Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis

Abstract

Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans. Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.

Multiple sclerosis and the role of immune cells

“…Several combinations have been tested, some show more promise than others. It was for instance described how patients treated with a short induction of mitoxantrone followed by longer term GA therapy showed a reduction in new relapses compared to GA alone, as well promising results regarding gadolinium enhanced lesion load [54][55][56][57] . This suggests possible synergistic effects among these drugs.…”

Acute myeloid leukemia developing in patients with autoimmune diseases

“…The first case report of t-AML (M3) in a multiple sclerosis patient was published in 1998. 80 Subsequently, a number of case reports and case series were published on t-AML in mitoxantrone treated patients, [81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96] as summarized in Table 4. Larger series of patients with multiple sclerosis treated Patients were exposed to a mean cumulative mitoxantrone dose of 60 mg/m 2 and were followed up for a mean of 36 months.…”

A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design

“…Cytotoxic drugs, depleting antibodies or agents designed to influence the homing of leukocytes have been shown to actively disable the immune response for prolonged periods beyond the pharmacokinetic washout period of the drug before immune reconstitution is achieved. [16][17][18] In addition, immunomodulators such as interferon beta or glatiramer acetate have been shown to influence the immune response to myelin antigen through several active processes, which may persist in the absence of therapy. [19][20][21][22] It could be envisaged that intervention with these DMTs could result in a legacy effect on disease activity, at least over the relatively short observation period of 12 months, as defined by the TERMS protocol.…”