Patient preferences for stopping tyrosine kinase inhibitors in chronic myeloid leukemia

Background

We used an interview-assisted survey of patients with chronic myeloid leukemia (cml) at a single tertiary care centre to explore patient reactions to and preferences for, and the risk-acceptability of, stopping tyrosine kinase inhibitor (tki) treatment.

Methods

The study included patients with confirmed cml currently being treated with a tki. The survey was conducted by structured interview using a standard form. Patient preferences were explored in a case-based scenario using 0%–100% visual analog scales and 5-point Likert scales. Data were analyzed using proportions for dichotomous variables and medians and interquartile ranges for continuous variables.

Results

Of 63 patients approached, 56 completed the survey. Participant responses suggest that the idea of stopping tki use is appealing to many patients if there is a chance of long-term stable disease and a high probability of response upon restarting a tki. Participants were more likely to stop their tki as the risk of relapse decreased. Participants reported loss of disease control and failure of disease to respond to treatment as important concerns if they chose to stop their tki.

Conclusions

Given the current 60% estimated rate of relapse after discontinuation of tki therapy, most patients with cml chose to continue with tki. However, at the lower relapse rates reported with second-generation tkis, participants were more undecided, demonstrating a basic understanding of risk. Contrary to our hypothesis, neither compliance nor occurrence of side effects significantly affected patient willingness to stop their tki.     

Managing chronic myeloid leukemia patients intolerant to tyrosine kinase inhibitor therapy

The outcomes for patients with chronic myeloid leukemia have improved dramatically with the development and availability of BCR–ABL1 tyrosine kinase inhibitors (TKIs) over the past decade. TKI therapy has a superior safety profile compared with the previous standard of care, interferon-α, and most adverse events (AEs) observed with front-line and second-line TKI treatment are managed with supportive care. However, some patients are intolerant to TKI therapy and experience AEs that cannot be managed through dose reduction or symptomatic treatment. Careful management of AEs helps patients to remain adherent with treatment and increases their chances for successful outcomes. Proactive vigilance for potential AEs and treatment strategies that reduce symptom burden will help to minimize patient intolerance. This review discusses the most common AEs associated with intolerance to TKI therapy and treatment strategies to help manage patients at risk for or experiencing these events.     

Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia

In patients with chronic myeloid leukemia (CML), the hallmark Philadelphia chromosome is the marker of disease that can be detected by conventional metaphase cytogenetics, fluorescence in situ hybridization, or polymerase chain reaction. The current "gold standard" of treatment response is cytogenetic response. Cytogenetic response to imatinib is strongly associated with disease progression and survival. Various strategies aimed at improving cytogenetic response have been explored, such as escalation of imatinib and switching to the newer breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene (BCR-ABL) inhibitors dasatinib and nilotinib. Data from recent randomized trials of dasatinib and nilotinib as first-line therapy of newly diagnosed chronic-phase CML suggest that these agents are more effective than imatinib in achieving 6-month and 12-month complete cytogenetic responses. However, it is still too early to know whether or not this early response will translate into a long-term survival advantage. In addition, more sensitive assays to detect residual disease also may be associated with improved long-term outcomes. The deepest measure of response-a complete molecular response-may help identify patients who can stop taking imatinib for the short term, although the long-term consequences of this strategy remain unknown.     

Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy

BACKGROUND:

The annual incidence of chronic myeloid leukemia (CML) in the United States is approximately 4800 cases. With the success of tyrosine kinase inhibitor (TKI) therapy, the all‐cause annual mortality rate was reduced to 2%. Therefore, the prevalence of CML is increasing over time. Estimating the CML prevalence and plateau prevalence is important in the implementation of health care strategies and future therapeutic trials. The objective of this report was to estimate the increasing prevalence and plateau prevalence of CML in future years.

METHODS:

The prevalence of CML was estimated based on several parameters: the annual mortality rate on TKI therapy compared with a age‐matched, normal population; the incidence of CML; the anticipated population growth in the United States; and aging of the population.

RESULTS:

On the basis of these calculations, the mortality ratio of patients with CML compared with an age‐matched normal population was approximately 1.53. The estimated prevalence of CML is approximately 70,000 in 2010, 112,000 in 2020, 144,000 in 2030, 167,000 in 2040, and 181,000 in 2050, when it will reach a near plateau prevalence.

CONCLUSIONS:

The current results indicated that the prevalence of CML will continue to increase to reach a near plateau prevalence 35 times the annual incidence. These estimates should be considered in health care policies and in the design of future studies in CML. Cancer 2012;118: 3123–27. © 2012 American Cancer Society.     

Bosutinib: a third generation tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia

Bosutinib is an oral tyrosine kinase inhibitor (TKI) with very potent dual inhibitory activity against SRC and abelson gene. Bosutinib was approved in 2012 for the treatment of resistant Philadelphia chromosome positive chronic myeloid leukemia (CML). Bosutinib is a very effective TKI against all phases of intolerant or resistant CML regardless of the presence or absence of an abelson gene domain mutation, except for cases with detectable T315I or V299L. Bosutinib is overall well tolerated and associated with a unique, but manageable toxicity profile. Factors that influence the prescribing pattern of this drug are complex and include physicians’, and increasingly patients and families’ preference, patients’ comorbid conditions, schedule of administration, as well as financial factors. This paper provides an overview of CML, the TKI market, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of bosutinib.     

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: Definitions and clinical implications

Tyrosine kinase inhibitor (TKI) treatment targeting breakpoint cluster region-Abelson murine leukemia virus, the cause of chronic myeloid leukemia (CML), has revolutionized therapy for patients with this disease. The majority of patients with CML maintain favorable responses with long-term imatinib therapy; however, the availability of the second-generation TKIs nilotinib and dasatinib limits the need for patients intolerant to imatinib to continue with therapy. Unfortunately, there is currently no standard definition of intolerance to imatinib. Common Toxicity Criteria for grading adverse events, designed to identify acute toxicities, are often used to determine intolerance. However, because CML therapies are long-term, patient quality of life may provide a better measure of true intolerance. Several general methods of quantifying patient quality of life are in use for patients with CML, and a CML-specific variant of the M. D. Anderson Symptom Inventory is in development. An appropriate and consistent definition of intolerance will provide clinicians with an algorithm for managing their patients with severe or chronic adverse events during treatment with imatinib. As more long-term data become available for newer TKIs, the definition of intolerance in the context of CML treatment will continue to evolve to maximize the likelihood of durable responses and superior quality of life for patients.     

Suboptimal responses in chronic myeloid leukemia: implications and management strategies

The high response rates and increased survival associated with imatinib therapy prompted a paradigm shift in the management of chronic myeloid leukemia. However, 25% to 30% of imatinib-treated patients develop drug resistance or intolerance, increasing the risk of disease progression and poor prognosis. In 2006, the European LeukemiaNet proposed criteria to identify patients with a suboptimal response to, or failure associated with, imatinib; these recommendations were updated in 2009. Suboptimal responders represent a unique treatment challenge. Although they may respond to continued imatinib therapy, their long-term outcomes may not be as favorable as those for optimally responding patients. Validation studies demonstrated that suboptimal responders are a heterogeneous group, and that the prognostic implications of suboptimal response vary by time point. There are few data derived from clinical trials to guide therapeutic decisions for these patients. Clinical trials are currently underway to assess the efficacy of newer tyrosine kinase inhibitors in this setting. Identification of suboptimal responders or patients failing treatment using hematologic, cytogenetic, and molecular techniques allows physicians to alter therapy earlier in the treatment course to improve long-term outcomes.     

Bruton tyrosine kinase inhibitors for the frontline treatment of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (cll) is the most commonly diagnosed adult leukemia in Canada. Biologic heterogeneity of cll between patients results in variable disease trajectories and responses to therapy. Notably, compared with patients lacking high-risk features, those with such features—such as deletions in chromosome 17p, aberrations in the TP53 gene, or unmutated immunoglobulin heavy chain variable region genes—experience inferior outcomes and responses to standard chemoimmunotherapy. Novel agents that target the B cell receptor signalling pathway, such as Bruton tyrosine kinase (btk) inhibitors, have demonstrated clinical efficacy and safety in patients with treatment-naïve cll, particularly those with high-risk features. However, given the current lack of head-to-head trials comparing btk inhibitors, selection of the optimal btk inhibitor for patients with cll is unclear and requires consideration of multiple factors. In the present review, we focus on the efficacy, safety, and pharmacologic features of the btk inhibitors that are approved or under clinical development, and we discuss the practical considerations for the use of those agents in the Canadian treatment landscape.     

The effect of interleukin 11 on thrombocytopenia associated with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia

BACKGROUND.: During therapy with tyrosine kinase inhibitors (TKIs), approximately 20% to 50% of patients with chronic myeloid leukemia (CML) develop grade >/=3 thrombocytopenia leading to treatment interruptions and dose reductions. Interleukin 11 (IL-11) reduces the incidence and the severity of thrombocytopenia in solid tumors. METHODS.: The authors investigated the efficacy and safety of low-dose IL-11 for improving thrombocytopenia associated with TKI therapy in 14 patients with CML. The starting dose of IL-11 was 10 mug/kg 3 times weekly, and the dose was escalated by 1 dose level every 2 weeks if the patients had no sustained platelet increase. RESULTS.: The median patient age was 52 years. The median platelet count at the time IL-11 was started was 37 x 10(9)/L. All patients had prior TKI dose reductions. After the initiation of IL-11, 8 of 14 patients (57%) had an increase in platelet count with a median peak platelet count of 110 x 10(9)/L. One additional patient had no platelet increase but was able to tolerate an imatinib dose increase. Eleven patients had a decrease in the number of days of TKI therapy interruption secondary to thrombocytopenia after the initiation of IL-11 (6% of total treatment time vs 34% of total treatment time before IL-11). Therapy was well tolerated. CONCLUSIONS.: The current results indicated that IL-11 may correct thrombocytopenia associated with TKI therapy for patients with CML and that it has a favorable toxicity profile. Cancer 2008. (c) 2008 American Cancer Society.     

Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib

BACKGROUND:

Anemia is a frequent side effect of imatinib in patients with chronic myeloid leukemia (CML). Erythropoietic‐stimulating agents have been used for treatment of imatinib‐induced anemia. There are no data on long‐term safety of erythropoietic‐stimulating agents in CML patients.

METHODS:

The records of chronic phase CML patients who received treatment with imatinib were reviewed for use of erythropoietic‐stimulating agents and occurrence of thrombotic events. Data on cytogenetic response and survival were analyzed by use of erythropoietic‐stimulating agent.

RESULTS:

A total of 608 patients were included, and 217 patients received erythropoietic‐stimulating agents. There were 30 thrombotic episodes. Patients who received erythropoietic‐stimulating agents had a higher rate of thrombosis (8.5% vs 2.6%, P = .0025). There was no difference in cytogenetic response rate and survival by use of erythropoietic‐stimulating agent. Development of grade 3‐4 anemia occurred in 62 (10%) patients and was associated with significantly worse response and survival in patients in late chronic phase. By multivariate analysis, use of erythropoietic‐stimulating agents was not a risk factor for event‐free survival.

CONCLUSIONS:

In our cohort of chronic phase CML patients, use of erythropoietic‐stimulating agents did not impact survival or cytogenetic response rate, but was associated with a higher thrombosis rate. Severe anemia is associated with worse survival and response. Cancer 2011. © 2010 American Cancer Society.