Hematopoietic Stem Cell Therapy for Patients With Refractory Myasthenia Gravis

There will be no randomization in this study. All subjects who are determined to be eligible
for the study treatment will receive high dose cyclophosphamide and ATG followed by infusion
of autologous peripheral blood stem cells. The procedures the subject will undergo are as
follows:

1. Physician visit to determine potential eligibility for the study. Subjects will be
evaluated by a transplant physician and a neurologist. They will have a complete
physical examination and will provide a full medical history at these visits. The study
will be described in detail by the transplant physician and nurse and the consent form
will be provided to be taken home to read.

2. Insurance verification. Subjects who remain interested in pursuing the study treatment
and who have refractory myasthenia gravis will proceed to the insurance verification
phase. Third party payment or self-pay must be verified before subjects can proceed.

3. Consent form. Prior to proceeding, the appropriate signatures will be obtained on the
consent form. Subjects will be given an opportunity to ask further questions of the
attending physician and transplant nurse prior to signing the consent form.

4. Pre-transplant testing. To determine final eligibility for the study, subjects will
undergo a series of tests/procedures. These include: CXR; electrocardiogram; MUGA or
echocardiogram; pulmonary function test; CT scan of the sinuses; CT scan of the chest to
r/o thymoma; dental examination; urinalysis; and blood testing to include CBC,
chemistries, liver and kidney function tests, coagulation studies, viral studies and,
for females, a pregnancy test. All pre-transplant testing is routine medical testing
done to verify diagnosis and to insure adequate organ function and absence of viral
illnesses which would preclude a safe transplant course.

5. Autologous peripheral blood stem cell collection. Subjects who are proceeding to
transplant will undergo a routine procedure for the mobilization and collection of
peripheral blood stem cells. This includes the administration of IV cyclophosphamide,
given as an inpatient requiring an overnight stay, followed by the subcutaneous
administration of G-CSF, to be self-administered as an outpatient. Approximately ten
days after the administration of IV cyclophosphamide, the peripheral blood stem cells
will be collected as an outpatient in the Blood Center. A pheresis catheter will be
placed for this purpose on the first day of leukopheresis. Leukopheresis will be
continued on a daily basis until an adequate number of peripheral blood stem cells have
been collected (a maximum of four leukophereses may be performed). G-CSF will continue
to be administered until leukopheresis is completed. The pheresis catheter will be
discontinued when stem cell harvesting is completed. Processed cells will be frozen and
stored until they are reinfused after the conditioning regimen.

6. PICC line placement. Subjects will have a double lumen PICC line placed prior to the
administration of study treatment for the administration of chemotherapy, IV fluids,
blood products and the withdrawal of blood samples. The placement of a PICC line is a
routine medical procedure.

7. Study treatment. Subjects will undergo conditioning which will include four days of
intravenous high dose cyclophosphamide and three days of intravenous anti-thymocyte
globulin (ATG). Both cyclophosphamide and ATG are common immune suppressive agents. The
previously collected peripheral blood stem cells will be reinfused following the
completion of the conditioning regimen.

8. Post-treatment follow-up. Subjects will have a history and physical by the transplant
physician and neurologist at 3 months, 6 months, 12 months, and yearly for 5 years. In
addition, routine urinalysis and blood testing will be performed at these same intervals
to include CBC, chemistries, kidney and liver function tests.

Inclusion Criteria (Patients must fulfill all of the following)

1. Established diagnosis of myasthenia gravis defined as clinical evidence of muscle
weakness and fatigue ability and supported, an abnormal EMG-NCV repetitive nerve
stimulation (or single-fiber EMG) or Lambert-Eaton Myasthenic Syndrome without
evidence of malignancy.

2. Ages 15-65 years.

3. Positive antibody preferred (anti-AchR, MuSK, voltage gated calcium channel,
anti-striational).

4. Failure of thymectomy (except for Lambert-Eaton Myasthenic Syndrome).

5. Failure anticholinesterase therapy, corticosteroids, and at least two of the
following: azathioprine, cyclosporin, CellCept, cyclophosphamide, plasma exchange, or
IVIG. Failure is defined as at least 6 months of the above drug therapy and an
Osserman score of IIB, III, or IV and not clinically improving.

And at least one of the following:

1. History of myasthenia crises (requiring mechanical ventilation) despite thymectomy and
immunosuppressive therapy.

2. Hospitalized or on ventilator support for myasthenia gravis within the last 18 months
despite thymectomy and immunosuppressive therapy.

3. Inability to maintain nutrition due to muscle weakness.

4. A Karnofsky performance status of 70% or less (may or may not be able to care for
self, but unable to carry on normal activity or unable to do active work).

Exclusion Criteria

1. Significant end organ damage such as:

1. LVEF <40% or deterioration of LVEF during exercise test on MUGA or
echocardiogram.

2. Untreated life-threatening arrhythmia, active ischemic heart disease or heart
failure.

3. DLCO < 40% of predicted value.

4. Serum creatinine > 2.5 mg/dl.

5. Liver cirrhosis, transaminases >3x of normal limits, or bilirubin >2.0 unless due
to Gilberts disease.

2. HIV positive.

3. Uncontrolled diabetes mellitus, or any other illness that in the opinion of the
investigators would jeopardize the ability of the patient to tolerate aggressive
treatment.

4. Prior history of malignancy except localized basal cell or squamous skin cancer. Other
malignancies for which the patient is judged to be cured by local surgical therapy,
such as (but not limited to) head and neck cancer, or stage I or II breast cancer,
will be considered on an individual basis.

5. Positive pregnancy test, inability or unable to pursue effective means of birth
control, failure to willingly accept or comprehend irreversible sterility as a side
effect of therapy.

6. Psychiatric illness or mental deficiency making compliance with treatment or informed
consent impossible.

7. Inability to give informed consent

8. Congenital myasthenia gravis

9. Neonatal myasthenia gravis

10. Osserman grade 1 or 2

11. Pure red cell aplasia

12. Any patient on insulin