Hematopoietic Stem Cell Transplant in Devic's Disease
Condition: Devic's Disease
MeSH terms: Neuromyelitis Optica
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Hematopoietic Stem Cell Transplantation; Cyclophosphamide; G-CSF; rATG; Mesna; Rituximab; Methylprednisolone
Intervention type(s): Procedure; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Infusion of participant's own stem cells; A medication used as chemotherapy and to suppress the immune system; A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream; A rabbit polyclonal antibody to lymphocytes; A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder; Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer; A corticosteroid medication used to suppress the immune system and decrease inflammation
Other intervention name(s): Cytoxan; Neosar; Neupogen; Filgrastim; Granix; Zarxio; Thymoglobulin; Anti-Thymocyte Globulin; Mesnex; Rituxan; Solu-Medrol; Depo-Medrol
Intervention MeSH terms: Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Rituximab; Thymoglobulin; Antilymphocyte Serum; Prednisolone hemisuccinate; Prednisolone phosphate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: High dose immunosuppressive therapy; Hematopoietic stem cell support