Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis

Abstract

The safety and efficacy of pulse cyclophosphamide (CTX) therapy was investigated in patients with very active secondary progressive multiple sclerosis, characterized by frequent relapses and rapid disability progression. For this purpose the clinical and MRI effects were assessed. Sixteen patients, 11 female and 5 male, were experiencing rapidly deteriorating disease, characterized by frequent and severe relapses as well as rapid progression (defined by an increase of more than 1 EDSS point in a period of 1 year). Mean relapse rate in the two years preceding CTX therapy was 3.0 +/-1.4. Mean EDSS was 4.0+/-1.4 one year before therapy and 5.6+/-1.0 at study entry. Treatment consisted in administration of high dose intravenous CTX every four weeks for one year and then every eight weeks for an additional twelve months. CTX dose was tailored to the patient's white blood cell response, and ranged from 800 to 1,200 mg/m(2) body surface. MRI was performed before therapy and then at 12 (Y1) and 24 (Y2) months. Eight patients with similar clinical features constituted a control group. CTX therapy was safe and well tolerated, and no severe side effects were observed. The EDSS decreased to 4.3+/-1.6 at Y1 (Y0 vs.Y1: p< 0.001) and to 4.1+/-1.6 at Y2 (Y0 vs.Y2: p< 0.001). Only four patients experienced relapses during the first year of therapy, while no relapses were observed during the second year of therapy. The mean relapse rate during therapy was 0.25 +/-0.45 (p< 0.0001). No increase in T2 lesion load was observed over the two years. A significant clinical and MRI deterioration was observed in the control group. Therapy with pulse CTX was able to stop disease activity and progression in patients with rapidly evolving secondary-progressive MS.

Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis

“…This finding strongly confirms previous reports and indicates that immunosuppressive therapy should be initiated as soon as the disease is clinically confirmed to have entered the progressive phase. Although no placebo group was included owing to the study's design and ethical considerations, we know from a previous study [15] that untreated rapidly deteriorating SPMS, with similar EDSS score, will continue to progress fast to more severe and irreversible levels of disability.…”

“…Monotherapy use of Mito or Cy [15,[19][20][21][22][23][24] or either used in combination with immunomodulatory agents [25][26][27] has considerably increased over the last years. Despite the risk of dramatic adverse events, like severe acute or delayed heart failure [28] and acute myeloid leukaemia [20][21][22][23][24][25][26][27][28][29][30], Mito has become, after approval by the FDA and EMEA, a first-line rescue therapy for RRMS patients who do not respond to IMA and for rapidly deteriorating SPMS [31][32][33][34].…”

“…Cy, although used in many MS Centres in Europe and the US [35], is not approved for MS and can be used in Italy only when informed consent is obtained. Indeed, although Cy has been demonstrated to arrest disease activity and progression in severe cases of MS [11][12][13][14][15] and to induce relevant anti-inflammatory modification of the immune system of MS patients [36][37][38], it is widely believed that the risk/benefit ratio is particularly high in Cy-treated patient.…”

“…Cyclophosphamide (Cy), although rejected as immunosuppressive therapy for MS by a recent Cochrane analysis [6] based on the pivotal studies on ''progressive'' MS [7][8][9][10], was shown to arrest clinical deterioration in RRMS patients unresponsive to immunomodulatory agents (IMA) and in those rapidly evolving into the secondary progressive phase of the disease [11][12][13][14][15][16]. Both drugs may have considerable dose-depending side effects, and their choice mainly depends on the treating neurologist's clinical experience of and on the presence of significant heart and bladder dysfunctions.…”

Review: Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms

“…The results were very encouraging: no further relapses were reported, and stabilization of EDSS scores occurred for up to 18 months. In 2003, Perini and Gallo [2003] reported an open-label study of 24 patients with active refractory MS who received monthly IV CYC and IV MP for 1 year followed by CYC therapy in alternate months for one extra year. They noticed significant improvement in EDSS scores, relapse rate and surrogate disease makers on magnetic resonance imaging (MRI).…”