Hematopoietic Stem Cell Transplant in Devic's Disease
Hematopoietic Stem Cell Transplant in Devic's Disease
This study is designed to examine whether treating Devic's disease patients with high dose
 cyclophosphamide together with rabbit antithymocyte globulin (rATG)/rituximab (drugs which
 reduce the function of the immune system), followed by return of previously collected
 patient's stem cells will result in improvement in Devic's disease. Stem cells are
 undeveloped cells that have the capacity to grow into mature blood cells, which normally
 circulate in the blood stream. The purpose of the intense chemotherapy is to destroy the
 cells in patient's immune system, which may be causing his/her disease. The purpose of the
 stem cell infusion is to produce a normal immune system that will no longer attack patient's
 body. The purpose of study is to examine the safety and efficacy of this treatment. The drugs
 used in this study treatment are drugs for commonly used for immune suppression.
Neuromyelitis optica (NMO, Devic's disease) is an autoimmune, inflammatory, demyelinating
 central nervous system disorder in which a person's own immune system attacks the optic
 nerves and spinal cord and is characterized by concurrence of optic neuritis and transverse
 myelitis, typically associated with a lesion in the spinal cord extending over three or more
 vertebral segments. Although it is most commonly relapsing, it is distinct from multiple
 sclerosis in that it is more severe, tends to spare the brain, and is associated with a
 longitudinally extensive lesion on spinal cord MRI. Furthermore, NMO is associated with a
 highly specific serum autoantibody marker, NMO-immunoglobulin G (IgG), which targets the
 water channel aquaporin-4. The disease follows a relapsing course in more than 90% of
 patients.

 At present, parenteral corticosteroids are widely employed as first-line treatment of optic
 neuritis and myelitis attacks, whereas therapeutic plasmapheresis is applied in the case of
 corticosteroids failure. Various strategies for the prevention of NMO relapses have been
 employed in small case series with modest activity. Immune based therapies, in order to be
 effective, need to be started early in the disease course while Devic's disease is
 predominantly an immune-mediated and inflammatory disease. Since 50% of patients with NMO are
 confined to a wheelchair within 5 years of onset, new therapies are needed in this disease.

 We now propose, as a phase I study, complete immune ablation and subsequent reconstitution
 with autologous stem cells.

 Based on the experience of the pilot studies, the current protocol will mobilize stem cells
 with granulocyte-colony stimulating factor (G-CSF) and cyclophosphamide and collect stem
 cells by apheresis. A subsequent bone marrow harvest will be performed only if needed to
 supplement the peripheral blood stem cells (PBSC). Based on experience of autoimmune flares
 in patients receiving G-CSF alone for mobilization, patients will be mobilized with
 cyclophosphamide 2.0 g/m2 and G-CSF 5- 10 mcg /kg.

 In order to avoid cumulative cardiac toxicity from cyclophosphamide and to allow culture of
 hematopoietic stem cell (HSC) product, three weeks must separate the administration of
 cyclophosphamide for mobilization and for conditioning.

 Cyclophosphamide 50 mg/kg/day will be given IV over 2 hours in 500 cc of normal saline. If
 actual weight is < ideal weight, cyclophosphamide will be given based on actual weight. If
 actual weight is > ideal weight, cyclophosphamide will given as adjusted weight. Adjusted
 weight = ideal weight + 25% (actual weight minus ideal weight).

 Hydration-guidelines, normal saline (NS) at 150-200 ml/hr should be given 2 hours before
 cyclophosphamide and continued until 24 hours after the last cyclophosphamide dose. The rate
 of hydration will be aggressively adjusted. Twice daily weights will be obtained. Amount of
 fluid can be modified based on patient's fluid status.

 r ATG 0.5 mg/kg given on day -5, then 1.0 mg/kg given on day -4, then 1.5 mg/kg given on days
 -3 through -1. rATG is infused over 10 hours. Premedicate with Acetaminophen 650 mg po and
 Diphenhydramine 25 mg po/IV 30 minutes before the infusion.

 Rituxan ( Rituximab ) - The dose of 500 mg of Rituximab will be diluted in 500 ml 0.9 % NS
 and infused per standard Rituximab infusion guidelines, given on days -6 and on day + 1.
 Following the guidelines, Rituximab will be started at 50 mg/hr. If no reaction occurs, the
 dose will be increased by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr.

 G-CSF - guidelines, 5-10 mcg/kg/day will be started day + 5 and continued until the absolute
 neutrophil counts reaches at least 1,000/µl.
Inclusion Criteria:

 -  Age between 16-65, at the time of pretransplant evaluation

 -  An established diagnosis of Devic's disease (more than one acute attack)

 -  NMO- IgG aquaporin-4 autoantibody positive

 Exclusion Criteria:

 -  Paraplegia or quadriplegia and legal blindness (defined as visual acuity of 20/200 or
 less in the better eye with the best correction possible)

 -  Any illness that in the opinion of the investigators would jeopardize the ability of
 the patient to tolerate aggressive chemotherapy

 -  Prior history of malignancy except localized basal cell, squamous skin cancer or
 carcinoma in situ of the cervix. Other malignancies for which the patient is judged to
 be cured, such as head and neck cancer, or breast cancer will be considered on an
 individual basis

 -  Positive pregnancy test

 -  Inability or unwillingness to pursue effective means of birth control. Effective birth
 control is defined as 1) refraining from all acts of vaginal intercourse (ABSTINENCE);
 2) consistent use of birth control pills; 3) injectable birth control methods
 (Depo-provera, Norplant); 4) tubal sterilization or male partner who has undergone
 vasectomy; 5) placement of an intrauterine device (IUD); or 6) use, with every act of
 intercourse, of diaphragm with contraceptive jelly and/or condoms with contraceptive
 foam

 -  Failure to willingly accept or comprehend irreversible sterility as a side effect of
 therapy

 -  forced expiratory volume at one (FEV1) / forced vital capacity (FVC) < 60% of
 predicted after bronchodilator therapy (if necessary)

 -  Diffusing capacity of lung for carbon monoxide (DLCO) < 50% of predicted

 -  Resting left ventricular ejection fraction (LVEF) < 50 %

 -  Serum creatinine > 2.0 mg/dl

 -  Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins

 -  Presence of metallic objects implanted in the body that would preclude the ability of
 the patient to safely have MRI exams

 -  Bilirubin > 2.0 mg/dl

 -  Platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul

 -  Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with
 treatment or informed consent impossible

 -  Active infection except asymptomatic bacteriuria

 -  Inability to give informed consent

 -  HIV positive

 -  Transaminases > 3x of normal limits, liver cirrhosis