High Dose Cyclophosphamide Followed by Glatiramer Acetate in the Treatment of Relapsing Remitting Multiple Sclerosis
High Dose Cyclophosphamide Followed by Glatiramer Acetate in the Treatment of Relapsing Remitting Multiple Sclerosis
The purpose of this study is to determine if high-dose cyclophosphamide followed by a
 maintenance dose of glatiramer acetate is safe in patients with relapsing remitting multiple
 sclerosis (MS). The investigators hypothesize that institution of glatiramer acetate
 treatment following high-dose cyclophosphamide treatment will extend the period of disease
 free activity and further reduce the disability in patients with relapsing remitting multiple
 sclerosis. The investigators plan to investigate the properties of glatiramer acetate against
 the recurrence of MS disease activity following high dose cyclophosphamide induced cessation
 detectable autoimmunity. The investigators hypothesize that glatiramer acetate, given in the
 phase of immune reconstitution after high-dose cyclophosphamide, may bias the immune system
 to a more tolerated state, thus leading to more stable and potentially permanent remissions.
Multiple sclerosis (MS) is an autoimmune disease characterized by progressive immune-mediated
 destruction of myelin and axons within the CNS. Despite the development, approval and
 clinical utilization of several medicines for patients with MS, most patients continue to
 accrue progressive disability. High-dose cyclophosphamide is chemotherapy treatment option
 for severe, refractory, immune-mediated illnesses such as MS. There is growing evidence that
 high dose cyclophosphamide is well tolerated and effective in MS. Our experience with 9
 patients who underwent treatment at the Johns Hopkins Hospital yielded impressive results
 with a significant 40% reduction in baseline disability and an 81% reduction in MRI
 gadolinium enhancing lesions. Five out of 9 patients had recurrence of new brain MRI lesions
 during 24 months of follow-up, recurring in 4 patients during the first year of follow-up.
 Our findings suggest that high-dose cyclophosphamide holds promise in inducing remission and
 reducing disability in relapsing remitting MS however the recurrence of MS disease activity
 (evidenced by worsening disability, clinical exacerbations or ongoing MRI evidence of new
 lesions) suggests that high-dose cyclophosphamide given as a treatment on its own, is not
 sufficient to induce long-term remission.

 Glatiramer acetate has been shown to be a more general suppressor of autoimmune disease,
 inhibiting the onset of experimental animal models of uveoretinitis, rheumatoid arthritis,
 immune rejection of grafts against host and host against graft disease, and inflammatory
 bowel disease. Glatiramer acetate was originally developed based on the observation that it
 inhibited the onset of clinical disease in an animal model of multiple sclerosis,
 experimental autoimmune encephalomyelitis (EAE). Glatiramer acetate suppression of EAE was
 found to be a general phenomenon not restricted to a particular species, disease type or
 encephalitogen used for the induction of EAE. A unique feature of glatiramer acetate is its
 promiscuous binding with high affinity to various class II MHC molecules and it potent
 induction of Th2 regulatory T cells. Moreover glatiramer acetate has subsequently been shown
 to be a more general suppressor of autoimmune disease, inhibiting the onset of experimental
 uveoretinitis, immune rejection of grafts against host and host against graft disease, and
 experimental inflammatory bowel disease.

 We plan to investigate the properties of glatiramer acetate against the recurrence of MS
 disease activity following high dose cyclophosphamide induced cessation detectable
 autoimmunity. This study is a prospective, open-label two-year follow-up study in 12 patients
 with relapsing-remitting MS who are unable to tolerate or have failed to optimally respond to
 conventional therapy and are at high risk of disease progression and loss of function.
 Patients who elect to enter the study will be given a single course of high-dose,
 cyclophosphamide regimen without transplantation. Patients will then receive 20 mg of
 glatiramer acetate subcutaneously 4 to 6 weeks after the last dose of high-dose
 cyclophosphamide, to allow the immune system to have time to begin to reconstitute without
 glatiramer acetate but still provide sufficient time for glatiramer acetate to vaccinate
 against recurrence of MS disease activity.

 The primary outcome of this pilot study will be to determine if high followed by a
 maintenance dose of glatiramer acetate is safe in this patient population. We hypothesize
 that institution of glatiramer acetate treatment following high-dose cyclophosphamide
 treatment will extend the period of disease free activity and further reduce the disability
 in patients with relapsing remitting MS.
Inclusion criteria

 1. Males and females between the ages of 18 and 70 years, inclusive.

 2. Diagnosis of clinically definite MS according to the McDonald Criteria.

 3. Must have been on conventional immunomodulatory treatment (interferon beta-1a,
 glatiramer acetate, or natalizumab) for at least 3 months OR have not tolerated
 conventional treatment OR have refused to start conventional treatment.

 4. 2 or more total gadolinium enhancing lesions on each of two pretreatment MRI scans at
 screening and enrollment.

 5. Subject must have EDSS ranging from 1.5 to 6.5.

 6. Subject must have had at least one clinical exacerbation in the last year and this
 must have occurred after having been on Avonex, Betaseron, Copaxone, Rebif or
 Natalizumab therapy for at least 3 months. This does not apply if subject has refused
 to start conventional therapy.

 7. Subject must have had a sustained (≥ 3 months) increase of > 1.0 on the EDSS
 (historical estimate allowed) between 3.0 and 5.5 or > 0.5 between 5.5 and 6.5 (while
 on therapy).

 8. Written informed consent prior to any testing under this protocol, including screening
 tests and evaluations that are not considered part of the subject's routine care.

 9. Women of childbearing potential should have a negative pregnancy test prior to entry
 into the study.

 Exclusion criteria

 1. Any risk of pregnancy--ALL female patients must have an effective means of birth
 control or be infertile due to hysterectomy, fallopian tube surgery, or premature
 menopause.

 2. Cardiac ejection fraction of < 45%.

 3. Serum creatinine > 2.0.

 4. Patients who are pre-terminal or moribund.

 5. Bilirubin > 2.0, transaminases > 2x normal.

 6. Patients with EDSS < 3.0 or > 6.5.

 7. Patients with pacemakers and implants who cannot get serial MRIs.

 8. Patients with active infections until infection is resolved.

 9. Patients with WBC count < 3000 cells/µl, platelets < 100,000 cells/µl and untransfused
 hemoglobin < 10 g/dl.