Comparative Safety and Health Care Expenditures Among Patients With Chronic Myeloid Leukemia Initiating First-Line Imatinib, Dasatinib, or Nilotinib

PURPOSE: Tyrosine kinase inhibitors (TKIs) have dramatically improved survival for patients with chronic myeloid leukemia (CML). No overall survival differences were observed between patients initiating first- and second-generation TKIs in trials; however, real-world safety and cost outcomes are unclear. We evaluated comparative safety and health care expenditures between first-line imatinib, dasatinib, and nilotinib among patients with CML. PATIENTS AND METHODS: Eligible patients had one or more fills for imatinib, dasatinib, or nilotinib in the MarketScan Commercial and Medicare Supplemental databases between January 1, 2011, and December 31, 2016 (earliest fill is the index date), 6 months pre-index continuous enrollment, CML diagnosis, and no TKI use in the pre-index period. Hospitalizations or emergency department visits (safety events) were compared across treatment groups using propensity-score-weighted 1-year relative risks (RRs) and subdistribution hazard ratios (HRs). Inflation-adjusted annual health care expenditures were compared using quantile regression. RESULTS: Eligible patients included 1,417 receiving imatinib, 1,067 receiving dasatinib, and 647 receiving nilotinib. The 1-year risk of safety events was high: imatinib, 37%; dasatinib, 44%; and nilotinib, 40%, with higher risks among patients receiving dasatinib (RR, 1.17; 95% CI, 1.06 to 1.30) and nilotinib (RR, 1.07; 95% CI, 0.93 to 1.23) compared with those receiving imatinib. Over a median of 1.7 years, the cumulative incidence of safety events was higher among patients receiving dasatinib (HR, 1.23; 95% CI, 1.10 to 1.38) and nilotinib (HR, 1.08; 95% CI, 0.95 to 1.24) than among those receiving imatinib. One-year health care expenditures were high (median, $125,987) and were significantly higher among patients initiating second-generation TKIs compared with those receiving imatinib (difference in medians: dasatinib v imatinib, $22,393; 95% CI, $17,068 to $27,718; nilotinib v imatinib, $19,463; 95% CI, $14,689 to $24,236). CONCLUSION: Patients receiving imatinib had the lowest risk of hospitalization or emergency department visits and 1-year health care expenditures. Given a lack of significant differences in overall survival, imatinib may represent the ideal first-line therapy for patients, on average.

Download Full-text

HSR19-090: Changes in Adherence to Tyrosine Kinase Inhibitor Treatment Patterns Among Patients With Chronic Myeloid Leukemia and the Impact on Costs: 2001–2017

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2018.7191 ◽

2019 ◽

Vol 17 (3.5) ◽

pp. HSR19-090

Author(s):

Henry J. Henk ◽

Lena E. Winestone ◽

Jennifer J. Wilkes ◽

Laura Becker ◽

Pamela Morin ◽

...

Keyword(s):

Health Care ◽

Chronic Myeloid Leukemia ◽

Healthcare Costs ◽

Myeloid Leukemia ◽

First Line ◽

Tki Treatment ◽

The Impact ◽

Care Costs ◽

Over Time ◽

Privately Insured

Background: Chronic myeloid leukemia (CML) treatment improved considerably after introduction of oral tyrosine kinase inhibitors (TKI). As a result, the number of patients living with CML may reach 250,000 by 2040. We track changes in TKI treatment adherence since 2001 and provide an early assessment of treatment costs following the availability of second-generation TKIs and generic imatinib. Methods: A retrospective cohort from the OptumLabs Data Warehouse, which includes claims data for privately insured and Medicare Advantage (MA) enrollees in a large private U.S. health plan with medical and pharmacy benefits, was used. Patients with CML initiated TKI treatment between May 2001 and October 2016 and were continuously enrolled in the health plan 6 months prior through 12 months following TKI start. Adherence was defined by medication possession ratio (MPR1=total days’ supply of imatinib in 1st year divided by 365, 1=perfect adherence). Total health care costs include medical and prescription medication benefits. MPR1 was modeled using ordinary least squares regression. The association between MPR1 and healthcare costs was estimated using a generalized linear model specified with a gamma error distribution and a log link. Results: We identified 1,793 eligible patients. First-line TKI has changed over time (dasatinib and nilotinib represent 45% of all 2016 starts; imatinib 55%). From 2001 to 2016, adherence increased (Table 1). MPR1 was higher in men and increased with age until age ∼62 after which it declined. MPR1 was lower for patients with more comorbid conditions prior to treatment. Overall, MPR1 was inversely associated with total health care costs (medical and pharmacy) among privately insured (P<.001) but not MA enrollees. The net impact of MPR1 on total healthcare costs diminished over time (P<.001) where a 10% point decrease in MPR1 was associated with 12% and 4% lower total costs, prior to and following availability of 2nd generation TKIs, respectively. When examining medical costs only, MPR1 was inversely associated with medical costs for both privately insured (P<.001) and MA enrollees (P=.016). Conclusions: We found that adherence to TKI treatment increased over time. While imatinib is still used more frequently than other TKIs as first-line therapy, second-generation TKIs are becoming increasingly used as first-line agents. Possible cost-offsets are decreasing over time but it may be too early to formally evaluate the impact of generic imatinib.

Download Full-text

B3a2 Transcript Is an Independent Factor for the Achievement of a Deep Molecular Response in Chronic Phase - Chronic Myeloid Leukemia Patients Treated with Imatinib in First-Line

Blood ◽

10.1182/blood-2018-99-114036 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1749-1749 ◽

Cited By ~ 1

Author(s):

Matheus Sebastian Da Silva ◽

Eliana C Miranda ◽

Marcia Torresan Delamain ◽

Gislaine Oliveira Duarte ◽

Bruna R Vergilio ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Chronic Myeloid Leukemia ◽

Cumulative Incidence ◽

Myeloid Leukemia ◽

Molecular Response ◽

Imatinib Treatment ◽

Independent Factor ◽

First Line ◽

Molecular Responses

Abstract Introduction: The achievement of a deep and sustained molecular response after treatment with tyrosine kinase inhibitors (TKI) is one of the requirements for therapy discontinuation in chronic myeloid leukemia (CML) patients. Objectives: This study aimed to evaluate the proportion of CML patients treated with imatinib in first-line that achieve MR4.5 (BCR-ABL transcripts ≤ 0.0032% in the international scale) after imatinib treatment and the predictive factors for this response. The secondary objectives were to evaluate the rate of MMR (PCR ≤0.1%), MR4.0 (PCR ≤ 0.01%), time to molecular responses, event-free survival, progression-free and overall survival. Patients and methods: This is a retrospective analysis of CP-CML patients treated in first-line with imatinib in a single center. Patients diagnosed after 2006 were managed according to the European Leukemia Net recommendations. All patients started CML imatinib within six months from diagnosis. The type of BCR-ABL1 transcript was determined by multiplex RT-PCR from cDNA synthesized from total leukocytes RNA at diagnosis. BCR-ABL transcripts by quantitative real-time polymerase chain reaction were assessed at baseline, and then every three months for the first year until reaching a stable major molecular response, then every 3-6 months. The SPSS software was used for the Cox Regression model for univariate and multivariate analysis, using backward Wald. The cumulative incidence was calculated with the R Program, with Gray test for curve comparisons. Event-free, progression-free and overall survivals were calculated with the Kaplan-Meier method, and the curves were compared with the log-rank test. Results: From January 2005 to December 2015 172 patients were treated with imatinib, median age 48 years (18-93), 55.8% male. Sokal score: 31% low-risk, 40% intermediate-risk and 29% high-risk. The median follow-up was 56 months (0-157). The Cumulative Incidence (CI) of MMR was 48% in 24 months and 84% in 5 years, while the CI of MR4.0 and MR4.5 was 63% and 51%, respectively, in 5 years. The median time to MMR, MR4.0 and MR4.5 was 16.7 (2-102), 31 (5-150) and 36 months (7-153), respectively. The univariate regression factors related to MR4.5 achievement were: age >48 years (HR 1.79; 95%CI: 1.08-2.98; P=0.023); days between diagnosis and imatinib start (HR=0.99; 95%CI: 0.98-0.99, P=0.020); e14a2 (b3a2) transcript (HR= 3.37; 95%CI: 1.67-6.81; P=0.001), which was the only factor in the multivariate analysis. Imatinib was discontinued in 96/172 (55.8%) patients due to resistance (36.5%), intolerance (20.8%), clinical trials (25%), death (15.6%) and adherence (2.1%). Eighteen out of 67 (26.8%) patients that achieved MR4.5 are currently participating in a discontinuation trial. Overall survival, PFS and EFS were 92%, 87% and 61% in 5 years. Conclusion: Approximately half of the patients that start imatinib in first-line obtain deep molecular responses within five years and could be candidates for treatment discontinuation. B3a2 transcript was an independent factor for MR4.5 achievement in the multivariate analysis, confirming the results of other studies that have reported earlier and deeper molecular responses in patients with b3a2 transcripts. Disclosures De Paula: Hematology and Transfusion Medicine Center, University of Campinas: Employment. Pagnano:Abbvie: Consultancy; EMS: Other: Financial support for participation in congress; Shire: Other: Lecture; Novartis: Consultancy.

Download Full-text

Evaluating Real-World Effectiveness and Safety of Generic and Brand-Name Imatinib in Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2021-149309 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3614-3614

Author(s):

Michele Muir ◽

Jasmine Johnson ◽

Sitong Shu ◽

Hui-Han Chen ◽

Sachiko Ozawa ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Primary Endpoint ◽

Real World ◽

Myeloid Leukemia ◽

Statistical Significance ◽

The United States ◽

Emergency Department Visits ◽

Imatinib Treatment ◽

First Line ◽

Branded Product

Abstract Introduction: Generic formulations of imatinib were approved and commercially available in the United States starting in 2016, introducing vast cost savings to the standard treatment of chronic myeloid leukemia (CML). While bioequivalence studies of generic formulations are required for Food and Drug Administration approval, the safety of generic drug supply chains have come into question. There is limited real-world data comparing the effectiveness and safety profiles of generic formulations to the original. This study aimed to evaluate the effectiveness and safety of generic imatinib compared to the branded product. Methods: This retrospective study included patients treated at UNC Medical Centers who were diagnosed with CML and treated with imatinib at any time during their course of treatment. Data was retrieved from the institution's electronic health record and collected over the first 6 months of imatinib treatment to include both safety and effectiveness outcomes. The primary endpoint was to compare generic versus branded product effectiveness, as defined by the European LeukemiaNet (ELN) guidelines (achieving BCR-ABL/ABL ratio of <10% and <1% at 3 and 6 months, respectively). The secondary endpoints included comparisons of generic vs branded product safety, measured via patient adverse drug events (ADEs), all-cause hospitalizations, and early treatment discontinuation. Patients were excluded from primary endpoint evaluation and only included for safety endpoint analysis if they were not treated with imatinib first-line and if duration of imatinib treatment was less than 6 months. Results: Fifty-one CML patients met criteria with no significant differences in age or gender between the generic (n = 23) and brand (n = 28) imatinib groups (Table 1). First-line therapy was composed of 83% of patients on generic imatinib and 29% of patients on brand imatinib. Of those receiving first-line imatinib therapy, there was no difference in molecular responses at 3 and 6 months between generic and brand imatinib (p = 0.71). Brand imatinib was associated with numerically lower CML-related emergency department visits and hospitalizations when compared to generic imatinib, although this difference was not statistically significant (p = 0.12). Rates of discontinuation were numerically lower for brand imatinib although overall time to discontinuation was shorter for generic imatinib (Table 1). Conclusions: This study demonstrates real-world treatment effectiveness and safety of generic and brand imatinib in clinical practice. Generic imatinib appears to be associated with higher rates of CML-related ED visits and hospitalizations although sample size was small and statistical significance was not reached. Further analyses of comparisons and continuation of data collection will provide a more robust assessment to compare the effectiveness and safety of generic and brand imatinib in the real-world setting. Figure 1 Figure 1. Disclosures Muluneh: Novartis: Other: Spouse works for Novartis.

Download Full-text

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

Journal of Global Oncology ◽

10.1200/jgo.19.00012 ◽

2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Fadia Elias ◽

Anthony Gebran ◽

Christina Said ◽

Russell V. Beker ◽

Walid Ammar

Keyword(s):

Health Care ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Budget Impact ◽

Kinase Inhibitor ◽

Normal Population ◽

Chronic Phase ◽

Health Care Expenditures ◽

Molecular Response ◽

Treatment Free Remission

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.

Download Full-text

Factors that Influence Emergency Department Visits for Asthma

Canadian Respiratory Journal ◽

10.1155/1999/743628 ◽

1999 ◽

Vol 6 (5) ◽

pp. 429-435 ◽

Cited By ~ 13

Author(s):

SC Tough ◽

PA Hessel ◽

FHY Green ◽

I Mitchell ◽

S Rose ◽

...

Keyword(s):

Risk Factors ◽

Health Care ◽

Emergency Department ◽

Acute Exacerbation ◽

Emergency Department Visit ◽

Emergency Departments ◽

Health Care Expenditures ◽

Emergency Department Visits ◽

Smoking History ◽

Bivariate Analysis

BACKGROUND: Asthma can usually be controlled through allergen avoidance and/or appropriate medication. An emergency department visit for an acute exacerbation of asthma often represents a breakdown in asthma management. Emergency department treatment results in significant health care expenditures and reflects a compromised quality of life.OBJECTIVES: To identify risk factors associated with an emergency department visit for asthma.METHODS: This case-control study compared 299 people (76% of 390 cases contacted) who attended one of two emergency departments in Alberta in 1992 and 1993 for an acute exacerbation of asthma (cases) with 212 unmatched community controls with asthma who were located by random digit dialing. Cases and controls were asked to complete a mailed questionnaire to obtain data regarding severity, visits to doctors and emergency departments, medication use, allergies and other triggers, and smoking history. Data analysis included bivariate analysis of risk factors and multivariate model development using logistic regression.RESULTS: The response rate was similar between cases and controls. Cases were younger than controls (odds ratio [OR] 2.16, 95% CI 1.34 to 3.48) and more often reported their asthma to be severe (OR 4.25, 95% CI 2.24 to 8.06), and had experienced nocturnal symptoms (stratified OR range 1.36 to 6.82). Cases used more health care services in the previous year, had been admitted to hospital at some time for asthma (OR 1.62, 95% CI 1.10 to 2.38) and used more medication than controls.CONCLUSIONS: Physicians and other health care workers should be sensitive to the risk factors and target interventions to high risk individuals.

Download Full-text

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

Era s journal of medical research ◽

10.24041/ejmr2020.34 ◽

2020 ◽

Vol 7 (2) ◽

pp. 205-211

Author(s):

Kaynat Fatima ◽

Syed Tasleem Raza ◽

Ale Eba ◽

Sanchita Srivastava ◽

Farzana Mahdi

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Protein Kinases ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Line Treatment ◽

First Line ◽

First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

Download Full-text

Characteristics of BCR/ABL1 kinase domain mutations in the patients with chronic myeloid leukemia who are primary resistant to the imatinib therapy

Biolohichni systemy ◽

10.31861/biosystems2019.01.027 ◽

2019 ◽

Vol 11 (1) ◽

pp. 27-33

Author(s):

I Dmytrenko ◽

J Minchenko ◽

I Dyagil

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

High Efficiency ◽

Kinase Domain ◽

Imatinib Therapy ◽

Missense Mutations ◽

Primary Resistance ◽

Kinase Domain Mutations

The chronic myeloid leukemia (CML) development is associated with the formation of the BCR/ABL1 fusion gene and the BCR/ABL1 protein with increased tyrosine kinase activity. Despite the high efficiency of targeted therapy, up to 30% of patients do not respond on such therapy i.e. are primary resistant. The presence of BCR/ABL1 kinase domain mutations is considered to be one of the reasons of tyrosin kinase inhibitors resistance. To evaluate the frequency of BCR/ABL1 kinase domain mutations in Ukrainian cohort of CML patients with primary resistance to imatinib therapy, we retrospectively studied BCR/ABL1 kinase domain mutations in peripheral blood of 107 CML patients. The nucleotide sequence was determined by direct sequencing by Sanger. Mutations were reported in 45 of 107 (41.7%) CML patients. Two mutations at a time were revealed in 8 patients. So a total of 53 mutations were found out. Among them 49 were missense-mutations and 4 - deletions of different regions of the BCR/ABL1 kinase domain gene. The missense-mutations F359I/V (12 patients), T315I (8 patients) and G250E (6 patients) were most common. By localization, the mutations majority (23 of 53) was in the P-loop, 10 mutations - in the contact site, 13 mutations - in the catalytic domain and 6 – in the A-loop. Of the detected mutations, 26 (49%) resulted in a disruption of the hydrogen bond between BCR/ABL1-tyrosine kinase and imatinib. Significant reduction in overall survival was found in patients with BCR/ABL1 kinase domain mutations compared with patients with wild-type of BCR/ABL1 gene (p=0.018). The estimated 3-year overall survival was 83.4% (95% CI: 77.0%-89.8%) and 94.3% (95% CI: 91.0%-97.3%), respectively. Therefore, mutations of the BCR/ABL1 kinase domain are one of the mechanisms of primary resistance in CML patients on imatinib therapy. The occurrence of BCR/ABL1 gene mutations impairs the prognosis of imatinib therapy response.

Download Full-text