Hematopoietic Stem Cell Transplantation in Chronic Inflammatory Demyelinating Polyneuropathy
Condition: Chronic Inflammatory Demyelinating Polyneuropathy
MeSH terms: Polyneuropathies; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
Study type: Interventional
Phase: Phase 2

Summary: 
      Chronic inflammatory demyelinating polyneuropathy is disease believed to be due to immune
      cells, cells which normally protect the body, but are now attacking the nerves in the body.
      As a result, the affected nerves fail to respond, or respond only weakly, to stimuli causing
      numbing, tingling, pain, and progressive muscle weakness.The likelihood of progression of the
      disease is high. This study is designed to examine whether treating patients with high dose
      cyclophosphamide (a drug which reduces the function of the immune system) and ATG (a protein
      that kills the immune cells that are thought to be causing disease), followed by return of
      the previously collected blood stem cells will stop the progression of CIDP. 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 high dose cyclophosphamide and ATG is to
      destroy the cells in the immune system. The purpose of the stem cell infusion is to evaluate
      whether this treatment will produce a normal immune system that will no longer attack the
      body.
    

Detailed description: 
      Selection of the Regimen for Immunosuppressive Therapy

      Cyclophosphamide with ATG is a common conditioning regimen with two decades of experience in
      the treatment of aplastic anemia, and has been used safely without reported mortality in the
      treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid
      arthritis.Cy / ATG is not associated with late malignancies or cataracts. Both
      cyclophosphamide and anti-thymocyte globulin (horse or rabbit ATG) are potent
      immunosuppressive agents. ATG contributes additional immunosuppression without additional
      cytotoxicity. ATG given shortly pre-transplant will contribute to the elimination of host T
      lymphocytes that survive cyclophosphamide SLE, an autoimmune disease responsive to
      cyclophosphamide, responds well to a CY / ATG conditioning regimen, but we have recently
      found that patients with either systemic lupus erythematosus (SLE) or neuromyelitis optica
      respond faster and may have more durable remissions to a regimen of "rituxan sandwich" in
      which rituxan is infused before and after standard cytoxan, rATG. For these reasons, "rituxan
      sandwich" will be the conditioning regimen utilized in this study.

      5.2 Method of Harvesting 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 collect stem cells by apheresis, with
      subsequent bone marrow harvest 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.

      5.3 Cyclophosphamide

      Cyclophosphamide (CY) is an active agent in patients with a wide variety of malignancies. It
      is used frequently in the therapy of lymphoid malignancies and has potent immunosuppressive
      activity. It is frequently used as a cytotoxic and immunosuppressive agent in patients
      undergoing marrow transplants and as a treatment for patients with autoimmune diseases. It is
      an alkylating agent that requires hepatic metabolism to the active metabolites, phosphoramide
      mustard and acrolein. These active metabolites react with nucleophilic groups. It is
      available as an oral or intravenous preparation. Bioavailability is 90% when given orally.
      The half-life of the parent compound is 5.3 hours in adults, and the half-life of the major
      metabolite phosphoramide mustard is 8.5 hours. Liver or renal dysfunction will lead to
      prolonged serum half-life. CY is administered intravenously at a dosage of 50 mg/kg on each
      of 4 successive days (use adjusted ideal body weight if patient's actual body weight is
      greater than 100% ideal body weight). The major dose limiting side effect at high doses is
      cardiac necrosis. Hemorrhagic cystitis can occur and is mediated by the acrolein
      metabolite.This can be prevented by co-administration of MESNA or bladder irrigation. Other
      notable side effects include nausea, vomiting, alopecia, myelosuppression and SIADH. Refer to
      institutional manuals for more information about administration, toxicity and complications.

      5.4 Rabbit-Derived Anti-Thymocyte Globulin (rATG)

      Rabbit-derived anti-human thymocyte globulin (rATG) is a gamma globulin preparation obtained
      from hyperimmune serum of rabbits immunized with human thymocytes. rATG has been used
      predominately in solid organ transplant immunosuppressive regimens. rATG is a predominantly
      lymphocyte-specific immunosuppressive agent. It contains antibodies specific to the antigens
      commonly found on the surface of T cells. After binding to these surface molecules, rATG
      promotes the depletion of T cells from the circulation through mechanisms which include
      opsonization and complement-assisted, antibody-dependent, cell-mediated cytotoxicity. The
      plasma half-life ranges from 1.5 12 days. rATG is administered intravenously at a dose of 0.5
      mg/kg recipient body weight on day -6 and at a dose of 1.0 mg/kg recipient body weight on
      days -5, -4, -3, -2, and -1. Unlike equine ATG, rabbit ATG does not require a pre-infusion
      skin test to check for hypersensitivity. Methylprednisolone 250 mg will be given before every
      dose of rATG. Additional medications such as diphenhydramine may be given at the discretion
      of the attending physician. Although rare, the major toxicity is anaphylaxis; chills, fever,
      pruritus or serum sickness may occur.

      5.5 Rituxan Rituximab is a chimeric monoclonal antibody used in the treatment of B cell
      non-Hodgkin's lymphoma, B cell leukemia, and numerous autoimmune disorders. The recommended
      adult dosage for patients with low grade or follicular non-Hodgkin's lymphoma (NHL) is 375
      mg/m2 infused intravenously and for adult patients with autoimmune diseases a standard 500 mg
      is generally given intravenously. The infusion may be given at weekly intervals for four
      total dosages or once every 2 weeks and repeated 2-3 times. Acetaminophen and diphenhydramine
      hydrochoride are given 30-60 minutes before the infusion to help reduce side effects. If
      given as a retreatment the dosage is the same. The majority of side effects occur after or
      during the first infusion of the drug. Some common side effects include dizziness, feeling of
      swelling of tongue or throat, fever and chills, flushing of face, headache, itching, nausea
      and vomiting, runny nose, shortness of breath, skin rash, and fatigue.
    

Intervention name(s): hematopoietic stem cell transplantation
Intervention type(s): Biological
Intervention description(s): Autologous hematopoietic stem cell transplantation
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment