High Dose Chemo With Stem Cell Transplant as Treatment for Multiple Sclerosis That Failed Prior Treatment

Multiple sclerosis is an inflammatory autoimmune disease characterized by loss of myelin and
axonal damage, having typical contrast-enhanced MRI foci as an imaging counterpart. MS shows
three main patterns of clinical course: relapsing/remitting, primary progressive and
secondary progressive.Concerning disease pattern, secondary progressive is the standard
indication, to avoid overtreatment in relapsing/remitting patients or ineffectual treatment
in primary relapsing patients.

Currently, MS is the most common autoimmune disease that have been treated with autologous
HPC transplants (Fagius et al, 2009; Burt et al, 2009; Saccardi et al, 2006). More than 350
consecutive cases have been reported by the EBMT over the last decade. Most patients who
underwent autologous HPC transplant for MS in the early studies had secondary progressive
MS, and relatively fewer had relapsing remitting disease, with a Kurtzke Expanded Disability
Status Scale (EDSS) of 3.0-9.5 at the time of transplant. Significant objective and
subjective improvements have been reported in up to 70% of these patients.

The following conditioning regimens will be used, with Alemtuzumab, Fludarabine, and
Cyclophosphamide will be used for all patients. Prophylaxis of Acyclovir, Levaquin, and
Fluconazole will be given to prevent infections. The autologous HPC will be infused within
48-72 hours of completing the chemotherapy. The patients will receive additional supportive
care medications and treatments as necessary. Neutrophil engraftment will be defined as the
day on which the ANC rises to > 500 cells/ml for two consecutive days. Platelet engraftment
will be defined as the first day on which the platelet count rises to > 20,000/ml over a
7-day interval without transfusion support.

Inclusion Criteria:

Age between 18-60, inclusive

Patients carry a diagnosis of multiple sclerosis, according to the McDonald's criteria for
diagnosis (Polman et al, 2011).

Must have a neurologist providing the primary care for the MS and be willing to be
evaluated for the multiple sclerosis by the two neurologists who are the co-investigators
in the protocol.

Must be documented to be HIV negative.

An EDSS of 3.5 - 5.5

Patients must be able to give written consent.

Inflammatory disease despite primary disease modifying therapy with at least 6 months of
interferon and another disease modifying therapy, including fingolimod,glativamir,
natalizumab, and mitoxantrone. Failure is defined as two or more clinical relapses with
documented neurologic changes (excluding sensory changes) within the year prior to the
study. (NOTE: Relapses must have required treatment with corticosteroids). Failure may
also be defined as one relapse (excluding sensory changes) treated with methylprednisone
and, on a separate occasion within the previous 12 months, evidence of active inflammation
(i.e. gadolinium enhancement on MRI scan of the CNS).

No previous history of allergic reaction to cyclophosphamide, G-CSF or mesna

Patients must not be pregnant

Failure to accept or comprehend irreversible sterility as a potential side effect of
therapy.

Life expectancy of more than 6 months

No evidence of myelodysplastic syndrome on peripheral blood smear

Not allergic to cyclophosphamide, mesna, fludarabine or alemtuzumab

Baseline serum creatinine must be <1.5 mg/dL, left ventricular ejection fraction >55%,
adequate pulmonary functions (oxygen saturation at room air of >90%), and AST and ALT not
> 2x upper limits of normal, and no history of previous or active malignancy, except for
localized cutaneous basal or squamous cell carcinoma in situ of the cervix.

Exclusion Criteria:

Diagnosis of primary progressive MS.