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

Abstract

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.

Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS

“…As observed by others, 7,17 we found no association of cardiac events with sex or age; we also found no association with MS disease duration at start of treatment. None of these indicators can be regarded as helpful prognostic factors for mitoxantrone associated cardiotoxic events.…”

“…GEE analyses revealed no significant predictors of increased AST (figure e-1D). DISCUSSION The incidence of subclinical cardiotoxicity was higher than that reported in the phase II/III mitoxantrone clinical trials 2,4 and by some, 11,17,18 although not all, [12][13][14][15] postmarketing studies. This adverse event is considered moderate by recognized standard criteria, 16 but the potential longterm consequences are unknown.…”

Cardiac effects of mitoxanthrone therapy in patients with multiple sclerosis

“…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.…”

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

“…In one series of 73 patients, no cardiotoxicity was observed, although 2 patients receiving at least 4 doses of MX were lost to follow-up. 18 Similarly, in another Class III study of 50 prospectively assessed patients, no decrease in LVEF was seen during 2 years of therapy, although cardiac function was not assessed in 3 years of follow-up after discontinuation of MX. 19 A recent Class III study of 100 patients with aggressive RRMS receiving induction MX therapy noted asymptomatic worsening LVEF in 3 patients following MX therapy.…”