Cyclophosphamide (Cytoxan) In MS

Design
A 2-year open-label trial of patients with aggressive Relapsing/Remitting Multiple Sclerosis (RRMS) given an ImmunoAblative regimen of HiCy (50 mg/kg/d for 4 consecutive days) with no subsequent ImmunoModulatory Therapy unless disease activity reappeared that required rescue therapy.

Setting
The Johns Hopkins University Multiple Sclerosis Center, Baltimore, Maryland. Patients A total of 21 patients with RRMS were screened for eligibility and 9 patients were enrolled in the trial.

Patients were required to have 2 or more Gadolinium-enhancing lesions on each of 2 pretreatment Magnetic Resonance Imaging scans, at least 1 clinical exacerbation in the 12 months prior to HiCy treatment, or a sustained increase of 1.0 point or higher on the Expanded Disability Status Scale (EDSS) in the preceding year.

Intervention
Patients received 50 mg/kg/d of Cyclophosphamide intravenously for 4 consecutive days, followed by 5 mug/kg/d of Granulocyte Colony-Stimulating Factor 6 days after completion of HiCy treatment, until the absolute Neutrophil count exceeded 1.0 x 10(9) cells/L for 2 consecutive days.

Main Outcome Measures
The primary outcome of the study was the safety and tolerability of HiCy in patients with RRMS.

Secondary outcome measures included a change in Gadolinium-enhancing lesions on Magnetic Resonance images and a change in disability measures (EDSS and Multiple Sclerosis Functional Composite).

Results
Nine patients were treated and followed up for a mean period of 23 months. Eight patients had failed conventional therapy and 1 was treatment naive.

The median age at time of entry was 29 years (range, 20-47 years).

All patients developed transient total or near-total Pancytopenia as expected, followed by Hematopoietic recovery in 10 to 17 days, stimulated by Granulocyte Colony-Stimulating Factor.

There were no deaths or unexpected serious adverse events. There was a statistically significant reduction in disability (EDSS) at follow-up (mean [SD] decrease, 2.11 [1.97]; 39.4%; P = .02).

The mean (SD) number of Gadolinium-enhancing lesions on the 2 pretreatment scans were 6.5 (2.1) and 1.2 (2.3) at follow-up (81.4% reduction; P = .01).

Two patients required rescue treatment with other ImmunoModulatory therapies during the study owing to MS exacerbations.

Conclusion
Treatment with HiCy was safe and well tolerated in our patients with MS. Patients experienced a pronounced reduction in disease activity and disability after HiCy treatment.

This ImmunoAblative regimen of Cyclophosphamide for patients with aggressive MS is worthy of further study and may be an alternative to Bone Marrow Transplantation.

Published online June 9, 2008 (doi:10.1001/archneurol.65.8.noc80042).

The study's aim was to compare the efficacy and safety of intravenous Cyclophosphamide (CTX) and Mitoxantrone (MITO) as second-line therapy in a clinical sample of active Relapsing/Remitting (RR) or Secondary/Progressive (SP) Multiple Sclerosis subjects.

MITO was administered at a dosage of 8 mg/m(2) monthly for 3 months, then every 3 months, until a dosage of 120 mg/m(2) was reached.

CTX was administered at a dosage of 700 mg/m(2) monthly for 12 months, then bimonthly for another 24 months.

We used the Kaplan-Meier curves to assess time to the first relapse in RR and SP patients with relapses, and time to progression on the Expanded Disability Status Scale (EDSS) in all the patients.

MRI was assessed at baseline and after 12 months. Moreover, side effects were recorded.

Seventy-five patients received MITO (31 RR, 44 SP) and 78 CTX (15 RR, 63 SP). The two groups differ only in terms of a significantly higher proportion of RR patients in the MITO group.

After a mean follow-up of 3.6 years there was no significant difference in terms of time to the first relapse (MITO 2.6 years, CTX 2.5 years; p=0.50).

Whereas time to disease progression was slightly shorter in MITO than in CTX group (MITO 3.8 years, CTX 3.6 years; p=0.04).

After 12 months of treatment, active MRI scans were reduced by 69% in MITO and 63% in CTX patients (p=0.10). Discontinuation due to side effects was more frequent in CTX.