Abstract
Objectives: Imatinib (Glivec) has been covered by critical disease insurance for treatment of chronic myeloid leukemia (CML) in Jiangsu province of China since 2013. Further, free molecular monitoring has been provided to patients at top clinical centers as part of a pilot study that has changed the local treatment pattern and outcomes of patients with CML. This study evaluates the impact of medical insurance coverage and the molecular monitoring frequency on outcomes of patients with CML treated at a central hospital in Jiangsu, China, according to patient-level data.
Methods: The study investigated 335 CML patients receiving medical treatment in a central hospital between January 1, 2011 and December 31, 2014. Demographic and clinical characteristics were extracted from the patients’ clinical records. Univariate and multivariate analyses using the logistic regression model were performed to identify the differences in outcomes of major molecular response (MMR) or complete cytogenetic response (CCyR) between patients who were insured vs uninsured, or between patients with frequency of PCR monitoring ≤2 times vs ≥3 times per year.
Results: Both the achievement of MMR (BCR-ABLIS ≤0.1%) (50.4% vs 37.5%) and CCyR (80.7% vs 62.8%) at 12 months have shown significant differences that favored patients with insurance coverage of imatinib, while there was no significant difference in the outcome of BCR-ABLIS ≤1% between insured and non-insured groups (56.0% vs 51.3%) at 6 months. The long-term results at 24 months demonstrated that there was a statistically significant difference in MMR rates between the group with 3 or more PCR monitoring tests per year and the group of patients with 2 or less PCR tests per year (76.9% vs 52.2%).
Conclusions: The study findings suggest that CML patients benefit from insurance coverage of imatinib and higher frequency (≥3) of regularly scheduled molecular monitoring PCR in China.
Background
Chronic myeloid leukemia (CML) is a progressive disease that occurs in all age groupsCitation1. The median age of disease onset in China is 45–50 years oldCitation2–5, which is younger than the 67-year-old median in western countriesCitation6. CML incurs a heavy financial burden to patients as well as their families. Traditional therapy such as interferon and hydroxyurea cannot achieve satisfactory disease remission, and bone marrow or stem cell transplant is limited by donor resources and operation conditionCitation7–9.
Imatinib is an oral tyrosine kinase inhibitor (TKI) and the first-targeting therapy, becoming the standard of therapy for patients with CML. In recent years, the use of imatinib and later-generation TKIs has revolutionized treatment of patients with CMLCitation7. In the phase III, randomized, open-label international study of interferon-ɑ plus cytarabine vs imatinib (IRIS) trial [9], high survival rates were demonstrated for imatinib-treated patients at 5 years of follow-up, with event-free survival (EFS) rates without progression to accelerated phase (AP) or blast crisis (BC) at 83% and 93%, and overall survival (OS) rates of 89%, respectivelyCitation10.
Imatinib has not only produced unprecedented response rates in CML that are durable for years, but has also raised response assessment to the molecular standardCitation11. According to European LeukemiaNet recommendations, molecular response is best assessed, according to the international scale, as the ratio of BCR-ABL1 transcripts to ABL1 transcripts, or other internationally recognized control transcripts, and it is expressed and reported as a percentage of BCR-ABL1 on a log scale, where 10%, 1%, 0.1%, 0.01%, 0.0032%, and 0.001% correspond to a decrease of 1, 2, 3, 4, 4.5, and 5 logs, respectively, below the standard baseline used in the IRIS studyCitation12. A BCR-ABL1 expression of 0.1% or less corresponds to major molecular response (MMR). The IRIS trial demonstrated that the patients who achieved MMR (BCR-ABLIS <0.1%) by 18 months had remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 yearsCitation9.
A cytogenetic response is indicated by the number (or percentage) of Ph + cells contained in the bone marrow. A complete cytogenetic response (CCyR) indicates that no Ph + metaphases are present in the sample and, thus, is an important predictor of the long-term outcome of treatmentCitation13. The probability of loss of CCyR by 7 years was only 3% for patients in MMR at 18 months vs 26% for patients with CCyR but not MMR (p < 0.001)Citation9. Poor primary response or relapse after initial response both suggest the need to change therapy, e.g. to nilotinibCitation14, which is recommended for the treatment of imatinib-resistant CML and for people with CML for whom treatment with imatinib has failed because of intoleranceCitation15. Molecular monitoring plays an essential role in the clinical management of CML patients, as demonstration of milestone molecular responses during TKI therapy is associated with clinical response, including overall survival (OS), progression-free survival (PFS), and event-free survival (EFS). Due to the strong association between molecular-response milestones and long-term treatment outcomes, molecular results now guide clinical decision-making. Quantitative reverse-transcriptase-PCR (qRT-PCR) assessment of BCR-ABL1 transcript levels has become the standard of care in CML. However, further developments are required to assess leukemic burden more efficiently, monitor minimal residual disease, detect mutations that drive resistance to TKI therapy, and identify predictors of response to TKI therapy. Cartridge-based BCR-ABL1 quantitation, digital PCR, and next generation sequencing are examples of technologies which are currently being explored, evaluated, and translated into the clinicCitation16.
Regular molecular monitoring could be critical in CML management, as information on molecular response provides opportunities for timely treatment adjustments, which could reduce disease progression and increase survivalCitation17. The latest guideline for management of chronic myeloid leukemia from the Chinese Society of Hematology, Chinese Medical Association recommends that molecular treatment response should be measured every 3 months using RQ-PCR until stable MMR achievementCitation18. However, a recent study found that compliance to regular PCR monitoring by CML patients was inconsistentCitation19; when comparing patients with no PCR or 1–2 PCR tests per year to those with 3–4 PCR tests per year, increased frequency of monitoring was associated with a lower risk of progressionCitation17.
In the Jiangsu province of China, imatinib and nilotinib have been covered by medical insurance of critical diseases since 2013 as a pilot of national critical-disease policy. With insurance coverage, CML patients only need to co-pay 25% of the drug cost for imatinib, in addition, with the Glivec International Patient Assistance Program (GIPAP) through the Chinese Charity Federation, for every purchase of the first 3-month supply of imatinib, there will be a complimentary supply of 9 months for eligible CML patientsCitation20.
To date, no studies have investigated the clinical outcome impact of insurance coverage and molecular monitoring frequency on achievement of molecular responses in China, although some studies have been carried out in the USCitation17,Citation21. In the current study, we aimed to investigate the impact of insurance coverage with imatinib and the frequency of PCR monitoring (≤2 vs ≥3 tests per year) on response achievement—including BCR-ABLIS ≤1%, MMR, and CCyR status of CML patients in China using patient-level data from the First Affiliated Hospital of Soochow University in Jiangsu province of China.
Methods
Study population
With ethical approval obtained, this retrospective patient-level data study was based on a sample of 335 patients with newly-diagnosed CML who were treated with TKI or other drugs between January 1, 2011 and December 31, 2014 at the First Affiliated Hospital of Soochow University in Jiangsu province of China, which is a top level and key general hospital in Jiangsu province approved by the Chinese Ministry of Health. The Department of Hematology at the hospital is a national treatment center, with a 75,000 patient turnover per year, and key member of PCR international standardization alliance; its uniform test provides standardized, reproducible results across laboratory settingsCitation22.
Demographic and clinical characteristics included age, gender, CML-related clinical information such as Sokal score at the time of CML diagnosis, insurance coverage status, and frequency of PCR testing, which is complimentary and is provided free to CML patients as part of the pilot. The frequency of PCR testing was defined by the average frequency of molecular monitoring calculated over the observation period during which treatment and clinical status, such as remission or progression according to the PCR testing results and death, were recorded at different time points. The patients were categorized into two groups: (A) 0–2 PCR tests per year and (B) ≥ 3 PCR tests per year.
Outcome measurement
The main outcomes of the study were the achievements of molecular response in BCR-ABLIS ≤1% at 6 months; MMR at 12 and 24 months; and the achievements of early CCyR at 12 months since the initiation of CML therapies. These outcomes were compared between the patients with or without insurance coverage and between patients whose frequency of PCR monitoring was ≤2 times or ≥3 times per year. A CCyR is defined as absence of the Philadelphia chromosome among at least 20 cells in metaphase in a bone marrow aspirateCitation13, while a MMR is reached if the standardized BCR-ABL:ABL ratio is less than 0.1%, which is equivalent to a 3-log reduction from the 100% baseline for untreated patientsCitation13.
Statistical analyses
The patients’ characteristics and treatment outcomes were compared between insured and uninsured patient groups using a Chi-squared test for binary variables and independent t-tests for continuous variables. In addition, logistic regression was used to investigate the association between treatment outcomes and variables such as insurance coverage status and frequency of PCR monitoring separately. The regression model was adjusted for controlling for the potential confounding factors such as age, gender, and baseline Sokal score.
All statistical analyses were performed with Predictive Analytics SoftWare (PASW) 18.0 (Statistical Package for the Social Sciences, Chicago, IL), with statistical significance defined as a two-tailed p < 0.05.
Results
Among the 335 patients with chronic-phase CML included in this study, there were 305 patients treated with first-line Glivec therapy. Two hundred and twenty-five patients had the insurance coverage for TKI and 110 patients did not have the insurance coverage for TKI, although the diagnoses of the CML were covered by the insurance in both groups of patients. The average age in the sample was 43 years. The patients’ characteristics are presented in .
Table 1. Patients’ characteristics.
At month 6 after patients received therapy, there was no significant difference in molecular response status of BCR-ABLIS ≤1% between insured and non-insured groups (56.0% vs 51.3%; ); at month 12 the MMR status was achieved in 50.4% of patients with insurance coverage and 37.5% among those without insurance coverage. The difference at month 12 was statistically significant after adjusting for potentially confounding factors such as age, gender, and Sokal risk at baseline ().
Table 2. BCR-ABLIS ≤ 1% at the 6th month.
Table 3. MMR at the 12th month.
The results of CCyR at month 12 were also significantly different between insured and uninsured groups (80.7% vs 62.8%; ) in both the crude and adjusted analyses.
Table 4. CCyR at the 12th month.
The association between PCR monitoring frequency and treatment outcome of MMR at month 24 was also investigated. The MMR achievement was less in the group of patients with 2 or less PCR tests per year, compared to patients with 3 or more PCR tests per year ().
Table 5. MMR at the 24th month.
Discussion
This study is the first attempt to evaluate the impact of medical insurance coverage and molecular monitoring frequency on outcomes of patients with CML treated at a central hospital in Jiangsu province of China using real world evidence. The patient level data were collected from the First Affiliated Hospital of Soochow University in Jiangsu province of China, which is a locally representative, top-level, and key general hospital in Jiangsu province approved by the Chinese Ministry of Health. The patient cohort observed was also typically representative as the Department of Hematology at the hospital is a national key discipline of clinical medicine with national level laboratories for the needs of diagnosis, treatment, and research. The Department of Hematology has been a national treatment center with a yearly outpatient and inpatient volume of ∼75,000Citation22.
TKI therapies including imatinib have dramatically improved the survival of the patients, and changed the natural history of CML, transforming the disease from a life-threatening to a chronic oneCitation7. Thus, imatinib and nilotinib have been recommended as the standard first-line treatment for CML globally, including ChinaCitation18,Citation23. Following national critical disease insurance policy, Jiangsu province covered imatinib and nilotinib for CML treatment as a pilot due to a breakthrough therapeutic effect. Our study verified that the insurance coverage policy for TKI is significantly associated with positive MMR (BCR-ABLIS ≤0.1%) and CCyR outcomes as early as month 12 after receiving treatment. This observation could be attributed to the significantly higher proportion of TKI utilization among insured than uninsured patients. Insurance coverage changed the treatment pattern and outcomes of CML in Jiangsu, as most of the patients can afford to take imatinib as a first line treatmentCitation24, which is consistent with the clinical recommendations in the Chinese guidelines for CML managementCitation18.
In the US, use of TKIs was associated with a 30% reduction in non-pharmaceutical medical spending for CML patients, which is roughly equal to 40% of the incremental pharmaceutical cost associated with using TKI therapy. The net annual cost of TKI therapy is ∼$15,000, which is well within the range of conventional cost-effectiveness thresholdsCitation25; however, lack of insurance is certainly a barrier to accessing specialty cancer medications. As spending on cancer medications increase, both public and private insurers have adopted a more aggressive approach to managing reimbursement, distribution, and benefit designsCitation25.
A health economic evaluation showed that imatinib is a cost-effective treatment for CML in China also. In newly-diagnosed CML-CP, the cost per responder for patients treated with imatinib is much lower than that for patients treated with interferon. In the cost-utility analysis, the ICER is below the cost-effectiveness threshold recommended by the World Health Organization for developing countriesCitation26.
In this study the long-term results at 24 months demonstrated that more patients with 3 or more PCR monitoring tests per year achieved a MMR status; compared to patients with 2 or less PCR tests per year, the difference was statistically significant. PCR has been utilized widely to measure treatment response for CML, established through multiple clinical studies as significant predictors of progression-free survival (PFS) and overall survival (OS) in CMLCitation27–29. Through public–private partnership between public payers, hospitals, and manufacturers of TKIs in some provinces of China, CML patients have access to free PCR monitoring regularly for assessment of the treatment outcomes. The public–private partnership refers to the government, earnings, and non-profit enterprises engaging in mutual co-operation for certain projects, and is an important pattern while it is still at innovation stage in China.
Furthermore, the insurance coverage of imatinib with the Patient Assistance Program may improve treatment compliance as the eligible CML patients are reminded via prescriptions to claim the complimentary supply of the drug. In addition, regular molecular monitoring can detect treatment failure as early as 3 months after starting therapy, which can help clinicians adjust the treatment regimens in time at the same time as enhancing patient compliance, and CML patients can altogether avoid bone marrow aspiration for cytogenetic testing if they achieve MMR by 12 monthsCitation17.
Molecular detection and monitoring have been found to be important in clinical diagnosis, effectiveness, and predicting prognosis in treating CMLCitation25. Moreover, the value of PCR was found in detecting BCR/ABL fusion gene in monitoring the response to therapy in chronic myeloid leukemia patients, as the tests can be used to evaluate the efficacy of the therapy and to detect minimal residual disease in CML patientsCitation30.
Another study has shown that, among US community-based CML-CP patients who took imatinib as first-line therapy, patients subjected to an average of 3–4 PCR tests per year experienced lower risk of progression and longer PFS compared to patients who had no PCR tests. This suggested that patients benefited from regularly scheduled PCR testing. Furthermore, among CML patients initiating first-line TKIs, those with 3–4 PCR tests a year incurred fewer inpatient admissions, emergency room visits, and lower in-patient and medical service costs compared to patients with no testing, where the progression-related in-patient costs accounted for the majority of inpatient cost differences. These findings underscore the importance of molecular monitoring in CML patients.
Studies also have shown that imatinib can be safely discontinued in patients with a complete molecular remission of at least 2 years. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitorsCitation31. With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that imatinib can safely be discontinued in patients with a sustained deep molecular response with no late molecular recurrenceCitation32.
This study was subject to limitations as the patient level data were collected from Jiangsu province so can only represent this province; the varied cost and efficacy data and reimbursement system in other regions of China still need to be observed and further studied. Although every effort has been made to ensure the accuracy, errors may occur in electronic medical record systems. There could also be some confounders such as quality of healthcare and physician expertise that cause biases in comparison among the study groups. These issues could be resolved by collecting multi-center data from bigger samples of patient population with the development of a uniform provincial electronic medical records system. We did not include the predicted medication adherence in the study, as this information was not available, being a retrospective study, which indeed is a limitation, although we did see CML patient benefit from insurance coverage of TKI and more frequent PCR monitoring, assuming better affordability and medication adherence.
Conclusions
With the insurance coverage of imatinib and nilotinib in Jiangsu province of China, insurance coverage for TKI therapies and PCR testing frequency of 3 times or more were statistically significantly associated with both the achievement of MMR and CCyR status among patients with CML. These findings suggest that CML patients will benefit from insurance coverage of TKI and a regular PCR monitoring of at least 3 times per year in China, as these initiatives lead to a more consistent clinical practice with the Chinese treatment guideline’s recommendation.
Transparency
Declaration of funding
This project was sponsored by Novartis.
Declaration of financial/other relationships
TX and SCT are current employees of IMS Health, who received funds from Novartis for this study. CL is an employee of Novartis Pharmaceuticals Corporation. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgments
The authors thank Shuli Qu and Pengzhen Liu from IMS Health for their support in the literature search and review for relevant local data inputs in the analyses.
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