Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone

Goffette, Sophie; Pesch, Vincent Van; Vanoverschelde, Jean-Louis; Morandini, Emmanuel; Sindic, Christian

doi:10.1007/s00415-005-0839-3

Cited by 47 publications

(30 citation statements)

References 27 publications

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“…12 One Class III study of 96 patients who received a cumulative dose of 48 mg/m 2 of MX over 1 year reported asymptomatic decreased LVEF in 6 patients. 13 Three of these patients had LVEF Ͻ50% at 6 months and discontinued therapy.…”

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confidence: 99%

Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis [RETIRED]

et al. 2010

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Objective: The chemotherapeutic agent mitoxantrone was approved for use in multiple sclerosis (MS) in 2000. After a review of all the available evidence, the original report of the Therapeutics and Technology Assessment Subcommittee in 2003 concluded that mitoxantrone probably reduced clinical attack rates, MRI activity, and disease progression. Subsequent reports of decreased systolic function, heart failure, and leukemia prompted the US Food and Drug Administration to institute a "black box" warning in 2005. This review was undertaken to examine the available literature on the efficacy and safety of mitoxantrone use in patients with MS since the initial report.Methods: Relevant articles were obtained through a review of the medical literature and the strength of the available evidence was graded according to the American Academy of Neurology evidence classification scheme. Results:The accumulated Class III and IV evidence suggests an increased incidence of systolic dysfunction and therapy-related acute leukemia (TRAL) with mitoxantrone therapy. Systolic dysfunction occurs in ϳ12% of patients with MS treated with mitoxantrone, congestive heart failure occurs in ϳ0.4%, and leukemia occurs in ϳ0.8%. The number needed to harm is 8 for systolic dysfunction and 123 for TRAL. There is no new efficacy evidence that would change the recommendation from the previous report. Conclusions:The risk of systolic dysfunction and leukemia in patients treated with mitoxantrone is higher than suggested at the time of the previous report, although comprehensive postmarketing surveillance data are lacking. Neurology ® 2010;74:1463-1470 GLOSSARY AAN ϭ American Academy of Neurology; CHF ϭ congestive heart failure; CML ϭ chronic myeloid leukemia; FDA ϭ Food and Drug Administration; LVEF ϭ left ventricular ejection fraction; MIMS ϭ Mitoxantrone in Multiple Sclerosis Group; MS ϭ multiple sclerosis; MX ϭ mitoxantrone hydrochloride; NNH ϭ number needed to harm; RRMS ϭ relapsing-remitting multiple sclerosis; SPMS ϭ secondary-progressive multiple sclerosis; TRAL ϭ therapy-related acute leukemia; TTA ϭ Therapeutics and Technology Assessment.

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confidence: 99%

Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis [RETIRED]

et al. 2010

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“…This would also justify the observed higher proportion of heart events in our cohort although the reported risk is not significant, probably because of the low number of events. Other explanations for differences in observed results may depend on the criteria and methodology used in other studies to define and to assess the presence and the severity of heart diseases [10,11]. As already mentioned, the distribution of clinical phenotypes of MS patients included in the study, as well as age at initiation of MTX therapy, have to be considered possible factors determining a modification of the observed effects when comparing present results with those from other studies [12].…”

Section: Discussionmentioning

confidence: 85%

Cardiovascular comorbidity in multiple sclerosis patients treated with Mitoxantrone therapy: a cohort study

Ragonese

Aridon

Realmuto

et al. 2017

Mult Scler Demyelinating Disord

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Background: Mitoxantrone (MX) has been used as second line therapy for aggressive multiple sclerosis (MS). Potential cardiotoxic effects of MX limit its use; a cumulative dose of up to 100 mg/m2, has been long considered relatively safe. We calculated the frequency of cardiac side effects in MS patients treated with MX. Methods: We performed a cohort study including all MS patients treated with MX at the Neurological Department of the University Hospital of Palermo, Italy. Two hundred-sixty-four MS patients diagnosed according to validated criteria were included and followed-up until the end of September 2010. Patients were treated with MX as a second line therapy if they had no previous heart diseases determined by clinical evaluation, electrocardiography, and echocardiography. Treatment administration was made at a monthly dose of 8 mg/m 2 for the first three months and at a dose of 12 mg/m2 every three months. Echocardiography was routinely performed every six months. Treatment was stopped before reaching the final dose if signs had appeared of impaired heart function, confirmed left ventricular ejection fraction reduction lower to 50%, or a confirmed reduction of more than 10% with respect to the first examination. Results: Heart involvement was observed in 12.4% of treated individuals, and symptomatic congestive heart failure occurred in 2.7% of the cohort. A patient had a myocardial infarction, and 3.1% showed electrocardiographic anomalies not present at baseline. Conclusion: Our study confirms that cardiac adverse events associated with MX are more common than previously reported.

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“…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].…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac effects of mitoxanthrone therapy in patients with multiple sclerosis

et al. 2016

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A b s t r a c tBackground: Mitoxanthrone (MTX) is a synthetic anthracycline antibiotic that has been used for several years in the treatment of patients with primary progressive, secondary progressive, and relapsing remitting multiple sclerosis (MS) who do not respond to other drugs. MTX has antineoplastic, immunomodulatory, and antibacterial properties. 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 sequelae of MTX treatment are drug cardiotoxicity and a potential to induce leukaemia. Drug toxicity results from its affinity to iron ions. The resulting complex strongly induces formation of free oxygen radicals and increases lipid peroxidation. Asymptomatic reduction in left ventricular ejection fraction (LVEF) by two-dimensional (2D) echocardiography, cardiomyopathy, and congestive heart failure have been observed in patients with MS at a rate of about 2.6-5%. Few studies evaluated cardiotoxicity of MTX in MS patients. Most previous studies were performed in small groups of cancer patients and cardiac evaluation was limited to physical examination. Aim:To evaluate the effect of MTX treatment on LVEF by 2D echocardiography. The study group included primary progressive MS in 40 (56%) patients, secondary progressive MS in 5 (7%) patients, and relapsing remitting MS in 27 (37%) patients. MTX was administered at 12 mg/m 2 of body surface area every 3 months (up to the total dose of 140 mg/m 2 ). MTX treatment was initiated in patients with no signs of heart failure 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. The effect of MTX treatment on LVEF was evaluated by comparing baseline LVEF with LVEF measurements before the last MTX dose. Statistical analysis was performed using the Student t test. Results:The mean LVEF before administration of the first MTX dose was 65 ± 3.3%. The lowest LVEF at the final 2D echocardiographic examination was 60 ± 2.1%. We did not find a significant LVEF reduction during MTX treatment in MS patients compared to baseline values. Severe myocardial dysfunction manifesting with significant LVEF reduction by 2D echocardiography or clinical evidence of heart failure was not noted in any patient in the study group. Conclusions:Our study showed no significant LVEF reduction during MTX monotherapy in MS patients without a history of a cardiac disease and with normal echocardiographic findings at baseline. Long-term cardiac effects of MTX require further studies.

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Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone

Cited by 47 publications

References 27 publications

Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis [RETIRED]

Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis [RETIRED]

Cardiovascular comorbidity in multiple sclerosis patients treated with Mitoxantrone therapy: a cohort study

Cardiac effects of mitoxanthrone therapy in patients with multiple sclerosis

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