Hematopoietic Stem Cell Transplantation in Chronic Inflammatory Demyelinating Polyneuropathy

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.

Inclusion criteria:

- Definite CIDP according to the European Federation of Neurological
Societies/Peripheral Nerve Society (EFNS/PNS) criteria

AND

- Clinically typical or atypical CIDP

AND

- Failure to tolerate or respond to, or an incomplete response to, or relapse after at
least 3 months of conventional treatment consisting of corticosteroids (equivalent
dosage of prednisone 1.0/mg/day to 0.75mg/kg/day to start with adequate tapering
trials of no less than 0.5mg/kg/day), and/or either intravenous immunoglobulin (IVIg)
or plasmapheresis or cytoxan or rituxan

- Failure to respond to therapy is defined by:

1. Persistent muscle weakness Grade 3/5 or worse (MRC) in at least one muscle or
grade 4/5 in at least two muscle groups OR

2. Persistent dysphagia documented by either aspiration or insufficient clearing on
videofluoroscopic examination.

OR

3. Persistent incapacitating sensory loss (e.g. gait ataxia, falls > 1/month)

AND

4. If patients are on IVIG or plasmapheresis, neurologic condition is documented to
deteriorate (for example, new or increase finger tip paresthesias or increased
leg heaviness) upon stopping IVIG (or plasmapheresis)@

- Monoclonal gammopathy of undetermined significance (MUGS) (in which the pathogenesis
of are thought to be the same as CIDP) will be allowed provided bone marrow aspirate
and biopsy rules out multiple myeloma.

- Other immune mediated or suspected immune mediated neuropathies such as multifocal
motor neuropathy or anti-myelin-associated glycoprotein (anti-MAG) neuropathy may be
treated but will be analyzed and reported separately.

Exclusion Criteria:

- Any evidence of hereditary cause for neuropathy that is known or likely hereditary
demyelination neuropathy because of family history, foot deformity, mutilation of
hands or feet, retinitis pigmentosa, ichthyosis, or liability to pressure palsies.

- Diphtheria, drug, or toxin exposure likely to be cause of neuropathy

- Conditions in which the pathogenesis of the neuropathy may be different from CIDP such
as: Lyme disease (Borrelia burgdorferi infection), POEMS syndrome, Osteosclerotic
myeloma, malignancies such as Waldenstrom macroglobulinemia, and Castleman's)

- Multiple myeloma

- HIV positive

- Insulin dependent Diabetes mellitus

- Chronic active hepatitis

- Age > 65 years old or < 18 years old

- Significant end organ damage such as (not caused by CIDP):

1. Left ventricular ejection fraction (LVEF) <40% or deterioration of LVEF during
exercise test on multigated acquisition scan (MUGA) or echocardiogram.

2. Untreated life-threatening arrhythmia.

3. Active ischemic heart disease or heart failure or myocardial infarction within
the last 6 months

4. Diffusing capacity of lung for carbon monoxide (DLCO) <40% or forced expiratory
volume at one second (FEV1) / forced expiratory volume (FEV) < 50%

5. Serum creatinine >2.0.

6. Liver cirrhosis, transaminases > 2 x of normal limits or bilirubin >2.0 unless
due to Gilbert disease.

- Prior history of malignancy except localized basal cell or squamous skin cancer or
other localized cancer considered cured only by surgery

- Positive pregnancy test, inability or unwillingness to pursue effective means of birth
control, or failure to willingly accept or comprehend irreversible sterility as a side
effect of therapy.

- Psychiatric illness or mental deficiency making compliance with treatment or informed
consent impossible.

- Inability to give informed consent.

- Major hematological abnormalities such as platelet count less than 100,000/ul or
absolute neutrophil count (ANC) less than 1000/ul.

- Failure to collect at least 2.0 x 106 cluster of differentiation 34 (CD34+) cells by
apheresis and, if necessary, bone marrow harvest is a contraindication to treatment,
i.e., receiving the conditioning regimen.