ≥1 diagnoses for solid tumor during the 24-month period prior to first-line chemoimmunotherapy initiation, (2) ≥1 diagnoses for metastatic cancer during the 24-month period prior to first-line chemoimmunotherapy initiation, and (3) ≥2 diagnoses for other blood cancers (ie, lymphoma other than FL or leukemia) during the 24-month period prior to first-line chemoimmunotherapy initiation but ≥6 months before the first FL diagnosis.
Patient demographics and clinical characteristics were evaluated during the 12-month period prior to first-line initiation. Treatment patterns were evaluated until the end of the observation period and included the number and proportion of patients using each of the following regimens: chemoimmunotherapy regimens, anti-CD20 immunotherapy-only regimens, chemotherapy-only regimens, allogeneic hematopoietic stem-cell transplant, and novel therapy regimens.2,9 In addition, the duration of each line of therapy was evaluated, defined as the time between the start of therapy and initiation of the next line of therapy or the end of continuous eligibility or data availability, whichever occurs first (if there are no additional lines of therapy).
All-cause, cancer-related, and FL-related healthcare resource utilization and direct healthcare costs (payers’ perspective) were reported during each line of therapy and each OCM episode. Healthcare resource utilization included outpatient, inpatient, emergency department, and other services (ie, durable medical equipment and dental and vision care). Healthcare costs included total costs (sum of medical and pharmacy costs), medical costs (sum of outpatient, inpatient, emergency department, and other costs), and pharmacy costs. Cancer-related healthcare resource utilization and medical costs were defined as claims with a diagnosis for any cancer, whereas cancer-related pharmacy costs were defined as claims for any antineoplastic agents used for the treatment of cancer and corticosteroids commonly used with antineoplastic agents (ie, prednisone, dexamethasone, and methylprednisolone). FL-related healthcare resource utilization and medical costs were defined as claims with a diagnosis for FL, diffuse large B-cell lymphoma, or unspecified lymphoma. FL-related pharmacy costs were defined as claims for antineoplastic agents used for the treatment of FL.
Baseline characteristics and study outcomes were described using means, standard deviations (SDs), and medians for continuous variables and frequencies and proportions for categorical variables. To account for different lengths of observation periods among study patients, healthcare resource utilization and healthcare costs were reported PPPM. Healthcare costs were assessed from the payers’ perspective and adjusted for inflation (to 2020 US dollars) using the medical care component of the Consumer Price Index.
Baseline Demographics and Clinical Characteristics
Among 5203 patients with FL who received first-line chemoimmunotherapy, 966 (18.6%) patients did not respond to therapy within 24 months of initiation (ie, early treatment failure; Figure 1). After applying all study inclusion and exclusion criteria, 644 patients were included in the study. Baseline demographics and clinical characteristics of the study participants are presented in Table 1. At first-line chemoimmunotherapy initiation, the median age of patients was 60.0 years and 42.2% were female; during the 12-month baseline period, the mean Quan-Charlson Comorbidity Index score was 3.0. Most patients (69.4%) came from the South and North Central (ie, Midwest) regions. Approximately two-thirds of patients were covered by a commercial plan, whereas one-third of patients were covered by a Medicare Supplemental plan. The mean (median) time from FL diagnosis to first-line chemoimmunotherapy initiation was 7.5 (1.1) months. Patients’ mean (SD) monthly all-cause total healthcare costs were $2777 ($3378) during the 12-month period before the initiation of first-line therapy.
The mean (median) duration from the initiation of first-line chemoimmunotherapy therapy until the end of the observation period was 40.1 (30.9) months, whereas the mean (median) time to failure of first-line chemoimmunotherapy was 9.5 (8.8) months (mean [median] duration of active chemoimmunotherapy treatment was 5.1 [4.4] months). Among the current study population (N = 644), 245 (38.0%) received third-line therapy, and 100 (15.5%) received fourth-line or later therapy. Following first-line chemoimmunotherapy, the mean (median) line of therapy duration was 21.8 (12) months for second-line therapy, 14.5 (7.4) months for third-line therapy, and 11.5 (6.9) months for fourth-line or later therapy. The mean (median) duration of active treatment was 6.9 (3.7) months for second-line therapy, 4.5 (2.2) months for third-line therapy, and 4.8 (2.7) months for fourth-line or later therapy.
Figure 2 presents a breakdown of lines of therapies used based on year of initiation of first-line treatment. Among patients who received first-line chemoimmunotherapy before 2015 (n = 497), the most common first-line regimens were R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; 35.4%), bendamustine plus rituximab (23.7%), and R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone; 22.7%). For patients who initiated first-line chemoimmunotherapy in 2015 or later (n = 147), bendamustine plus rituximab use was more prevalent (44.9%), followed by R-CHOP (33.3%) and R-CVP (4.8%). Over time, chemoimmunotherapy use in second-line remained stable at approximately 50%; R-CHOP was the most common second-line chemoimmunotherapy regimen (14.1%), followed by bendamustine plus rituximab (7.3%) and R-CVP (2.8%). Novel therapy-based regimens (eg, lenalidomide) were increasingly used in later lines, and this trend was more pronounced for patients who initiated first-line chemoimmunotherapy in 2015 or later (second-line, 10.9%; third-line, 24.1%; fourth-line or later, 46.7%) relative to those who initiated first-line chemoimmunotherapy before 2015 (second-line, 5.6%; third-line, 11.0%; fourth-line or later, 37.6%).
Healthcare Resource Utilization
All-cause monthly healthcare resource utilization increased with each subsequent line of therapy and each OCM episode (Table 2). The proportion of patients with an inpatient admission increased from 36.5% in first-line to 45.0% in second-line, 49.0% in third-line, and 63.0% in fourth-line or later. Most notably, there was an increase in the mean number of inpatient admissions PPPM (from 0.12 to 0.29 between first-line and fourth-line or later; from 0.10 to 0.31 between first-line and fourth-line or later OCM episode) and mean days of inpatient stay (from 0.64 to 1.93 between first-line and fourth-line or later; from 0.72 to 2.20 between first-line and fourth-line or later OCM episode). For cancer-related and FL-related monthly healthcare resource utilization, a similar pattern of increased healthcare resource utilization was observed with each subsequent line of therapy and each OCM episode.
Total all-cause costs PPPM were $17,218 in first-line and $16,806 in second-line; these costs increased to $22,879 in third-line and $28,420 in fourth-line or later (Figure 3A and 3B). This was primarily driven by FL-related costs, which were $12,972 in first-line and $12,658 in second-line, and then increased to $14,352 in third-line and $20,204 in fourth-line or later. Other cancer-related costs (ie, other than FL) also increased from $1675 in first-line to $1772 in second-line, $5324 in third-line, and $5703 in fourth-line or later. Similarly, total all-cause healthcare costs PPPM increased with each subsequent OCM episode from $20,196 in first-line OCM to $20,611 in second-line OCM, $29,273 in third-line OCM, and $31,092 in fourth-line or later OCM. This was also driven by an increase in FL-related costs from $15,230 in first-line OCM to $22,507 in fourth-line or later OCM and an increase in other cancer-related costs from $2049 in first-line OCM to $5674 in fourth-line or later OCM.
When stratifying healthcare costs by place of service (Figure 3C and 3D), the increase in all-cause total costs PPPM was driven by an increase in inpatient costs PPPM from $2986 in first-line to $5707 in second-line, $8530 in third-line, and $11,658 in fourth-line or later. The increase in total costs between first-line and fourth-line or later OCM episodes was also driven by an increase in inpatient costs PPPM from $3175 to $12,962.
The present study found that 18.6% of patients did not respond to first-line chemoimmunotherapy for FL within 24 months of treatment initiation. This is consistent with previous studies reporting that approximately 20% of patients initiating first-line chemoimmunotherapy progress within 24 months.8,26-28 Of note, depending on the definition, the time to progression may be calculated from the date of diagnosis, treatment initiation, or treatment completion.8,26-28 Among patients who did not respond to first-line chemoimmunotherapy in the present study, approximately 50% were started on another chemoimmunotherapy regimen in second-line. Although this finding highlights a lack of treatment options (especially in earlier years, which may not reflect the current standard of care), an increasing proportion of patients in more recent years received novel therapy regimens (eg, lenalidomide plus rituximab, recently approved in second-line for FL) in later lines of therapy. Mean total all-cause healthcare costs increased in later lines of therapy for both the observed duration of the line of therapy and during the first 6 months of the line of therapy.
Although studies of contemporary treatment patterns are scarce in the literature, previous evidence regarding treatment patterns observed up to 2015 is generally consistent with the present findings. In observational studies assessing second- or later-line treatment patterns during study periods spanning from 2005 to 2015, rituximab-based regimens were the most common regimens across all lines of therapy, whereas the use of novel/investigational therapies only increased slightly in later lines.22,23,29-31 In a 2007 to 2015 electronic health records (EHRs) study of patients with FL with early progression by Morrison and colleagues,32 at least half of all patients in the second- or later-line settings received chemoimmunotherapy. Unlike the present study, chemoimmunotherapy regimens remained predominant in third-line. An analysis of data from 2004 to 2007 by Link and colleagues30 corroborated the findings obtained by Morrison and colleagues32 by showing that >60% of patients with FL who were refractory to rituximab in first-line went on to also receive a rituximab-based regimen in second-line. Overall, the treatment patterns observed in these previous studies reflect an earlier time frame when rituximab-based regimens were predominant. In contrast, the present study highlights the growing adoption of regimens consisting of novel targeted therapies and alternate CD20 monoclonal antibodies among patients with FL with early progression of disease.
There is a dearth of studies to date focusing on healthcare costs and utilization among patients with FL with early progression after first-line therapy. One 2011 study of EHRs33 found that costs within US community-based oncology practices during a 6-month follow-up period were $3527 PPPM for patients whose disease progressed versus $860 PPPM for patients whose disease did not progress. Of note, costs in that study (particularly in the inpatient setting) may have been underestimated due to the possibility of patients receiving care outside of the oncology network. By capturing costs of care across different places of service over a longer follow-up, the current study highlights the substantial contribution of inpatient costs to the overall economic burden of patients with FL with early treatment failure.
The findings in the present study corroborate previous evidence of a substantial economic burden among patients with FL. In one retrospective study by Morrison and colleagues22 using claims data from 2008 to 2015, patients with FL incurred total all-cause healthcare costs over a 2-year follow-up of $10,460 PPPM. Consistent with the present study, the majority of the overall costs in this study were composed of medical costs that were primarily FL-related ($6482 PPPM). A study by Fowler and colleagues29 using MarketScan data between 2010 and 2013 observed high total all-cause costs of patients with FL that increased from second-line to fourth-line or later (from $10,466 PPPM in second-line to >$29,000 PPPM in fourth-line or later), aligned with results from the present study. An analysis of SEER (Surveillance, Epidemiology, and End Results)-Medicare data (2000-2014) found that FL became more expensive in the second and third years post-diagnosis, potentially due to relapse/progression, the aggressive nature of grade III FL, and the noncurable nature of FL with current treatment options.34
Historically, patients with relapsed or refractory FL have had limited treatment options and poor survival outcomes versus patients without disease progression.8,32 In recent years, the treatment landscape for relapsed or refractory FL has rapidly evolved, as evidenced by the increased use of novel targeted therapies and bendamustine plus rituximab in the current study. In particular, the increasing use of lenalidomide in 2015 and later (most commonly in combination with rituximab) suggests a shift toward the growing adoption of novel therapies. In the coming years, treatment patterns will likely continue to evolve due to the recent approval of other novel therapies, including a PI3K inhibitor,13 an EZH2 inhibitor,14 and CD19 CAR T-cell therapy.12,15 Additional novel therapies that continue to be investigated include the BTK inhibitor ibrutinib, the B-cell lymphoma-2 inhibitor venetoclax, and bispecific T-cell engagers.21 Ibrutinib,19 which has been previously approved for the treatment of other B-cell malignancies, is currently being investigated in phase 3 studies for patients with relapsed or refractory FL (eg, phase 3 SELENE study17) and treatment-naïve patients (ie, phase 3 PERSPECTIVE study35). Nevertheless, the costs of care remain high among patients with FL with early progression, particularly when hospitalization is required. With a rapidly growing number of novel targeted therapies available to patients after failure of first-line chemoimmunotherapy, treatment costs will likely increase, given higher drug costs, but also because of increased efficacy, which will delay disease progression and thus increase time on therapy, particularly for treatments for which the recommendation is to treat patients until disease progression instead of a fixed treatment duration (eg, 6 cycles of chemoimmunotherapy). Focus on costs will remain critical to ensure that higher treatment costs are offset by lower medical costs (such as hospitalization costs) associated with improved clinical outcomes.
The present study was subject to certain limitations. In particular, patients may have used antineoplastic agents for cancers other than FL. This risk was minimized by the exclusion of patients with solid tumors or other blood cancers, the inclusion of a 24-month washout period without any antineoplastic agents prior to first-line therapy initiation, and the requirement of having ≥1 diagnoses for FL prior to first-line therapy initiation. However, despite the use of a 24-month washout period, some patients in remission for an extended period may have been included in the study sample; therefore, the line of therapy number may not have been appropriately identified (eg, a second-line therapy could mistakenly have been identified as a first-line therapy). This may have had an impact on costs in the current study, because patients with long remission may represent milder FL cases with potentially lower costs. Another limitation was the lack of availability of certain information in claims data, such as the reason a patient would stop treatment or re-start the same treatment; similarly, it was not possible to determine if a medication was used for maintenance at a particular point in time. In addition, costs may be underestimated if patients use other means for obtaining their treatment (eg, drug samples), which may not be captured in claims data. A limitation of the OCM analysis was the assumption that every practice observed in the MarketScan database uses the OCM, even though there are only 126 practices currently participating in the OCM, according to the Centers for Medicare & Medicaid Services.25,36 Given the descriptive nature of this study, no statistical adjustments were made. Lastly, results may not be generalizable to all patients with FL, because only commercially insured patients and Medicare Supplemental beneficiaries were analyzed.
In this US-based retrospective study, 18% of patients with FL did not respond to first-line chemoimmunotherapy within 24 months of initiation. Approximately 50% of these patients went on to receive another chemoimmunotherapy regimen in second-line, highlighting that this remains an area of unmet need and reflects the continued need for alternative treatment options in this population. Although available treatments for patients with relapsed or refractory FL have historically been limited, the present study also observed a growing adoption of novel targeted therapies and bendamustine-based chemoimmunotherapy in recent years. Despite this progress, the costs of care among patients not responding to first-line chemoimmunotherapy were substantial, especially when hospitalization was required. With a rapidly growing number of available novel targeted therapies and likely higher costs associated with these treatments, focus on costs remains critical to ensure that higher treatment costs are offset by lower medical costs associated with improved clinical outcomes.
Medical writing assistance was provided by Mona Lisa Chanda, PhD, an employee of Analysis Group, Inc, a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC.
Funding for this article was provided by Janssen Scientific Affairs, LLC, which was involved in the study design, interpretation of results, and manuscript preparation.
Author Disclosure Statement
Dr Leslie is on the Speaker’s Bureau of BeiGene, Celgene/BMS, Epizyme, and Karyopharm; on the Speaker’s Bureau of, has provided consulting to, and has participated in Advisory Boards of AstraZeneca, Janssen, Kite/Gilead, Pharmacyclics, Seattle Genetics, and TG Therapeutics; and has participated in the Advisory Board of and provided consulting to AbbVie, ADC Therapeutics, and Bayer. Mr Emond, Ms Lafeuille, Ms Vermette-Laforme, and Mr Lefebvre are employees of Analysis Group, Inc, a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, which funded the development and conduct of this study and manuscript. Dr Huang is an employee of and owns stocks of Johnson & Johnson.
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