Stem Cell Transplantation for Stiff Person Syndrome (SPS)

Study Overview
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Brief Summary
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Non-myeloablative regimens (as the investigators use herein) are designed to maximally suppress the immune system without destruction of the bone marrow stem cell compartment. When using a non-myeloablative regimen recovery occurs without infusion of stem cells and the stem cells are autologous. While not necessary for recovery, stem cell infusion may shorten the interval of neutropenia and attendant complications. Thus in reality there is no transplant only an autologous supportive blood product. Based on our encouraging results of non-myeloablative hematopoietic stem cell transplantation, for patients with multiple sclerosis and chronic inflammatory demyelinating polyneuropathy, the investigators will investigate the role of non-myeloablative hematopoietic stem cell transplantation for patients with SPS who require assistance to ambulate.

Detailed Description
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Pre-study Testing History and physical Electrocardiogram (EKG) Dobutamine stress echocardiogram High-resolution computed tomography of the chest (HRCT) Blood draw for laboratory tests- these tests will include a complete blood count, evaluating liver and kidney function, assessing immune system, tissue typing, and checking for certain germs that can cause infections, including a pregnancy test for females and prostate-specific antigen (PSA) for male as well as testing for HIV Pulmonary Function Test (PFT) Electromyography (EMG) Magnetic Resonance Imaging (MRI) of the Abdomen and Pelvis Magnetic Resonance Imaging (MRI) of the Spinal Cord Magnetic Resonance Imaging (MRI) of the Brain with Gadolinium (only if PERM of cerebellar ataxia) Colonoscopy Mammogram (if female) Timed ambulation Quality of Life Questionnaires [ Short Form (36) Health Survey (SF36) and Barthel Index] Chronic Pain Acceptance Questionnaire (CPAQ) Rankin Functional Scale Modified Ashworth Scale Purkinje Cell Cytoplasmic Antibody, Type 1 (PCA-1), Purkinje Cell Cytoplasmic Antibody, Type 2 (PCA-2) antibody (only if cerebellar ataxia) Spinocerebellar ataxia (SCA) 1, 2, 3, 4, 5, 6, 7, 8 genes (only if ataxia) Study Treatment Stem Cell Collection: Cyclophosphamide 2.0 gm/m2 will be given on day 0, G-CSF 5-10 mcg/kg/day subcutaneous (SQ) will start on day +5 and will continue until apheresis is discontinued. Apheresis will begin when the absolute neutrophil count (ANC) > 1.0 x 109/L and continue until >2.0 x 106 cluster of differentiation 34 (CD34)+ cells/kg patient weight are cryopreserved. A 10-15 liter apheresis will be performed unless stopped earlier for clinical judgment of toxicity (e.g., numbness, tetany). A maximum of four apheresis will be performed.

Official Title
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Non-myeloablative Hematopoietic Stem Cell Transplantation for Stiff Person Syndrome (SPS) and Anti-GAD Antibody Variants: Progressive Encephalomyelitis With Rigidity and Myoclonus (PERM), and Adult Onset Autoimmune Anti-GAD Positive Cerebellar Ataxia

Conditions
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Stiff-Person Syndrome

Intervention / Treatment
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* Biological: Autologous Hematopoietic Stem Cells
* Drug: Cyclophosphamide
* Drug: Mesna
* Drug: rATG
* Drug: Methylprednisolone
* Drug: G-CSF
* Drug: Rituxan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Stiff-person Syndrome and Age between 18 and 60 years old Failure of medically tolerable doses (20-40 mg/day) of diazepam Failure of either intravenous immunoglobulin (IVIg) and or plasmapheresis Stiffness in the axial muscles, prominently in the abdominal and thoracolumbar paraspinal muscle leading to a fixed deformity (hyperlordosis) Superimposed painful spasms precipitated by unexpected noises, emotional stress, tactile stimuli Confirmation of the continuous motor unit activity in agonist and antagonist muscles by electromyography when off diazepam and anti-spasmatic medications Absence of neurological or cognitive impairments that could explain the stiffness Inability to run or walk, or abnormal gait Diagnosis of a SPS variant- Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) defined as: Acute onset of painful rigidity and muscle spasms in the limbs and trunk Brainstem dysfunction (nystagmus, opsoclonus, ophthalmoparesis, deafness, dysarthria, dysphagia) Profound autonomic disturbance. Positive serology for GAD65 (or amphiphysin) autoantibodies, assessed by immunocytochemistry, western blot or radioimmunoassay (>1000 u/ml) MRI may show increased signal intensity throughout the spinal cord and the brainstem Diagnosis of a SPS variant - anti-GAD positive cerebellar ataxia Subacute or chronic onset of cerebellar symptoms-gait or limb ataxia, dysarthria, nystagmus Positive serology for GAD65 (or amphiphysin) autoantibodies, assessed by immunocytochemistry, western blot or radioimmunoassay (>1000 u/ml) Anti-GAD antibody in cerebrospinal fluid Abnormal MRI imaging of brainstem or cerebellum other than cerebellar atrophy Negative history of toxin or alcohol Absence of Vitamin B12 or Vitamin E deficiency Absence of positive HIV, syphilis or whipple disease Absence of consanguinity, positive family history for ataxia or positive genetic screen for spinocerebellar ataxia (SCA) 1, SCA 2, SCA 3, SCA 6, SCA 7 or SCA 8 mutation Exclusion Criteria: Current or prior history of a malignancy or paraneoplastic syndrome Inability to sign and understand consent and be compliant with treatment Positive pregnancy test Inability to or comprehend irreversible sterility as a possible side effect Amphiphysin antibody positive Left ventricular ejection fraction (LVEF) < 45% or ischemic coronary artery disease on dobutamine stress echocardiogram Diffusing capacity of the lungs for carbon monoxide (DLCO) < 60% predicted Serum creatinine > 2.0 mg/dl Bilirubin >2.0 mg/dl Platelet count < 100,000 / ul, white blood cell count (WBC) < 1,500 cells/mm3 History of toxin or alcohol abuse History of Vitamin B12 or Vitamin E deficiency Positive HIV, syphilis, or whipple disease Consanguinity, positive family history for ataxia or positive genetic screen for SCA1, SCA2, SCA3, SCA6, SCA 7 or SCA8 mutation (if ataxia present) Absence of at least one SPS associated antibody such as anti-GAD, or gamma-aminobutyric acid (GABA)-A receptor associated protein, or synaptophysin, or gephyrin, or GABA-transaminase

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hematopoietic Stem Cell Transplantation<br>The conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5, 1.0 mg/kg on days -4 and -3, and then 1.5 mg/kg on days -2 and -1. Methylprednisolone 1000 mg will be infused intravenously before each dose of rATG. Autologous hematopoietic stem cells will be infused intravenously on day 0. A granulocyte-colony stimulating factor (G-CSF) 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Intravenous Rituxan (500mg) will be administered on days -6 and +1. | Biological: Autologous Hematopoietic Stem Cells<br>* The stem cells will be collected from patient's blood during mobilization. Then the patient will be given high dose chemotherapy in accordance with approved recommendations for use in conditioning regimens for stem cell transplant in autoimmune diseases. Autologous Hematopoietic Stem Cell Transplantation is to re-infuse immature cells that can re-establish blood production and patient's immune system.<br>Drug: Cyclophosphamide<br>* An alkylating agent which causes prevention of cell division by forming adducts with DNA<br>* Other names: Endoxan;Drug: Mesna<br>* Medication used to decrease the risk of hemorrhagic cystitis prophylaxis<br>* Other names: Mesnex;Drug: rATG<br>* A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells<br>* Other names: Thymoglobulin;Drug: Methylprednisolone<br>* Steroid<br>* Other names: Solu-Medrol;Drug: G-CSF<br>* Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream<br>* Other names: Zarxio;Drug: Rituxan<br>* A chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders<br>* Other names: Rituximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Number of Participants who Did Not Experience Treatment-Related Mortality | Mean 3.6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of Muscle Relaxation Anti-spasmatic Medications | Decrease (50%) and complete discontinuation of muscle relaxation anti-spasmatic medications | Mean 3.6 years | 
| Short-form 36 Quality of Life Questionnaire (SF-36 QOL) | Improvement is defined as a statistically significant change in SF-36 QOL score. The scale is 0-100. The lower the score the worse quality of life. | mean 3.6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoimmune Diseases, Autologous Hematopoietic Stem Cell Transplantation