Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis.
OBJECTIVE
To explore the safety and effectiveness of high-dose cyclophosphamide (HiCy) without bone marrow transplantation in patients with aggressive multiple sclerosis (MS).


METHODS
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.


METHODS
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.


METHODS
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.


CONCLUSIONS
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).
Krishnan
Chitra
C
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-5371, USA.
Kaplin
Adam I
AI
Brodsky
Robert A
RA
Drachman
Daniel B
DB
Jones
Richard J
RJ
Pham
Dzung L
DL
Richert
Nancy D
ND
Pardo
Carlos A
CA
Yousem
David M
DM
Hammond
Edward
E
Quigg
Megan
M
Trecker
Carrilin
C
McArthur
Justin C
JC
Nath
Avindra
A
Greenberg
Benjamin M
BM
Calabresi
Peter A
PA
Kerr
Douglas A
DA
D000328:Adult; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D004185:Disability Evaluation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D016896:Treatment Outcome
D003520:Cyclophosphamide