Cardiac effects of mitoxanthrone therapy in patients with multiple sclerosis

Żanna Pastuszak, Kazimierz Tomczykiewicz, Renata Piusińska-Macoch, Adam Stępień

Military Institute of Medicine, Warsaw, Poland

Address for correspondence:
Żanna Pastuszak, MD, PhD, Military Institute of Medicine, ul. Szaserów 128, 04–141 Warszawa, Poland, e-mail: zanna.pastuszak@hotmail.com
Received: 28.03.2015 Accepted: 31.08.2015 Available as AoP: 23.09.2015

INTRODUCTION

Mitoxanthrone (MTX) is a synthetic anthracycline antibiotic, an anthraquinone derivative that has antineoplastic, immunomodulatory, and antibacterial properties [1, 2]. In 1987, it was licensed for the treatment of leukaemias. It is also used in the treatment of breast, prostate, hepatic, ovarian, and gastric cancers. In the clinical practice, a beneficial effect of MTX has been observed on a decrease of the number of relapses and progression of disability in patients with primary progressive, secondary progressive, and relapsing remitting multiple sclerosis (MS) who do not respond to the treatment with interferon (IFN) β1a and β1b and glatiramer acetate [1, 3]. MTX is a small molecules that crosses the blood-brain barrier [4]. It affects both proliferating and non-proliferating cells. It inhibits topoisomerase II activity, DNA replication, and RNA synthesis. MTX reduces T lymphocyte, B lymphocyte, and macrophage activity, and decreases antibody production [1, 3, 5]. MTX is an inhibitor of antigen presentation, and secretion of INFγ, interleukin 2 and tissue necrosis factor α [6]. It induces apoptosis of other immunocompetent cells, such as T lymphocytes and dendritic cells [7]. Due to poor bioavailability following oral administration, MTX is administered in the treatment of MS at a standard dose of 12 mg/m2 of body surface area (BSA) every 3 months up to the total dose of 120–140 mg/m2 [3, 6, 8]. The most common adverse effects of MTX include nausea and vomiting, hair loss, increased risk of urinary and respiratory tract infections, and amenorrhea. Less frequent problems include leukopenia, thrombocytopenia, anaemia, and an increase in hepatic enzyme and bilirubin levels. Other severe limitations of MTX treatment are drug cardiotoxicity and a potential to induce leukaemia [3, 8, 9]. Congestive heart failure (HF) develops in about 2.6–5% of the treated patients [10]. Toxicity of MTX results from its quinone structure which may be reduced to semiquinone, releasing a free electron which is transferred to an oxygen moiety, initiating the free radical cascade. Cardiac toxicity of MTX is related to the presence of abundant amounts of lipids in the inner mitochondrial membrane, which bind to MTX particles. The drug also shows affinity to iron ions. The resulting complex strongly induces formation of free oxygen radicals. Few studies evaluated cardiotoxicity of MTX in MS patients. The aim of the study was to evaluate the effect of MTX treatment on left ventricular ejection fraction (LVEF) by two-dimensional (2D) echocardiography.

METHODS

Our study was a retrospective evaluation of 72 patients with MS aged 25–63 years who were treated at the Department of Neurology, Military Institute of Medicine, Warsaw, in 2002–2014. Multiple sclerosis was diagnosed based on the 2001 McDonald criteria updated in 2005 [11]. The study group included 72% women and 28% men. The mean age was 47 ± 10.64 years (47.9 years in women and 44.6 years in men). The study group included 40 (56%) patients with primary progressive MS, 5 (7%) patients with secondary progressive MS, and 27 (37%) patients with relapsing remitting MS. Patients were administered MTX in an intravenous infusion at 12 mg/m2 of BSA every 3 months (up to the total dose of 140 mg/m2). The patients received 1–5 drug doses. Total dose ranged from 18 to 144 mg, mean 65 mg. MTX treatment was initiated in patients with no signs of HF on physical examination, normal electrocardiogram (ECG), normal LVEF by 2D echocardiography, and normal laboratory test findings including complete blood count and hepatic and renal function parameters. Each MTX administration was preceded by 2D echocardiography with LVEF measurement, ECG, and physical examination of the cardiovascular system. LVEF was calculated using the formula: LVEF = 7 / (D + 2.4) × D3, where D is the left ventricular diameter. The effect of MTX treatment on LVEF was evaluated by comparing baseline LVEF with LVEF measurements before the last MTX dose at 3–15 months of treatment. The study did not include follow-up after termination of MTX therapy. Statistical analysis was performed using the Student t test.

RESULTS

The mean LVEF before administration of the first MTX dose was 65 ± 3.3% (lowest value 60%, highest value 78%). In the study group (n = 72), 2D echocardiography was normal in 58 (90%) patients and showed minor abnormalities in 7 (10%) patients, including left ventricular hypertrophy, interatrial septal aneurysm, right ventricular dilatation, trace aortic regurgitation, and mild atrioventricular valve insufficiency which were not contraindications to MTX therapy (Table 1). The lowest LVEF at the final 2D echocardiographic examination was 60% and the highest LVEF was 70% (mean 65 ± 2.1%). We did not find a significant LVEF reduction during MTX treatment in MS patients compared to baseline values (p = 0.083) (Table 2). Severe myocardial dysfunction manifesting with significant LVEF reduction by 2D echocardiography or clinical evidence of HF was not noted in any patient in the study group.

Table 1. Echocardiographic findings in multiple sclerosis patients selected for mitoxanthrone therapy

Table 2. Left ventricular ejection fraction (LVEF) by two-dimensional echocardiography before and after mitoxanthrone treatment (Student t test)

DISCUSSION

Severe limitations of MTX use include drug cardiotoxicity and a potential to induce leukaemia [3, 8, 9]. The mechanism of these adverse effects has not been fully elucidated. It is probably related to the ability of the drug to induce formation of chelate complexes with iron ions which stimulate formation of reactive oxygen species that damage cardiomyocytes [1, 12]. Another possible reason for MTX cardiotoxicity is the presence of abundant amounts of lipids in the inner mitochondrial membrane, which bind to MTX particles [1]. Other reports indicated that cardiac toxicity of MTX increases with the drug dose [13–15]. These data were obtained in patients who received MTX for the treatment of neoplastic disease. Few studies evaluated the effect of MTX on the myocardium during MTX monotherapy of MS. Single cases of asymptomatic LVEF reduction by 2D echocardiography, cardiomyopathy, and congestive HF were reported in MS patients. While symptomatic HF develops in about 0.2–0.5% of patients treated with MTX, asymptomatic LVEF reduction is 3 times more common [16]. It was shown that cardiac toxicity increases with higher infusion rate and dose of the drug. It is recommended to administer the drug in an intravenous infusion lasting no less than 30 min and not to exceed the total dose of 140 mg/m2 of BSA [17]. MTX should not be used in patients with LVEF below 50% [3, 18]. The Food and Drug Administration recommends echocardiography with evaluation of LVEF before each MTX administration. A decrease in LVEF by more than 10 percentage points compared to baseline or below 50% is an indication to withdraw treatment [3]. In addition to cardiomyopathy and congestive HF, other manifestations of cardiac toxicity of MTX include tachycardia and cardiac arrhythmia [1]. The authors of the recommendations of the National Team of Cardiologic and Oncologic Supervision on cardiac safety of breast cancer patients described morphological and functional myocardial changes due to anthracycline administration as chemotherapy-related cardiac dysfunction (CRCD) type I. They also discussed three possible types of cardiac dysfunction resulting from the use of this class of drugs: perimyocarditis, early-onset HF developing during oncological treatment or soon after its termination, and late-onset HF manifesting several years after oncological treatment [19].

In our study, we did not find a significant reduction in LVEF by 2D echocardiography measured before the last dose of the drug compared to baseline pretreatment values. We also did not find any case of LVEF reduction below 50% or by 10 percentage points compared to baseline. It should be noted, however, that LVEF measured by 2D echocardiography is not a sensitive method, with differences of up to 10% noted between subsequent measurements without significant cardiac damage. A more sensitive method to monitor cardiomyocyte damage is troponin level measurement. The authors of the recommendations of the National Team of Cardiologic and Oncologic Supervision advise troponin measurement soon after the infusion is terminated, at 24 h and 72 h, and at 1 month after anthracycline administration [19]. Patients in our study did not report chest pain or palpitation, and we noted no case of HF symptoms during MTX treatment. Similar conclusions were arrived at by Zingler et al. [20] who evaluated LVEF by echocardiography in 73 patients with MS and found no significant LVEF reduction during treatment. In that study group, however, 1 case of atrial fibrillation episode was noted after the second MTX dose in a patients with hypertension and previous myocardial infarction. In another study by Ghalie et al. [21] in a much larger population of 1378 patients treated with MTX, symptoms of congestive HF developed in only 2 cases, and asymptomatic LVEF reduction below 50% was noted in 2.18% of patients, more frequently with higher drug doses above 100 mg/m2 of BSA [21–23]. In another study in 93 patients, asymptomatic LVEF reduction resulted in treatment termination in 5 patients. In 4 of these patients, LVEF normalised within few months. In 1 patient, myocardial infarction occurred at 18 months after treatment termination [9]. Deobuverie et al. [1] noted 2 cases of LVEF reduction below 45% in a group of 307 patients with primary progressive and relapsing remitting MS treated with MTX. Fewer data are available on long-term cardiac effects of MTX treatment. Goffette et al. [10] described 3 patients in whom congestive HF developed at 24, 29, and 60 months after administration of the last MTX dose. Two of these patients were previously treated with cyclophosphamide which might have increased the cardiotoxic effect of MTX [10]. During 3 years of follow-up, Hartung et al. [8] reported 4 cases of asymptomatic LVEF reduction in a group of 196 patients, with no case of congestive HF resulting from MTX treatment [8].

CONCLUSIONS

In summary, previous studies indicate that the risk of cardiac damage during MTX monotherapy in MS patients without a history of cardiac disease and with normal baseline echocardiography is low. Further studies are required to investigate long-term cardiac effects of MTX. Cardiac damage manifesting with LVEF reduction may occur years after treatment completion. The utility of cardiac monitoring using more sensitive methods such as high-sensitivity cardiac troponins or cardiac magnetic resonance imaging should be considered [19].

Conflict of interest: none declared

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