Noninvasive Assessment of Mitoxantrone Cardiotoxicity in Relapsing Remitting Multiple Sclerosis

Castro, S. De; Cartoni, Domenico; Millefiorini, Enrico; Funaro, Stefania; Gasperini, Claudio; Morino, Stefania; Tallarico, Demetrio; Beni, Sergio

doi:10.1002/j.1552-4604.1995.tb05021.x

Cited by 40 publications

(22 citation statements)

References 17 publications

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“…Patients treated with mitoxantrone are at increased risk for cardiac toxicity as manifested by cardiomyopathy, reduced left ventricular ejection fraction, and irreversible congestive heart failure. 37,38 Recently, an analysis of the clinical data from three combined clinical trials of mitoxantrone (mean cumulative dose ϭ 60.5 mg/m 2 ) in MS has been reported. 39 Although the occurrence of congestive heart failure was low (0.2%) in this study group, an asymptomatic reduction in ejection fraction (Ͻ50%) was almost three times less likely (1.8%) at cumulative doses of Ͻ100 mg/m 2 compared to cumulative doses above this.…”

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confidence: 99%

“…Because of concerns about such poten-tial cardiac toxicity, a cumulative dose of mitoxantrone more than 140 mg/m 2 is not recommended for treatment of MS, although doses of up to 96 mg/m 2 seem to be safe. 37 At a dose of 12 mg/m 2 administered every 3 months, this limitation (140 mg/ m 2 ) translates to a maximum duration of therapy of only 2 to 3 years. Such a therapeutic approach may be inadequate in a disease that will likely require ongoing treatment over many years.…”

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The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

et al. 2003

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Abstract-Mitoxantrone is the first drug approved for the treatment of secondary progressive multiple sclerosis (SPMS) in the United States. This assessment considers use of mitoxantrone in the treatment of MS. Mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). Also, mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is worsening (Type B recommendation). The potential for serious toxicity of mitoxantrone, however, must be taken into account when considering this therapy in individual patients. Moreover, because the potential clinical benefits on disease progression appear to be only modest, the results of the single phase III trial should be replicated in another (and hopefully much larger) clinical study before this agent is widely recommended for the treatment of patients with MS. NEUROLOGY 2003;61:1332-1338 Mitoxantrone hydrochloride (Novantrone) is an anthracenedione that has been used as an antineoplastic agent to treat hormone-refractory prostate cancer and acute nonlymphocytic leukemia in adults. It exerts its antineoplastic action by intercalating into DNA and producing both DNA strand-breaks and interstrand cross-links; it also interferes with RNA synthesis and markedly inhibits the enzyme topoisomerase II, which aids in the DNA repair process. [1][2][3][4] In the treatment of MS, mitoxantrone represents the latest in a long line of general immunosuppressive agents studied in this disease. Previously, most such agents have not shown clear-cut benefits in this condition. [5][6][7][8][9][10] On the basis of a phase III clinical trial in Europe, 11,12 and an earlier phase II study, 13 mitoxantrone recently received an expanded indication from the Food and Drug Administration (FDA) for use in secondary progressive MS (SPMS), in progressiverelapsing MS, and for patients with worsening relapsing-remitting (RR) MS. This last category is defined as patients whose neurologic status remains significantly abnormal between MS attacks.Mitoxantrone is the first drug approved for these indications in the United States, and it is the purpose of this assessment to consider both the evidence leading to the recent FDA approval as well as the appropriate clinical role of this agent in the management of patients with MS.Description of the analytic process. Articles for this review were searched in Medline under the keywords mitoxantrone and MS. Forty-one articles were identified by this search. The abstracts of these articles were reviewed and the original articles were selected for inclusion in the analysis only if they were either controlled trials or case series using mitoxantrone in the treatment of MS. Five such articles were identified, in addition to the phase III trial. 11,12 In addition, the reference lists of the articles found in this manner were also reviewed to identify articles or abstracts not found by the computer search.Analysis of the evidence. Followi...

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The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

et al. 2003

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“…Until now, only a few studies have investigated the safety of mitoxantrone when used as a single-agent therapy in MS. They were mainly based on clinical examination [13,14,15,16] or included only a limited number of patients with short follow-up times [17, 18]. In this prospective study, the potential cardiotoxicity of mitoxantrone in MS patients was evaluated by repetitive cardiac monitoring before each treatment course.…”

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confidence: 99%

Assessment of Potential Cardiotoxic Side Effects of Mitoxantrone in Patients with Multiple Sclerosis

Zingler

Näbauer²,

Jahn

et al. 2005

Eur Neurol

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Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m² body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 ± 12 years, range 20–75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 ± 33.8 mg. The mean follow-up time was 23.4 months (range 10–57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses.

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“…Cardiotoxicity still remains the major side effect of this treatment but occurs in a dose-dependent manner and therefore requires careful monitoring of cardiac function [12]. …”

Section: Introductionmentioning

confidence: 99%

Effects of Mitoxantrone on Multiple Sclerosis Patients’ Lymphocyte Subpopulations and Production of Immunoglobulin, TNF-alpha and IL-10

Gbadamosi¹,

Buhmann²,

Tessmer³

et al. 2003

Eur Neurol

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We designed this longitudinal study to clarify the short- and long-term effects of mitoxantrone on the immune system in a subgroup of multiple sclerosis patients treated at our centre. After 14 days we found a highly significant sustained reduction of leucocytes, primarily affecting neutrophils and most lymphocyte subsets except for naive and activated T lymphocytes. The CD4/CD8 ratio and serum immmunoglobulin levels were not affected. Furthermore, whole blood-stimulated mononuclear cell IL-10 production showed a significant lower level 2 weeks treatment, whereas basal IL-10 as well as stimulated and basal TNF-α secretion showed no significant changes. Longitudinal data disclosed a persistent decrease of B lymphocytes, while secretion of immunoglobulins, IL-10, and TNF-α was not altered in the follow-up. In conclusion, we confirmed a selective short-term effect of mitoxantrone therapy on most lymphocyte subpopulations, but not on immunoglobulines or the pro- and anti-inflammatory cytokines TNF-α and IL-10, which do not serve as possible response markers.

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Noninvasive Assessment of Mitoxantrone Cardiotoxicity in Relapsing Remitting Multiple Sclerosis

Cited by 40 publications

References 17 publications

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

Assessment of Potential Cardiotoxic Side Effects of Mitoxantrone in Patients with Multiple Sclerosis

Effects of Mitoxantrone on Multiple Sclerosis Patients’ Lymphocyte Subpopulations and Production of Immunoglobulin, TNF-alpha and IL-10

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