Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS

Abstract

Background: Mitoxantrone is used for aggressive multiple sclerosis (MS), but concerns about safety, including cardiotoxicity and other laboratory measures, prevail.

Objective: To evaluate the incidence and potential predictors of adverse events associated with mitoxantrone at the MS Clinic, University of British Columbia, Canada.

Methods: Retrospective review of patients treated with mitoxantrone by standard protocol; maximum cumulative dose = 120 mg/m². Left ventricular ejection fraction (LVEF) was measured with regular multiple-gated acquisition (MUGA) scans; blood cell counts and biochemical liver tests were performed before infusions. Generalized estimating equations were used to examine potential predictors of adverse events (graded according to the Common Toxicity Criteria, version 4) in patients with normal baseline and ≥1 follow-up MUGA or laboratory assessment.

Results: All 163 patients (58% women) treated with mitoxantrone from 1999 to 2007 were reviewed. Mean baseline age was 41.9 (SD 10.8) years, cumulative dose was 59.7 (SD 26.0) mg/m², and median follow-up duration was 14 months (maximum 6.5 years). By study end, 14% developed de novo cardiotoxicity (grade ≥2) as measured by decreased LVEF, 27% neutropenia (grade ≥1), 15% anemia (grade ≥1), and 15% liver toxicity (grade ≥1). Possible predictors of adverse events included sex, age, disease duration, and cumulative dose; only women exposed to a higher cumulative dose were at a greater risk of anemia (adjusted odds ratio 1.26, 95% confidence interval 1.08–1.48 per 10 mg/m²).

Conclusions: Based on cardiac and laboratory assessments, mitoxantrone was reasonably well tolerated. However, cardiotoxicity was evident after doses well below current maximum recommended levels. A dose-response effect was not apparent. Findings emphasize the importance of monitoring; the long-term effects of mitoxantrone in multiple sclerosis require investigation.