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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 2  |  Page : 71-75

Imatinib-induced cardiotoxicity: A study to evaluate cardiac functions in patients on imatinib therapy for chronic myeloid leukemia


Department of Medicine, VMMC and Safdarjung Hospital, New Delhi, India

Date of Submission03-Feb-2021
Date of Decision17-Jul-2021
Date of Acceptance12-Aug-2021
Date of Web Publication04-Aug-2022

Correspondence Address:
Dr. Pushpa Kumari
Department of Medicine, VMMC and Safdarjung Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_9_21

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  Abstract 

INTRODUCTION: The success of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia (CML) has increased the focus on survivorship and late toxicity in oncological care. Cardiovascular (CV) health has emerged as an important consideration in patients of CML. Some studies have shown an increased incidence of CHF with Imatinib therapy. This study was conducted to assess the cardiac functions in patients of CML on Imatinib therapy.
METHODS: Seventy newly diagnosed CML patients started on Imatinib therapy having normal baseline cardiac functions as assessed by two-dimensional echocardiography and multigated acquisition (MUGA) scan were included in the study. Further assessment of cardiac functions at 3, 6, and 12 months was done by MUGA scan.
RESULTS: At 3, 6, and 12 months of follow-up, 7.14%, 10%, and 11.43% of patients, respectively, showed evidence of cardiotoxicity in the form of reduced ejection fraction and wall abnormalities on MUGA scan (P = 0.58, 0.013, and 0.006, respectively).
CONCLUSION: Cardiac dysfunction was seen in 11.43% of patients on Imatinib therapy for CML, though none of them were symptomatic. CML patients on Imatinib therapy must be monitored for cardiac functions, especially if they have other CV risk factors.

Keywords: Cardiotoxicity, chronic myeloid leukemia, Imatinib, N-terminal pro b-type natriuretic peptide


How to cite this article:
Chakravarthy P S, Kumari P, Gupta DK, Bhowmick M, Naik M D, Priyanka G. Imatinib-induced cardiotoxicity: A study to evaluate cardiac functions in patients on imatinib therapy for chronic myeloid leukemia. J Appl Hematol 2022;13:71-5

How to cite this URL:
Chakravarthy P S, Kumari P, Gupta DK, Bhowmick M, Naik M D, Priyanka G. Imatinib-induced cardiotoxicity: A study to evaluate cardiac functions in patients on imatinib therapy for chronic myeloid leukemia. J Appl Hematol [serial online] 2022 [cited 2022 Aug 15];13:71-5. Available from: https://www.jahjournal.org/text.asp?2022/13/2/71/353280


  Introduction Top


The use of tyrosine kinase inhibitors (TKI's) in the treatment of chronic myeloid leukemia (CML) has changed the natural history and prognosis dramatically. With the use of Imatinib, the first approved TKI, the 10-year survival rate has gone up to 83.3%.[1]

The success of TKI's, the chronicity of treatment, and its impact on overall patient survival (90% at 5 years) have introduced survivorship as a new theme in patient care.[2] The introduction of TKIs represented a unique concept of indefinite cancer therapy; hence, long-term safety of treatment needs to be considered.

The cardiovascular (CV) side effects of TKIs include QT prolongation, congestive heart failure, new-onset hypertension, myocardial infarction, peripheral vascular disease, and pulmonary hypertension. Early data regarding Imatinib indicated an acceptable CV profile.[3],[4] Although one case series suggested a signal for congestive heart failure, subsequent long-term follow-up of patients on Imatinib revealed a low incidence of congestive heart failure.[2],[4] Indeed, some preclinical data suggested that Imatinib may have favorable metabolic and vascular effects.[5],[6]

The incidence of CV adverse events has been found to be more with newer generation TKIs than with Imatinib.

There is currently a dearth of data with respect to the mechanisms of drug toxicities, the subsets of patients at risk, and prevention and treatment strategies to mitigate CV complications in patients with CML.

Rates of cardiotoxicity associated with TKIs are not well known mainly because clinical trials usually do not include predefined cardiac endpoints or the assessment of left ventricular function before and during treatment.

This study was conducted to assess the cardiac functions in patients of CML on Imatinib therapy and its correlation with the duration of therapy.


  Methods Top


This was a prospective observational cohort study with a follow-up of 12 months, conducted in a north Indian hospital. Newly diagnosed patients of Philadelphia chromosome-positive CML, more than 12 years of age with normal baseline two-dimensional (2D) echocardiography, and no previous history of CV diseases were included in the study. They were initiated on Imatinib therapy. Patients of CML with abnormal 2D echocardiography findings were excluded from the study. Approval from the institutional ethical committee and written informed consent from all the subjects enrolled in the study were obtained. All the patients underwent the following investigations: complete blood count, urine R/M, skiagram chest, kidney function test, liver function test, fasting blood glucose, and lipid profile. N-terminal pro b-type natriuretic peptide (NT-pro BNP) levels, 2D echocardiography, and multigated acquisition (MUGA) scan were done to assess cardiac functions at baseline. MUGA scan was repeated at 3, 6, and 12 months. MUGA scan was done using technetium-99 as radioisotope and images were captured using a gamma camera. The camera illuminates the tagged blood, and in the process, we can evaluate the filling and pumping properties of the heart. The physical structures can be evaluated by comparing the illuminated blood pool to the darkened walls on the image.

Hochhaus et al. in their study observed that CV events were reported in 2.1%–13.4% of patients.[1] Taking this value as reference, the minimum required sample size with 8% margin of error and 5% level of significance was calculated to be 70 patients. The total sample size taken was 70.

Statistical analysis

Categorical variables were presented in number and percentage (%) and continuous variables were presented as mean ± standard deviation and median. Normality of data was tested by Kolmogorov–Smirnov test. Logistic regression was used to find out predictors of cardiac function. Quantitative variables were compared using unpaired t-test/Mann–Whitney test (when the data sets were not normally distributed) between the two groups. Qualitative variables were compared using Chi-square test/Fisher's exact test.

P < 0.05 was considered statistically significant.

The data were entered in Microsoft EXCEL spreadsheet and analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0 (IBM, Chicago, USA).


  Results Top


Seventy newly diagnosed patients of CML started on Imatinib therapy were included in the study. Twenty-one patients (30%) were female, while 49 patients (70%) were male. Twenty-one patients were in the 31–40-year age group, while there were 13 patients each in the 21–30 and 41–50 age group. Ten patients were in the 51–60 age group. Sixty-nine patients (98.57%) presented in chronic phase, while only one patient (1.43%) presented in accelerated phase.

Fourteen patients had hypertension, while nine patients had diabetes mellitus. None of the patients had any history of CV ailments. All the recruited patients had normal baseline echocardiography and normal MUGA scan findings with normal left ventricular ejection fraction (LVEF) and no wall abnormalities. NT-pro BNP levels were evaluated in the patients at baseline. Sixty-two patients had NT-pro BNP levels in normal range, while eight patients had increased levels of NT-pro BNP at baseline.

At 3 monthly follow-up, five patients (7.14%) showed abnormal MUGA scan with reduced ejection fraction and wall abnormalities. The remaining 65 patients had normal MUGA scan with no loss of follow-up (P = 0.058). At 6-month follow-up, seven patients (10.0%) showed abnormal MUGA scan. The remaining 90% of patients had normal MUGA scan with no loss of follow-up (P = 0.013). At 12-month follow-up, eight patients (11.43%) showed abnormal MUGA scan. The remaining 62 patients had normal MUGA scan with no loss of follow-up by 12 months (P = 0.006).

Majority of CML patients with abnormal MUGA scan findings were found to be more than 50 years of age (n = 7), while 1 patient was in 41–50 age group. None of the patients below 40 years of age had evidence of cardiotoxicity at 12 months (P = 0.0001) [Table 1].
Table 1: Association of age, gender, baseline N-terminal pro b-type natriuretic peptide, diabetes, and hypertension with Imatinib-induced cardiotoxicity

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Two patients (3.23%) with normal NT-pro BNP at baseline later showed cardiotoxicity, while six patients (75%) with initial abnormal NT-pro BNP showed abnormal MUGA scan findings at 12 months (P < 0.0001) [Table 1].

Out of nine patients having diabetes mellitus, six patients showed cardiotoxicity (P < 0.0001), while among 14 patients with hypertension, five patients showed abnormal MUGA scan findings at 12-month follow-up (P = 0.006) [Table 1].


  Discussion Top


The study included a total of 70 newly diagnosed Philadelphia chromosome-positive CML patients with normal left ventricular function as assessed by 2D echocardiography and MUGA scan at baseline. Majority of CML patients were found to be in the age group of 15–40 years (60%). This finding varies from existing literature where the median age of CML has been established between 55 and 65 years. Compared to existing data, our patients demonstrated a trend toward an earlier age of onset and presentation. All the patients were started on Imatinib therapy.

On follow-up, patients with reduced ejection fraction and wall abnormalities as assessed by MUGA scan were 5 (7.14%), 7 (10%), and 8 (11.43%) at 3, 6, and 12 months, respectively. Cardiotoxicity was more frequent in patients with baseline high NT-pro BNP than with normal NT-pro BNP (P < 0.0001).

The presence of cardiotoxicity showed predominance in the age group of 41–60 years. In a study conducted by Atallah et al., a total of 1276 patients were enrolled in Imatinib clinical trials. The incidence of new-onset CHF increased with increasing age. None of the patients who were younger than 45 years developed symptoms of CHF. The incidence was 0.3% (1 in 322 patients) among patients aged 45–55 years, 1.7% (5 in 291 patients) among those aged 56–65 years, 2.8% (6 in 211 patients) for patients aged 66–75 years, and 9.3% (4 of 43 patients) for those aged 76–85 years. Overall, 8 cases were considered possibly associated with Imatinib treatment.[7]

Kerkelä et al. in their study described a series of 10 patients developing significant LV dysfunction during therapy with Imatinib mesylate. All ten individuals had normal LVEF before Imatinib therapy was started (56% ±7%). After a mean of 7.2% ±5.4 months of therapy, patients presented with heart failure symptoms with LVEF declining to 25% ±8%. The myocardial biopsy performed on two of the patients showed dilated sarcoplasmic reticulum with membrane whorls in the myocytes and abnormal mitochondria likely of toxin-induced myopathy as opposed to ischemic cardiomyopathy.[8]

Previously, Park et al. had reported the development of heart failure in two patients on Imatinib therapy and suggested the utility of brain natriuretic peptide for early diagnosis in this context.[9]

There have been conflicting reports regarding cardiotoxicity with Imatinib. Indeed, some preclinical data suggest that Imatinib may have favorable metabolic and vascular effects.[5],[6] In some animal models, Imatinib reversed experimentally induced pulmonary hypertension,[10],[11],[12] while some studies have shown an increased incidence of congestive heart failure with them.

Fluid retention leading to edema has been reported in 60%–70% of patients taking Imatinib, while dyspnea has been documented in up to 15% of patients.[13]

TKI inhibits tyrosine kinase in both cancerous and noncancerous cells. Imatinib inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Their action on normal tissues explains their side effects. The role of ABL in cardiac myocytes may be important but is not clearly known. It mediates oxidant stress-induced death in fibroblasts, whereas it is protective in osteoclasts.[14] The mechanism leading to cell death is probably the induction of the endoplasmic reticulum (ER) stress response, where the formation of misfolded proteins in the ER induces cellular apoptosis.

Newer TKIs are burdened with more cardiotoxicity than Imatinib, which majorly appears to be vascular leading to ischemic and thrombotic events. Subclinical left ventricular dysfunction has also been seen in them.[15] The pathophysiology of ischemic events, such as peripheral arterial disease and accelerated atherosclerosis, is attributed to the inhibition of Src, KIT, and PDGFR. These kinases are important for the regulation of vascular tone, endothelial function, and the release of antithrombotic substances (t-PA, heparin).[16]

Perik et al. in their study documented that Imatinib treatment for GIST was not associated with an increase in plasma NT-proBNP levels or incidence of CHF.[17] Verweij et al. did not find an excess of cardiac events in their study of 946 patients on Imatinib.[18] However, their CV assessment was based on physical examination and chest X-ray only. Hochhaus et al. found in their study that CV adverse events occurred more frequently with nilotinib than with Imatinib.[1] The cumulative incidence of CV events in both groups increased with longer follow-up. Baseline Framingham scores were predictive of risk of developing CV events. In a recent study, Novo et al. concluded that Imatinib is a relatively safe drug, while the latest generation TKI (nilotinib, dasatinib, and ponatinib) may cause a burden of CV complications.[16]

Our study showed that cardiotoxicity associated with Imatinib was seen with increasing age. Patients who were diabetic or hypertensive had more odds of developing cardiotoxicity. Furthermore, patients with raised baseline NT-pro BNP levels were more likely to develop cardiotoxicity. The incidence of cardiotoxicity has been found to be high in our study as compared to some previous studies (1%–2%). A possible explanation may be that many of the previous studies have done cardiac evaluation in symptomatic patients only, while we did the cardiac evaluation with 2D echocardiography and MUGA scan in all the patients irrespective of symptoms. Noteworthy none of our patients was symptomatic. In addition, majority of the patients with evidence of cardiotoxicity had diabetes, hypertension, or a baseline increased NT-pro BNP level.

NT-pro BNP seems to be an important marker for determining the subset of patients that can be prone to the cardiotoxic effects of Imatinib and for the follow-up of patients on Imatinib. NT-pro BNP is a versatile biomarker released from the myocardium in response to cardiac volume overload and consequent wall stress. This leads to increasing circulating natriuretic peptides according to the severity of cardiac disease. A total of 8 patients showed increased values of NT-pro BNP at baseline, out of which 6 developed cardiotoxicity later (P < 0.001) making it the sensitive and specific marker for monitoring patients on Imatinib therapy.

Risk stratification for CV risk has been assessed in a recent Italian study on patients on nilotinib. The investigators used a Systemic COronary Risk Evaluation (SCORE) risk assessment tool from the European Society of Cardiology that classifies patients into three groups: low risk, intermediate risk, and high risk.

SCORE risk estimation is based on the following risk factors age, sex, smoking, systolic blood pressure, and total cholesterol level and estimates fatal CV events over a 10-year period. This assessment was applied to 82 patients with CML who had 48 months of follow-up on nilotinib. Overall, 8.5% had arterial events. None of the low-risk patients had events, 10% with moderate risk had events, and 29% of high-risk patients had events.[19] The application of risk assessment prospectively in large numbers of CML patients treated with a variety of agents may help decide what group of patients should give which drug as a frontline therapy.[20]

In high-risk patients, incorporation of CV disease prevention and management is crucial for patients on Imatinib also. Indeed, at many tertiary care centers, direct referrals are made to a cardiologist when a patient with CML is started on a TKI and CV risk is high.

There are few clinical trials that prospectively examined Imatinib-mediated cardiotoxicity. Most of the studies have been retrospective. Data from retrospective studies and series of cases reveal that toxic effects in the heart can appear early and may be reversible after the institution of medical treatment for heart failure together with withdrawal of the drug in some cases. Long-term studies are needed to support that this early reversibility of the induced LV dysfunction is maintained during longer follow-up. Being aware of the risk of using these drugs, a multidisciplinary approach between hematologists/oncologists and cardiologists is particularly important for early detection and institution of appropriate treatment to prevent irreversible myocardial injury.

One of the strengths of this study was the correlation of cardiac function with the duration of TKI therapy. Another point of note was the correlation of NT-pro BNP levels and MUGA scan in CV function evaluation.

Limitations of the study included inability to assess response to TKI and small sample size. The sample size is small because the study reflects the experience of a single center. Certainly in future, the sample size will have to be expanded for greater statistical significance. Furthermore, the true impact on the long term prognosis of CML patients taking TKIs for lifetime could not be commented upon due to limited follow-up period. Further studies in this area are required to assess the impact of TKIs on CV health and long-term CV morbidity.


  Conclusion Top


Given the high prevalence of CV disease in the general population, CV disease prevention and treatment strategies are relevant considerations for every patient with CML. The realization that TKIs may increase CV disease risk adds further urgency to development of ways to mitigate CV risk in this population. Further long-term, large studies are needed to assess the CV effects of Imatinib on patients on long-term therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term Outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med 2017;376:917-27.  Back to cited text no. 1
    
2.
Druker BJ, Guilhot F, O'Brien SG. IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-17.  Back to cited text no. 2
    
3.
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-7.  Back to cited text no. 3
    
4.
García-Pagán JC, Gracia-Sancho J, Bosch J. Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J Hepatol 2012;57:458-61.  Back to cited text no. 4
    
5.
Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:935-42.  Back to cited text no. 5
    
6.
Louvet C, Szot GL, Lang J, Lee MR, Martinier N, Bollag G, et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A 2008;105:18895-900.  Back to cited text no. 6
    
7.
Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007;110:1233-7.  Back to cited text no. 7
    
8.
Kerkelä R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908-16.  Back to cited text no. 8
    
9.
Park YH, Park HJ, Kim BS, Ha E, Jung KH, Yoon SH, et al. BNP as a marker of the heart failure in the treatment of imatinib mesylate. Cancer Lett 2006;243:16-22.  Back to cited text no. 9
    
10.
Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galié N, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: Results of the randomized IMPRES study. Circulation 2013;127:1128-38.  Back to cited text no. 10
    
11.
Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-21.  Back to cited text no. 11
    
12.
Shah AM, Campbell P, Rocha GQ, Peacock A, Barst RJ, Quinn D, et al. Effect of imatinib as add-on therapy on echocardiographic measures of right ventricular function in patients with significant pulmonary arterial hypertension. Eur Heart J 2015;36:623-32.  Back to cited text no. 12
    
13.
Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 2002;8:935-42.  Back to cited text no. 13
    
14.
Orphanos GS, Ioannidis GN, Alexandros G. Ardavanis cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncologica 2009;48:964-70.  Back to cited text no. 14
    
15.
Chen MH, Kerkelä R, Force T. Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation 2008;118:84-95.  Back to cited text no. 15
    
16.
Novo G, Di Lisi D, Bronte E, Macaione F, Accurso V, Badalamenti G, et al. Cardiovascular toxicity in cancer patients treated with tyrosine kinase inhibitors: A real-world single-center experience. Oncology 2020;98:445-51.  Back to cited text no. 16
    
17.
Perik PJ, Rikhof B, de Jong FA, Verweij J, Gietema JA, van der Graaf WT. Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity. Ann Oncol 2008;19:359-61.  Back to cited text no. 17
    
18.
Verweij J, Casali PG, Kotasek D, Le Cesne A, Reichard P, Judson IR, et al. Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: Analysis of EORTC-ISG-AGITG study 62005. Eur J Cancer 2007;43:974-8.  Back to cited text no. 18
    
19.
Breccia M, Molica M, Zacheo I, Serrao A, Alimena G. Application of systematic coronary risk evaluation chart to identify chronic myeloid leukemia patients at risk of cardiovascular diseases during nilotinib treatment. Ann Hematol 2015;94:393-7.  Back to cited text no. 19
    
20.
Tefferi A. Nilotinib treatment-associated accelerated atherosclerosis: When is the risk justified? Leukemia 2013;27:1939-40.  Back to cited text no. 20
    



 
 
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