Secular trend in disease burden of leukemia and its subtypes in China from 1990 to 2019 and its projection in 25 years.

Leukemia and its subtypes impose a major public health challenge in China. Identifying the secular trend of leukemia burden is critical to facilitate optimal healthcare planning and improve the management of leukemia. The incidence rates of leukemia from 1990 to 2019 were collected from the Global Burden of Disease Study 2019 database according to the following: subtype (acute lymphocytic leukemia [ALL], acute myeloid leukemia [AML], chronic lymphocytic leukemia [CLL], chronic myelogenous leukemia [CML], and other leukemia subtypes), sex, and age group. The average annual percentage changes and relative risks were calculated using joinpoint regression and the age-period-cohort model, respectively. The Bayesian age-period-cohort model was also applied to predict the future trend of the incidence of leukemia and its subtypes in the next 25 years. From 1990 to 2019, the age-standardized incidence rates (ASIRs) of leukemia slightly declined in males and females, which is similar to the trend of other leukemia subtypes. However, the four major leukemia subtypes, namely, ALL, AML, CLL, and CML, have been on the rise over the past three decades. The incidence rates of leukemia in children and the elderly were considerably higher than those in other age groups in males and females. Age effects were the most influential risk factor for leukemia incidence. Period effects showed that the risks of leukemia and its subtypes incidence increased with time. For cohort effects, the risks of leukemia and its subtypes were higher among the early-born cohorts compared with the late-born cohorts. The ASIRs of leukemia and its subtypes will continue to increase in the next 25 years. The burden of leukemia and its subtypes is expected to continue to increase in the next 25 years in males and females. A comprehensive understanding of the risk characteristics and disease pattern of leukemia and its subtypes is needed to formulate timely and effective intervention measures to reduce the leukemia burden in China.

[Prevalence of Adverse Effects of Tyrosine Kinase Inhibitors Used in Management of Chronic Myeloid Leukemia at Sidi Bel-Abbès University Hospital Center]. / Prévalence des Effets Indésirables des Inhibiteurs de Tyrosine Kinase Utilisés dans le Traitement de la Leucémie Myéloïde Chronique au CHU de Sidi Bel-Abbès.

INTRODUCTION: Chronic myeloid leukemia (CML) is a malignant hemopathy within the framework of chronic myeloproliferative syndromes, predominant on the granular line. Her drug treatment is based on tyrosine kinase inhibitors (TKIs) which inhibit the abnormal BCR-ABL protein kinase that causes CML and thus block the signals that cause cancer cells to multiply abnormally. However, other proteins are also inhibited, so they can cause a wide range of adverse effects (AEs). The objective of this study was to study the prevalence of AEs of TKIs used in the therapeutic management of CML by the hematology department of University Hospital Center (UHC) of Sidi Bel-Abbes in Algeria and that of the ITK discontinuation following an AE. MATERIALS AND METHODS: It was a retrospective descriptive study carried out over a period of four months, from April 01st, 2021 to July 31st, 2021, on CML patients treated with TKI in the hematology department of Sidi Bel-Abbes HUC in Algeria. The primary outcome measure was the prevalence of AEs associated with the use of normal dosages or overdose of the following TKIs: Imatinib, Dasatinib and Nilotinib. Data were collected from patient charts, filled by doctors of hematology department, using questionnaire, and analyzed by Statistical Package for the Social Sciences software, version 20. RESULTS: A total of 40 patients were included, including 22 women, mean age 51.55±11.66years (23-78). Twenty-six patients reported at least one AE. Among the 106 AEs declared, 69 AEs (65.09 %) declared with Imatinib, 26 AEs (24.53 %) with Dasatinib and 11 AEs (10.38 %) with Nilotinib. A predominance of musculoskeletal effects 43 (40.56 %), followed by general disorders 18 (17 %), myelosuppression 14 (13.20 %) and digestive system 12 (11.32 %). AEs were responsible for permanent discontinuation of ITK in three cases (11.54 %), including two cases (07.70 %) on Imatinib because of neutropenia and one case (03.84 %) onDasatinibsuffering from pleural effusion. AEs could be controlled in 13 (50 %) of cases, including 9 (34.62%) by temporary discontinuation and 4 (15.38 %) by reducing the dosage, allowing improvement of symptoms and continuation or reintroduction of treatment. CONCLUSION: The prevalence of AEs was high in the studied population, their occurrence was inevitable, good management of AEs from the start of treatment is necessary to avoid switching to another TKI, especially in good responders. It is recommended to establish a low-sodium diet beforehand for all TKIs and a low-carbohydrate diet, especially for Nilotinib, and not to rush to stop the TKI because most often, EIs regress over time in order to allow good therapeutic adherence and obtain better results.

Comparative Assessment of Echocardiographic Patterns Among Chronic Myeloid Leukemia Patients on Tyrosine Kinase Inhibitor and Healthy Controls.

PURPOSE: Chronic myeloid leukemia (CML) is one of the common hematological malignancies in Nigeria. Cardiac abnormalities are associated with CML irrespective of treatment with tyrosine kinase inhibitors such as imatinib, which is available gratis in Nigeria. OBJECTIVE: To assess the prevalence and patterns of cardiac dysfunction among patients with CML irrespective of treatment with imatinib using transthoracic echocardiography, and 12-lead surface electrocardiography. PATIENTS AND METHODS: CML patients without Imatinib, CML patients with imatinib, and apparently healthy (age- and sex-matched) controls were 70 each in the study. Various echocardiographic parameters were measured and data obtained were analyzed, and the level of significance was taken as p < 0.05. RESULTS: Of 70 CML patients with imatinib, 54.3% were men and 45.7% were women, while the CML group without imatinib had 62.9% men and 37.1% women, non-CML control had 54.3% men and 45.7% women. The average hematocrit was significantly lower in the CML group without Imatinib compared with the other groups (p<0.001). And, 12.9% and 17.1% of CML groups with and without imatinib had LVH, respectively, and none of the non-CML controls had LVH (P<0.041). Impaired left ventricular relaxation in 25.71% and 28.57% of CML patients with and without imatinib respectively but only 8.57% of the non-CML control had impaired left ventricular relaxation (p=0.236). Mitral valve regurgitation was the most frequent valvular abnormality across the groups. Pulmonary hypertension in 17.4% and 20% of CML patients with and without imatinib, respectively, but none of the non-CML controls had pulmonary hypertension (p<0.001). Pericardial effusion in 32.86% and 45.71% of CML patients with and without imatinib, respectively, but none of the non-CML controls had pericardial effusion (p<0.001). There was no significant difference in the QTC interval across the three groups. CONCLUSION: Cardiac abnormalities are present in CML patients with or without Imatinib treatment, with significant prevalence than what is seen in the non-CML control group.

Safety and cost-effectiveness of ponatinib versus other tyrosine kinase inhibitors as second-line therapy in patients with chronic myeloid leukemia in the United States.

To evaluate the cost-effectiveness of ponatinib compared with second-line TKIs in the treatment of adult patients with CML who failed, or were intolerant to, first-line TKIs. A Markov state transition model was conducted. Model transition, adverse-effect probabilities, utility data and medical costs were obtained from clinical trials and literature. Measurements included medications, follow-ups, adverse events, allogeneic stem cell transplantation and quality-adjusted life years (QALYs). Univariable and Bayesian multivariable probabilistic sensitivity analyses were conducted using Monte Carlo simulations. Dasatinib resulted in an ICER of $79,086/QALY compared to nilotinib. Ponatinib yielded an ICER of $176,278/QALY and $141,563/QALY compared to dasatinib and nilotinib, respectively. Dasatinib was the optimal treatment at a $100,000/QALY threshold. The probability (36%-40%) for ponatinib or dasatinib optimal treatment was associated with thresholds of $160,000-$180,000/QALY. Dasatinib and ponatinib can be considered cost-effective options and provide clinical benefits compared to other second-line TKIs for CML in the US.

Magnitude and Temporal Trend of the Chronic Myeloid Leukemia: On the Basis of the Global Burden of Disease Study 2019.

PURPOSE: To map the magnitudes and temporal trends of chronic myeloid leukemia (CML) along with its attributable risk factors, providing the essential foundation for targeted public policies at the national, regional, and global levels. MATERIALS AND METHODS: We retrieved annual data on CML burden in 204 countries and regions from the Global Burden of Disease Study 2019 in 1990-2019. The estimated annual percentage change (EAPC) was calculated to quantify the temporal trends of CML burden by region, sex, and age group. RESULTS: Globally, the age-standardized incidence rate of CML declined weakly over the past few years (EAPC: -1.04), but the number of incident cases increased by 54.1% to 65.8 × 103 in 2019. By contrast, a dramatic drop in death and disability-adjusted life years (DALYs) rate (EAPCs: -2.55; -2.69) led to a reduction in deaths and DALYs, especially in high-income regions. In 2019, the highest age-standardized death rate was observed in Ethiopia (1.89 per 100,000). The death rate of CML was pronounced among the population age above 70 years. DALYs of CML worldwide were primarily attributable to smoking (12.2%), high body mass index (5.0%), occupational exposure to benzene (0.9%), and occupational exposure to formaldehyde (0.3%) in 2019. CONCLUSION: Although the mortality rate of CML has decreased significantly, the management of patients with CML cannot be neglected, especially in elders and developing regions.

Use of the «BCR/ABL - multitest¼ kit in the algorithm of laboratory diagnostics of oncohematological diseases: economic aspects.

Abnormal mRNAs of the hybrid BCR-ABL gene in the majority of cases initiate the synthesis of proteins with a mass of 210 kDa (p210), 190 kDa (p190), and 230 kDa (p230). Expression of the p210 variant is most common in CML (95% of cases), while the p190 and p230 variants are less common (1-4%). On the contrary, p190 predominates in ALL. Measurement of BCR/ABL gene expression is included in clinical guidelines for the diagnosis of CML and ALL as sequential tests in accordance with their occurrence. At the same time, in the context of primary patients testing with suspected hematological malignancies with a low prevalence of BCR-ABL positive patients in the cohort of examined individuals, sequential testing is associated with low cost-effectiveness. Purpose: approbation of a parallel algorithm for detecting all three (p210, p190 and p230) using the multiplex RT-PCR format implemented in the «BCR/ABL-MULTITEST¼ reagent kit. We used anonymized blood samples from patients with suspected CML, as well as samples from ALL patients before starting therapy. Testing of blood samples was carried out using two variants of the algorithm: sequential determination of individual BCR-ABL transcripts and parallel determination using the developed set of reagents «BCR/ABL-MULTITEST¼. To detect the p210 transcript, a commercial kit «AmpliSens® Leukemia Quantum M-bcr-FRT¼ (Central Research Institute of Epidemiology of Rospotrebnadzor, Russia) was used. Simultaneously, a test was used to detect all three variants of BCR-ABL transcripts using the «BCR/ABL - MULTITEST¼ reagent kit based on a monochrome multiplex reaction «in one test tube¼. Reverse transcription were carried out using the REVERTA-L reagent kit (Central Research Institute of Epidemiology of Rospotrebnadzor, Russia) in accordance with the manufacturer's instructions. Using the reagent kits «BCR/ABL-MULTITEST¼ and «AmpliSens® Leukemia Quantum M-bcr-FRT¼ there is a high level of correlation of quantitative results of determining the chimeric transcript BCR-ABL р210 (r = 0.99). When using the proposed parallel algorithm with the primary use of the «BCR/ABL-MULTITEST¼ reagent kit, out of 95 patients with suspected CML, 9 samples with p210 transcript were identified, one with p190 BCR / ABL, and in one case a transcript variant characteristic of chronic neutrophilic leukemia - p230 BCR / ABL. The estimated cost for detecting one positive case of BCR-ABL when using the parallel diagnostic algorithm «BCR/ABL-MULTITEST¼ with a focused flow of studies is reduced by about 2 times due to a decrease in the amount of laboratory plastic used and the volume of the reaction mixture, as well as the absence of the need for repeated separate tests to detect p190 and p230. The use of the multiplex PCR-RT test system «BCR/ABL-MULTITEST¼ allows detecting in one test tube all three main variants of BCR-ABL transcripts - p210, p190, p230 and achieving significant resource savings when examining a cohort of patients with suspected CML and ALL and low frequency of positive samples.

Arterial hypertension assessment in a population with chronic myeloid leukemia.

Treatment of chronic myeloid leukaemia (CML) is based on tyrosine kinase inhibitors (TKI), whose introduction in 2001 improved the survival rate after 5 years from 40 to 90%. The longevity increase has been accompanied by a higher incidence of cardiovascular events (CVE) that can be explained due to the sum of cardiovascular risk factors (CVRF) together with the secondary effects of the TKI. The effect of the TKI over the blood pressure control is still unknown. An observational cross-sectional study of patients with CML under treatment with TKI (imatinib, dasatinib and nilotinib) was conducted. Blood pressure was analyzed through sphygmomanometer and 24-h ambulatory blood pressure monitoring (ABPM). A total of 73 patients were included, 57 treated with a single line of treatment. 32.9% of the total of individuals under this study showed uncontrolled blood pressure according to the ABPM. The factors related to uncontrolled BP were overweight, dyslipidemia, alcohol use, pulse wave velocity a high/very high cardiovascular risk. The subjects who received treatment with nilotinib did present worse control of their blood pressure in ABPM than those treated with imatinib and dasatinib (p = 0.041). This finding could indicate that an uncontrolled blood pressure is implied in the pro-inflammatory and pro-atherogenic mechanism underlying the development of the cardiovascular disease in those patients under treatment with nilotinib. The ABPM is a useful tool in the diagnosis and treatment of HT, being the reason why it should be included in the assessment of patients with CML whose HT diagnosis proves uncertain.

Trend in Tyrosine Kinase Inhibitor Utilization, Price, and Out-of-Pocket Costs in Patients With Chronic Myelogenous Leukemia.

PURPOSE: Treatment of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs) has improved survival but is associated with significant financial burden. We measured the annual trend in TKI utilization, Medicare gross payment, and patient out-of-pocket (OOP) expenditure from 2007 to 2016. METHODS: We used SEER linked to Medicare part-D claims data to identify prevalent CML cases from 2007 to 2016. TKI utilization was measured as the proportion of cases with at least one TKI fill in each year. Average TKI gross payment and median per-member per-month OOP expenditure were calculated from claims data and plotted annually from 2007 to 2016. Year-to-year percent change in gross payment and OOP expenditure was compared with inflation indices. RESULTS: The cohort included 3,189 CML cases with at least one TKI claim. The proportion of prevalent patients with a TKI fill in a year increased from 17.9% in 2007 to 52.8% in 2015. The average annual gross payment per 30-day supply of a TKI increased by an average of 12.8% throughout the period from $9,000 to $10,000 US dollars in 2016. There was no increasing trend in median OOP expenditure per 30-day supply, which varied between $450 and $600 US dollars. CONCLUSION: Rising TKI use and TKI drug prices place considerable financial pressure on Medicare part-D insurers. Although there was no increasing trend in OOP expenditure, it may be burdensome for Medicare patients who are likely retired on a fixed income. Our findings support legislation that mitigates increasing drug prices to protect the Medicare system and its beneficiaries.

Ethnic and border differences on blood cancer presentation and outcomes: A Texas population-based study.

BACKGROUND: The Texas/Chihuahua (US/Mexico) border is a medically underserved region with many reported barriers for health care access. Although Hispanic ethnicity is associated with health disparities for many different diseases, the population-based estimates of incidence and survival for patients with blood cancer along the border are unknown. The authors hypothesized that Hispanic ethnicity and border proximity is associated with poor blood cancer outcomes. METHODS: Data from the Texas Cancer Registry (1995-2016) were used to investigate the primary exposures of patient ethnicity (Hispanic vs non-Hispanic) and geographic location (border vs non-border). Other confounders and covariates included sex, age, year of diagnosis, rurality, insurance status, poverty indicators, and comorbidities. The Mantel-Haenszel method and Cox regression analyses were used to determine adjusted effects of ethnicity and border proximity on the relative risk (RR) and survival of patients with different blood cancer types. RESULTS: Hispanic patients were diagnosed at a younger age than non-Hispanic patients and presented with increased comorbidities. Whereas non-Hispanics had a higher incidence of developing blood cancer compared with Hispanics overall, Hispanics demonstrated a higher incidence of acute lymphoblastic leukemia (RR, 1.92; 95% CI, 1.79-2.08; P < .001) with worse outcomes. Hispanics from the Texas/Chihuahua border demonstrated a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) compared with Hispanics living elsewhere in Texas. CONCLUSIONS: Hispanic ethnicity and border proximity were associated with a poor presentation and an adverse prognosis despite the younger age of diagnosis. Future studies should explore differences in disease biology and treatment strategies that could drive these regional disparities.

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.

Using the SEER-Medicare Data to Assess Incident Chronic Myeloid Leukemia and Bladder Cancer Cases Missed by Cancer Registries.

The growing use of oral systemic therapies and transition of some cancer treatments to the outpatient setting makes capturing all cancer case patients more difficult. We aim to develop algorithms to identify potentially missed incident case patients and estimate impact on incidence rates. We reviewed claims from SEER-Medicare 5% noncancer control patient sample to identify potentially missed chronic myeloid leukemia (CML) and bladder case patients based on diagnosis codes, cancer-related treatments, and oncology consultations. Observed rates of definite missed CML and definite and probable missed bladder case patients were calculated and the impact of missed case patients of these two cancers on SEER 65+ incidence rates were estimated. From 2008 to 2015, the algorithm estimated 781 definite CML case patients missed, increasing the number by 10.7%. From 2007 to 2015, the algorithm estimated 4629 definite and 5772 probable bladder case patients missed, increasing the number by 3.8% to 8.1%. Our algorithms offer potential methods for identifying missed case patients and validating the completeness of cancer registries.

Budget impact analysis of treatment-free remission in nilotinib-treated Japanese chronic myeloid leukemia patients.

Treatment-free remission (TFR), in which patients discontinue pharmacotherapy and remain in molecular remission, is an emerging treatment goal for patients with chronic myeloid leukemia (CML). Attainment of TFR requires an increased frequency of molecular monitoring, to ensure that patients maintain a deep molecular response. The objective of this analysis was to assess the economic impact of stopping nilotinib among Japanese TFR-eligible patients. A Markov model evaluated the economic impact of TFR among the study population, TFR-eligible CML patients diagnosed since 2012. The model compared patients who had discontinued tyrosine kinase inhibitor (TKI) treatment (ie, attempted TFR) with patients that continued TKI treatment. A 3-y time horizon was modeled from a Japanese public payer perspective. Costs associated with drug treatment, hospital/physician visits, and molecular monitoring were considered. TFR-eligible patients were calculated from Japanese CML incidence rates and efficacy was derived from nilotinib trials. Japanese co-payment maximums were utilized to assess the patient perspective. An estimated 761 and 140 patients were eligible for first- and second-line nilotinib, respectively, in 2019. Assuming that 100% of eligible patients complied, TFR was associated with cost savings of ¥7 625 174 640 (US$66 567 775) over 3 y. In scenarios with reduced willingness to attempt TFR, cost savings persisted. Achievement of TFR was estimated to markedly reduce out-of-pocket expenses for CML patients, regardless of the timing of relapse. Stopping nilotinib for TFR-eligible patients in Japan may result in significant cost savings to both payers and patients. Monitoring costs contributed little to overall annual costs and decreased over time.

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.

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).

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP.

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.

Analysis of the cost-effectiveness of treatment strategies for CML with incorporation of treatment discontinuation.

The cost of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) is a substantial economic burden. In Japan, imatinib, dasatinib, and nilotinib are now approved as first-line treatment of CML in chronic phase. Recent "stop TKI" trials have shown that TKIs can be safely discontinued in nearly one-half of patients with sustained deep molecular response (DMR). In this study, we analyzed the cost-effectiveness of a simulated 10 years of CML treatment including stop TKI in both the United States and Japan. We constructed Markov models to compare 4 strategies in which treatment was initiated with imatinib, dasatinib, nilotinib, or any of these TKIs at the physician's discretion. Treatment was switched to another TKI in the case of intolerance or resistance to the initial TKI, and TKIs were discontinued if DMR persisted for 2 years. "Imatinib first" offered 7.34 quality-adjusted life years (QALYs) at the cost of $1 022 148 in the United States (US dollars) and ¥32 526 785 in Japan (Japanese yen). In comparison with imatinib first, the incremental cost-effectiveness ratio per QALY of "dasatinib first" (7.68 QALY, $1 236 052, ¥51 506 254), "nilotinib first" (7.64 QALY, $1 245 667, ¥39 635 598), and "physician's choice" (7.55 QALY, $1 167 818, ¥41 187 740) was $641 324, $696 717, and $666 634 in the United States and ¥54 456 325, ¥23 154 465, and ¥39 635 615 in Japan, respectively. None of the 3 strategies met the willingness-to-pay threshold. The results were robust to univariate and multivariate sensitivity analyses. Imatinib first was shown to be the most cost-effective approach even with the incorporation of stop TKI.

Using healthcare claims data to analyze the prevalence of BCR-ABL-positive chronic myeloid leukemia in France: A nationwide population-based study.

BACKGROUND: Data on Chronic Myeloid Leukemia (CML) prevalence are scarce. Here we provide an estimation of the prevalence of CML in France for the year 2014 using French national health insurance data. METHODS: We selected patients claiming reimbursement for tyrosine kinase inhibitors (TKI) or with hospital discharge diagnoses for CML, BCR/ABL-positive or with full reimbursement of health care expenses for myeloid leukemia. We built an algorithm which we validated on a random sample of 100 potential CML patients by comparing the results obtained using the algorithm and the opinion of two hematologists who reviewed the patient demographics and sequence of care abstracted from claims data (internal validity). For external validity, we compared the number of incident CML patients identified using the algorithm with those recorded in French population-based cancer registries in departments covered by such a registry. RESULTS: We identified 10 789 prevalent CML patients in 2014, corresponding to a crude prevalence rate of 16.3 per 100 000 inhabitants [95% confidence interval (CI) 16.0-16.6]: 18.5 in men [18.0-19.0] and 14.2 in women [13.8-14.6]. The crude CML prevalence was less than 1.6 per 100 000 [1.2-2.0] under age 20, increasing to a maximum of 48.2 [45.4-51.2) at ages 75-79. It varied from 10.2 to 23.8 per 100 000 across French departments. The algorithm showed high internal and external validity. Concordance rate between the algorithm and the hematologists was 96%, and the numbers of incident CML patients identified using the algorithm and the registries were 162 and 150, respectively. CONCLUSION: We built and validated an algorithm to identify CML patients in administrative healthcare databases. In addition to prevalence estimation, the algorithm could be used for future economic evaluations or pharmaco-epidemiological studies in this population.

The potential health gain and cost savings of improving adherence in chronic myeloid leukemia.

Healthcare costs are rising due to an increase in chronic diseases, including chronic myeloid leukemia (CML) due to improved survival. In CML care, patient adherence and physician adherence are key elements. We assessed the potential health gain and cost savings when both are improved, using a decision analytic model that integrated various sources of evidence. The current situation was compared to a theoretical situation in which either patient or physician adherence is improved, in terms of costs and quality-adjusted life years (QALYs). Current patient adherence rate is 74%, improvement to 100% resulted in 0.1031 QALYs gained and a saving of €17,509 per patient over a 25-year period. Improving physician adherence from 72% to 100%, resulted in 0.0380 QALYs and €7606. Enhancement of either adherence results in substantial health gain and cost savings. Regarding the rising healthcare costs, new strategies should focus on improving adherence to keep healthcare affordable in the future.

Impact of earlier versus later monitoring on disease progression and healthcare costs among patients with chronic myeloid leukemia in the United States.

We evaluated the impact of molecular monitoring earlier as compared to later in the course of chronic myeloid leukemia (CML) on disease progression and healthcare costs in the real-world setting in the US. Patients with a diagnosis of CML were identified from the MarketScan claims databases (1 January 2006 to 30 June 2016). Multivariable regression analyses were used to control for differences in patient cohorts with earlier versus later monitoring. Of the 2730 CML patients in the study population, 60% (n = 1633) received earlier monitoring and 40% (n = 1097) received later monitoring only. After adjusting for differences in patient characteristics, patients with earlier monitoring had a lower likelihood of CML progression during the follow-up period (odds ratio: 0.72, confidence interval: 0.53-0.96; p = .03) and lower total healthcare costs ($6794 versus $9782 per-patient-per-month, p < .001) than patients with later monitoring. Patients who are monitored earlier in the course of CML may have better outcomes and lower total costs of 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.