Rheumatoid Arthritis:Tolerance Induction by Mixed Chimerism
| Status: | Terminated |
|---|---|
| Conditions: | Arthritis, Rheumatoid Arthritis |
| Therapuetic Areas: | Rheumatology |
| Healthy: | No |
| Age Range: | 18 - 60 |
| Updated: | 8/1/2018 |
| Start Date: | September 2002 |
| End Date: | June 2016 |
Rheumatoid Arthritis: Tolerance Induction by Mixed Chimerism
Rheumatoid arthritis disease is believed to be due to immune cells, cells that normally
protect the body and are now causing damage to the body. Risk of death is highest in people
with twenty or more joints actively involved with disease, positive rheumatoid factor, an
elevated sedimentation rate (laboratory measures of active inflammation), and patients with
limitation of daily activities (trouble doing simple things like opening a carton of milk).
In these high risk patients, life is significantly shortened. Death is usually from heart
disease, kidney failure, neck dislocation, broken hip bones, or blood clots to the lung. In
this study we use moderate dose chemotherapy (cyclophosphamide and fludarabine) and
CAMPATH-1H (a protein that kills the immune cells that are thought to be causing the
disease), followed by infusion of blood stem cells that have been collected from the
patient's brother or sister (allogeneic stem cell transplant). The purpose of the moderate
dose chemotherapy and CAMPATH-1H is to destroy the cells in the immune system and to allow
the cells from the patient's brother or sister to grow. The purpose of the stem cell infusion
is to restore blood cell production, which will be severely impaired by the moderate dose
chemotherapy and CAMPATH-1H, and to produce a normal immune system that will no longer attack
the body.
protect the body and are now causing damage to the body. Risk of death is highest in people
with twenty or more joints actively involved with disease, positive rheumatoid factor, an
elevated sedimentation rate (laboratory measures of active inflammation), and patients with
limitation of daily activities (trouble doing simple things like opening a carton of milk).
In these high risk patients, life is significantly shortened. Death is usually from heart
disease, kidney failure, neck dislocation, broken hip bones, or blood clots to the lung. In
this study we use moderate dose chemotherapy (cyclophosphamide and fludarabine) and
CAMPATH-1H (a protein that kills the immune cells that are thought to be causing the
disease), followed by infusion of blood stem cells that have been collected from the
patient's brother or sister (allogeneic stem cell transplant). The purpose of the moderate
dose chemotherapy and CAMPATH-1H is to destroy the cells in the immune system and to allow
the cells from the patient's brother or sister to grow. The purpose of the stem cell infusion
is to restore blood cell production, which will be severely impaired by the moderate dose
chemotherapy and CAMPATH-1H, and to produce a normal immune system that will no longer attack
the body.
Peripheral blood stem cell mobilization (PBSC)
PBSC will be mobilized with G-CSF (dose may be adjusted down to 5-10 ug/kg/day by PI for
toxicity, e.g. flu-like symptoms) with stem cell collection beginning on day 4 or 5.
Leukapheresis may be repeated up to four consecutive days.
Conditioning Regimen Immune Ablation:
Fludarabine 25 mg/m2/d x 5 days (dosage should be based on adjusted body weight) will be
given IV over 30 minutes in 100 cc of normal saline.
Cyclophosphamide 50 mg/kg/d x 4 days (dosage should be based on adjusted body weight) will be
given IV over 1 hour in 500 cc of normal saline.
CAMPATH-1H 30 mg/day x 3 days (no dose adjustment) will be given IV over 2 hours in 100 cc of
normal saline. Premedication with acetaminophen 650mg & benadryl 25-50mg PO/IV will be given
30-60min before infusion. These medications can be repeated as needed.
Hydration approximately 200 cc /hour beginning 6 hours before cyclophosphamide and continued
until 24 hours after the last cyclophosphamide dose.
G-CSF will be continued until absolute neutrophil count reaches 1,000 cells/ml for three
days.
Cyclosporine will be started at 200 mg po BID and adjusted by HPLC levels to between 150-250
or by toxicity (e.g. tremor, renal insufficiency, TTP, etc.). CSA will be continued for 6
months unless stopped for toxicity
Mycophenolate Mofetil (Cellcept) will be given 1 gram po BID and may be adjusted by toxicity
(e.g. cytopenia). Cellcept will be continued for 6 months unless stopped for toxicity.
PBSC will be mobilized with G-CSF (dose may be adjusted down to 5-10 ug/kg/day by PI for
toxicity, e.g. flu-like symptoms) with stem cell collection beginning on day 4 or 5.
Leukapheresis may be repeated up to four consecutive days.
Conditioning Regimen Immune Ablation:
Fludarabine 25 mg/m2/d x 5 days (dosage should be based on adjusted body weight) will be
given IV over 30 minutes in 100 cc of normal saline.
Cyclophosphamide 50 mg/kg/d x 4 days (dosage should be based on adjusted body weight) will be
given IV over 1 hour in 500 cc of normal saline.
CAMPATH-1H 30 mg/day x 3 days (no dose adjustment) will be given IV over 2 hours in 100 cc of
normal saline. Premedication with acetaminophen 650mg & benadryl 25-50mg PO/IV will be given
30-60min before infusion. These medications can be repeated as needed.
Hydration approximately 200 cc /hour beginning 6 hours before cyclophosphamide and continued
until 24 hours after the last cyclophosphamide dose.
G-CSF will be continued until absolute neutrophil count reaches 1,000 cells/ml for three
days.
Cyclosporine will be started at 200 mg po BID and adjusted by HPLC levels to between 150-250
or by toxicity (e.g. tremor, renal insufficiency, TTP, etc.). CSA will be continued for 6
months unless stopped for toxicity
Mycophenolate Mofetil (Cellcept) will be given 1 gram po BID and may be adjusted by toxicity
(e.g. cytopenia). Cellcept will be continued for 6 months unless stopped for toxicity.
Participant Inclusion Criteria:
- Age > 18 and < 60 years at time of pre-transplant evaluation.
- An established clinical diagnosis of rheumatoid arthritis by American College of
Rheumatology criteria.
- Patients must have failed an autologous hematopoietic transplant or have failed to
respond to either methotrexate or leflunomide in combination with a TNF inhibitor.
Failure is defined as an inability to tolerate treatment with at least 6 swollen
joints and 20 involved joints or inability to answer at least 70% of HAQ questions
with "no difficulty" despite 2 or more months of treatment.
- Ability to give informed consent.
- Patient must have a HLA matched sibling donor at the A, B, C, and DR loci to
proceed or HLA matched cord blood donor.
- If donor is HLA matched cord blood, cord blood stem cells will be obtained from
the NMDP (1-800-548-1375) and one or two units of HLA matched cord blood will be
infused on day zero.
Participant Exclusion Criteria
- History of coronary artery disease, or documented congestive heart failure.
- HIV positive.
- Uncontrolled diabetes mellitus, or any other illness that in the opinion of the
investigators would jeopardize the ability of the patient to tolerate aggressive
chemoradiotherapy.
- Prior history of malignancy except localized basal cell or squamous skin cancer. Other
malignancies for which the patient is judged to be cured by local surgical therapy,
such as head and neck cancer, or stage I breast cancer will be considered on an
individual basis.
- Positive pregnancy test, inability or unwillingness to pursue effective means of birth
control, 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.
- FEV1/FVC < 70% of predicted, DLCO < 40% of predicted.
- Resting LVEF < 45 %.
- Bilirubin > 2.0 mg/dl (unless due to Gilberts), transferase (AST) > 2.5 x upper limit
of normal.
- Serum creatinine > 2.0 mg/dl.
Donor Exclusion Criteria
- Age < 18 years.
- Positive for HIV-1, HIV-2, HTLV-I, HTLV-II.
- Active hepatitis B or C.
- History of a malignancy except for a localized cancer such as skin cancer that is
deemed cured.
- History of myocardial infarction or congestive heart failure.
- Inability to give informed consent.
- Current pregnancy.
We found this trial at
1
site
303 E Chicago Ave
Chicago, Illinois 60611
Chicago, Illinois 60611
(312) 503-8194
Principal Investigator: Richard Burt, MD
Northwestern University Feinberg School of Medicine Northwestern University Feinberg School of Medicine, founded in 1859,...
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