Vascular safety profile of new generation BCR-ABL tyrosine kinase inhibitors in the treatment of chronic myeloid leukaemia

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1 45 Vascular safety profile of new generation BCR-ABL tyrosine kinase inhibitors in the treatment of chronic myeloid leukaemia H. Haguet, MBS 1,2, J. Douxfils, PharmD, PhD1, F. Mullier, PharmD, PhD2, C. Chatelain, MD1, C. Graux, MD, PhD3, J-M. Dogné, PharmD, PhD1 SUMMARY Tyrosine kinase inhibitors targeting BCR-ABL have been a real revolution in the treatment of chronic myeloid leukaemia, greatly improving surrogate outcomes and overall survival. However, new generation BCR-ABL tyrosine kinase inhibitors have recently been associated with occurrence of cardiovascular events. Indeed, during ponatinib clinical development, a high rate of patients with chronic myeloid leukaemia developed a vascular occlusive event. Retrospective analyses also demonstrated an increased incidence of similar events with nilotinib. Recently, a meta-analysis of randomised clinical trials confirmed this risk with nilotinib and ponatinib, but also identified dasatinib at higher risk of cardiovascular events than imatinib. Sub-analysis of this meta-analysis and retrospective studies indicated predominance of arterial events rather than venous. The number of patients treated with dasatinib and nilotinib has considerably increased since they have been approved in first-line indication for patients with chronic-phase chronic myeloid leukaemia. In this context, the evaluation of the benefit-risk profile of these treatments is important, and implementation of measures to minimise the onset of cardiovascular events are required. They should include the selection of patients treated with new generation tyrosine kinase inhibitors, the monitoring of cardiovascular events and risk factors during treatment, and if required, the treatment of cardiovascular comorbidities. The pathophysiology of these events is probably multifactorial. Numerous hypotheses have already been advanced and suggest a worsening of the metabolic syndrome, an increase of atherosclerosis development and an impact of new generation tyrosine kinase inhibitors on off-targets related to vascular function. (BELG J HEMATOL 2017;8(2):45-52) INTRODUCTION Tyrosine kinase inhibitors (TKIs) have been designed to target BCR-ABL, inhibit the catalytic activity of the kinase by occupying the ATP-binding site and consequently, inhibit the activation of signalling downstream pathways. 2 This approach was a real breakthrough in 1 Department of Pharmacy, University of Namur, Namur Thrombosis and Haemostasis Centre (NTHC), Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium, 2Haematology laboratory, Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Haemostasis Centre (NTHC), Namur Research Institute for Life Sciences (NARILIS), Yvoir, Belgium, 3Department of Haematology, Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Haemostasis Centre (NTHC), Namur Research Institute for Life Sciences (NARILIS), Yvoir, Belgium. Please send all correspondence to: H. Haguet, MBS, Namur Thrombosis and Haemostasis Centre (NTHC), Department of Pharmacy, Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium, tel , fax , . helene.haguet@unamur.be. Conflict of interest: F. Mullier reports personal fees from Boehringer Ingelheim, Bayer Healthcare and Bristol-Myers Squibb-Pfizer outside the submitted work. C. Graux reports personal fees from Novartis, Celgene, and Amgen, outside the submitted work. The other authors have no conflicts of interest to disclose. Keywords: arterial occlusive disease, BCR-ABL positive, chronic, leukaemia, myelogenous, protein kinase inhibitors, review, venous thrombosis. VOLUME8M A R C H2017

2 REVIEW HEMATOLOGY 46 the treatment of Philadelphia-positive (Ph+) chronic myeloid leukaemia (CML). The approval of the first BCR-ABL TKI, imatinib, significantly improved the 10-year overall survival of patients with CML in chronic phase (CP) from almost 20 to 80-90%. 3 However, resistances against imatinib emerge in 20% of patients, and a further 20% do not tolerate it. 4 To overcome resistance, second and third generations TKIs have been developed. The current treatment aim is to achieve deep and stable molecular response (i.e. MR4 or higher molecular response stable for at least two years) to potentially try treatment discontinuation. In comparison with imatinib, the second generation TKIs dasatinib and nilotinib have demonstrated a higher rate of newly diagnosed patients reaching these criteria, leading to the approbation of these two drugs in first-line setting to treat patients with CP-CML. 5 Current guidelines do not recommend a particular TKI (imatinib, dasatinib or nilotinib) for initial treatment of CP-CML. 6 The approval of dasatinib and nilotinib in this indication increased the number of patients exposed to these drugs, thereby increasing the need of correct benefit-risk profile assessment for these treatments. The other two new generation BCR-ABL TKIs, ponatinib and bosutinib, are approved for the treatment of patients with CML resistant or intolerant to first-line treatment and, for ponatinib, in patients with the T315I mutation. 7 During ponatinib phase I (NCT ) and phase II (NCT ) clinical trials, at least 27% of patients developed arterial or venous thrombosis, causing the temporal suspension of ponatinib marketing in the United States, the early termination of the phase III clinical trial (NCT ) and the design of a risk management plan. 8,9 Several and serious cases of peripheral arterial occlusive diseases (PAOD) were also reported with nilotinib Little is known regarding these risks with bosutinib and dasatinib, but no signals were identified during clinical trials. The aim of this article is to provide an actual review of the risk of cardiovascular events with new generation BCR-ABL TKIs, and raise potential measures to minimise this risk. A review of the pathophysiology of these events will also be provided. CARDIOVASCULAR SAFETY PROFILE OF NEW GENERATION TKIS RISK OF VASCULAR OCCLUSIVE EVENTS WITH NEW GENERATION TKIS The assessment of the cardiovascular risk during oncology clinical trials is challenging, and the occurrence of vascular occlusive events in patients with CML receiving BCR-ABL TKIs has probably been underestimated during clinical development. 13 Indeed, Chai- Adisaksopha et al. have recently demonstrated, through a meta-analysis, higher incidence of major arterial events in observational studies than clinical trials. 14 This may be explained by the exclusion of patients with severe cardiac or metabolic comorbidities (e.g. exclusion of patients with prior history of myocardial infarction) in most of the clinical trials. 13 Moreover, vascular occlusive events might be associated with relatively common comorbidities and are less likely to be reported as drug-related because of the prevalence of the underlying conditions. This is particularly relevant in patients with CML, a population with a median age at diagnosis of approximately 60 years in Europe, who generally have several comorbidities. 15,16 Therefore, the combination of data from clinical trials through a meta-analysis increases the statistical power to detect cardiovascular events. Our research group recently demonstrated through a meta-analysis of ten randomised clinical trials, a 3-fold increase of the risk of vascular occlusive events with new generation TKIs compared with imatinib in patients with CML (OR PETO, 3.45; 95%CI, ) (Figure 1). 1 Stratifications by treatment indicated that nilotinib (OR PETO, 3.42; 95%CI, ), dasatinib (OR PETO, 3.86; 95%CI, ) and ponatinib (OR PETO, 3.47; 95%CI, ) were all associated with a significant increase of this risk. The meta-analysis indicated a non-significant trend with bosutinib toward increased rate of vascular occlusive events (OR PETO, 2.77; 95%CI, ). 1 Yet, the statistical power of the bosutinib sub-analysis is low (only one trial included, few events in both arms) and bosutinib cardiovascular safety requires additional investigation. ARTERIAL AND VENOUS OCCLUSIVE EVENTS ASSOCIATED WITH BCR-ABL TKIS Additional sub-analysis of the meta-analysis demonstrated that both venous and arterial occlusive events were increased with new generation TKIs compared with imatinib. 17 However, the absolute risk of arterial occlusive disease overshadows the risk of venous thrombosis in patients with CML treated with new generation TKIs. 17 This distinction is important to determine the best strategies to minimise the risk of vascular occlusive events and to direct mechanistic studies. Ponatinib, nilotinib and dasatinib were all associated with a higher risk of arterial occlusive events than imatinib. 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3 47 FIGURE 1. Forest plot of the vascular occlusive events in patients with Ph+ leukaemia treated with new generation TKIs versus imatinib. These results are in accordance with the phase II (NCT ) and phase III (NCT ) ponatinib clinical trials, in which more than 20% of ponatinib-treated patients developed arterial occlusive events compared with only 5% that developed venous thromboembolic events. 18,19 During clinical trials, nilotinibtreated patients also reported lower rate of venous thromboembolism than arterial occlusive disease. 20 This risk is present both in patients previously treated with imatinib and in untreated patients. 17 A limitation of our meta-analysis is that imatinib might bias the pro-thrombotic effect observed with new generation TKIs, as it was the only comparator used in randomised clinical trials. Interestingly, rates of vascular occlusive events were low in imatinib arms, and several studies reported that imatinib might actually reduce the development of atherosclerosis CLINICAL FEATURES OF VASCULAR OCCLUSIVE EVENTS WITH NEW GENERATION TKIS The absolute rate of vascular occlusive events differs between new generation TKIs and varies among retrospective studies (Table 1). This variation depends of the size of the cohort, the population, the definition of a cardiovascular event (e.g. inclusion of hypertension) and the length of follow-up. Dosage of nilotinib and ponatinib has been reported to impact the incidence of these events. 24,25 With nilotinib, vascular occlusive events occurred between 1.2% to almost 15% of patients with CML. 26 The link between nilotinib and cardiovascular events has clearly been described in casereports and retrospective analyses, and was confirmed by temporal association (i.e. stabilisation or improvement of the cardiovascular events following nilotinib suspension; reoccurrence of the side effect associated with nilotinib rechallenge). 27,28 Moreover, the measure of the ankle-brachial index (ABI) in both imatinib- and nilotinib-treated patients to evaluate the total number of patients with PAOD (i.e. symptomatic and asymptomatic patients) revealed a significant increased rate of pathological ABI (<0.9) with nilotinib compared with imatinib, but also compared with the normal population. 29 However, the comparison with the normal population was performed using historical data, which might bias the analysis. Finally, the risk of vascular events with nilotinib appears persistent over time, with linear increase of this risk and no plateau obtained after almost 100 months of follow-up. 24,30 Oppositely, the rate of vascular occlusive events is not constant over time in ponatinib-treated patients. Vascular occlusive events appeared more frequently during the first and second year of treatment (14.5% and 14.1%; respectively) than after (10.5% during the third year, 7.2% after three years). 19 Since the risk of vascular occlusive events with dasatinib was recently identified, the frequency of these events has not yet been reported and needs to be assessed. CARDIOVASCULAR RISK MINIMISATION MEASURES Risk minimisation measures have already been applied with ponatinib but still need to be implemented with dasatinib and nilotinib. 31 They should include the selection of patients treated with new generation TKIs, the monitoring during treatment and, if required, the treatment of cardiovascular comorbidities. VOLUME8M A R C H2017

4 REVIEW HEMATOLOGY 48 SELECTION OF BCR-ABL TKI FOR PATIENTS WITH CML The choice of first-line therapy should be based on the aim of treatment, the safety profile of the TKIs and the patient s characteristics in order to select patients who will benefit from new generation TKIs, and avoid new generation TKIs when a safer alternative treatment (i.e. imatinib) is available. For elderly patients, improving the survival is the predominant objective, and imatinib remains an excellent choice of first-line treatment. 4 Oppositely, patients with a life expectancy greater than ten years aimed to achieve a deep molecular response to potentially try drug cessation. 4 In this context, dasatinib and nilotinib seem more appropriate. 4 The choice of first-line treatment also requires a screening for potential risk factors to identify patients at low- and intermediate-risk of cardiovascular events. 32 Several case-reports, retrospective and prospective analyses investigated relationships between pre-existing risk factors and vascular occlusive events. They demonstrated that arterial occlusive events developed predominantly in patients with at least one risk factor prior to nilotinib or ponatinib initiation (i.e. hypertension, diabetes, hyperlipidaemia, obesity, smoking or prior vascular disease) (Table 1). 12,33-35 Recently, the Systematic Coronary Risk Evaluation (SCORE) chart (i.e. score offering a 10-year risk estimation of fatal cardiovascular disease) has been retrospectively applied in nilotinibtreated patients, and demonstrated accurate capacity to classify patients according to their cardiovascular risk. 36 Yet, this score does not take into account hyperglycaemia and hypercholesterolemia, and two other predictive algorithms were experienced in the same population (i.e. the Fragmingham risk score and the QRISK2). 37 Even if the three scores effectively predicted patients at high-risk of cardiovascular events, the QRISK2 algorithm demonstrated a greater ability to identify high-risk patients. 37 Similar analyses should be performed prospectively in larger population to confirm the usefulness of these algorithms, and should also be assessed with other new generation TKIs. Choices of second- and third-line treatment are based on the mutational analysis and the medical condition of the patient. In case of intolerance or resistance, it is recommended to switch to one of the other TKI approved for first-line. 38 If failure occurs, a more potent TKI is preferred. In this setting, ponatinib, and to a lesser extent bosutinib, should be considered as potential treatment. 38 If the patient developed the T315I mutation, ponatinib is clearly the rationale choice since it is reserved for patients with serious conditions, and must be avoided in patients with good prognosis, such as patients with CML in chronic phase without the T315I mutation. 38 MONITORING OF RISK FACTORS AND VASCULAR OCCLUSIVE EVENTS DURING TREATMENT WITH BCR-ABL TKIS The monitoring of vascular occlusive events is necessary throughout the duration of treatment with a new generation TKI. Indeed, events developed with nilotinib with a mean delay of several years but with large variability between patients (from a few months to more than six years). 24 Time to event tends to be longer in young patients and in patients without cardiovascular risk factors at baseline, whereas it appears shorter with dasatinib (19-22 months) and ponatinib ( months). 19,27,39-41 Physicians should regularly reassess patients cardiovascular risk factors in all patients treated with a new generation TKI (i.e. not only those with prior risk factors). 42 Indeed, most cardiovascular events occurred with ponatinib and nilotinib in patients with prior cardiovascular risk factors, but a few events also occurred in young patients without risk factors. 39,43 This monitoring should cover arterial hypertension, hypercholesterolemia, diabetes, obesity and smoking. Metabolic disorders (hyperglycaemia and hypercholesterolemia) should especially be monitored with nilotinib, as it was demonstrated that nilotinib could quickly induce them (i.e. within three months). 44 Nilotinib-induced hypercholesterolemia appeared reversible after treatment cessation and manageable by statins or lifestyle and dietary measures. However, there is currently no proof that the decrease of total cholesterol and LDL by statins reduces cardiovascular morbidity and mortality associated with nilotinib. Diabetes and arterial hypertension should be managed during new generation TKI treatment following standard of care. The effect of antiplatelet therapies is currently unknown. To date, only one retrospective study evaluated the impact of aspirin on the prevention of vascular occlusive events, and did not demonstrate any effect. 46 Discovery of biomarkers able to predict cardiovascular events in patients treated with new generation TKIs are needed. With this aim, a recent prospective study analysed the association between hyperhomocysteinemia and cardiovascular events in nilotinib- and imatinib-treated patients. Homocysteine is a sulphur containing amino acid derived from methionine linearly VOLUME8M A R C H20172

5 49 TABLE 1. Characteristics of vascular occlusive events associated with three new generation BCR-ABL TKIs. BCR-ABL TKIs Characteristics Nilotinib Ponatinib Dasatinib Relative risk of VOE* (OR; 95%CI) 3.42 ( ) ( ) ( )1 Absolute risk of VOE % 26 AOE. 12.2%/year 19 VTE. 2.1%/year 19 Unknown VOE-associated risk factors Age >60 years 39 Dyslipidaemia 27 Gender. male 24 High dose (800mg/day) 24 Age >60 years Prior history of VOE Arterial hypertension Diabetes High dose (45mg/day) Unknown Time to event months months 19, months 40 Relevant side effects associated with TKI Hyperglycaemia, Arterial hypertension Pulmonary hypertension 58 hypercholesterolemia 54 * In comparison with imatinib. Retrospective studies are discording considering gender as risk factor of CV events with nilotinib. AOE. arterial occlusive events; TKI. tyrosine kinase inhibitor; VOE. vascular occlusive events; VTE. venous thromboembolism. linked to cardiovascular event onset. No significant difference was reported in median homocysteine level between patients treated with imatinib and nilotinib, but a significant increase of cardiovascular events was reported when homocysteine is above a threshold (i.e μmol/l). 24 Nevertheless, it is currently unknown if high level of homocysteine is the cause or the consequence of cardiovascular events, and there is no relationship between the level of homocysteine and the type of event. 24 POTENTIAL MECHANISMS INVOLVED IN THE PATHOGENESIS OF ARTERIAL OCCLUSIVE EVENTS BCR-ABL TKIs have different vascular safety profiles from each other, and several potential mechanisms could be suggested to explain the vascular occlusive events. 18 Based on the current knowledge and a comprehensive review of the literature, we could hypothesise distinct options: either new generation TKIs increase the risk of arterial occlusive events, imatinib decreases the burden of atherosclerosis or both mechanisms occur. OFF-TARGET EFFECTS OF TYROSINE KINASE INHIBITORS BCR-ABL TKIs are not highly specific to BCR-ABL, and can therefore inhibit other kinases at diverse potency and activity. 20 All new generation BCR-ABL TKIs are less specific than imatinib, and ponatinib and dasatinib are able to inhibit a large panel of tyrosine kinases. 47 These off targets include tyrosine kinases involved in vascular biology. Therefore, inhibition of these kinases might be involved in the occurrence of vascular occlusive events. 20 Several hypotheses have already been emitted and include the inhibition of PDGFR, a tyrosine kinase involved in the migration and proliferation of VSMCs. 48 The VEGFR family is inhibited by ponatinib at physiological concentration, and is involved in the maintenance and integrity of the endothelium. 47,48 The tyrosine kinases DDR1 and TIE2 are also suspected to be implicated in the occurrence of vascular occlusive events and are associated with atherosclerosis and vascular function respectively. 35,48 Finally, the alteration of BCR-ABL itself has been reported to potentially be involved in the development of dyslipidaemia and atherosclerosis, due to its effect on the insulin receptor pathway. 48 VOLUME8M A R C H2017

6 REVIEW HEMATOLOGY 50 KEY MESSAGES FOR CLINICAL PRACTICE 1 Nilotinib, dasatinib and ponatinib increase the risk of vascular occlusive events. 2 This risk is predominantly arterial but new generation TKIs also increase risk of venous thromboembolic events. 3 Risk factor assessment and monitoring should be implemented in patients treated with new generation TKIs. 4 Underlying mechanisms of arterial occlusive events are currently unknown and should be investigated. IMPACT OF BCR-ABL TKIS ON ATHEROSCLEROSIS Atherosclerosis is a potential mechanism for several reasons. Foremost, this is the main pathological process underlying cardiovascular disease. 44 Secondly, nilotinib-treated patients with high vascular risk at baseline develop higher rates of vascular occlusive events, supporting the hypothesis that nilotinib may aggravate pre-existing atherosclerotic lesions. 26,42 With nilotinib, the development of arterial occlusive events tends to take longer than cardiovascular events associated with ponatinib. 30 One reasonable hypothesis is that nilotinib aggravates pre-existing arteriosclerotic lesions. 20 In vivo and in vitro investigations demonstrated that nilotinib promotes plaque formation and atherosclerosis in ApoE knock-out mice, and inhibits the migration and proliferation of endothelial cells. 49,50 Moreover, nilotinib also promotes the expression of adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in these cells. 49,50 The rapid onset of arterial occlusive events with ponatinib may suggest an increased risk of plaque rupture or erosion that lead to the genesis of arterial thrombosis. To date, no investigation has been performed on dasatanib. Conversely, imatinib has been associated with potential reduction of atherosclerosis development, which may be explained by a decrease in the uptake of LDL by macrophages, and a reduction of the activity of two metalloproteinases involved in atherosclerosis (i.e. MMP-2 and MMP-9). 23 Imatinib also decreases smooth muscle cell viability and prevents their growth and migration, two phenomena implicated in atherosclerosis development. 51 IMPACT OF BCR-ABL TKIS ON GLUCOSE AND LIPID METABOLISM As previously described, nilotinib is strongly associated with metabolism impairment, and induces rapid elevation in blood glucose, total cholesterol and LDL level The development of diabetes-like PAOD (i.e. involvement of small vessels of the lower extremities) in nilotinibtreated patients confirmed the suspicion of nilotinib impact on metabolism. 35 The cause of nilotinib-induced hypercholesterolemia is currently unknown, but could be due to increased hepatic synthesis or impaired cholesterol clearance from the bloodstream. 44 It has been reported that glucose metabolism is rather altered via a rapid development of tissue insulin resistance and compensatory hyperinsulinemia, without impairment of β-cell function. 53 One hypothesis is that hyperglycaemia leads to an increase of PAI-1 plasma level, which decreases the fibrinolysis and accelerates atherosclerosis by exposing vascular luminal wall surfaces. 55 Insulin resistance is also associated with endothelial damage and increased levels of several prothrombotic factors. 49,56 The metabolic effect of nilotinib was confirmed in vivo, in a mouse model of hind limb ischemia, in which it was found that nilotinib slows blood flowrecovery after induction of ischemia. 49 The fact that nilotinib induces metabolic disorders (i.e. hyperglycaemia and hypercholesterolemia) is a possible mechanism by which nilotinib accelerates atherosclerosis, but is not sufficient to explain all the cases (i.e. in case of low time to event). 29 Conversely, dasatinib and imatinib are associated with improvement of glycaemic control in diabetic patients. 57 In a rat model, imatinib decreased insulin resistance and hepatic glucose production, and in prediabetic mice, imatinib reversed type 1 diabetes and attenuated diabetes-induced atherosclerosis. 20,57 However, to date, no relationship between metabolism dysregulation and development of cardiovascular events has been established with new generation TKIs. 42 CONCLUSIONS Recently, nilotinib and dasatinib have been approved VOLUME8M A R C H20172

7 51 as first-line treatment for patients with CP-CML, which extends the number of patients exposed to these drugs. However, additionally to ponatinib, these two treatments have recently been associated with increased risk of arterial occlusive events. Therefore, selection of patients receiving new generation TKIs as first-line treatment should be performed based on disease characteristics, patient risk factors and the aim of treatment. Physicians should also perform monitoring of cardiovascular events and risk factors during treatment in every patient. To date, the pathophysiology of these events is still unknown but future research should assess the impact of these treatments on atherosclerosis. REFERENCES 1. Douxfils J, Haguet H, Mullier F, et al. Association between bcr-abl tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: A systematic review and meta-analysis. 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