Devic's Disease Clinical Trial
Official title:
Trial of High Dose Immunosuppressive Therapy With Hematopoietic Stem Cell Support 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.
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