Endothelial function in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors is not related to cardiovascular risk assessed by the Systematic Coronary Risk Estimation 2 algorithm
Key words: cardiovascular risk, chronic myeloid leukemia, endothelial function, SCORE2, tyrosine kinase inhibitor
CC BY 4.0
Endothelial function in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors is not related to cardiovascular risk assessed by the Systematic Coronary Risk Estimation 2 algorithm
CC BY 4.0
Introduction: Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML), but are endowed with negative effects on endothelial function.
Objectives: We aimed to characterize endothelial function in patients with CML treated with various TKIs.
Patients and methods: A total of 48 patients diagnosed with chronic‑phase CML treated with TKIs, such as imatinib, bosutinib, nilotinib, ponatinib, and asciminib were included. Endothelial function was assessed in the brachial artery and microcirculation based on flow‑mediated dilation (FMD), reactive hyperemia peripheral arterial tonometry (RH‑PAT) and flow‑mediated skin fluorescence (FMSF).
Results: Reactive hyperemia index, FMD, reactive hyperemia response (RHR), normoxia oscillatory index, and hyperemic response index did not differentiate between the group of patients with low / moderate risk in the Systematic Coronary Risk Estimation 2 (SCORE2), SCORE2‑Older Persons (SCORE2‑OP), and those with high / very high risk scores. Among the patients with low / intermediate risk based on the SCORE2 algorithm, some had lower (below the first quartile) values of the endothelial parameters, reflecting impaired endothelial function, as compared with the high / very high risk patient population. Lower values of the endothelial function parameters were associated with overall long‑term treatment with TKIs or ponatinib. Importantly, endothelial function assessed by FMSF (RHR) negatively correlated with total duration of TKI treatment, also after adjustment for age.
Conclusions: Endothelial function in CML patients treated with TKIs was not related to cardiovascular risk based on SCORE2/SCORE2‑OP algorithms but correlated with CML‑specific factors, including duration of TKI treatment. FMSF‑based assessment of skin microcirculation was a sensitive method for detecting the vascular effects of TKIs.
What's new?
Endothelial function in patients with chronic myeloid leukemia (CML) treated with various tyrosine kinase inhibitors (TKIs) was comprehensively analyzed in the conduit arteries and microcirculation using flow‑mediated dilation, reactive hyperemia peripheral arterial tonometry, and flow‑mediated skin fluorescence (FMSF). Using this approach, we demonstrated that endothelial function was not related to cardiovascular risk evaluated with the Systematic Coronary Risk Estimation 2 (SCORE2) / SCORE2‑Older Persons algorithms but was dependent on CML‑specific factors, including total duration of TKI treatment. In particular, our results suggest that CML may impact microcirculation of the skin, reflecting a systemic nature of the microvascular dysfunctional state in CML patients, which seemed to be further modulated by TKI treatment. On the practical side, our results suggest that FMSF‑based assessment of skin microcirculation may prove useful in detecting vascular effects of TKIs and guiding the vascular safety of TKI therapy.
Introduction
Tyrosine kinase inhibitors (TKIs) greatly improved prognosis and clinical outcomes of a majority of chronic myeloid leukemia (CML) patients, but at the same time the use of these drugs presents cardiovascular risks.1-4 Indeed, since the introduction of imatinib, the first generation TKI (1GTKI), the annual mortality in CML has decreased from 10%–20% to 1%–2%.5 However, approximately 40%–50% of patients treated with imatinib require treatment with a second or third‑generation TKI (2GTKI or 3GTKI) to achieve an optimal response.6 These newer drugs, when compared with imatinib, entail increased cardiovascular risks.1-4,7-9 In our previous study, which included patients with CML treated with imatinib, 22 patients (8.24%) experienced cardiovascular adverse events (CAEs),8 even though it seems to be generally accepted that the impact of imatinib on cardiovascular risks is minimal.7,8 Importantly, overwhelming evidence exists that documents an increase in the risk of cardiovascular events in patients with CML treated with nilotinib,1-4,9,10 with incident rates reaching 10.6% at 5 years and 24.8% at 10 years in the ENEST (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) study.11 Although bosutinib, another 2GTKI, was initially supposed to produce neutral effects on the cardiovascular system,12 Cortes et al13 concluded that vascular events occurred in 8.9% of the patients treated with this TKI. Finally, in terms of ponatinib, the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial14 showed that a 5‑year cumulative incidence rate of arterial occlusive events in patients with CML treated with ponatinib was as high as 31%. This study was recently reassessed by an independent adjudication committee. Adjudicated adverse outcome events (AOEs) were determined based on events that met the specified criteria for each end point. These criteria included several different factors, such as revascularization, shifts in cardiac biomarkers, and diagnostic substantiation based on imaging methods, such as computed tomography or magnetic resonance imaging. The frequency of adjudicated AOEs in patients with chronic‑phase CML (CP‑CML) was lower when compared with nonadjudicated AOEs (21%; 57/270), but still very high, with 95% (54/57) of them classified as serious AOEs.15 Asciminib, the first allosteric inhibitor of TKI that targets the myristol pocket of the Abelson kinase, was expected to be less toxic than ponatinib.16 The ASCEMBL study (Efficacy of CML‑CP Patients Treated with ABL001 versus Bosutinib, Previously Treated with 2 or More TKIs)17 revealed that the frequency of arterial occlusive events was 5.1% (n = 8) following treatment with asciminib and 1.3% (n = 1) after bosutinib.
The detrimental effects of TKIs on cardiovascular homeostasis could be at least partially attributed to the effects of these drugs on endothelial function. In fact, in vitro studies in human endothelial cells revealed that nilotinib upregulated proatherogenic adhesion proteins (intracellular adhesion molecule 1, E‑selectin, vascular cell adhesion molecule 1), and suppressed endothelial cell proliferation, migration, and tube formation, while in in vivo studies nilotinib augmented atherosclerosis in apolipoprotein E –/– mice and blocked reperfusion and angiogenesis in a hind‑limb‑ischemia model of arterial occlusion.18 In the same experimental settings, imatinib produced no negative effects. In several other studies, ponatinib- and other TKI‑related effects, including disturbed cell permeability, migration, wound closure, tube formation, and cell viability on the endothelium, were reported.19 Finally, although ponatinib inhibited platelet activation and aggregate formation under increased shear stress,20 this TKI induced prothrombotic angiopathy in mice21 and stroke in a zebrafish model.22 Taken together, it seems that ponatinib and other TKIs induce arterial thrombosis through endothelial dysfunction.23
Despite emerging evidence from preclinical studies concerning the negative effects of TKIs on endothelial function,1-4,9 clinically relevant data evaluating the endothelial function in CML patients treated with various TKIs in a prospective manner are lacking.
Therefore, the aim of this study was to characterize endothelial function profiles in patients diagnosed with CP‑CML and treated with various TKIs in relation to cardiovascular risk factors. Our comprehensive approach included endothelial function assessment in the conduit arteries and in microcirculation based on flow‑mediated dilation (FMD), reactive hyperemia peripheral arterial tonometry (RH‑PAT), and flow‑mediated skin fluorescence (FMSF).
Patients and methods
Patients
This was a prospective cross‑sectional study of 48 adult patients (25 women, 23 men; median [interquartile range, IQR] age, 52 [44.75–61.75] years) diagnosed with CP‑CML and treated with a 1GTKI (imatinib), 2GTKIs (bosutinib, nilotinib), 3GTKI (ponatinib), and asciminib. Patients treated with dasatinib were excluded from the study as a nonrepresentative group. Medical data were extracted from medical records. Basic laboratory blood tests were performed and Systematic Coronary Risk Estimation 2 (SCORE2) and SCORE2‑Older Persons (SCORE2‑OP) algorithms were calculated for each patient. Endothelial function was assessed between January and June 2022. The study was approved by the Bioethical Committee of the Jagiellonian University, Kraków, Poland (1072.6120.122.2021), and conducted in accordance with the Declaration of Helsinki. The patients provided their written informed consent to participate in the study.
Noninvasive assessment of endothelial function
On the vascular testing day, the patients were examined between 7:30 AM and 10:30 AM while they were fasting and had abstained from caffeine, vitamins, supplements, and exercise. Tests were performed to obtain a hemodynamic steady state while the patient was in a supine position in a quiet, semidarkened, and temperature‑controlled (22–25 °C) room after a 20‑minute rest.
Flow‑mediated dilation
FMD was examined in the brachial artery (diameter, 3–5 mm) of the right arm, according to a standard protocol,24 using an ultrasound probe of 14 MHz (Siemens Acuson S2000, Warszawa, Poland). To ensure stability and fixed position of the ultrasound probe during recording that started 1 minute before the artery occlusion and ended 4 minutes after the occlusion release, the ultrasound probe was fixed with a stereotactic probe holding device (Quipu Studio, Pisa, Italy). Offline analysis of FMD changes was performed with commercially available software (Cardiovascular Suite, Quipu, Pisa, Italy), and a number of parameters describing FMD responses were used as shown in Supplementary material, Figure S1.
Reactive hyperemia peripheral arterial tonometry
Reactive hyperemia was evaluated using the noninvasive RH‑PAT on the index finger according to a standard protocol (EndoPAT 2000; Itamar Medical, Caesarea, Israel). RH‑PAT was measured simultaneously with FMD upon release of a blood pressure cuff during the reactive hyperemia phase. The following parameters were measured: heart rate (HR, bpm), reactive hyperemia index (RHI), natural logarithm RHI (LnRHI), augmentation index (AI, %), and AI normalized to HR of 75 bpm (AI75, %).25 The parameters were calculated automatically using Endo‑PAT 2000 software (version 3.2.4) provided by the manufacturer (EndoPAT2000).
Flow‑mediated skin fluorescence
FMSF was quantified using the AngioExpert device (Angionica, Łódź, Poland)26-28 after concurrent FMD and RH‑PAT measurements and subsequent 15‑minute acclimatization period according to a previously described protocol.26-28 Offline analysis of FMSF response using Angionica software included a number of parameters as exemplified in Supplementary material, Figure S2.
Systematic Coronary Risk Estimation 2 and Systematic Coronary Risk Estimation 2‑Older Persons
The SCORE2 and SCORE2‑OP (jointly termed SCORE2 in this study) were assessed according to the published guidelines.29,30 Eight patients with cardiovascular comorbidities, including 4 with type 2 diabetes, were not assessed according to the SCORE2 algorithm, in accordance with the 2021 European Society of Cardiology guidelines.29 Five patients younger than 40 years old were also not assessed with this algorithm. Of 4 European regions stratified on the standardized cardiovascular disease (CVD) mortality risk (low, moderate, high, and very high), Poland belongs to the high‑risk region, and all patients included in the study came from Poland. In the analysis of the relationship between SCORE2 and endothelial parameters, we used a subgroup of patients eligible for SCORE2 stratification. We divided this subpopulation into 2 groups of high to very high risk and of moderate to low risk.
Statistical analysis
Quantitative variables were presented as median with IQR. The Wilcoxon rank‑sum test was used for comparisons. When comparing more than 2 categories, the Kruskal–Wallis test was used with the pairwise Wilcoxon rank‑sum test comparisons, and P value was adjusted using the Holm method. Qualitative variables were expressed as numbers (percentage), and the Fisher test or the χ2 test was used for comparisons, as appropriate. The Spearman correlation coefficient was calculated to assess the relationship between quantitative variables. Two‑sided P values below 0.05 were considered significant. Statistical analysis was performed with the R Project for Statistical Computing software version 4.2.1 (R Foundation for Statistical Computing, Free Software Foundation Inc., Vienna, Austria).
Results
Clinical characteristics of the patients
The clinical characteristics of 48 patients included in the study are presented in Table 1. The median (IQR) age of all patients at the study entry was 52 (44.75–61.75) years, and 52.1% of them were women. As many as 17 patients were treated with imatinib, 6 with bosutinib, 12 with nilotinib, 6 with ponatinib, and 7 with asciminib. The participants treated with bosutinib were older (median, 68.5 [66.25–70] years) than those treated with imatinib (median, 52 [42–57] years) (P = 0.04). Seventeen patients (35%) had cardiovascular comorbidities at the study entry. Eight of them had CVD with high cardiovascular risk (4 patients had type 2 diabetes, 3 coronary artery disease, and 1 chronic kidney disease). Three individuals (6.3%) suffered from CAEs during TKI therapy, 2 of them developed hypertension (1 was treated with asciminib and 1 with ponatinib), and 1 person treated with imatinib suffered from deep vein thrombosis. Blood test results in the CML patients treated with TKIs are presented in Supplementary material, Table S1.
Parameter | All TKIs (n = 48) | Asciminib (n = 7) | Ponatinib (n = 6) | Nilotinib (n = 12) | Bosutinib (n = 6) | Imatinib (n = 17) | P value |
Data are presented as number (percentage) of patients or median (interquartile range).
a Significant difference between the bosutinib and imatinib groups (P = 0.04)
b Patients below 40 years old were not assessed with the SCORE2/SCORE2‑OP.
c Disease disqualifying from SCORE2/SCORE2‑OP evaluation based on the ESC guidelines.29
Abbreviations: NA, not applicable; SCORE2, Systematic Coronary Risk Estimation 2; SCORE2‑OP, Systematic Coronary Risk Estimation 2‑Older Persons; TKI, tyrosine kinase inhibitor | |||||||
Women | 25 (52.1) | 4 (57.1) | 3 (50) | 6 (50) | 4 (66.7) | 8 (47.1) | 0.97 |
Age at study entry, y | 52 (44.75–61.75) | 52 (48.5–65) | 54.5 (48.5–59) | 48.5 (39.75–55) | 68.5 (66.25–70) | 52 (42–57) | 0.04a |
Any comorbidities | 34 (70.8) | 4 (57.1) | 6 (100) | 8 (66.7) | 4 (66.7) | 12 (70.6) | 0.53 |
Cardiovascular comorbidities | 17 (35.4) | 2 (28.6) | 3 (50) | 2 (16.7) | 4 (66.7) | 6 (35.3) | 0.1 |
Dose of TKI at study entry, mg | NA | 80 (80–80) | 18.75 (15–39.38) | 500 (400–800) | 500 (350–500) | 400 (400–400) | NA |
Overall time of TKI treatment, mo | 98.52 (43.06–169.3) | 47.6 (43.11–66.65) | 94.22 (45.1–115.18) | 100.57 (61–178.82) | 102.62 (47.93–147.85) | 110 (53–171) | 0.68 |
SCORE2 / SCORE2‑OP | |||||||
High / very high | 22 (45.8) | 1 (14.3) | 3 (50) | 5 (41.7) | 4 (66.67) | 9 (52.9) | 0.45 |
Low / intermediate | 13 (27.1) | 3 (42.9) | 1 (16.7) | 4 (33.3) | 0 | 5 (29.4) | |
Not assessed with SCORE2 / SCORE2‑OP | |||||||
<40 years oldb | 5 (10.4) | 1 (14.3) | 0 | 2 (16.7) | 0 | 2 (11.8) | 0.45 |
Disease associated with high riskc | 8 (16.7) | 2 (28.6) | 2 (33.3) | 1 (8.3) | 2 (33.3) | 1 (5.9) | |
Endothelial function in high / very high vs low / intermediate cardiovascular risk patients according to the Systematic Coronary Risk Estimation 2 algorithm
In our study group, 35 patients were eligible for SCORE2 calculation. Five of them had very high cardiovascular risk, 17 had high cardiovascular risk, and in 13 remaining patients this risk was low to moderate.
Values of the main endothelial parameters, that is, FMD, RHI, hyperemic response index (HR index), reactive hyperemia response (RHR), and normoxia oscillatory index (NOI) were not significantly different in the low / moderate and high / very high cardiovascular risk groups as assessed with the SCORE2 algorithm (Table 2; Supplementary material, Figure S3). Only a few exceptions differentiating these 2 groups were found among ancillary parameters in the FMD and FMSF assays. The patients with high / very high cardiovascular risk according to the SCORE2 had lower values of shear rate maximum (SR Max), SR at 30 and 60 seconds of the hyperemic response, neurogenic component at rest, hypoxia sensitivity (HS), logarithmic HS (logHS), myogenic component at reperfusion, and a parameter representing flow motion during the reperfusion phase (Fmindex[R]), in comparison with the low / moderate risk patients (Table 2).
Risk category according to SCORE2 | Low / intermediate risk | High / very high risk | P value | ||
Data are presented as median (interquartile range) with the Wilcoxon rank‑sum test P value.
P values <0.05 were considered significant.
a Recovery diameter of the brachial artery in the last 30 s of FMD examination (usually 4 min after the end of occlusion)
b Oscillations at baseline and at reperfusion were grouped into 3 different frequency intervals: ≤ 0.021 Hz, 0.021–0.052 Hz, and 0.052–0.15 Hz, corresponding to endothelial, neurogenic, and myogenic activity, respectively.
c Endo, neuro, and myo denote contribution of the endothelial, neurogenic, and myogenic component at rest.
d Endo(R), neuro(R), and myo(R) denote contribution of the endothelial, neurogenic, and myogenic component at reperfusion stage.
e Endo, neuro, myo denote the fraction of endothelial, neurogenic, and myogenic activity at rest.
f Endo(R), neuro(R), myo(R) denote the fraction of endothelial, neurogenic, and myogenic activity at reperfusion stage.
Abbreviations: AI, augmentation index; AI 75, augmentation index normalized to heart rate of 75 bpm; a.u., arbitrary unit; FMD, flow mediated dilation; FMDr, FMD for recovery diameter; Fm index, basal flowmotion at rest; Fm index(R), flowmotion during reperfusion; FMSF, flow‑mediated skin fluorescence; HR index, hyperemic response index; HR max, maximum hyperemic response; HS, hypoxia sensitivity; IR index, ischemic response index; IR max, maximum IR; log HS, logarithm of HS, LnRHI, natural logarithm of RHI; RHI, reactive hyperemia index; MR, metabolic recovery; MSA, mean squared amplitude; NOI, normoxia oscillatory index; PSD, power spectra density at rest; PSD(R), PSD at reperfusion; RHI, reactive hyperemia index; RH‑PAT, reactive hyperemia peripheral arterial tonometry; RHR, reactive hyperemia response; SR, shear rate; SR area to Max, SR area to maximum diameter; SR Max, maximum shear rate; others, see Table 1 | |||||
FMD | |||||
Evaluable patients, n | 12 | 18 | – | ||
FMD, % | 5.7 (3.93–12.44) | 5.53 (2.18–8.93) | 0.6 | ||
FMDr, % | 4.54 (4.02–7.27) | 3.32 (1.08–5.85) | 0.31 | ||
Brachial artery diameter, mm | Basic diameter | 3.64 (3.34–4.1) | 4.04 (3.57–4.86) | 0.17 | |
Maximum diameter | 4.06 (3.69–4.35) | 4.33 (3.78–4.95) | 0.29 | ||
Recovery diametera | 3.63 (3.35–4.12) | 4.5 (3.66–4.81) | 0.05 | ||
At 30 s of HR | 3.91 (3.74–4.17) | 3.92 (3.74–4.79) | 0.64 | ||
At 60 s of HR | 4.05 (3.94–4.32) | 4.26 (3.74–4.97) | 0.68 | ||
Shear rate | Basic, s-1 | 232.65 (184.48–335.7) | 210.2 (159–248.33) | 0.2 | |
Maximum, s-1 | 1189.6 (1082.53–1540.05) | 865.9 (751.42–1127) | 0.02 | ||
SR area, a.u. | 2 328 724 (309 471–4 764 725) | 1 254 437 (345 258–3 663 692) | 0.79 | ||
SR area to Max, a.u. | 523 552 (54 086–1 871 737) | 624 815 (153 360–1 417 380) | 0.88 | ||
SR at 30 s of HR, s-1 | 586.7 (554.2–624.9) | 445.8 (338.75–537.12) | 0.01 | ||
SR at 60 s of HR, s-1 | 417.1 (359.72–446.75) | 284.55 (232.45–378.17) | 0.01 | ||
SR area to 30 s of HR, a.u. | 412 273 (36 601–834 367) | 356 049 (43 194–788 535) | 0.82 | ||
SR area to 60 s of HR, a.u. | 1 112 072 (54 072–1 871 737) | 628 532 (183 978–1 473 313) | 0.95 | ||
RH‑PAT | |||||
Evaluable patients, n | 13 | 21 | – | ||
RHI | 2.02 (1.93–2.24) | 2.29 (1.65–2.45) | 0.64 | ||
Heart rate, bpm | 70 (66–81) | 68 (65–75) | 0.49 | ||
AI, % | 4 (1–12) | 12 (3–17) | 0.32 | ||
AI 75, % | 4 (0–7) | 6 (–2 to 15) | 0.38 | ||
LnRHI | 0.77 (0.66–0.89) | 0.83 (0.5–0.9) | 0.84 | ||
FMSF | |||||
Evaluable patients, n | 13 | 21 | – | ||
IR index, % | 10.1 (5.59–11.49) | 9.83 (6–12.98) | 0.97 | ||
HR index, % | 10.53 (8.41–11.8) | 7.28 (6.74–10.3) | 0.05 | ||
IR max, % | 12.89 (8.46–14.23) | 12.97 (9.02–16.87) | 0.85 | ||
HR max, % | 18.23 (17.62–24.1) | 17.75 (15.88–20.95) | 0.22 | ||
RHR, % | 30.04 (24.85–32.41) | 25.07 (16.62–33.51) | 0.15 | ||
NOI, % | 72.24 (54.21–86.15) | 77.55 (64.67–86.58) | 0.55 | ||
MR, % | 79.02 (73.34–86.17) | 72.86 (61.87–80.1) | 0.17 | ||
HS | 38.07 (27.3–57.48) | 14.64 (4.19–34) | 0.02 | ||
LogHS | 1.58 (1.44–1.76) | 1.17 (0.62–1.53) | 0.02 | ||
PSD × 106, MSA | 93.49 (22.06–115.46) | 23.39 (13.77–58.16) | 0.12 | ||
PSD(R) × 106, MSA | 92.89 (71.79–174.54) | 54.63 (15.74–75.65) | 0.06 | ||
Fm index, a.u. | 94.66 (25.19–118.16) | 26.49 (16.67–59.53) | 0.12 | ||
Fm index(R), a.u. | 107.47 (82.23–176.35) | 70.27 (20.97–86.16) | 0.03 | ||
Contribution of relative components of microcirculation oscillationsb, % | Endoc | 34.88 (19.23–40.24) | 48.86 (23.68–59.26) | 0.36 | |
Neuroc | 27.38 (20.3–41.22) | 27.7 (19.43–37.95) | 0.71 | ||
Myoc | 31.44 (15.99–46.34) | 22.45 (13.21–36.67) | 0.23 | ||
Endo(R)d | 20.42 (6.68–34.73) | 36.81 (32.18–45.7) | 0.05 | ||
Neuro(R)d | 27.67 (11.35–38.03) | 26.84 (15.36–34.68) | 0.93 | ||
Myo(R)d | 40.82 (35.27–56.77) | 31.65 (24.19–41.15) | 0.05 | ||
Fraction of flowmotion at rest (Fm index) and during the reperfusion phase (Fm index [R])b | Endoe | 18.27 (5.56–50.85) | 9.47 (4.12–18.21) | 0.24 | |
Neuroe | 21.94 (11.31–28.44) | 7.98 (3.41–11.4) | 0.03 | ||
Myoe | 13.69 (6.43–21.52) | 6.28 (2.09–17.32) | 0.11 | ||
Endo(R)f | 16.38 (12.49–26.71) | 22.25 (5.64–35.04) | 0.99 | ||
Neuro(R)f | 19.81 (16.45–32) | 10.46 (6.7–18.96) | 0.13 | ||
Myo(R)f | 38.82 (27.3–57.48) | 14.64 (4.19–34) | 0.02 | ||
- Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic‑phase chronic myeloid leukemia. Blood. 2012; 120: 3898‑3905. | Crossref
- Cortes JE, Kim D‑W, Pinilla‑Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome‑positive leukemias. N Engl J Med. 2013; 369: 1783‑1796. | Crossref
- Cortes JE, Jones D, O’Brien S, et al. Nilotinib as front‑line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010; 28: 392‑397. | Crossref
- Gover‑Proaktor A, Granot G, Pasmanik‑Chor M, et al. Bosutinib, dasatinib, imatinib, nilotinib, and ponatinib differentially affect the vascular molecular pathways and functionality of human endothelial cells. Leuk Lymphoma. 2019; 60: 189‑199. | Crossref
- Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol. 2018; 93: 442‑459. | Crossref
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