Chronic myelogenous leukemia (CML) is a hematologic malignancy occurring primarily in adults, with a median age of 65 years at diagnosis.1 The overall age-adjusted incidence rate of CML was approximately 2.04 per 100,000 individuals in 2016, and it is estimated that 8990 new cases of CML will be diagnosed in 2019 in the United States.1 CML is caused by a translocation of the breakpoint cluster region (BCR) gene on chromosome 22 and the Abelson (ABL) oncogene on chromosome 9, creating a shortened chromosome 22 known as the Philadelphia chromosome (Ph).2 This forms the BCR-ABL fusion gene that produces a tyrosine kinase protein (BCR-ABL oncoprotein), which causes abnormal proliferation of myeloid cells.3
The US Food and Drug Administration (FDA) approval of imatinib, the first-generation tyrosine kinase inhibitor (TKI) targeting the BCR-ABL fusion gene, dramatically changed the treatment landscape for CML and significantly improved survival outcomes for patients with this disease. Patient care has further advanced with the FDA approval of second-generation TKIs, which, along with imatinib, have prolonged survival in patients with chronic-phase CML to approach that of age-matched controls.4
Currently, 4 TKIs are FDA approved for front-line therapy of chronic-phase CML, including imatinib, dasatinib, nilotinib, and bosutinib.4-8 Ponatinib is indicated for patients with refractory disease and for a small subset of patients with T151-positive CML.9 Although imatinib is the most prescribed agent in the front-line setting, several factors must be considered when selecting the proper TKI therapy for patients with CML, including disease risk level, CML mutation type, individual TKI toxicity profile and the potential interaction with the patient’s comorbidities, speed to cytogenetic response targets, and ease of administration.10
The current National Comprehensive Cancer Network (NCCN) CML guidelines recommend that the choice of a TKI for first-line therapy be based on the patient’s disease risk level in concert with these additional factors, with all approved agents as Category 1 recommendations (indicating the highest level of evidence) for patients with low-risk disease and second-generation TKIs (ie, dasatinib, nilotinib, and bosutinib) retaining Category 1 recommendation status for intermediate- and high-risk disease.3 Notably, in the absence of treatment initiation within the chronic phase, the natural course of CML follows a triphasic progression from the indolent chronic phase to an accelerated phase, in which the disease takes on aggressive features, such as cytogenetic abnormalities, and ultimately on to a terminal blast crisis, in which blast cells proliferate uncontrollably.4 Patients in the terminal blast crisis phase of CML may require advanced high-cost care, including stem-cell transplant for eligible patients.4
Since the loss of patent exclusivity and the entry of a generic version of imatinib in the United States in February 2016, US payers have started realizing cost-savings; however, generic prices have taken 2 years to decline substantially. A previous study estimated the projected impact of the entry of generic imatinib in the first 2 years from the perspective of a US payer based on projected prices using an Excel-based model.11 This model, which used market share and pricing projections before imatinib’s loss of exclusivity, estimated that the 2-year cost-savings would be $6.8 million (28.8%) in a commercial plan and $22.9 million (28.8%) in a Medicare plan. The adoption of step-therapy formulary management was expected to lower incremental TKI spending nominally, by 1.1% and 2.2% for the commercial and Medicare plans, respectively.
In the 2 years since imatinib’s loss of patent exclusivity, real-world market share and pricing information have become available, and modeling assumptions should be updated to reflect this reality. In the present analysis, we updated the model to evaluate the realized and projected impact of generic imatinib and the impact of step-edit formulary management on cost-savings over a 5-year period from imatinib’s loss of exclusivity.
Furthermore, we examined and quantified, from a US health plan perspective, the cost-savings from the substitution of brand-name imatinib with generic imatinib relative to the potential savings from requiring step therapy through generic imatinib before a second-generation TKI. We assessed these savings for a hypothetical 1-million-member commercial plan and a 1-million-member Medicare plan and at a US national level for all commercially and Medicare-insured patients.
We updated the previously published model exploring the impact of brand-name imatinib’s loss of patent exclusivity and the formulary management of TKIs to reflect the current real-world use and pricing of TKIs.11 The Excel-based model represented the pharmacy budget of hypothetical 1-million-member commercial or Medicare plans for the TKIs that are indicated for the treatment of CML (ie, imatinib, dasatinib, and nilotinib).
The cost-savings were calculated over a 5-year period as the realized savings accrued by payers since imatinib’s loss of patent exclusivity to the most recent data available at that time (February 2016-September 2018) and the projected future savings (2018-2021). Using the same methods, we repeated the analyses for the entire commercially and Medicare-covered population in the United States to estimate the overall pharmacy cost-savings for TKIs at a national level.
We fitted logarithmic regression models to historical market share data to project the use of brand-name TKIs and generic imatinib up to 5 years after imatinib’s loss of patent exclusivity (Figure 1).10 Similar to the original model, TKIs with < 5% market share were not considered, which included ponatinib and bosutinib. Market share was calculated based on observed trends and did not include the potential changes among second-generation TKIs that might have occurred in the absence of generic imatinib’s entry into the market after the loss of exclusivity of brand-name imatinib.
We used historical wholesale acquisition cost pricing for the period between January 2016 and September 2018.12 The daily drug costs in September 2018 for brand-name imatinib, generic imatinib, dasatinib, and nilotinib were $337, $12, $430, and $455, respectively.12 The daily drug costs assume standard first-line CML starting doses per the respective drug’s prescribing information.5-7 Future drug prices were assumed to remain constant from September 2018 to the end of the model’s time horizon (ie, February 2021); the lowest price among generic imatinib manufacturers for the 400-mg dose was used.
The default patient copay values were based on the average patient out-of-pocket costs for dispensed claims for commercial and Medicare members. The default copayments were assumed to be $25 per generic imatinib prescription, $110 per brand-name imatinib prescription, $80 per brand-name dasatinib prescription, and $78 per brand-name nilotinib prescription.13 The maximum patient out-of-pocket costs were limited to $7350 annually for an individual commercial plan member and to $5100 annually for a Medicare plan member.14,15 The model assumed that payers pay the list wholesale acquisition cost for all brand-name TKIs, including brand-name imatinib. All pricing data included in the model were based on published sources using proprietary sources.12
Commercial and Medicare plan analyses assumed a hypothetical 1-million-member population each. The population of the US national level analyses included 216,203,000 commercial insurance enrollees and 53,372,000 Medicare enrollees (US census data).16 We analyzed the prevalence based on claims data in the Truven MarketScan database and estimated the size of the patient population who received a TKI by applying these age-stratified (18-64 years; ≥65 years) prevalence rates to the hypothetical plan. Data on the incidence and prevalence of CML were taken from the Surveillance, Epidemiology, and End Results Cancer Statistics Review, and all incident cases of CML were assumed to be managed with a TKI.1
In our hypothetical commercial and Medicare 1-million-member plans, the numbers of patients with CML receiving treatment with TKIs were estimated to be 96 and 289, respectively, with 11 (11.6%) patients in the commercial plan and 74 (25.5%) patients in the Medicare plan estimated to have newly diagnosed CML.
We assumed the prevalence of CML to be constant over time, and the standard TKI dose and frequency were based on the prescribing information for the treatment of newly diagnosed patients with Ph-positive chronic-phase CML. Patients were assumed to continue using therapy and to be fully adherent to the therapy during the entire year. The prevalence of TKI treatment that is indicated for use in patients with CML was consistent with the previously published model (Table).10
Formulary Management: Step-Edit Therapy
We assumed that policies requiring step-edit therapy would only affect patients who are treatment-naïve and that health plans would not switch successfully managed patients from a second-generation TKI to generic imatinib. The potential impact of implementing formulary restrictions in the TKI class in the next 3 years was explored by applying a step-edit therapy to require a trial of generic imatinib before the use of second-generation TKIs for patients with incident CML.
The administrative cost for the health plans was set at $20 for prior authorization.17 The time required for completing prior authorizations and the cost burden imposed on prescriber practices and patients to get access to necessary therapies were not included in the analysis. The proportion of prior authorizations approved was set at 60% for commercial plans and 84% for Medicare plans based on the weighted average of dasatinib and nilotinib prior authorization approvals in commercial and Medicare health plans claims analyses from October 2017 to March 2018.18
Commercial Plan of 1 Million Members
In our new analysis, a commercial plan with 1 million members was estimated to save $0.5 million (3%) of the TKI pharmacy budget for CML in the first year and $3.9 million (19%) in the second year after imatinib’s loss of patent exclusivity (Figure 2).
The projected savings from generic imatinib entry alone (ie, without step-edit formulary management) increased significantly to $7.8 million (37%), $8.3 million (39%), and $8.6 million (40%) in the third, fourth, and fifth years, respectively, after the loss of patent exclusivity (Figure 2), and continued to result in significantly greater projected savings than the initiation of step-edit therapy during that same time period (Figure 3). Initiating a step-edit therapy for treatment-naïve patients with CML in the commercial plan was associated with limited projected incremental savings of $0.3 million (1.5%) annually over the next 3 years (years 3, 4, and 5).
Medicare Plan of 1 Million Members
We estimated that a Medicare plan with 1 million members saved $1.7 million (2.5%) of the TKI pharmacy budget for CML in the first year and $14.1 million (19%) in the second year after imatinib’s loss of patent exclusivity (Figure 2). The projected cost-savings from generic imatinib entry alone (without step-edit formulary management) significantly increased to $27.8 million (37%), $29.5 million (39%), and $30.8 million (40%) in the third, fourth, and fifth years, respectively, after the loss of exclusivity (Figure 2).
Initiating a step-edit therapy for newly diagnosed patients with CML in the Medicare plan was again associated with projected small incremental savings of $0.9 million (1.2%) annually over the next 3 years (years 3, 4, and 5).
Overall Spending and Savings
We calculated that in the first 2 years of generic imatinib’s entry, US payers saved $2.5 billion—12.6% of the total spending on this drug class. In the next 3 years, the estimated savings with generic imatinib entry and without formulary management strategies are expected to grow to 38.5%, resulting in additional savings of $3.8 billion, $4.1 billion, and $4.2 billion in years 3, 4, and 5, respectively, for a cumulative savings of $12.2 billion (rounded numbers).
Furthermore, over the 5-year period, the estimated savings are expected to total $15 billion in the absence of step-edit formulary management. In fact, nearly all potential savings for this drug class over the next 3 years (years 3, 4, and 5 from imatinib’s loss of exclusivity) come from generic imatinib’s market entry alone, with limited additional savings from step-therapy formulary management estimated to be 1.7% (or $176 million) annually.
In 2015, a hypothetical model that estimated the economic impact of the availability of generic imatinib for payers in the United States forecasted that the loss of patent exclusivity would result in >$6 million in savings for a 1-million-member commercial plan during a 2-year period, or 28.8% of the total pharmacy spending on TKIs for the treatment of CML.10 The forecasted savings were even greater in the 1-million-member Medicare plan ($22.9 million, or 28.8%) as a result of higher TKI utilization rates.10 This current update to the original model, using real-world market share and pricing data, reveals that the savings for commercial and Medicare plans were slower to accumulate within the first 2 years after loss of patent exclusivity than was originally forecasted (a total of $4.4 million and $15.8 million, respectively).
The reduction in plan savings during the first 2 years is attributed to higher-than-anticipated pricing for generic imatinib, but its price has steadily decreased and continues to decline. Furthermore, continued price reductions for generic imatinib resulting from competition from additional market entrants have progressed to a 96% price discount from the brand-name drug at the time of this current analysis. This large discount is expected to result in substantial cost-savings to US payers that are expected to materialize over the next 3 years, independent of step-edit formulary management strategies.
Based on the current projections for a 1-million-member commercial plan, savings from generic imatinib’s entry (and without step-edit formulary management) are estimated to significantly increase to $7.8 million (37%), $8.3 million (39%), and $8.6 million (40%) in the third, fourth, and fifth years, respectively, after the loss of patent exclusivity. For a 1-million-member Medicare plan, the projected savings from generic imatinib’s entry (and without step-edit formulary management) are now estimated to significantly increase to $27.8 million (37%), $29.5 million (39%), and $30.8 million (40%), respectively, in the third, fourth, and fifth years after the loss of patent exclusivity. Similar to the initial analysis by Bloudek and colleagues,11 the projected incremental savings through the use of step-therapy formulary management restrictions is associated with a limited incremental savings of $0.3 million (1.2%) for commercial and $0.9 million (1.5%) for Medicare plans annually over the next 3 years (years 3, 4, and 5).
Of note, the limited savings projected from step-therapy formulary management included a conservative $20 administrative cost per prior authorization for health plans. The actual savings may be less when considering that the time and resource burdens for prescriber practices and patients are also substantial. To complete prior authorizations for necessary therapies, it is estimated that prescriber practices average almost 20 hours weekly between physician, nursing, and clerical hours.19 This prior authorization administrative burden equates to $2161 to $3430 annually per physician in a primary care setting.20
Compared with step-therapy formulary management, there may be greater opportunities to manage the treatment costs for CML and to make patient outcomes better through initiatives that aim to improve patient adherence; meet guideline recommendations for molecular monitoring; identify at-risk populations, pediatric patients, and elderly patients who are not eligible for stem-cell transplant; and ultimately, to support optimal treatment selection.
In fact, overly restrictive formularies may be associated with unintended prescribing patterns that do not align with NCCN recommendations, which note that based on individual TKI toxicity profiles, second-generation TKIs dasatinib or bosutinib may be preferred for patients with heart disease, arrhythmias, pancreatitis, and/or hyperglycemia, whereas nilotinib or bosutinib may be preferred for patients with a history of lung disease or those who are at risk for pleural effusion.3,21 Notably, in a recent, large retrospective analysis of 1120 patients with CML utilizing 2 US claims databases, up to 57% of patients had comorbidities relevant to the selection of TKI for the treatment of CML.21
Furthermore, regular molecular monitoring for disease response to treatment (or lack thereof) has been associated with reduced disease progression, presumably by assisting in the timely detection of primary or secondary resistance to first-line TKI therapy in patients with chronic-phase CML.22 The NCCN guidelines recommend that molecular testing (ie, a quantitative reverse transcription polymerase chain reaction) be performed every 3 months in patients who start TKI therapy to evaluate potential resistance to their current TKI therapy, and, if confirmed, a switch in TKI therapy can be initiated to prevent disease progression to an accelerated phase of CML or to blast crisis.3
However, a retrospective review of more than 1200 patients with CML across 2 insurance databases showed that less than 30% of patients had molecular monitoring at least 3 times during the first year after diagnosis.23 Furthermore, in an insurance database review, patients with CML who did not have the recommended monitoring had poor outcomes, increased hospitalizations, and greater total treatment costs than patients who received recommended monitoring.23,24
In addition, in an economic model, the total healthcare costs (including those associated with detected progression and molecular monitoring at 3 tests annually) were $1142 per patient per year (PPPY) for patients with monitoring and $6982 for patients without monitoring.21 This equates to a total cost-savings of $584,005 with full adherence to monitoring versus no monitoring in a 100-patient hypothetical cohort.21 In addition, the ability to detect resistance to a TKI early, before disease progression, facilitates switching to second-line therapy within the chronic phase and potentially avoids the costly sequelae and the poor patient outcomes that occur with more advanced CML disease.
As previously noted, without effective treatment in the chronic phase of CML, the disease will progress to the more aggressive accelerated phase and finally to blast crisis. Poor adherence to TKI therapy in the chronic phase has been noted as one of the main drivers for loss of response to treatment and subsequent progression to the more costly and potentially fatal accelerated phase and blast crisis in CML.25-27
The progression of CML from the chronic phase is associated with a significant cost increase. In a claims analysis of 587 patients with CML that included Medicare beneficiaries, the annual per-patient total healthcare cost was more than 6 times higher in patients with disease progression from chronic-phase CML than in patients without disease progression ($320,635 PPPY vs $49,710 PPPY; P < .001) after adjusting for patient age, sex, geographic region, health plan type, comorbidities, and follow-up duration.22
Our updated model was developed for illustrative purposes to explore the impact of generic imatinib and step-edit formulary management on pharmacy spending for the most frequently used TKIs for the treatment of CML in patients with commercial or Medicare plans. The limitations of this study are inherent in any economic modeling analysis in that a variety of assumptions regarding the model population, treatment patterns, and costs (as previously noted) were involved. Furthermore, only TKI treatments for CML with ≥5% market share were included in this model, and market share projections using a logarithmic regression model may differ from the actual future market shares.
It took 2 years for the price of generic imatinib to decline substantially; the lower generic drug prices in year 3 may have a relatively larger impact on the market share than anticipated. However, our model aligned well with the observed trends, and because the realized cost-savings from generic imatinib entry have already materialized, our model projects a stabilizing shift in market share in the future.
All drug pricing data included in the model were based on published sources and did not represent actual pricing to any party; the model did not consider potential price increases among brand-name drugs that might have happened in the absence of generic imatinib entry into the market. Patients were assumed to continue therapy and to be fully adherent to the prescribed therapy during the entire year; actual adherence rates of less than 100% would result in pharmacy savings for the plan.
Finally, guidelines do not imply comparable efficacy, safety, or interchangeability among the TKIs. Comparisons of costs under different scenarios are beyond the scope of this study.
In the United States, payers have realized considerable savings in the first 2 years since brand-name imatinib’s loss of patent exclusivity. Because the price of generic imatinib has steadily declined, it is estimated that the cost-savings to US payers will increase substantially over the next 3 years, independent of formulary management consisting of step-edit therapy with the use of generic imatinib.
Formulary management restricting access to second-generation TKIs may result in minimal additional savings. Initiatives that aim to improve patient adherence, meet guideline recommendations for molecular monitoring, and support optimal treatment selection would afford all stakeholders the opportunity to manage the costs of patient care by also improving patient outcomes.
The authors thank Scott Keating, MS, of Bristol-Myers Squibb, for assisting in the preparation of this manuscript.
Funding for this study was provided by Bristol-Myers Squibb.
Author Disclosure Statement
Dr Campbell and Dr Blazer are employees of Xcenda, which received funding for this study; Dr Bloudek is a consultant to Bristol-Myers Squibb; Mr Brokars and Dr Makenbaeva are employees of, and own stock in, Bristol-Myers Squibb.
Dr Campbell is Assistant Director, Scientific Consulting, and Dr Blazer is Associate Director, Scientific Consulting, Xcenda, Palm Harbor, FL; Dr Bloudek is President, Curta, Seattle, WA; Mr Brokars is Health Outcomes Research Director, and Dr Makenbaeva is Group Director, Worldwide Health Economics and Outcomes Research Communications Lead, Bristol-Myers Squibb, Princeton, NJ.
Part of this analysis was presented in abstract/poster form at the 2018 American Society of Hematology annual meeting in San Diego, CA.
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- Gleevec (imatinib mesylate) tablets, for oral use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; July 2018.
- Sprycel (dasatinib) tablets, for oral use [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; December 2018.
- Tasigna (nilotinib) capsules, for oral use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; July 2018.
- Bosulif (bosutinib) tablets, for oral use [prescribing information]. New York, NY: Pfizer; August 2019.
- Iclusig (ponatinib) tablets, for oral use [prescribing information]. Cambridge, MA: Takeda Pharmaceuticals; October 2018.
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- Q1Medicare.com. 2020-2006 Medicare Part D Standard Benefit Model Plan parameters. https://q1medicare.com/PartD-The-MedicarePartDOutlookAll Years.php. Accessed September 26, 2019.
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- Jabbour EJ, You M, Le TK, et al. Prevalence of comorbidities relevant to the choice of second-generation (2-G) tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML) in the United States using real-world claims databases. Blood. 2018;132(suppl 1):4265.
- Jabbour EJ, Siegartel LR, Lin J, et al. Economic value of regular monitoring of response to treatment among US patients with chronic myeloid leukemia based on an economic model. J Med Econ. 2018;21:1036-1040.
- Guérin A, Chen L, Dea K, et al. Association between regular molecular monitoring and tyrosine kinase inhibitor therapy adherence in chronic myelogenous leukemia in the chronic phase. Curr Med Res Opin. 2014;30:1345-1352.
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