Peripheral arterial occlusive disease (PAOD) occurs in patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs). The risk of developing PAOD on TKI therapy is unknown and causality has not been established. Patients with CML-CP from three randomized phase III studies (IRIS, TOPS and ENESTnd) were divided into three cohorts: no TKI (cohort 1; n=533), nilotinib (cohort 2; n=556) and imatinib (cohort 3; n=1301). Patients with atherosclerotic risk factors were not excluded. Data were queried for terms indicative of PAOD. Overall, 3, 7 and 2 patients in cohorts 1, 2 and 3, respectively, had PAOD; 11/12 patients had baseline PAOD risk factors. Compared with that of cohort 1, exposure-adjusted risks of PAOD for cohorts 2 and 3 were 0.9 (95% CI, 0.2–3.3) and 0.1 (95% CI, 0.0–0.5), respectively. Multivariate logistic regression revealed that nilotinib had no impact on PAOD rates compared with no TKI, whereas imatinib had decreased rates of PAOD compared with no TKI. Nilotinib was associated with higher rates of PAOD versus imatinib. Baseline assessments, preferably within clinical studies, of PAOD and associated risk factors should occur when initiating TKI therapy in CML; patients should receive monitoring and treatment according to the standard of care for these comorbidities.
Protein kinase function in vascular endothelial cells and/or cardiac myocytes may be unintentionally altered by tyrosine kinase inhibitors (TKIs) used for the treatment of cancer.1, 2 TKIs, including sunitinib and sorafenib, have been shown to affect the vasculature, as well as the overall cardiovascular safety, of patients with metastatic renal cell carcinoma.3, 4, 5 Recently, there have been several reports of peripheral arterial occlusive disease (PAOD) in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) who are treated with the TKI nilotinib.6, 7, 8, 9, 10, 11 PAOD is characterized by the presence of a stenosis or occlusion in the arteries of the limbs and is usually caused by atherosclerosis, which is a systemic disease.12 Nilotinib is a more potent and selective inhibitor of the tyrosine kinase activity of Abl, and the oncogenic BCR-ABL kinase, than imatinib and is associated with greater response and protection from progression in CML-CP, albeit with a higher incidence of laboratory abnormalities including hyperglycemia and hypercholesterolemia in comparison with imatinib.13 The prevalence of PAOD increases with age and is associated with common cardiovascular risk factors, including hypercholesterolemia, hypertension, diabetes, smoking, family history and preexisting vascular disease.14, 15, 16, 17 In patients with these risk factors, the prevalence of PAOD, including asymptomatic PAOD, is 1 in 3 (as measured by an ankle brachial index (ABI) of ⩽0.90, if documented in the medical record, or if there was a history of limb revascularization).12 While the condition is asymptomatic in ∼50% of patients, those with symptomatic PAOD can experience claudication (15%), limb symptoms (33%) or critical limb ischemia (2%) and may require serious interventions, including amputation.14, 15, 16 PAOD co-manifests and derives from similar risk factors as cardiovascular disease or atherosclerosis.18 Arterial events including PAOD have also been recently reported with the TKI ponatinib, which was recently granted accelerated FDA approval for the treatment of patients with CML in any phase, who have failed or become intolerant to prior TKI therapy, leading to a boxed warning for arterial thrombosis.19 All patients who had received ponatinib had received prior therapy with other TKIs, with over half having received three or more TKIs including imatinib and/or nilotinib and/or dasatinib, often for extended periods of time.
Reports of PAOD in patients with CML-CP treated with nilotinib have come from case studies6, 7 and from a prospective analysis that included on-treatment screening from two centers where these cases were reported.8, 20 This analysis reported elevated rates of PAOD for nilotinib as compared with imatinib by screening with on-treatment ABI and showed an elevation of both cholesterol and LDL in nilotinib-treated patients. Further cases from other sites have been reported in patients on the Evaluating Nilotinib Efficacy and Safety in clinical Trials—newly diagnosed patients (ENESTnd) study.13 With a minimum of 4 years of follow-up in ENESTnd, nine cases of PAOD were seen exclusively in the two nilotinib arms while no such cases were seen in the imatinib control arm.
The present retrospective cohort analysis was conducted using data from the Novartis clinical trial database to assess the incidence of PAOD in 2390 patients with newly diagnosed Ph+ CML-CP treated with nilotinib, imatinib, or no TKI (a control cohort of patients treated only with interferon [IFN] and Ara-C).
Patients and methods
Patients, study design and treatments
This analysis was based on a database of pooled randomized, multicenter, clinical data from patients with newly diagnosed CML-CP in the International Randomized Study of Interferon and STI571 (IRIS), Tyrosine Kinase Dose Optimization Study (TOPS) and ENESTnd studies.21, 22, 23 From this population of 2390 patients, three cohorts of patients were generated for analysis, on the basis of which, treatment was given: cohort 1, no TKI exposure (IFN+Ara-C only, n=533); cohort 2, nilotinib only (300 or 400 mg twice daily (BID), n=556) and cohort 3, imatinib only (400 mg once daily (QD) or 400 mg BID, n=1301). All patients in cohort 2 are nilotinib-treated patients from the ENESTnd study, with a minimum of 3 years of follow-up. Following the performance of this analysis, two additional events occurred on the nilotinib 400 mg BID arm between 3 and 4 years; these events were not included in the current statistical analysis. Patients with risk factors for PAOD or a history of symptomatic PAOD were not excluded from any studies. Patients with certain risk factors for cardiovascular disease were excluded by means of trial design as follows: IRIS, patients >70 years of age were excluded; ENESTnd, patients with a history of clinically documented myocardial infarction, unstable angina (last 12 months) or other clinically significant heart disease were excluded. Patients with known PAOD prior to enrollment in the clinical studies analyzed were excluded from this analysis.
The case definition for PAOD included atherosclerotic and thrombotic events, excluding functional (vasoreactive), embolic or aneurysmal disorders, in the arteries of lower and upper extremities, in accordance with American College of Cardiology/American Heart Association guidelines.24 Terms indicative of PAOD included: arterial disorder, peripheral ischemia, arterial insufficiency, arteriosclerosis obliterans, peripheral vascular disorder, arterial occlusive disease, femoral arterial stenosis, arterial stenosis, femoral artery occlusion, peripheral artery angioplasty, arterial stenosis limb, intermittent claudication, peripheral revascularization, arterial thrombosis limb and peripheral arterial occlusive disease.
The reported cumulative incidence of PAOD represents the crude rate and does not account for duration of exposure; thus, exposure-adjusted incidence rate was also evaluated, as the median durations of therapy differed substantially among cohorts. Relative risks with 95% CI based on exposure-adjusted incidence rates are presented for cohorts 2 (nilotinib only) and 3 (imatinib only) compared with cohort 1 (no TKIs), and for cohort 2 (nilotinib only) compared with cohort 3 (imatinib only).
A multivariate logistic regression analysis using the best-subsets variable selection method was performed to investigate if any of a number of covariates (risk factors) may have had an impact on the occurrence of PAOD as the response variable. Cohort (that is, treatment) was included as a covariate. The following risk factors at baseline were included in the model selection: age group (<65 years vs ⩾65 years), sex (male vs female), hypercholesterolemia (present vs absent), hypertension, diabetes, smoking, elevated lipids and preexisting vascular disease. Family history for PAOD or related risk factors was not readily available and, hence, was not included in this analysis. To assess the effect of cohort on PAOD occurrence, while controlling the most important risk factors identified in the previous step, adjusted odds ratios with the respective 95% CIs were calculated using exact multivariable logistic regression. The occurrence of PAOD was adjusted for exposure time, which was calculated for each patient as the time between the date of first study drug intake and the date of PAOD occurrence, death or the end of the reporting period, whichever occurred first. The Akaike Information Criterion was used as a measure to select the ‘best’ model. Analyses were performed using the LOGISTIC procedure with the EXACT option with SAS software version 9.2 (SAS, Cary, NC, USA).
Patients with newly diagnosed CML-CP who received at least one dose of study drug (safety population) in one of the three Novartis randomized phase 3 clinical trials (IRIS, TOPS and ENESTnd) were included in this analysis. The IRIS trial included patients with newly diagnosed CML-CP who received either imatinib 400 mg QD (n=551) or IFN+Ara-C (n=533).23 The TOPS trial included patients with newly diagnosed CML-CP who received either imatinib 400 mg QD (n=157) or imatinib 400 mg BID (n=316).22 The ENESTnd trial included patients with newly diagnosed CML-CP who received either nilotinib 300 mg BID (n=279), nilotinib 400 mg BID (n=277) or imatinib 400 mg QD (n=280).9, 21, 25
Patients in the IFN+Ara-C arm of the IRIS trial were grouped into cohort 1 (no TKIs; n=533), and this arm was used as the comparator arm for the nilotinib and imatinib cohorts. All patients in the nilotinib arms of the ENESTnd trial, with 3 years of follow-up, comprised cohort 2 (nilotinib only; n=556), and patients in the imatinib arm of the IRIS trial, both arms of the TOPS trial and the imatinib arm of the ENESTnd trial were grouped into cohort 3 (imatinib only; n=1301).
As seen in Table 1, baseline characteristics were similar across the three cohorts. Overall, 10–12% of patients in each cohort were aged ⩾65 years, and 33–36% of patients in each cohort demonstrated at least one risk factor for PAOD at the time of study entry. Patients treated with nilotinib (cohort 2) or imatinib (cohort 3) had median durations of TKI treatment of 36 (range, 0–47) and 45 (range, 0–67) months, respectively. Patients in cohort 1 (no TKIs) had a shorter median duration of therapy of 8 months (range, 0–65 months), likely due to early crossover to imatinib by patients in the IRIS trial.
A total of 12 patients with PAOD events were documented in this analysis, and the breakdown of the trial, therapy and the dose on which these events were observed on are provided in Table 2. Across the three cohorts, 3/533 (0.6%) patients in cohort 1 (no TKIs), 7/556 (1.3%) patients in cohort 2 (nilotinib only) and 2/1302 (0.2%) patients in cohort 3 (imatinib only) experienced a documented PAOD event. Of the seven patients with a reported PAOD event on nilotinib (four at 300 mg once daily (BID) and three at 400 mg BID), one was previously described by le Coutre et al.,8 as this patient was treated as part of the ENESTnd study. A total of three reports of patients who experienced a PAOD event while on imatinib therapy (two grade 2, one grade 3) were excluded from the cohort 3 analysis. Each of the three patients had a documented PAOD event prior to study entry, together with at least three atherosclerotic risk factors at baseline. While these patients experienced new or worsening PAOD events on imatinib, they were removed from the analysis as they were known to be affected by PAOD at baseline.
Among the 12 patients with reported PAOD events across all three cohorts, 11/12 patients (92%) were known to have underlying risk factors for PAOD (Table 3). Most events (8/12, 67%) were of grade 1 or 2, with grade 3/4 PAOD events observed in patients from cohort 2 (n=3) and cohort 3 (n=1). One patient in cohort 2 had bilateral PAOD events that led to a vascular graft occlusion and amputation of the right lower leg; this patient had baseline risk factors including smoking and hypercholesterolemia. Overall, the time to onset of events varied from case to case, but there were no apparent trends or differences in time to onset of events across the three cohorts.
As seen in Table 4, the exposure-adjusted relative risk was 0.9 (95% CI, 0.2–3.3) for cohort 2 (nilotinib only), and 0.1 (95% CI, 0.0–0.5) for cohort 3 (imatinib only), suggesting no increased incidence of PAOD in cohort 2 (nilotinib only) or cohort 3 (imatinib only), compared with that in cohort 1 (no TKIs). The exposure-adjusted relative risk for cohort 2 (nilotinib only) compared with cohort 3 (imatinib only) was 10.8 (95% CI, 2.2–52.0).
Multivariable logistic regression analysis was performed to determine if known risk factors for PAOD at baseline might have influenced the incidence of PAOD in each cohort. The variables selected by the best-subsets selection method shown to be associated with the occurrence of PAOD were the following baseline risk factors: age >65 years, lipids and vascular disease. Based on the final model using exact multivariable logistic regression methodology, the analysis showed that there was no difference between the nilotinib-only cohort and the no-TKIs cohort in the incidence of PAOD, after adjustment for the significant risk factors at baseline (odds ratio 0.906; 95% CI, 0.206–5.453; Table 5). Interestingly, the imatinib-only cohort showed a decreased incidence of PAOD versus the no-TKI cohort (odds ratio 0.062; 95% CI, 0.005–0.544). The odds ratio when comparing the nilotinib-only cohort and the imatinib-only cohort was 14.587 (95% CI, 2.732–145.64).
Consistent with prior reports of individual cases, this retrospective cohort analysis indicates a higher incidence of PAOD events in patients with CML-CP receiving nilotinib, than in those receiving imatinib. Although asymptomatic PAOD is common in the general population, occurring in an estimated 12–20% of adults aged 55 to 70 years,14, 15, 16 the incidence of asymptomatic or symptomatic PAOD in patients with CML-CP is currently unknown, and thus it is unknown whether the incidence is different from that in the age-matched general population. PAOD was not reported in trials of CML-CP prior to the TKI era—the survival of patients with CML-CP has been very significantly prolonged by imatinib therapy. It is unknown whether the possibly increasing prevalence of PAOD has any relationship to increased survival in patients in CML-CP or an altered natural history of atherosclerotic disease in such patients. TKI therapy has changed the natural history of CML, making the disease a chronic one for the majority of patients. In other patient populations, with similarly improved survival due to chronic therapies (such as HIV26 and hemophilia27), atherosclerotic disease has been observed at rates similar to, or in some cases higher than, the general population.
PAOD is a non-reversible event and the risk of developing PAOD increases over time. The current retrospective analysis suggests a low incidence of PAOD events for patients treated with either nilotinib or imatinib compared with the age-matched general population, despite the fact that most patients in this analysis had CML and many had one or more PAOD risk factors. The time to onset of PAOD events in the nilotinib cohort ranged from ∼1–2 years, which is consistent with previous reports documenting rapid onset of PAOD following initiation of nilotinib therapy where patients may have had underlying or asymptomatic PAOD.6
Intracohort comparisons between nilotinib and imatinib revealed higher rates of PAOD with nilotinib compared with imatinib. Nilotinib therapy has been associated with elevated glucose and lipids in some patients. Imatinib has been reported to lower fasting blood glucose levels,28 to protect from diabetes mellitus-associated arteriosclerosis in a disease model in mice,29 to reverse pulmonary arterial hypertension30 and to attenuate in-stent restenosis in an animal model.31 It has also been hypothesized that inhibition of the platelet-derived growth factor receptor (PDGFR) may contribute to the effects of imatinib on the vasculature, although nilotinib also targets PDGFR with a similar potency to that of imatinib.32, 33 There are no clinical data in humans demonstrating a protective effect of imatinib with regard to the risk of PAOD or other forms of atherosclerosis. Nilotinib is associated with elevations of serum glucose and lipids in many patients and has been shown to inhibit the discoidin domain receptor 1 (DDR1) receptor,34 which may have a role in the mediation of atherosclerosis.35 However, it is unclear whether inhibition of DDR1,36, 37, 38 or the activity of DDR1, would attenuate or accelerate atherosclerosis in humans.
There are several limitations to the current analysis. Patients in each cohort were treated under different clinical study protocols and with different cardiac inclusion/exclusion criteria. The studies occurred at different time periods, with patients being treated over a 10-year period during which the CML-treatment landscape was dramatically altered by the approval of imatinib, the approval of second-generation TKIs and increasing knowledge of TKI adverse event profiles. These differences may well have impacts on the rates of reporting of events across studies. In all three studies, there was likely an under-reporting of PAOD risk factors at baseline. The risk factors provided in Table 1 reflect patient records, but importantly, these risk factors were not proactively collected for all patients, only reported to the investigator in some cases. Other important risk factors such as family history of cardiovascular disease were not collected or assessed. There was no assessment of asymptomatic PAOD at baseline in any of the studies. Thus, only clinically significant PAOD was captured. The common toxicity criteria grading system was used to define the severity of events in these trials, but other grading systems such as those of Rutherford or Fontaine may be more appropriate and accurate when describing the severity of PAOD events.24 Thus, caution should be used when interpreting these retrospective comparisons, and further investigation with prospective studies (including baseline and on-treatment ABI and/or relevant blood chemistry analyses) is required to better understand why the incidence of new and/or worsening PAOD-related events appears to be increased with TKI therapies and/or exposure. In patients with CML-CP treated with TKIs, screening for PAOD, or related risk factors at baseline, should be conducted, preferably in the context of a clinical study. An important point for future research is to determine the impact that CML itself has on PAOD risk, compared with that in a normal control adult population. However, cardiovascular events that are characteristic of Ph-negative chronic myeloproliferative neoplasms have not been described more frequently in CML patients.39 For physicians who encounter a CML-CP patient experiencing a PAOD event on any treatment, the current guidelines for proper diagnosis and management of PAOD, including lifestyle modifications, supervised exercise rehabilitation, pharmacotherapy for hypercholesterolemia and/or hypertension, and revascularization, should be implemented.24
This retrospective analysis provides a larger data set of analyzed patients in comparison with current published information. Reports of PAOD events were presented at the recent 2012 American Society of Hematology (ASH) Annual Meeting with 4 years of follow-up, showing two additional PAOD events between 3 and 4 years as mentioned above.40 Future updates on the ENESTnd study will be important as extensions of the currently reported data. In this currently reported analysis, nilotinib was associated with higher rates of reported PAOD events compared with imatinib—these data require further study with the type of prospective evaluation of patients as reported by Kim et al.41 The emerging data on PAOD should be considered in the context of nilotinib’s more favorable overall AE profile when compared with imatinib.9 Nilotinib remains the only approved TKI associated with a significant reduction of transformation to accelerated phase or blast crisis in patients with CML-CP. In patients with preexisting PAOD or other atherosclerotic diseases, nilotinib or ponatinib should be administered with particular caution—the rates of PAOD associated with dasatinib or bosutinib have not been specifically reported on. The currently reported data lend further urgency to the conduct of appropriate TKI cessation studies in patients with CML-CP who have a (yet to be defined) adequate molecular response to initial TKI therapy.
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Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The authors thank Michael Mandola, PhD, for medical editorial assistance with this manuscript.
FJG, MJM, PDLC, AH, and GS have consulted for, and received research funding from, Novartis. FH, C-EO, CM, and RCW are Novartis employees and stockholders.
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Cite this article
Giles, F., Mauro, M., Hong, F. et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 27, 1310–1315 (2013) doi:10.1038/leu.2013.69
- chronic myeloid leukemia
- tyrosine kinase inhibitor
- peripheral arterial occlusive disease
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