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.

Comparative efficacy and safety of tyrosine kinase inhibitors for chronic myeloid leukaemia: A systematic review and network meta-analysis.

BACKGROUND: The pharmacotherapy of chronic myeloid leukaemia (CML) is mainly based on tyrosine kinase inhibitors (TKIs). The aim of this study was to compare the efficacy and safety of all TKIs in CML patients. METHODS: We conducted a systematic review with network meta-analysis (NMA) of randomised controlled trials (RCTs), including imatinib, nilotinib, dasatinib, bosutinib, radotinib and ponatinib. Searches were performed in PubMed, Scopus, Web of Science and SciELo (March 2018). The NMAs were built for six outcomes at 12 months: complete cytogenetic response (CCyR), major cytogenetic response (MCyR), deep molecular response, major molecular response (MMR), complete haematologic response and incidence of serious adverse events. We conducted rank order and surface under the cumulative ranking curve (SUCRA) analyses. RESULTS: Thirteen RCTs were included (n = 5079 patients). Statistical differences were observed for some comparisons in all outcomes. Imatinib 400 mg was considered the safest drug (SUCRA values of 10.3%) but presented low efficacy. Overall, nilotinib 600 mg was superior to the other TKI in efficacy (SUCRA values of 61.1% for CCyR, 81.0% for MMR, 90.0% for MCyR); however, no data on its safety profile at 12 months were reported. INTERPRETATION: Our results suggest that nilotinib should be upgraded to first-line therapy for CML, although further cost-effectiveness analyses, including the new TKI (i.e., ponatinib, radotinib), are needed.

Retrospective analysis of clinical outcomes of the patients with chronic myeloid leukemia who stopped administration of tyrosine kinase inhibitors: a single institution experience.

We describe herein the clinical outcomes of 16 patients with chronic myeloid leukemia in the chronic phase who stopped the administration of tyrosine kinase inhibitors (TKI) after maintaining undetectable levels of major BCR-ABL1, based on real-time quantitative polymerase chain reaction, for prolonged periods (undetectable MR for a median of 2,100 days (822-4,068). The reasons for discontinuing TKI were enrollments in a clinical trial testing discontinuation of these agents (n=9), adverse effects (n=2) or financial problems (n=5). After TKI discontinuation, patients were followed for a median of 551 days (154-2,446). A total of 8 patients (50%) experienced molecular relapse after a median of 119 days (28-171). Among them, 6 patients who lost major molecular response (MMR) were treated with imatinib (n=2) or dasatinib (n=4), while 2 patients who lost undetectable MR after discontinuing TKI (1 each had taken bostinib and imatinib) but maintained MMR were carefully monitored without re-administration of TKI. Of 6 patients who re-started TKI, 4 (67%) achieved undetectable MR but the other 2 achieved only MMR. The results of this small, retrospective study may support the current understanding of treatment discontinuation, possibly leading to a sustained deep molecular response in some patients.

Changing the cost of care for chronic myeloid leukemia: the availability of generic imatinib in the USA and the EU.

Imatinib is an oral tyrosine kinase inhibitor and considered to be the most successful targeted anti-cancer agent yet developed given its substantial efficacy in treating chronic myeloid leukemia (CML) and other malignant diseases. In the USA and the European Union (EU), Novartis' composition of matter patent on imatinib will expire in 2016. The potential impact on health system spending levels for CML after generic imatinib becomes available is the subject of significant interest among stakeholders. The extent of the potential savings largely depends on whether and to what extent prices decline and use stays the same or even increases. These are also empirical questions since the likely spending implications following generic imatinib's availability are predicated on multiple factors: physicians' willingness to prescribe generic imatinib, molecule characteristics, and health system priorities. This article discusses each of these issues in turn. We then review their implications for the development of country-specific cost-effectiveness models to predict the implications for cost and quality of care from generic imatinib.

Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia.

PURPOSE: The introduction of imatinib, a tyrosine kinase inhibitor (TKI), has greatly increased survival for patients with chronic myeloid leukemia (CML). Conversely, nonadherence to imatinib and other TKIs undoubtedly results in disease progression and treatment resistance. We examined trends in imatinib expenditures from 2002 to 2011 and assessed the association between copayment requirements for imatinib and TKI adherence. PATIENTS AND METHODS: We used MarketScan health plan claims from 2002 to 2011 to identify adults (age 18 to 64 years) with CML who initiated imatinib therapy between January 1, 2002, and June 30, 2011, and had insurance coverage for at least 3 months before through 6 months after initiation (N = 1,541). Primary outcomes were TKI discontinuation and nonadherence. The primary independent variable was out-of-pocket cost for a 30-day supply of imatinib. By using a propensity-score weighted sample, we estimated the risk of discontinuation and nonadherence for patients with higher (top quartile) versus lower copayments. RESULTS: Monthly copayments for imatinib averaged $108; median copayments were $30 (range, $0 to $4,792). Mean total monthly expenditures for imatinib nearly doubled between 2002 and 2011, from $2,798 to $4,892. Approximately 17% of patients with higher copayments and 10% with lower copayments discontinued TKIs during the first 180 days following initiation (adjusted risk ratio [aRR], 1.70; 95% CI, 1.30 to 2.22). Similarly, patients with higher copayments were 42% more likely to be nonadherent (aRR, 1.42; 95% CI, 1.19 to 1.69). CONCLUSION: Patients with higher copayments are more likely to discontinue or be nonadherent to TKIs. Given the importance of these therapies for patients with CML, our data suggest a critical need to reduce patient costs for these therapies.

Diagnostic discrimination and cost effective assay strategy for leukocyte alkaline phosphatase.

Decreased leukocyte alkaline phosphatase (LAP) is a first line test for chronic myelogenous leukemia (CML), generally preceding a diagnostic algorithm which also includes bone marrow biopsy, cytogenetic analysis, and molecular diagnostics. We found the analytical uncertainty of LAP assays to range from over 100% coefficient of variation at low scores to about 20% at high scores. However, the receiver-operator characteristics derived from LAP determinations in 50 consecutive cases suggest that a suitably high diagnostic decision threshold still can eliminate false negatives. As a consequence of such a strategy, as many as half the tested patients, classified unequivocally as the negatives, can avoid further invasive and costly workup. On the other hand, serial LAP determinations, whether performed to detect change to a lower or to a higher score, are unlikely to produce conclusive diagnostic signals exceeding analytical 'noise.'