Interventions to Improve Adherence to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Systematic Review.

BACKGROUND: Lack of adherence to tyrosine kinase inhibitors (TKIs) is a significant problem resulting in incomplete cytogenetic response and increased mortality in patients with chronic myeloid leukemia (CML). Few studies have been conducted on interventions to improve adherence. The authors conducted a systematic review to explore studies that examined the impact of strategies to improve TKI adherence among individuals with CML. METHODS: The first 2 authors completed a systematic literature review according to the guidelines in Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). Studies (n=2633) conducted between 1980 and 2019 were identified through 3 databases and examined for inclusion/exclusion criteria. RESULTS: Fourteen studies were identified which met the eligibility criteria. The studies only examined adherence to imatinib, dasatinib, or nilotinib. Ten of the 14 used large data sets (commercial health insurance plans or Surveillance Epidemiology and End Results [SEER] data) for analysis. The majority of the studies used a cohort design. Adherence was defined and measured in a variety of ways with most studies using 80% or higher as adequate adherence. Strategies not focused on health care costs used a multidisciplinary team approach. CONCLUSION: Development of evidence to improve treatment adherence to TKIs for CML have relied on large data sets rather than prospective trials. Current studies lack patient focused interventions.

Economics influences therapy decisions in chronic myeloid leukaemia: should it?

The question whether economic considerations should influence therapy decisions in persons with chronic myeloid leukaemia (CML) is complex touching on many metrics other than medicine including the perceptions, attitudes, and motivations of physicians, patients, their families, and payors', allocation of health care resources, and others. We discuss metrics whereby physicians, patients, and payors make CML therapy choices in settings where cost and availability are or are not considerations. We conclude that economic considerations strongly influence therapy decisions in CML. Whether this should be so and what impact it has on outcomes is also considered. Absent definitive data proving which therapy strategy is best allowing economic considerations to operate may not be as unreasonable or unethical as it appears. In some settings, it may be the best approach. However, because TKIs markedly prolong survival and may even cure some persons with CML, TKI therapy should be available to everyone with CML.

Assessment of Dasatinib Versus Nilotinib as Upfront Therapy for Chronic Phase of Chronic Myeloid Leukemia in Qatar: A Cost-Effectiveness Analysis.

BACKGROUND: The economic outcome research of approved tyrosine kinase inhibitors for treating the chronic phase of chronic myeloid leukemia in developing is scarce. The aim of this study was to assess the cost-effectiveness of dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia patients. METHODS: A decision tree model was developed linking clinical effectiveness (defined as major molecular response) and/or complete cytogenetic response, utility, and cost data over a 12-month period. Patients are recruited from Qatar Cancer Registry. The probability of primary clinical outcome is calculated from DASISION (dasatinib) and ENESTnd (nilotinib) trials. Direct healthcare costs were derived from the national healthcare payer system, whereas adverse effects data were derived from local incident reporting system. RESULTS: In the first-line treatments of chronic myeloid leukemia patients, nilotinib has greater major molecular response (39% nilotinib vs 12% dasatinib) and complete cytogenetic response (24% nilotinib vs 16% dastinib) response outcomes, and more adverse effects than dasatinib (13.3% vs 4%). Moreover, nilotinib is more cost-effective with annual costs (USD63,589.59) and after 12 months of follow-up. Despite the lower acquisition annual cost of dasatinib (USD59,486.30), the incremental cost-effectiveness ratio of nilotinib (vs dasatinib) per major molecular response/complete cytogenetic response achieved was USD15,481.10 per year. There were no cases in both arms that progressed to accelerated or blast phase. At a threshold of 3 times gross domestic product per capita of Qatar and according to World Health Organization recommendation, the nilotinib use is still cost-effective. CONCLUSION: Upfront therapy of chronic myeloid leukemia-chronic phase patients by nilotinib plan appears to be more cost-effective than dasatinib.

The costs of treating and not treating patients with chronic myeloid leukemia with tyrosine kinase inhibitors among Medicare patients in the United States.

BACKGROUND: Patients with high cost-sharing of tyrosine kinase inhibitors (TKIs) experience delays in treatment for chronic myeloid leukemia (CML). To the authors' knowledge, the clinical outcomes among and costs for patients not receiving TKIs are not well defined. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the authors evaluated differences in TKI initiation, health care use, cost, and survival among patients with CML with continuous Medicare Parts A and B and Part D coverage who were diagnosed between 2007 and 2015. RESULTS: A total of 941 patients were included. Approximately 29% of all patients did not initiate treatment with TKIs within 6 months (non-TKI users), and had lower rates of BCR-ABL testing and more hospitalizations compared with TKI users. Approximately 21% were not found to have any TKI claims at any time. TKI initiation rates within 6 months of diagnosis increased for all patients over time (61% to 85%), with greater improvements observed in patients receiving subsidies (55% to 90%). Total Medicare costs were greater in patients treated with TKIs, with approximately 50% because of TKI costs. Non-TKI users had more inpatient costs compared with TKI users. Trends in cost remained significant when adjusting for age and comorbidities. The median overall survival was 40 months (95% confidence interval [95% CI], 34-48 months) compared with 86 months (95% CI, 73 months to not reached), respectively, for non-TKI users versus TKI users, a finding that remained consistent when adjusting for age, comorbidities, and subsidy status (hazard ratio, 2.23; 95% CI, 1.77-2.81). CONCLUSIONS: Approximately 21% of all patients with CML did not receive TKIs at any time. Cost-sharing subsidies consistently are found to be associated with higher initiation rates. Non-TKI users had higher inpatient costs and poorer survival outcomes. Interventions to lower TKI costs for all patients are desirable.

Population-based utilization and costs associated with tyrosine kinase inhibitors for first-line treatment of chronic myelogenous leukemia among elderly patients.

BACKGROUND: Following approval of imatinib, a breakthrough tyrosine kinase inhibitor (TKI), survival significantly improved by more than 20% since 2001 among treated chronic myelogenous leukemia (CML) patients. Subsequently, more expensive second-generation TKIs with varying selectivity profiles have been approved. Population-based studies are needed to evaluate the real-world utilization of TKI therapies, particularly given their escalating costs and recommendations for maintenance therapy. OBJECTIVE: To assess the utilization patterns of first-line TKIs, overall and by specific agent, among elderly CML patients in the United States, and the cost implications. METHODS: CML patients aged 65 years and older at diagnosis between 2007 and 2015 were identified from population-based cancer registries in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The percentage of CML patients receiving imatinib, dasatinib, or nilotinib within the first year of diagnosis was calculated along with time to first-line treatment initiation. Bivariate comparisons and Cox proportional hazards models were used to identify factors associated with TKI initiation. Average monthly patient responsibility, including patient out-of-pocket (OOP) costs, stratified by Part D low-income subsidy (LIS) status were also calculated. RESULTS: Among the 1,589 CML patients included, receipt of any TKI within 1 year of diagnosis increased from 66.2% to 78.9%. In 2015, the distribution of first-line TKI therapies was 41.3% imatinib, 28.3% dasatinib, and 9.3% nilotinib. Almost 60% of patients initiated TKI treatment within 3 months of diagnosis. Multivariable analysis indicated that TKI use in the first year was lower among the very elderly (aged > 75 years vs. 65-69 years: HR = 0.72; 95% CI = 0.63-0.83), patients with more comorbidities (Hierarchical Condition Category risk score > 2 vs. HR = 0.74, 95% CI = 0.62-0.88), and patients ineligible for LIS (HR = 0.75; 95% CI = 0.65-0.87). Average monthly patient OOP cost was significantly lower for LIS-eligible versus LIS-ineligible patients: imatinib (2016: $12 vs. $487), dasatinib (2016: $34 vs. $557), and nilotinib (2016: $1 vs. $526). CONCLUSIONS: TKI use has increased significantly since 2007. While imatinib remained the most frequently prescribed first-line agent, by 2015 newer TKIs represented one third of the market share. Utilization patterns indicated persistent age, comorbidity, and financial barriers. TKI use is indicated for long-term therapy, and increased adoption of newer, more expensive agents raises concerns about the sustained affordability of CML treatment, particularly among unsubsidized patients. DISCLOSURES: No outside funding supported this study. There are no reported conflicts of interest.

Cost-Effectiveness of First-Line Tyrosine Kinase Inhibitor Therapy Initiation Strategies for Chronic Myeloid Leukemia.

OBJECTIVES: Overall survival in chronic myeloid leukemia (CML) in chronic phase is not significantly different by treatment with first-line tyrosine kinase inhibitors (TKIs), but emerging evidence reveals differences in costs and safety profiles. We evaluated the 1-year cost-effectiveness of TKI initiation with imatinib, dasatinib, or nilotinib among a hypothetical cohort of incident patients with CML from a US payer's perspective. METHODS: We constructed a decision analytic model to assess quality-adjusted life years (QALYs), healthcare costs, net monetary benefit, and incremental cost-effectiveness of treatment strategies. We used published studies and data from the IBM Watson Health MarketScan database for model parameters. To calculate TKI costs, we used the 2018 Federal Supply Schedule estimates for generic imatinib and branded second-generation TKIs. We evaluated cost-effectiveness under various willingness-to-pay thresholds. We accounted for uncertainty with deterministic and probabilistic sensitivity analyses. RESULTS: In the base-case analysis, imatinib was favored over dasatinib and nilotinib at a lower cost per QALY gained. Imatinib remained the favored strategy after 1-way variations in TKI costs, TKI switching, QALYs, adverse event risk, and CML progression. When we assessed model uncertainty with prespecified parameter distributions, imatinib was cost-saving compared with dasatinib in 40% of 100 0000 simulations and was favored over all simulations compared with nilotinib. First-line treatment with second-generation TKIs was cost-effective in 50% of simulations at a $200 000/QALY willingness-to-pay threshold. CONCLUSIONS: Generic availability of imatinib provides a more cost-effective treatment approach in the first year compared with other available TKIs for newly diagnosed patients with CML.

Expenditures for First- and Second-Generation Tyrosine Kinase Inhibitors Before and After Transition of Imatinib to Generic Status.

Importance: Imatinib introduced a paradigm shift in the treatment of patients with chronic myeloid leukemia (CML), allowing a lifespan that is almost comparable to the general population. However, the health care expenditures associated with imatinib have increased steadily since its introduction in 2001. Since the generic market entry of imatinib on February 1, 2016, it became possible to determine the effect of generic entry on the health care expenditures associated with imatinib, along with the concurrent pricing trends of second-generation tyrosine kinase inhibitors (TKIs). Objective: To compare health care expenditure related to imatinib treatment for patients with CML prior to its generic status with expenditures after, in a real-world setting. Design, Setting, and Participants: A retrospective cohort study using data from the Truven Health MarketScan Database was carried out including 1301 commercially insured patients or patients with Medicaid between the ages of 18 and 64 years with a CML diagnosis between September 1, 2014 and December 31, 2017. A single interrupted time series (ITS) method was used to evaluate monthly expenditures associated with imatinib for the health plan from September 1, 2014 to December 31, 2017, with imatinib switching to generic on February 1, 2016, as the interruption. The initial 6-month period postinterruption was excluded to allow for the new price structure to stabilize. Nilotinib and dasatinib were evaluated using a comparative ITS design. The analysis took place between September 1, 2014 to December 31, 2017. Main Outcomes and Measures: Commercial and Medicaid health plan expenditure and patient cost responsibility for 30-day blocks per patient for imatinib, dasatinib, and nilotinib were calculated from September 1, 2014 through December 31, 2017. Pricing was adjusted via 2017 consumer price index for medical services. Results: The sample included a total of 1301 patients (1102 commercially insured and 199 insured through Medicaid) with a median (range) age at diagnosis of 50 (18-62) years for commercially insured patients and 50 (47-52) years for patients with Medicaid. Of the 1301 patients, 704 (54.1%) were men. There was a significant pregeneric increase in expenditure (commercially insured: $143 per patient per month, P < .001; Medicaid: $152 per patient per month, P = .001). There was a significant reduction over the 6-month interruption period (February 2016 through August 2016) between the pregeneric and generic phase (commercial: $-3097 per patient, P < .001; Medicaid: $-2077 per patient, P = .002). Controlling for secular trends, this was followed by a small decline in expenditure during the generic phase (commercially insured: -$93 per patient per month; P = .03; Medicaid: -$182 per patient per month; P = .001). Nilotinib and dasatinib maintained an increasing trend in both the pregeneric and generic phase of imatinib, resulting in a significant difference-in-difference slope for commercially insured patients (nilotinib: -$186, P = .006; dasatinib: -$175, P = .007) and patients with Medicaid (nilotinib: -$299, P = .002; dasatinib: -$329, P < .001). There were no significant trends for patient cost responsibility. Conclusions and Relevance: The modest decline in expenditure associated with imatinib after generic entry accompanied by the increasing expenditure trends associated with the second-generation TKIs suggest a need for measures to facilitate cost reduction as well as standardization of CML treatment.

Oral Oncology Parity Laws, Medication Use, and Out-of-Pocket Spending for Patients With Blood Cancers.

BACKGROUND: In this study, we sought to estimate the association between oral oncology parity law adoption and anticancer medication use for patients with chronic myeloid leukemia or multiple myeloma. METHODS: This was an observational study of administrative claims from 2008 to 2017. Among individuals initiating tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia or immunomodulatory drugs for multiple myeloma, we compared out-of-pocket spending, adherence, and discontinuation before and after parity among individuals in fully insured plans (subject to parity) vs self-funded plans (exempt from parity) using propensity-score weighted difference-in-differences regression models. RESULTS: Among patients initiating TKIs (N = 2082) or immunomodulatory drugs (N = 3326) there were no statistically significant differences in adherence or discontinuation associated with parity. The proportion of patients with initial out-of-pocket payments of $0 increased in fully insured plans after parity from 5.7% to 46.1% for TKIs and from 10.9% to 48.8% for immunomodulatory drugs. Relative to changes in self-funded plans, those in fully insured plans were 4.27 (95% CI = 2.20 to 8.27) times as likely to pay nothing for TKIs and 1.96 (95% CI = 1.40 to 2.73) times as likely to pay nothing for immunomodulatory drugs after parity. Similarly, the proportion paying more than $100 decreased from 30.3% to 24.7% for TKIs and 30.6% to 27.5% for immunomodulatory drugs in fully insured plans after parity. Relative to changes in self-funded plans, those in fully insured plans were 0.74 (95% CI = 0.54 to 1.01) times as likely to pay more than $100 for TKIs and 0.85 (95% CI = 0.68 to 1.06) times as likely to pay more than $100 for immunomodulatory drugs after parity. CONCLUSIONS: Among patients initiating TKIs or immunomodulatory drugs, parity was not associated with better adherence or less discontinuation of therapy but yielded decreased patient out-of-pocket payments for some patients.

Cost effectiveness of therapeutic drug monitoring for imatinib administration in chronic myeloid leukemia.

BACKGROUND: Imatinib mesylate (IM) is a first-line treatment option for patients with chronic myeloid leukemia (CML). Patients who fail or are intolerant to IM therapy are treated with more expensive second and third-generation tyrosine kinase inhibitors. Patients show wide variation in trough concentrations in response to standard dosing. Thus, many patients receive subtherapeutic or supratherapeutic doses. Therapeutic drug monitoring (TDM) may improve dose management that, in turn, may reduce costs and improve outcomes. However, TDM also adds to the cost of patient care. The objective of this study was to determine the cost-effectiveness of TDM for generic IM therapy. METHODS: We developed a microsimulation model for the trough plasma concentration of IM which is related to a cytogenetic or molecular response. We compared two cohorts: one with TDM and one without TDM (NTDM). The lifetime incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life years (QALYs) as the effectiveness measure. One-way and probabilistic sensitivity analyses were performed. RESULTS: The lifetime cost and QALY of treatment with TDM were $2,137K [95% Ci: 2,079K; 2,174K] and 12.37 [95% CI: 12.07; 12.55], respectively. The cost and QALY of NTDM were $2,132K [95% CI: 2,091K; 2,197K] and 12.23 [95% CI: 11.96; 12.50], respectively. The incremental cost and QALY for TDM relative to NTDM was $4,417 [95% CI: -52,582; 32,097]) and 0.15 [95% CI: -0.13; 0.28]. The ICER for TDM relative to NTDM was $30,450/QALY. Probabilistic sensitivity analysis showed that TDM was cost-effective relative to NTDM in 90% of the tested scenarios at a willingness-to-pay threshold of $100,000/QALY. CONCLUSIONS: Although the impact of TDM is modest, the cost-effectiveness over a lifetime horizon (societal perspective, ($30,450/QALY) falls within the acceptable range (< $100k/QALY).

Meeting the needs of CML patients in resource-poor countries.

Subsequent to the development and global availability of BCR/ABL-targeted tyrosine kinase inhibitors (TKIs), the prognosis of patients with chronic myeloid leukemia (CML), at least those in the chronic phase, has markedly improved, and in the developed world, the average lifespan of these patients is now close to that of age- and sex-matched subjects without the disease. However, the situation in low- and middle-income countries (LMICs) may not be so rosy. Many important differences in hematological cancers, including CML, have been highlighted in various publications in LMICs vs developed countries. These include differences in incidence and prevalence rates, age and stage of disease at diagnosis, response rates, and survival. Some of the possible reasons proposed for these are varying socioeconomic milieu (impacting availability of effective drugs and essential monitoring), environmental factors (mainly exposure to viral infections and pesticides), nutritional factors with interplay of malnutrition and diet on drug absorption and blood levels, and possible unknown genetic factors. Although generic first-generation TKIs (imatinib) are available in many parts of the world, several challenges remain in providing optimal treatment to patients with CML in resource-poor countries. Some of these include availability of optimal and high-quality BCR/ABL testing, availability and expense related to use of second- and third-generation TKIs (nilotinib, dasatinib, bosutinib, and ponatinib) and hematopoietic stem cell transplantation, issues with compliance and toxicities of drugs, and ensuring a minimal standard-of-care treatment and monitoring for every patient diagnosed with CML. For the purpose of this article, the more objective country label-LMIC-coined by the World Bank will be used (gross national income per capita between $1026 and $3995; World Bank, June 2019). Some of these issues will be discussed in this article in greater detail by experts in the field in 3 different but interconnected sections.

Tyrosine Kinase Inhibitors Initiation, Cost Sharing, and Health Care Utilization in Patients with Newly Diagnosed Chronic Myeloid Leukemia: A Retrospective Claims-Based Study.

BACKGROUND: For newly diagnosed chronic myeloid leukemia (CML) patients, early access to tyrosine kinase inhibitors (TKIs) is a consistent predictor of adherence and optimal response. The expense of targeted therapies, however, may result in high out-of-pocket costs for initiating therapy that could be a barrier to starting treatment. OBJECTIVE: To examine the association between TKI out-of-pocket costs, initiation, and health care utilization and costs among patients who initiated TKI within 12 months after initial CML diagnosis. METHODS: Individuals aged 18-64 years with an initial diagnosis of CML were identified in the IBM MarketScan Commercial Database between April 11, 2011, and December 31, 2014. The association between cost sharing and TKI initiation was evaluated using a multivariable logistic regression model applied to patients receiving therapy within a month of diagnosis and within 1-12 months after diagnosis. Health care utilization was compared using negative binomial regression models. Health care cost differences between the 2 patient groups were estimated using generalized linear models. All models were controlled for potential confounding factors. RESULTS: The study sample consisted of 477 patients, with 397 (83.2%) patients initiating TKI within the first month of CML diagnosis and 80 (16.8%) after the first month. Out-of-pocket costs for the initial 30-day supply of TKI medications were not found to be a significant predictor of TKI initiation time. Patients initiating therapy within a month were less likely to have all-cause hospitalizations (IRR = 0.35; P = 0.02) or CML-specific hospitalizations (IRR = 0.27; P < 0.01). Over the 12-month follow-up period, they incurred $9,923 more in TKI pharmacy costs (P < 0.05), but patients initiating therapy after the first month of diagnosis incurred $7,582 more in medical costs, $218 more in non-TKI pharmacy costs, and $2,680 more in total health care costs (P > 0.05). CONCLUSIONS: Patients with TKI initiation within the first month of diagnosis had higher TKI pharmacy costs that were partially offset by lower medical and non-TKI pharmacy costs, resulting in lower overall total health care costs. Findings suggest that earlier TKI initiation may reduce the risks of hospitalizations, which could result in potential medical cost savings in the first 12 months of treatment. DISCLOSURES: No outside funding supported this study. The authors have no relationships or financial interests to report with any entity that would pose a conflict of interest with the subject matter of this article. A poster presentation of the study was made at the 11th American Association for Cancer Research (AACR) Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, on November 2-5, 2018, in New Orleans, LA.

Budget Impact of Treatment-Free Remission in Treating Chronic-Phase Philadelphia-Positive Chronic Myeloid Leukemia in Lebanon.

PURPOSE: Chronic myeloid leukemia (CML) ranks second in terms of disease-related health care expenditures at the Lebanese Ministry of Public Health (MoPH) after breast cancer. With the introduction of tyrosine kinase inhibitors (TKIs), survival of patients with CML has dramatically improved and approached that of the normal population. In recent years, several studies demonstrated that patients who achieve a deep molecular response while receiving TKI therapy could safely attempt treatment-free remission (TFR), the new treatment goal in patients with CML. The objective is to estimate the budget impact of TFR at the MoPH. METHODS: Analyses were done on 162 patients with CML receiving imatinib, nilotinib, or dasatinib, as first-line or second-line therapy, over a 4-year time horizon using MoPH drug pricing. The model assumed that patients could attempt TFR after 36 months of TKI therapy, where the last 24 months were at stable molecular response as per MoPH and National Comprehensive Cancer Network guidelines. Duration of TFR was based on European Stop Kinase Inhibitor treatment-free survival curve. RESULTS: Out of the 162 patients, 83 were eligible to attempt TFR, 36 patients were not eligible, 32 patients were lost to follow-up, two patients died as a result of CML progression, and five died as a result of other causes. The total cost of CML treatment with TFR from the time of analysis and over 4 years can be reduced by more than 7 million US dollars (57%). CONCLUSION: The model can be used to inform health care decision makers on the importance of TFR and the potential savings.

Treatment value of second-generation BCR-ABL1 tyrosine kinase inhibitors compared with imatinib to achieve treatment-free remission in patients with chronic myeloid leukaemia: a modelling study.

BACKGROUND: Treatment-free remission in chronic myeloid leukaemia-ie, achievement of a sustained deep molecular response leading to discontinuation of BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy-has become a potential aim of therapy. Highly priced second-generation TKIs might offer deep molecular response status more quickly and for more patients than imatinib; however, with the availability and lower cost of generic imatinib, the value of second-generation TKIs as frontline therapy for this particular treatment endpoint remains unknown. We aimed to assess the potential value of second-generation TKIs used as frontline therapy in patients with chronic myeloid leukaemia in chronic phase in relation to the probability of achieving sustained deep molecular responses compared with generic imatinib, and the associated cost of each modality. METHODS: We used a decision analytic model to consider the value of different TKI approaches from the payer's perspective. The proportion of patients achieving sustained deep molecular response after 5 years of treatment in chronic phase was estimated at 26% with imatinib and 44% with second-generation TKIs. We also modelled more favourable scenarios of the proportion of patients achieving such response with second-generation TKIs at 66%, 88%, and a near-perfect response of 99%. For each scenario, we examined the impact of the combination of health utilities for chronic-phase chronic myeloid leukaemia (base case 0·89, range 0-1) and the annual cost of second-generation TKIs (base case US$152 814 [ie, the price of nilotinib in the USA], range 0-240 000) on the cost-effectiveness of second-generation TKIs compared with generic imatinib. We used different price scenarios for generic imatinib in the USA (average price $35 000 per year; lowest price $4400 per year), Europe ($4000 per year), and developing countries ($2100 per year). We calculated incremental cost-effectiveness ratios (ICERs) and assessed cost-effectiveness by considering two societal willingness-to-pay thresholds: $50 000 per quality-adjusted life-year (QALY) in all markets and $200 000 per QALY in the USA. FINDINGS: In the base case, we obtained an ICER of $22 765 208, meaning that second-generation TKIs as frontline therapy to achieve sustained deep molecular response was not cost-effective under either of the societal willingness-to-pay thresholds. In our sensitivity analyses, none of the explored scenarios showed potential treatment value for use of second-generation TKIs at the current prices in the USA or at the price of $30 000-40 000 per year elsewhere. For example, considering a scenario in the USA using second-generation TKIs versus imatinib (annual price $4400 per year) with the potential benefit in favour of second-generation TKI (willingness to pay $200 000 per QALY, 66% of patients achieving sustained deep molecular response, and health utility of the chronic phase of 0·1), the cost of second-generation TKIs would need to be less than $25 000 per year to be a cost-effective option. Under the same conditions in developing nations, with a price of generic imatinib of $2100 per year and a willingness to pay of $50 000 per QALY, the annual price of second-generation TKIs should not exceed $10 000 per year of therapy. INTERPRETATION: Considering the current prices of second-generation TKIs and of generic imatinib under different pricing scenarios in the USA, Europe, and developing countries, second-generation TKIs at current prices do not offer good value as frontline therapy in chronic myeloid leukaemia in order to achieve sustained deep molecular response and treatment-free remission. FUNDING: National Cancer Institute.

Medicare and patient spending among beneficiaries diagnosed with chronic myelogenous leukemia.

BACKGROUND: The authors examined Medicare spending and patient spending in older patients with chronic myelogenous leukemia (CML) over the first 5 years from the time of CML diagnosis in the tyrosine kinase inhibitor (TKI) era. METHODS: Medicare beneficiaries with CML who were diagnosed between 2007 and 2012 at age >65 years were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (805 beneficiaries). A noncancer Medicare beneficiary sample was frequency-matched based on age, sex, and race/ethnicity (805 individuals). Patients were followed until 5 years from diagnosis, disenrollment, death, or December 31, 2014, whichever came first. Total Medicare spending, service-specific spending, and amount owed by patients was estimated monthly and then summed over 60 months and averaged to generate annual spending. RESULTS: The median age at the time of diagnosis of CML was 76 years (range, 66-102 years). Overall, 51.4% of patients received TKIs (27.8% received imatinib alone), 28% received non-TKI therapy, and 21% received no treatment. The 5-year survival rate for patients with ≥85% time receiving TKIs was 79% compared with 76% for noncancer controls versus 62% for those with <85% time receiving TKIs. Annual Medicare spending was found to be significantly higher for patients treated with TKIs ($143,053) compared with those treated without TKIs ($41,268 vs $10,498 for noncancer controls). Annual patient cost responsibility was $11,712 per patient receiving any TKIs versus $7330 for those receiving non-TKI outpatient chemotherapy versus $3561 for noncancer controls. CONCLUSIONS: Older patients with CML with adequate time receiving TKI therapy have 5-year survival rates that are comparable to those of their counterparts without cancer. However, TKI use is accompanied with significant Medicare and patient spending; patients receiving multiple TKIs (ie, dasatinib or nilotinib along with imatinib) constitute the group with the highest spending.

Cost variation and savings opportunities in the Oncology Care Model.

OBJECTIVES: This study seeks to identify service categories that present the greatest opportunities to reduce spending in oncology care episodes, as defined by the CMS Oncology Care Model (OCM). Regional variation in spending for similar patients is often interpreted as evidence that resources can be saved, because higher-spending regions could achieve savings by behaving more like their lower-spending counterparts. STUDY DESIGN: We used Surveillance, Epidemiology, and End Results Medicare data from 2006-2013 for this retrospective observational cohort study. Analysis focused on patients with non-small cell lung cancer, advanced (stage III or IV) breast cancer, renal cell carcinoma, multiple myeloma, or chronic myeloid leukemia. METHODS: Episodes were identified for patients with the 5 included cancers, following the episode definition used in the OCM. We estimated standardized episode-level spending for a standard patient across subcategories of care for each hospital referral region (HRR) defined by the Dartmouth Atlas. The contribution of each subcategory to interregional variation in total spending reflects that subcategory's potential to yield savings. RESULTS: Chemotherapy and acute inpatient hospital care tended to be the highest contributors to interregional variation. Imaging, nonchemotherapy Part B drugs, physician evaluation and management services, and diagnostics were negligible contributors to interregional variation for all 5 cancers. CONCLUSIONS: Chemotherapy and inpatient hospital care offer the most potential to reduce spending within OCM-defined episodes. Other sources of savings differ by type of cancer. Assuming patient outcomes are not compromised, low-spending HRRs may be models for lowering cost in cancer care.

Economic Evaluations of Tyrosine Kinase Inhibitors for Patients with Chronic Myeloid Leukemia in Middle- and High-Income Countries: A Systematic Review.

OBJECTIVES: The objective of this systematic review was to conduct a comprehensive assessment of economic evaluations of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML) in middle- and high-income countries. METHODS: A literature search was conducted in Embase, MEDLINE (via PubMed) and the Cochrane library on March 3, 2018 to identify economic evaluations of chronic myeloid leukemia that met the inclusion criteria. Data on such parameters as patient characteristics, cost components, and main outcomes were extracted from eligible studies. RESULTS: The literature review retrieved 798 studies, 17 of which fulfilled the eligibility criteria. Eight studies included an economic analysis on newly diagnosed patients with CML. Seven studies investigated people with CML who were resistant or intolerant to standard-dose imatinib. One article focused on chronic phase (CP)-CML patients who experienced failure with first-line treatment for interferon-α. The last study investigated advanced stages of CML patients. Most studies (n = 70.6%) were conducted in high-income countries. Only five studies (n = 29.4%) were performed in middle-income countries. Most studies used a Markov model. The time horizon varied from six months to life-time. CONCLUSIONS: Despite high costs, the included studies indicate that imatinib regimens are cost effective in newly diagnosed patients with CP-CML. For people with CML who are resistant or intolerant to standard-dose imatinib, dasatinib is likely to be a more cost-effective strategy in middle-income countries. More studies are necessary to assess the long-term efficacy and cost effectiveness of novel treatment options.

Economic value of regular monitoring of response to treatment among US patients with chronic myeloid leukemia based on an economic model.

BACKGROUND: Regular molecular monitoring with reverse-transcription quantitative PCR (RT-qPCR) analysis of BCR-ABL1 transcripts is associated with reduced disease progression among patients with chronic myeloid leukemia (CML). Molecular monitoring assists in the timely detection of primary or secondary resistance to tyrosine kinase inhibitor (TKI) therapy and is a recommended practice by the National Comprehensive Cancer Network guidelines. An economic model was developed to estimate the potential impact of CML monitoring vs lack of monitoring on patient healthcare costs. METHODS: An Excel-based decision-analytic economic model was developed from a US payer perspective. The model was used to estimate the expected healthcare cost differences between regular molecular monitoring of CML patients and lack of monitoring. CML progression rates among patients with vs without monitoring, the annual cost of CML progression, the average number of monitoring tests per year, and the average cost per RT-qPCR monitoring test were incorporated into the model. Univariate and multivariable sensitivity analyses were conducted. RESULTS: Based on estimates in published literature, disease progression to the accelerated/blast phase occurs among 0.35% of patients with monitoring and 5.12% of patients without monitoring, and the annual cost of CML progression is $136,308 per patient year. The analysis found that total healthcare costs, including the costs associated with CML progression and RT-qPCR monitoring tests (three tests per year), were $1,142 for patients with monitoring and $6,982 for patients without monitoring (difference = $5,840). In a hypothetical cohort of 100 patients with CML, achieving a 100% monitoring rate was associated with a total cost-savings of $584,005 compared to a 0% monitoring rate. This cost-savings remained consistent under both univariate and multivariable sensitivity analyses. CONCLUSION: Regular CML monitoring was associated with improved outcomes among CML patients and, consequently, reduced healthcare costs.

Burden of Infections Among Chronic Myeloid Leukemia Patients Receiving Dasatinib or Nilotinib: A Real-World Retrospective Healthcare Claims Study in the United States.

INTRODUCTION: Tyrosine kinase inhibitors (TKI) have been demonstrated to prolong survival in patients with chronic myeloid leukemia (CML). However, TKIs may be associated with an increased risk of infections. This study compared healthcare resource utilization (HRU) and costs among patients with CML receiving dasatinib or nilotinib, with a focus on infection-related economic outcomes. METHODS: Two large administrative databases were used to identify adult patients newly diagnosed with CML who initiated dasatinib or nilotinib as first- (1L) or second-line (2L) therapy and were classified into the following 1L (dasatinib 1L/nilotinib 1L cohorts) or 2L (dasatinib 2L/nilotinib 2L) cohorts based on the initiated 1L/2L TKI therapy. Infection-related HRU and healthcare costs were compared between cohorts, separately for 1L and 2L. RESULTS: Cohorts included 1156 patients in the dasatinib 1L and 677 patients in the nilotinib 1L cohorts, 322 patients in the dasatinib 2L, and 207 in the nilotinib 2L cohorts. In 1L and 2L, infection-related HRU was higher for dasatinib than nilotinib cohorts. Infection-related inpatient (IP) days constituted a larger proportion of all-cause IP days in the 1L/2L dasatinib than 1L/2L nilotinib cohorts (dasatinib 1L/2L: 53%/58%; nilotinib 1L/2L: 50%/46%). Compared to the nilotinib cohort, the dasatinib cohort had higher all-cause total costs per patient per year by US$17,901 in 1L and $28,625 in 2L. Of the total cost difference, infection-related were $6048 (34%) in 1L and $28,192 (99%) in 2L, largely driven by IP cost differences (1L/2L: 96%/98%). CONCLUSIONS: Dasatinib was associated with higher HRU and healthcare costs compared to nilotinib, particularly related to infections. FUNDING: Novartis Pharmaceutical Corporation.

Ponatinib for Treating Acute Lymphoblastic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (Incyte Corporation) of ponatinib (Inclusig®) to submit evidence of its clinical and cost effectiveness for previously treated Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and chronic myeloid leukaemia. This paper focusses on Ph+ ALL. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). This article presents the critical review of the company's submission by the ERG and the outcome of the NICE guidance. The clinical-effectiveness evidence in the company's submission was derived from a phase II, single-arm, open-label, non-comparative study. Given the lack of comparative evidence, a naïve indirect comparison was performed against re-induction chemotherapy comparing major cytogenetic response and complete remission. Best supportive care (BSC) was assumed to produce no disease response. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment for patients with Ph+ ALL. The company submitted a state transition model that analysed the incremental cost effectiveness of ponatinib versus re-induction therapy and BSC for the treatment of Ph+ ALL in patients whose disease is resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or who have the threonine-315-isoleucine mutation. This population was further subdivided into those who were suitable for allogeneic stem cell transplant (allo-SCT) and those who were not. The company's revised economic evaluation, following the clarification process, estimated incremental cost-effectiveness ratios (ICERs) in those suitable for allo-SCT of £31,123 per quality-adjusted life-year (QALY) gained for ponatinib compared with re-induction chemotherapy and £26,624 per QALY gained compared with BSC. For those for whom allo-SCT was unsuitable, the company-estimated ICER compared with BSC was £33,954 per QALY gained. Following a critique of the model, the ERG undertook exploratory analyses that, when combined, produced a range in ICERs (due to uncertainty of the most appropriate overall survival function) of dominant (being less expensive and providing more QALYs) to £11,727 per QALY gained compared with re-induction chemotherapy and between £7892 and £31,696 per QALY gained compared with BSC for those in whom allo-SCT was suitable. For those in whom allo-SCT was not suitable, the ERG estimated that ponatinib was dominant. During the consultation period, the company agreed a revised patient access scheme (PAS) that reduced the ICER ranges to £7156 to £29,995 per QALY gained versus BSC and to less than £5000 per QALY gained versus re-induction chemotherapy. In people for whom allo-SCT was unsuitable, ponatinib dominated BSC. The NICE appraisal committee concluded that ponatinib is a cost-effective use of UK NHS resources in the considered population, subject to the company providing the agreed discount in the PAS.