High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) Study

MS is a chronic autoimmune disease of the central nervous system in which myelin, the
protective coat that surrounds nerve cells, is damaged or destroyed by autoimmune T cells
and macrophages, leading to an eventual loss of neurologic function. In a pilot study in
Europe using high-dose chemotherapy, it was observed that 18 of 19 MS patients stabilized or
improved clinically, and only one patient showed a new lesion on magnetic resonance imaging
(MRI) of the brain at 4.5 years after treatment. Improvement was seen in quality-of-life
assessments.

In ITN033AI, high-dose chemotherapy with autologous CD34-selected hematopoietic cell
transplantation will be given to confirm the results from the pilot study and to offer
therapy to patients with early MS and a poor prognosis. Research studies will be performed
in addition to clinical assessments to better understand the effect of the treatment on the
activity of MS. High-dose chemotherapy will be used to deplete autoreactive immune cells.
These regimens also deplete the bone marrow, the source of blood-forming CD34+ stem cells
which causes very low blood counts. Therefore, the participant's autologous CD34+
hematopoietic stem cells will be collected before high dose immunosuppressive therapy is
given and then returned as a transplant post-chemotherapy. Patients will be followed closely
after the autologous transplantation since they will be at risk for infections after
treatment.

At the beginning of the study, participants will undergo a number of screening and baseline
procedures, including a physical exam, blood collection, MS-confirming neurology exams and
questionnaires, and MRI procedures. Participants will be given prednisone and
granulocyte-colony stimulating factor (G-CSF) to mobilize CD34+ hematopoietic stem cells
from the bone marrow into the peripheral blood. When the peripheral blood CD34+ cell count
reaches 20,000 cells/ml or greater, these cells will be collected by leukapheresis. In this
process, a catheter is placed into a large blood vessel, peripheral blood is withdrawn, and
a high speed sedimentation (leukapheresis) device is used to separate and retain the cells
required for autologous transplantation. Other blood cells are then returned to the
participant's body. In the laboratory, the CD34+ hematopoietic stem cell graft will be
selected and prepared from the leukapheresis collection, and stored until needed for
transplant. Seven or more days following the collection of their autologous graft,
participants will be hospitalized and receive high-dose chemotherapy consisting of
carmustine, etoposide, cytarabine, and melphalan (BEAM) and thymoglobulin. This is followed
by transplantation of the autologous hematopoietic cell graft. Participants will remain in
the hospital for observation during recovery of their peripheral blood cell counts, as
described in the protocol. Participants will receive G-CSF and blood transfusions, if
needed, and will be monitored for infections. Following discharge from the hospital, eight
study visits will occur over sixty months (five years). During these visits, participants
will undergo blood and urine collection, MRI studies, leukapheresis, and MS neurology exams
and will complete questionnaires.

Inclusion Criteria:

- Diagnosis of relapsing-remitting or progressive-relapsing multiple sclerosis for less
than 15 years using McDonald Criteria. More information on this criterion can be
found in the protocol

- Score between 3.0 and 5.5 on the Expanded Disability Status Scale (EDSS)

- T2 abnormalities on brain MRI consistent with MS

- Two or more relapses in 18 months time on interferon (IFN), glatiramer acetate (GA),
natalizumab or cytotoxic therapy with EDSS increase of 1.0 or greater for
participants with EDSS at screening of 3.0 to 3.5 (0.5 or greater for participants
with EDSS at screening of 4.0 to 5.5) sustained at least 4 weeks after at least one
of these relapses OR one relapse on IFN, GA, natalizumab or cytotoxic therapy with
EDSS increase of 1.5 or greater (1.0 for subjects with EDSS at screening of 5.5)
sustained at least 4 weeks, together with MRI changes consistent with poor prognosis.
More information on this criterion can be found in the protocol.

- On IFN or GA for at least 6 months before the relapses occur that are counted to
satisfy previous inclusion criterion OR have received adequate doses of natalizumab
or cytotoxic therapy on a treatment schedule before the relapses occur that are
counted to satisfy previous inclusion criterion

- Approval by an MS Review Panel to participate in the study. More information on this
criterion can be found in the protocol.

- In good clinical condition with adequate organ function and without coexisting
medical problems that would increase the risk to the participant

- Willing to use acceptable methods of contraception

- Willing and able to comply with all study requirements

- Willing to accept and comprehend irreversible sterility as side effect of therapy

Exclusion Criteria:

- Primary progressive MS

- Secondary progressive MS without relapses (i.e., progression without exacerbations or
relapses) for 12 or more months

- Neuromyelitis optica, a disease similar to MS

- Initiation of new immunosuppressant treatment after the participant becomes eligible
for the protocol or continuance of immunosuppressant drugs after the participant is
screened for the protocol. Treatment with IFN, GA, or corticosteroids is permitted
after the participant becomes eligible for the protocol.

- Lapse of greater than 6 months between the time a participant is eligible for the
protocol and initiation of protocol treatment except when judged acceptable by the MS
Review Panel

- Prior treatment with investigational immunosuppressive agents within 3 months of
study eligibility

- Positive baseline plasma and CSF testing for JC virus or a brain MRI that has changes
consistent with a diagnosis of progressive multifocal encephalopathy (PML)

- History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS)

- Active hepatitis B or C infection, cirrhosis, or HIV infection

- Uncontrolled diabetes mellitus

- Uncontrolled viral, fungal, or bacterial infection. Patients with asymptomatic
bacteriuria are not excluded.

- Any illness that would jeopardize the ability to tolerate aggressive chemotherapy

- Prior history of malignancy, except localized basal cell or squamous skin cancer.
Other malignancies for which the subject is judged cured by the administered therapy
will be considered on an individual basis.

- Hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins or to iron
compounds/medications

- Metallic objects implanted in the body that would affect MRI exams

- Psychiatric illness, mental deficiency, or cognitive dysfunction

- Pregnancy