Hematopoietic Stem Cell Therapy for Patients With Refractory Myasthenia Gravis
Condition: Myasthenia Gravis
MeSH terms: Myasthenia Gravis; Muscle Weakness
Intervention: Hematopoietic Stem Cell Transplantation; Cyclophosphamide; ATG (rabbit); Mesna; Methylprednisolone; G-CSF
Intervention description: Autologous Hematopoietic Stem Cell Transplantation
Intervention MeSH terms: Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Prednisolone hemisuccinate; Prednisolone phosphate
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 15 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Refractory Myasthenia Gravis; Autologous Stem Cell Transplantation; Cyclophosphamide and ATG

Summary:

      MG may be neonatal, congenital, or autoimmune. Neonatal MG arises from transplacental
      transfer of ACh receptor antibodies from a mother with autoimmune MG to the fetus. Neonatal
      MG resolves with post delivery clearance of maternal antibodies. Congenital MG results from a
      genetic defect in the ACh receptor. Patients with congenital MG do not have ACh receptor
      antibodies. Both neonatal and congenital MG are excluded from this study. Autoimmune MG,
      which is the most common form of MG, affects approximately 25,000 Americans. Like most
      autoimmune diseases, it is associated with particular HLA genotypes, has a female
      predominance, and environmental factors involved in breaking tolerance to the ACh receptor
      are unknown. Patients with refractory and severe autoimmune MG will be considered candidates
      for this study.

      The purpose of this study is to assess the toxicity/feasibility (phase I) of autologous
      hematopoietic stem cell transplantation for refractory myasthenia gravis.
    

Eligibility criteria:

        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