Abstract
With increasing focus on novel targeted therapies for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), this longitudinal claims-based study evaluated real-world CLL/SLL treatment sequences, particularly sequential targeted therapy. Among patients with first-line (1 L) treatment in 2014-2017 (N = 2,612; median follow-up = 3 years), the most common 1 L treatment was chemoimmunotherapy (CIT; 44.6%), followed by CD20 (25.2%) and Bruton’s tyrosine kinase inhibitors (BTKi; 21.7%). Among those with 1 L in 2018-2021 (N = 4,534; median follow-up = 1 year), these were BTKi (45.5%), CD20 (20.4%), CIT (17.5%), and B-cell lymphoma 2 inhibitor (8.3%). In 2014-2017, the proportion of patients receiving sequential targeted therapy in the first 2 LOTs was 11.2% (80.2% was BTKi→BTKi); in 2018-2021, this proportion was 34.3% (66.4% was BTKi→BTKi). Over time, there was a substantial increase in targeted therapy use in 1 L and sequential targeted therapy, particularly with BTKi→BTKi. Future studies should assess clinical outcomes to determine optimal sequences for CLL/SLL and reasons for restarting BTKi.
Introduction
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common lymphoid neoplasm characterized by clonal expansion of mature CD5+ B cells in the blood, bone marrow, and lymphoid tissues [Citation1]. In the United States (US), the age-adjusted annual incidence of CLL/SLL is 4.4 per 100,000 persons [Citation2]. CLL/SLL exhibits heterogeneous disease courses [Citation3]. Clinical guidelines recommend active surveillance for patients with early-stage, asymptomatic CLL/SLL, whereas treatment should be initiated in those with active, symptomatic disease [Citation4,Citation5].
The CLL/SLL treatment landscape, previously dominated by chemoimmunotherapy (CIT), has transformed considerably in the past decade since the US Food and Drug Administration (FDA) approval of the first orally administered targeted therapy for CLL/SLL in 2014 [Citation6]. To date, FDA-approved novel targeted therapies for CLL/SLL include the Bruton’s tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib, and zanubrutinib; the B-cell lymphoma 2 inhibitor (BCL2i) venetoclax; and the phosphatidylinositol 3-kinase inhibitors (PI3Ki) idelalisib and duvelisib [Citation6,Citation7]. Targeted therapies may be used alone or in combinations, and with or without anti-CD20 monoclonal antibodies (e.g. rituximab, ofatumumab, or obinutuzumab) [Citation4,Citation6].
With increasing data supporting the effectiveness of novel targeted therapies, particularly BTKi and BCL2i [Citation8–11], clinical guidelines have shifted from primarily recommending CIT toward increasing use of novel targeted therapies in both frontline and subsequent-line settings [Citation4,Citation5]. In addition, the use of sequential novel targeted therapies has been advocated in the literature [Citation12]. However, evidence to guide optimal sequencing of sequential novel targeted therapies remains lacking [Citation12]; guidelines support the sequence of either BTKi followed by BCL2i or BCL2i followed by BTKi [Citation4]. Furthermore, although CIT is no longer the mainstay CLL/SLL treatment, it may still be considered as an initial therapy for a subset of patients who are predicted to respond favorably (i.e. young patients with mutated IgHV who lack any 17p abnormality) [Citation4]. The evolution of CIT use in clinical practice over time since the advent of novel targeted therapies is unclear, with some evidence suggesting that some patients with CLL/SLL still initiate with CIT prior to receiving novel targeted therapies in the relapsed/refractory (R/R) settings [Citation13]. Consequently, varying treatment patterns may exist in the clinical management of CLL/SLL.
Earlier real-world US studies have reported that the most common therapy received by patients with treatment-naive CLL/SLL was CIT and by those with R/R disease was the BTKi ibrutinib (i.e. the first approved targeted therapy for CLL/SLL) [Citation14,Citation15]. Nonetheless, there has been limited research on real-world treatment sequences in CLL/SLL that includes more recently approved novel targeted therapies. Given the increasing focus on novel targeted therapies for CLL/SLL and the scarcity of evidence for modern CLL/SLL treatment patterns, we utilized contemporary claims-based data to study CLL/SLL treatment sequences, with a focus on sequential novel targeted therapy in the US over time.
Methods
Study design and data source
A retrospective longitudinal study was conducted using de-identified administrative claims data from the Optum Clinformatics DataMart database (07/2013–12/2021). The database contains commercial and Medicare Advantage health plan data of approximately 15–19 million enrolled members annually across all US census regions and includes data on patient demographics, dates of eligibility and death, claims for inpatient and outpatient visits with diagnoses and procedures, pharmacy encounters, costs of services, and laboratory tests and results.
The index date was defined as the date of initiation of the first observed line of therapy (LOT; defined in the Lines of therapy section) following the first observed CLL/SLL diagnosis. The baseline period was defined as the 6 months prior to the index date. The observation period spanned from the index date to the earliest of end of eligibility, data availability, or death.
Data are de-identified and comply with the patient requirements of the Health Insurance Portability and Accountability Act of 1996; therefore, no review by an institutional review board was required per Title 45 of CFR, Part 46.101(b)(4).
Sample selection and study cohorts
The patient selection flowchart is presented in . Patients were included in the overall data cohort if they 1) had ≥2 medical claims for CLL or SLL diagnosis based on International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification codes (ICD-9-CM code 204.1 and ICD-10-CM code C91.1 for CLL; ICD-10-CM code C83.0 for SLL) on distinct days; 2) were aged ≥18 years at first CLL/SLL diagnosis; 3) had ≥1 pharmacy or medical claim for CLL/SLL-related anticancer therapy (i.e. BTKi, BCL2i, CD20, chemotherapy, CIT, radiation therapy, chimeric antigen receptor [CAR] T-cell therapy, and hematopoietic stem cell transplantation [HSCT]); and 4) had ≥6 months of continuous enrollment prior to the index date. Patients were excluded if they had ≥1 pharmacy or medical claim for CLL/SLL-related anticancer therapy or ≥1 medical claim for another BTKi- or BCL2i-related malignancy (i.e. acute myeloid leukemia, chronic graft versus host disease, CLL/SLL, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom’s macroglobulinemia) or for metastatic solid tumor up to the 6 months prior to the first CLL/SLL diagnosis.
Figure 1. Patient selection flowchart.
1L: first line; BCL2i: B-cell lymphoma-2 inhibitor; BTKi: Bruton’s tyrosine kinase inhibitor; CLL: chronic lymphocytic leukemia; CPT: Current Procedural Terminology; HCPCS: Healthcare Common Procedure Coding System; ICD-9/10-CM: International Classification of Diseases, 9/10th Revision, Clinical Modification; ICD-9/10-PCS: International Classification of Diseases, 9/10th Revision, Procedure Coding System; NDC: National Drug Code; SLL: small lymphocytic lymphoma.
1Diagnosis of CLL was identified using ICD-9-CM code 204.1 and ICD-10-CM code C91.1; diagnosis of SLL was identified using ICD-10-CM code C83.0. Patients with one CLL diagnosis and one SLL diagnosis on different dates were included.
2CLL- or SLL-related anticancer therapies included BTKi, BCL2i, CD20, chemotherapy, chemoimmunotherapy, radiation therapy, chimeric antigen receptor T-cell therapy, and hematopoietic stem cell transplantation and were identified using NDC, HCPCS, CPT, and ICD-9/10-PCS codes.
3BTKi or BCL2i-related malignancies included acute myeloid leukemia, chronic graft versus host disease, CLL/SLL, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom’s macroglobulinemia and were identified using ICD-9/10-CM codes.
To assess longitudinal patterns, patients with CLL/SLL in the overall data cohort were classified into two temporal data cohorts based on the index date (i.e. the date of first observed LOT): patients with a 1 L in 2014–2017 and patients with a 1 L in 2018–2021.
Lines of therapy
LOTs were identified using a claims-based algorithm adapted from published literature [Citation16–19]. First line (1 L) was defined by all unique anticancer systemic agents received within the first 56 days following initiation of the first observed anticancer therapy, a period that permits to capture the first cycle of BCL2i used in combination with obinutuzumab or rituximab [Citation8,Citation20]. A LOT started with the initiation of a new agent that was not included in 1 L. Each new LOT was defined by the unique agents used within the first 56-day period following the initiation of the new LOT. The end of a LOT was defined as discontinuation (i.e. 90-day gap without any dispensing) of all agents in the LOT, a switch to another agent, or the addition of a new agent. Re-initiation of the same agents after a 90-day gap was considered a new LOT. Radiation therapy was not considered a LOT. If cellular therapy (i.e. HSCT or CAR T-cell therapy) was initiated within 90 days as any other agents, the antineoplastic therapy and the cell transplantation procedure were considered part of the same LOT to ensure conditioning and cell reinfusion are considered as one LOT.
Study outcomes
CLL/SLL treatment sequences across LOTs during the observation period were assessed in the overall and temporal data cohorts. The proportion of patients receiving BTKi and/or BCL2i as sequential targeted therapy in the first 2 LOTs was also described. For sequential BTKi, treatments were additionally described by agent (i.e. ibrutinib, acalabrutinib, zanubrutinib, and combinations thereof). Among patients in the overall cohort who had a new treatment after receiving sequential targeted therapies of two unique classes (i.e. BTKi and BCL2i), the treatment observed in the immediate next LOT was also reported.
Statistical analyses
Patient demographic (e.g. age, sex, race) and clinical characteristics (e.g. time from CLL/SLL diagnosis, baseline Charlson comorbidity index [CCI] and comorbidities) as well as treatments observed in each LOT were summarized descriptively using means (± standard deviations) and medians for continuous variables; and frequencies and proportions for categorical variables.
Sankey plots were used to describe the first three LOTs of CLL/SLL anticancer drug therapies at the class level (i.e. BTKi, BCL2i, CIT, chemotherapy, CD20, others [i.e. combinations of BTKi and BCL2i, or PI3Ki-based therapies]) during the observation period.
All analyses were performed using SAS Studio 3.8 (SAS Institute, Cary, NC).
Results
Sample characteristics
A total of 7,146 eligible patients were included in the overall data cohort. The temporal data cohorts comprised 2,612 patients with a 1 L in 2014–2017 and 4,534 patients with a 1 L in 2018–2021. Across cohorts, patients had a median age of 72–73 years at the time of 1 L initiation, 40.2–40.8% were female, and 74.9–75.5% were of white race. Most patients were covered under Medicare Advantage (72.7–82.2%). At baseline, the mean CCI score was 3.1–3.3 across cohorts, and the most common comorbidities were chronic pulmonary disease, renal disease, and peripheral vascular disease ().
Table 1. Patient demographic and clinical characteristics.
CLL/SLL treatment sequences
The CLL/SLL anticancer therapies observed in the first three LOTs of the overall data cohort are summarized in , and the classes of the therapies are visualized in a Sankey plot (). With a median follow-up time of 2 years after 1 L initiation, the most observed 1 L treatment was BTKi (36.8%), followed by CIT (27.4%), CD20 (22.2%), chemotherapy (7.6%), and BCL2i (5.4%). There were 1,738 patients with observed second-line (2 L) treatment, among which the most common treatment classes were BTKi (39.2%), CD20 (27.4%), and CIT (14.4%); among patients with observed third-line (3 L) treatment (N = 541), CD20 (37.9%), BTKi (27.0%), BCL2i (15.0%) were the most common. Across LOTs, only a small proportion of patients were observed to receive PI3Ki-based therapies (1 L: 0.2%; 2 L: 0.3%; 3 L: 0.7%). The treatment distribution in the fourth and fifth LOTs appeared similar to that in 3 L (data not shown).
Figure 2. Treatment sequences of patients with CLL/SLL – Sankey plot.
A Overall data cohort.
B 1L in 2014–2017.
C 1L in 2018–2021.
BCL2i: B-cell lymphoma-2 inhibitor; BTKi: Bruton’s tyrosine kinase inhibitor; CIT: chemoimmunotherapy; CLL/SLL: chronic lymphocytic leukemia/small lymphocytic lymphoma; L: line of therapy observed; LOT: line of therapy; PI3Ki: phosphatidylinositol 3-kinase inhibitor.
1Other includes combinations of BTKi and BCL2i, or PI3Ki-based therapies.
2LOT not observed were either a discontinuation of the previous LOT, a death, or an ongoing treatment of the previous LOT that has reached the end of the observation period.
Table 2. 1 L To 3 L treatments observed in the overall data cohort.
In the temporal data cohort, among patients with a 1 L in 2014–2017 (median follow-up = 3 years; ), the most common 1 L treatment class was CIT (44.6%), followed by CD20 (25.2%), BTKi (21.7%), chemotherapy (7.6%), and BCL2i (0.3%). For those with a 2 L treatment (N = 905), the most common treatment classes were BTKi (37.6%), CD20 (30.2%), and CIT (17.2%); for those with a 3 L treatment (N = 352), these were CD20 (36.9%), BTKi (25.9%), and BCL2i (13.9%). Among patients with a 1 L in 2018–2021 (median follow-up = 1 year; ), the most common 1 L treatment class was BTKi (45.5%), followed by CD20 (20.4%), CIT (17.5%), BCL2i (8.3%), and chemotherapy (7.6%). For those with a 2 L treatment (N = 833), the most common treatment classes were BTKi (40.9%), CD20 (24.4%), and BCL2i (14.9%); for those with a 3 L treatment (N = 190), these were CD20 (39.5%), BTKi (28.9%), and BCL2i (16.8%).
Sequential targeted therapy by class and by BTKi agent
Among patients in the overall data cohort who were observed to have ≥2 LOTs (N = 1,738; ), 22.3% had sequential targeted therapy in the first 2 LOTs, comprising 70.0% BTKi→BTKi, 23.8% BTKi→BCL2i, 3.6% BCL2i→BCL2i, and 2.6% BCL2i→BTKi. Among patients receiving sequential BTKi (i.e. BTKi restarters), the most common sequences by agent were ibrutinib→ibrutinib (61.6%) and ibrutinib→acalabrutinib (30.9%).
Table 3. Sequential targeted therapy by class and by BTKi agent among patients with ≥2 LOTs.
Stratified by timing of first observed LOT, the proportion of patients receiving sequential targeted therapy tended to be higher when 1 L was initiated in more recent years. Of the 905 patients with a 1 L in 2014–2017, 11.2% received sequential targeted therapy in the first 2 LOTs, among whom 80.2% had BTKi→BTKi; 17.8% had BTKi→BCL2i; 2.0% had BCL2i→BCL2i; and 0% had BCL2i→BTKi. The most common BTKi sequences by agent were ibrutinib→ibrutinib (81.5%) and ibrutinib→acalabrutinib (18.5%). Of the 833 patients with a 1 L in 2018–2021, the proportion of patients receiving sequential targeted therapy in the first 2 LOTs was 34.3%, comprising 66.4% BTKi→BTKi; 25.9% BTKi→BCL2i; 4.2% BCL2i→BCL2i; and 3.5% BCL2i→BTKi. The most common BTKi sequences by agent were ibrutinib→ibrutinib (53.2%) and ibrutinib→acalabrutinib (36.4%).
CLL/SLL treatment following a sequential targeted therapy
For patients who had received sequential targeted therapy of two unique treatment classes (i.e. BTKi and BCL2i) and had an observed new LOT, the new treatment tended to be in the same treatment class as that used in the previous LOT. Among the 13 patients in the overall data cohort who received BTKi in 1 L followed by BCL2i in 2 L, the most common treatment class observed in 3 L was BCL2i (53.8%; Supplementary Table S1).
Discussion
This claims-based longitudinal study found that in 2018–2021 relative to 2014–2017, there was a substantial increase in targeted therapy use and a corresponding decrease in CIT use across LOTs among patients with CLL/SLL in the US. Specifically, as 1 L treatment, BTKi use doubled from 21.7% to 45.5%, BCL2i use increased from 0.3% to 8.3%, whereas CIT use decreased from 44.6% to 17.5%. The use of BTKi and BCL2i in 2 L and 3 L also increased over time, albeit to a lesser extent, whereas PI3Ki-based therapies were minimally used across LOTs in both time periods. In addition, more patients received sequential targeted therapy in recent years, with the restarting of BTKi, particularly ibrutinib, being the most common strategy observed.
The observed shift in 1 L CLL/SLL treatment from CIT to targeted therapies, particularly BTKi, largely aligns with previous findings from US treatment patterns studies [Citation4,Citation14,Citation15]. Earlier studies with data cut prior to 2018 have reported CIT as the most common 1 L treatment received by approximately 40% of patients diagnosed with CLL/SLL (versus 44.6% in current cohort with a 1 L in 2014–2017) [Citation14,Citation15]. A more recent study by Mato and colleagues using data from the prospective CLL registry reported that both CIT and single-agent ibrutinib were equally used by 42% of previously untreated patients in 2016–2019; stratified by year, ibrutinib use in 1 L had gradually increased over time from 35% in 2016 to 64% in 2019 [Citation21]. While these results are consistent with the increasing use of BTKi in 1 L observed in the current study, it should be noted that treatments were categorized differently in the Mato et al. study. Due to the timing of that study, targeted agents such as venetoclax, acalabrutinib, and idelalisib that had just entered the US market at that time were grouped into ‘other novel agents,’ which together constituted less than 1% of 1 L treatment in 2016–2019. Furthermore, R/R patients in that study were not stratified by individual LOT. By comparison, the current study used more contemporary data that enabled the stratification of results by type of targeted therapies and by LOT, thereby providing a more up-to-date and comprehensive picture on the trends for treatment sequences used to manage CLL/SLL in US clinical practice.
The current study observed an increasing trend of sequential targeted therapy use over time, reflecting the changing CLL/SLL treatment landscape. For instance, the proportion of patients with BTKi in 1 L followed by BCL2i in 2 L was observed to be higher in 2018–2021 relative to 2014–2017, coinciding with the approval of the BCL2i venetoclax for 2 L + CLL/SLL in 2018 [Citation22]. Notably, the most common sequential targeted therapy sequence in both time periods assessed was BTKi→BTKi; and within the BTKi class, there appeared to be a high proportion of patients who received sequential ibrutinib. Yet, the second BTKi for CLL/SLL, acalabrutinib, was only approved in 2019 [Citation23]. Therefore, while a sequential BTKi treatment in 2018–2021 may suggest within-class switching (i.e. ibrutinib to acalabrutinib), this explanation may not apply to the period of 2014–2017, where the only approved BTKi for CLL/SLL was ibrutinib. Indeed, the sequential BTKi observed could also be due to the algorithm used to define LOTs in this study, which could misclassify a dose reduction or a treatment holiday (i.e. structured treatment interruption) as a treatment restart. For example, a dose reduction of ibrutinib could delay subsequent prescription fills, and if the delay was ≥90 days, the algorithm could misclassify the dose delay as a treatment discontinuation; in such case, the next ibrutinib fill would be considered a new LOT (i.e. the patient was considered to ‘restart’ ibrutinib). With this caveat, the current data suggest that with an early follow-up of 1–3 years following 1 L initiation, within-class switching and BTKi/ibrutinib dose reductions/treatment interruptions may have occurred more frequently than switching to another class of novel targeted therapy, likely reflecting poor tolerance rather than disease progression as a reason for changing LOT [Citation24]. Nonetheless, reasons for treatment changes are not available in claims data. Future studies with longer follow-ups may help better gauge the trends in novel targeted therapy sequences used and to help further delineate the reasons for the frequent BTKi/ibrutinib restarting observed.
Real-world studies have suggested that BTKi/ibrutinib dose reductions/treatment interruptions are often used in clinical practice to limit adverse events such as diarrhea, bleeding, and atrial fibrillation [Citation25–27]. Some studies have also suggested that clinical outcomes appear worse among patients with CLL/SLL who had dose reductions/treatment interruptions with ibrutinib [Citation28–30]. For example, in a retrospective study using medical records from the Mayo Clinic CLL Database, multivariable analyses showed that a temporary dose interruption of ibrutinib was associated with a significantly shorter event-free survival in patients with CLL compared with those without the interruption (hazard ratio: 2.37; p = 0.006) [Citation28]. Meanwhile, a prior claims-based analysis among patients with CLL/SLL who switched treatment from 1 L ibrutinib to 2 L acalabrutinib found that approximately 40% of patients experienced early discontinuation with acalabrutinib (median duration of the 2 L acalabrutinib treatment was 5.4 months), underscoring potential challenges of within-BTKi class switching in routine CLL/SLL management [Citation31]. Our current observations show a high level of BTKi/ibrutinib restarting, which could potentially be due to within-class switching and BTKi/ibrutinib dose reductions/treatment interruptions, suggesting there are still unmet therapeutic needs in CLL/SLL.
Despite the increase in sequential targeted therapy use in recent years, CD20 remained a common subsequent-line treatment, an observation consistent with a previous US report [Citation13]. Data from the current study also show that rituximab monotherapy accounted for the majority of the CD20 treatment. While the high-level use of CD20/rituximab monotherapy is generally not guideline-concordant [Citation4], it may be an option for R/R CLL/SLL or older patients as they become more frail later in the clinical course and cannot tolerate CIT/chemotherapy [Citation32]. The observation could also be partially due to the use of rituximab as maintenance therapy following initial CIT [Citation33] or as treatment for CLL-related complications (e.g. autoimmune hemolytic anemia) [Citation34]. Meanwhile, the heavy use of CD20 monotherapy may also suggest the potential lack of effective novel targeted therapy options for later LOTs among R/R patients with CLL/SLL [Citation35].
CLL/SLL clinical guidelines and practice have shifted toward increasing use of novel targeted therapies, and with growing treatment options, optimal sequencing of treatments has become an important clinical topic in CLL/SLL [Citation4,Citation12]. Available evidence from small series largely suggests that after progression with BTKi, the use of venetoclax is generally effective, and vice versa [Citation36–38]. As the use of targeted therapies is becoming more common in clinical practice to manage CLL/SLL across LOTs, future large-scale studies using more recent data should assess the real-world clinical outcomes associated with different CLL/SLL treatment sequences, such as those identified in the current study, to help inform optimal sequencing of CLL/SLL treatments. Further, real-world assessment of novel combinations (e.g. BTKi + BCL2i) and reversible BTKi will be important to ensure outcomes for CLL/SLL patients improve once these promising therapies become available [Citation12,Citation24].
The findings of this study should be interpreted in light of its limitations. First, the classification of anticancer agents within each LOT was based on a claims-based algorithm and may not reflect the actual treatment regimens received by patients. For example, the algorithm could misclassify treatments received in 1 L versus 2 L, depending on the timing of the addition of new agents to the treatment regimen. Additionally, a treatment could be misclassified as a 1 L if the patient had received other treatments prior to the 6 months pre-index that were not captured in the data. Second, claims data are subject to errors and omissions in diagnosis, procedure, and drug codes; thus, misclassification of patient and treatment characteristics may have occurred. For instance, molecular information (including TP53 and IgHV status) was not available. Third, patients without a claim for a disease, medication, or procedure were assumed to not have the disease or received the medication or procedure, which may not always be the case. Lastly, the follow-up time following 1 L was short (1–3 years); as such, a high proportion of patients were not observed to have a 2 L treatment. Future studies with longer follow-ups are warranted to provide additional information on treatment sequences over time.
Conclusions
This longitudinal real-world study found a substantial increase in patients with CLL/SLL receiving targeted therapies in 1 L over time. In particular, the proportion of patients receiving BTKi in 1 L doubled in 2018–2021 relative to 2014–2017 and accounted for almost half of the recent 1 L CLL/SLL initiations. A third of patients with 1 L observed in 2018–2021 received a targeted agent in 2 L, relative to about 1 in 10 patients in 2014–2017, with BTKi restarting being the most common strategy observed in this study with relatively short follow-up time. Future studies should assess clinical outcomes to determine optimal sequences for CLL/SLL as well as the reasons for restarting BTKi.
Authors’ contributions
All authors have made substantial contributions to the conception or design of the study, or the acquisition, analysis, or interpretation of data, drafting the manuscript and revising it critically for important intellectual content, and have provided final approval of this version to be published and agree to be accountable for all aspects of the work.
Ethics statement
Data are de-identified and comply with the patient requirements of the Health Insurance Portability and Accountability Act of 1996; therefore, no review by an institutional review board was required per Title 45 of CFR, Part 46.101(b)(4).
Previous presentations
Part of the material in this manuscript was presented at the 65th ASH Annual Meeting & Exposition held December 9-12, 2023, in San Diego, California, as a poster presentation.
Supplemental Material
Download PDF (120 KB)Acknowledgments
Medical writing assistance was provided by Flora Chik, PhD, MWC, an employee of Analysis Group, Inc, and funded by Merck & Co.
Disclosure statement
SFH has received consultancy fees from AbbVie, ADC Therapeutics, Arvinas, AstraZeneca, Bayer Healthcare, BeiGene USA, Inc., Epizyme, Inc., Genentech, Janssen Pharmaceuticals, Lilly USA, LLC, Merck, Novartis, Pharmacyclics LLC (an AbbVie Company), Seagen Inc, Servier Pharmaceuticals LLC, TG Therapeutics, and Tyme Inc. MC, DL, and MSD are employees of, and WYC, ND and LM are former employees of, Analysis Group, Inc., a consulting company that has provided paid consulting services to Merck & Co., Inc., which funded the development and conduct of this study and manuscript. EMS, SL, and MZHF are employees of Merck & Co., Inc. and owns stock/stock options. USA has attended internship programs in Merck & Co., Inc. and AbbVie. EDN is an employee of MSD (UK) Limited, London and owns stock/stock options of Merck & Co., Inc.
Data availability statement
The data that support the findings of this study are available from Optum, but restrictions apply to the availability of these data, which were used pursuant to a data use agreement. Data are available from the authors with the permission of Optum.
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References
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