Mitoxantrone in worsening secondary progressive multiple sclerosis: A prospective, open-label study.

BACKGROUND: An antineoplastic agent, mitoxantrone (MX) is used to treat neurologic disability and/or reduce the frequency of clinical relapses in patients with secondary progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (MS). Based on a MEDLINE search for literature concerning the use of IV MX in patients with secondary progressive MS (SPMS), there is a paucity of data to identify the clinical characteristics of responders.

OBJECTIVE: The aim of this study was to monitor the effects of IV MX in patients with SPMS and varied clinical characteristics whose condition continued to worsen despite receiving IV methylprednisolone treatment.

METHODS: This prospective, open-label study was conducted at the Multiple Sclerosis Clinic, Center for Neurologic Disorders, Milwaukee, Wisconsin. Male and female patients aged ≥18 years with SPMS whose neurologic condition, as assessed using routine neurologic examination, worsened despite at least one 5-day course of IV methylprednisolone treatment (1 g/d) were enrolled. Patients received premedication with an antiemetic and IV MX 12 mg/m(2) every 12 weeks for up to 2 years, with a total cumulative dose not to exceed 96 mg/m(2). All patients were followed up for 1 year after treatment cessation. Efficacy was assessed at baseline, end of treatment, and 1-year follow-up using the Extended Disability Status Scale (EDSS) (which measures the functional disability level) (0 = normal findings on neurologic examination to 10 = death from MS complications). Tolerability was assessed before, during, and immediately after each infusion and at 2 weeks after each infusion, using direct questioning of, and spontaneous reporting by, the patients; physical examination; and laboratory assessments. Cardiac multigated acquisition scanning was performed at baseline and every 24 weeks during the treatment period.

RESULTS: Forty-eight patients were enrolled (28 women, 20 men; mean [SD] age, 47.6 [8.6] years; mean [SD] disease duration, 12.5 [6.0] years; mean [SD] baseline EDSS score, 6.9 [1.2]). Twenty-three patients completed the entire course of treatment; the remaining 25 were withdrawn after 1 year of treatment due to lack of efficacy (22 patients), asymptomatic cardiac ejection fraction <40% (2), and severe septicemia and worsening of MS requiring extended respiratory support and hospitalization (1). Patients who completed only 1 year of treatment were younger compared with those who completed 2 years (mean age, 45.2 vs 50.1 years; P < 0.05). No significant change in mean EDSS score was found at the end of treatment or at 1-year posttreatment follow-up. In patients whose disability improved by 2-0.5 on the EDSS (11 patients at 1 year; 5 patients at 2 years), the degree of improvement noted at 1-year follow-up in patients with a baseline EDSS score 3.0 to 5.5 versus 6.0 to 7.5 and 8.0 to 9.0 was significant (both, P < 0.05). Severe adverse effects occurred in 14.6% of patients and included marked leukopenia (peripheral white blood cell count, <100 cells/μL) with urosepsis, requiring hospitalization in 7 patients, 1 of whom developed severe septicemia and worsening of MS, requiring >4 weeks of respiratory support. Cardiac ejection fraction decreased to <40% in 2 patients after 1 year of treatment (total dose, 48 mg/m(2)). These 2 patients were asymptomatic, but the investigators decided to discontinue treatment. Cardiac function returned to normal range (but not to near-baseline levels) within 12 weeks after treatment cessation. Although all patients were premedicated with antiemetics, 10 (20.8%) reported mild nausea (treated with repeat administration of antiemetics), and 2 of 16 (12.5%) premenopausal patients reported slightly increased bleeding during menstruation after l year of IV MX therapy, requiring no medical therapy or adjustment in the treatment protocol.

CONCLUSIONS: Based on the results of this study in this small group of patients with worsening SPMS, IV MX treatment for up to 2 years was not associated with a significant change in EDSS score at the conclusion of treatment or 1 year after treatment cessation.