Invited reviewRisk factors and mechanisms contributing to TKI-induced vascular events in patients with CML☆
Introduction
Chronic myeloid leukemia (CML) is a hematopoietic malignancy defined by uncontrolled, clonal expansion of myelopoietic cells carrying the BCR-ABL1 oncogene [1], [2]. The natural course of CML can be divided into a (mostly unrecognized) pre-leukemic (very early) phase with normal blood counts, and 3 clinically relevant phases: a chronic (indolent) phase (CP), an accelerated phase (AP), and a blast phase (BP) [1], [2], [3]. In CP, leukemic cells are largely addicted to the kinase activity of BCR-ABL1. As a result, the BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib is an effective agent in the treatment of patients with CP CML [4], [5], [6], [7]. However, not all patients enter long-term disease-free survival with imatinib. Other patients develop intolerance against the drug. Resistance against imatinib often develops in the context of BCR-ABL1 mutations [8], [9], [10], [11], [12], [13]. Other mechanisms of resistance have also been described. These include, among others, pharmacologic resistance, intrinsic stem cell resistance, and BCR-ABL1 amplifications [9], [11], [14], [15]. In addition, apart from BCR-ABL1, the CML clone acquires multiple additional mutations during disease evolution which may (also) contribute to drug resistance [16]. Furthermore, even before BCR-ABL1 is acquired, clonal hematopoiesis may exist and may contain clinically relevant mutations in various target genes [15], [16], [17]. This early clonal (pre-CML) phase may explain the rare occurrence of a ́BCR-ABL1-negativé, TKI-resistant, relapse [17].
The treatment of imatinib-resistant patients with CML is still a challenging problem in clinical hematology. For high-risk patients who are young and fit, stem cell transplantation (SCT) is often recommended [18], [19]. In other patients, second- or third-generation BCR-ABL1-targeting TKI, including nilotinib, dasatinib, bosutinib, or ponatinib, can be prescribed. Indeed, it has been reported in various studies that these agents exert major anti-leukemic effects in patients with imatinib-resistant CML [20], [21], [22], [23], [24], [25]. In addition, these TKI reportedly induce complete cytogenetic (CCyR) and major molecular (MMR) responses in most patients with freshly diagnosed CML [26], [27], [28], [29]. The efficacy of these drugs in newly diagnosed patients apparently exceeds the efficacy of imatinib, which may be explained by the very strong effect of these agents on wild type BCR-ABL1, their effects on various BCR-ABL1 mutants, as well as their effects on additional drug targets [30], [31], [32], [33]. However, many of these targets are also displayed by non-hematopoietic cells and therefore may be responsible for non-hematologic side effects, including vascular adverse events (VAE). In many CML patients treated with second-generation TKI, side effects are mild [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. However, in other patients, severe organ damage is found. Although not recognized in initial studies, VAE have recently been identified as a clinically relevant issue in TKI-treated patients [34], [35], [36].
Section snippets
Each of the second-generation BCR-ABL1 TKI exhibits a unique profile of adverse events (AE), but most TKI produce VAE
For each of the BCR-ABL1 TKI, specific profiles of AE have been reported (Table 1). Pleural and/or pericardial effusions occur typically and rather specifically in patients treated with dasatinib [21], [27], [37], [38], [39]. The frequency of pleural effusions is lower in cases receiving 100 mg dasatinib per day compared to those treated with 140 mg dasatinib daily [38], [39]. However, even at 100 mg daily, pleural effusions develop and accumulate over time [40]. Pulmonary hypertension and VAE
Frequencies of VAE in TKI-treated patients with CML
The exact incidence of VAE occurring during treatment with TKI is still a matter of debate. As mentioned before, this type of AE was overlooked in early reports of clinical trials − therefore the incidence of VAE in these studies could not be provided [20], [26]. In consecutive (mostly retrospective) analyses, the reported incidence of VAE in nilotinib-treated patients with CML varied from study to study, and from center to center. In larger multi-center trials the frequency of VAE observed
Risk factors predisposing for the development of VAE
VAE may preferentially develop in those TKI-treated patients who have pre-existing risk factors and co-morbidities. In most CML patients under nilotinib or ponatinib where recurrent VAE were reported, one or more risk factors for the evolution of atherosclerosis were identified [34], [35], [36], [44], [51], [52], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68]. These factors include age, sex, adiposity, arterial hypertension, smoking, diabetes mellitus, and hypercholesterolemia
Target cells of nilotinib and ponatinib potentially involved in TKI-induced VAE
A number of different target cells may be involved in TKI-induced VAE and TKI-mediated metabolic changes (Table 3). Because of the relatively short time-interval (often within 12 months) between drug exposure and occurrence of VAE, direct TKI effects on vascular cells have been postulated [36], [52], [67]. Some experts believe that nilotinib and ponatinib can even provoke vasospasms or rapid stenosis in larger or smaller arteries [50], [53]. Based on recent studies, there is now good evidence
Molecular targets and potential molecular mechanisms contributing to TKI-induced VAE
Nilotinib and ponatinib interact with a considerable number of clinically relevant (́vasculaŕ) targets in endothelial cells. Whereas many of these targets are also identified by imatinib, others are selectively recognized and blocked by nilotinib and/or ponatinib. Molecular nilotinib-targets that are spared by imatinib include Tie-2/TEK, ABL2, JAK1, and several MAP kinases (Table 4) [67], [79], [80]. Tie-2/TEK is a well-known vascular target that has been implicated in the pathogenesis of
Prevention of VAE in patients with CML by applying personalized medicine approaches
Based on the clinical impact of VAE concerning morbidity, mortality, and quality of life as well as the relatively good prognosis in CP CML, it seems of utmost importance to avoid drug-induced development of VAE in all patients, regardless of age and other factors. It is also important to state that VAE can develop at any age and that VAE may be a reason to exclude patients from SCT. A first important step in prevention is proper patient-selection and selection of the optimal second- or
Management of VAE in patients with CML
Once a VAE has been detected in a patient with TKI-treated CML, all relevant organs need to be examined for the presence of vascular changes. Then, the type of pathology and the grade of the arterial occlusive disease (e.g. PAOD grade) has to be determined. Management and treatment of these patients depend on the overall situation in each case. For example, in cases with grade I or II PAOD, optimal anti-PAOD therapy and elimination of cardiovascular risk factors as much as possible (smoking,
Concluding remarks and future perspectives
During the past few years, the mechanisms that may contribute to the development of cardiovascular events in TKI-treated patients with CML have been examined and have in part been deciphered. Accumulating evidence suggests that multiple mechanisms act together to cause VAE in these patients. Key factors are conventional cardiovascular risk factors, like age, diabetes mellitus, or hypertension; molecular risk factors such as age-related clonal (somatically mutated) hematopoiesis; and
Authorship
All authors contributed by joining in vital discussions, by drafting parts of the article, by preparing the Tables, and by critical reading the document. All authors approved the final version of the manuscript.
Disclosures
The authors declare that they have the following conflict of interest to disclose for this study: P.V. had a consultancy with Novartis, received a research grant from Novartis, and received honoraria from Novartis, BMS, Pfizer, and Ariad. G.H. received honoraria from Novartis and Ariad. G.H.S. received honoraria from Amgen, Astra Zeneca, Boehringer Ingelheim, BMS, Daiichi Sankyo, Elli Lilly, Medtronic, Menarini, Merck, Merck Sharp & Dohm, Novo-Nordisk, Novartis, Pfizer, Sanofi, Sanofi-Aventis,
Acknowledgements
This study was supported by: Austrian Science Fund (FWF), projects SFB F4701-B20 and SFB F4704-B20. We like to thank Uwe Rix for helpful discussion.
References (101)
- et al.
The biology of CML blast crisis
Blood
(2004) Perspectives on the development of a molecularly targeted agent
Cancer Cell
(2002)- et al.
Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment
Blood
(2008) - et al.
Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia
Blood
(2007) - et al.
Resistance to imatinib: mutations and beyond
Semin. Hematol.
(2010) - et al.
Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: a clinical perspective and emerging treatment options
Clin. Lymphoma Myeloma Leuk.
(2013) - et al.
Maciejewski JP. CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia
Blood
(2011) - et al.
Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: an evolving treatment paradigm
Clin. Lymphoma Myeloma Leuk.
(2015) - et al.
Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib
Blood
(2011) - et al.
Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure
Blood
(2012)
Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets
Blood
Extended kinase profile and properties of the protein kinase inhibitor nilotinib
Biochim. Biophys. Acta
Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors
Blood
Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia
Leuk. Res.
Nilotinib-associated vascular events
Clin. Lymphoma Myeloma Leuk.
Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial
Lancet Oncol.
Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure
Blood
Assessment of cardiovascular events in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors
Blood
Cardiovascular events among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs)
Blood
Analysis of clinical arterial and metabolic parameters in chronic phase CML patients on nilotinib in a single center cohort
Blood
Real-life comparison of severe vascular events and other non-hematological complications in CML patients treated with second line nilotinib or dasatinib
Blood
Peripheral arterial occlusive disease (PAOD) in chronic phase chronic myeloid leukemia patients treated with nilotinib
Blood
Identification of patients (pts) with chronic myeloid leukemia (CML) at high risk of artery occlusive events (AOE) during treatment with the 2nd generation tyrosine kinase inhibitor (TKI) nilotinib using risk stratification for cardiovascular diseases (CVD)
Blood
Adverse events (AE) under imatinib treatment over 10 years: results from 1501 patients of the randomized CML-study IV
Blood
Further evaluation of pro-Atherogenic and anti-Angiogenic effects of nilotinib in mice and in patients with Ph-Chromosome+ CML
Blood
Ponatinib exerts multiple effects on vascular endothelial cells: possible mechanisms and explanations for the adverse vascular events seen in CML patients treated with ponatinib
Blood
A genetic risk score for insulin resistance identifies patients with chronic myeloid leukemia treated with nilotinib developing diabetes
Blood
AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutationbased resistance
Cancer Cell
Pleiotropic role for monocyte C-fms protein in response to vascular injury: potential therapeutic target
Atherosclerosis
Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease
Kidney Int.
Endothelial IGF-1 receptor signalling in diabetes and insulin resistance
Trends Endocrinol. Metab.
Practical issues surrounding the explosion of tyrosine kinase inhibitors for the management of chronic myeloid leukemia
Blood Rev.
Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: an evolving treatment paradigm
Clin. Lymphoma Myeloma Leuk.
Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial
Lancet Oncol.
The biology of chronic myeloid leukemia
N. Engl. J. Med.
Chronic myeloid leukaemia as a model of disease evolution in human cancer
Nat. Rev. Cancer
Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia
N. Engl. J. Med.
Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV
Leukemia
Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia
Cancer Control.
New tyrosine kinase inhibitors in chronic myeloid leukemia
Haematologica
Monitoring response to tyrosine kinase inhibitor therapy, mutational analysis, and new treatment options in chronic myelogenous leukemia
J. Natl. Compr. Canc. Netw.
Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies
Leukemia
Emerging stem cell concepts for imatinib-resistant chronic myeloid leukaemia: implications for the biology, management, and therapy of the disease
Br. J. Haematol.
Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status
Leukemia
Diagnosing and managing advanced chronic myeloid leukemia
Am. Soc. Clin. Oncol. Educ. Book
Nilotinib in imatinib-resistant CML and philadelphia chromosome-positive ALL
N. Engl. J. Med.
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias
N. Engl. J. Med.
Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial
Br. J. Haematol.
Ponatinib in refractory Philadelphia chromosome-positive leukemias
N. Engl. J. Med.
Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia
N. Engl. J. Med.
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Supported by: Austrian Science Fund (FWF) SFB projects F4701-B20 and F4704-B20.