Non-myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (NST) for Patients With Refractory Crohn's Disease
Non-myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (NST) for Patients With Refractory Crohn's Disease
Allogeneic transplantation has been a high-risk procedure, although non-myeloablative
 conditioning regimens (mini-transplantation) minimizes regimen related toxicity. The
 investigators, therefore, propose a phase I study of matched sibling allogeneic hematopoietic
 stem cell transplantation with non-myeloablative conditioning. In addition, graft versus host
 disease (GVHD) will be virtually eliminated by CAMPATH that removes donor T cells from the
 graft.

 The goal is to assess the toxicity/efficacy (phase I) of allogeneic non-myeloablative
 hematopoietic stem cell transplantation for high-risk Crohn's disease. In simplistic terms,
 this protocol is designed to ablate an aberrant immune system and then, similar to the use of
 marrow transplants for immunodeficient patients, reconstitute a new immune system with
 lymphocyte depleted marrow.
PBSC will be mobilized with G-CSF 10 mcg/kg/day (dose may be adjusted down to 5 mcg/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 three consecutive days.

 Cyclophosphamide 60 mg/kg/day x 2 days will be given IV over 1 hour in 500 cc of normal
 saline.

 Dosage should be based on the lesser of adjusted body weight or actual weight. Mesna 50mg/day
 x 2 days will be given IV over 24 hours

 CAMPATH-1H 30mg/day x 2 days (no dose adjustment) will be given IV over 2 hours in 100 cc of
 normal saline. Premedication with Solumedrol 1g IV, Acetaminophen 650mg & benadryl 50mg PO/IV
 will be given 30-60min before infusion. Also while on CAMPATH, Chlorphenamine 4 mg PO TID,
 Singular 10 mg PO daily, Pepcid 40 mg PO BID and Claritin 10 mg PO daily will be given,
 adjusted as needed. These medications can be repeated or changed as needed.

 Fludarabine 30mg/m2 daily for 3 days (no dose adjustment) will be given IV over 30 minutes in
 100 cc normal saline.

 Hydration approximately 150ml/hr should begin 2 hours before cyclophosphamide and continue
 until 24 hours after the last cyclophosphamide dose. Daily weights will be obtained. Amount
 of fluid can be modified based on patient's fluid status.

 G-CSF will be continued until absolute neutrophil count reaches at least 1,000/ul.

 Cyclosporin will be started on day -2 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 30 days unless stopped for toxicity or needed to maintain donor engraftment.

 Cyclosporine and MMF guidelines dosage and duration can be modified according to
 investigators discretion based on side effects, renal function, CBC and GVHD status.
Patient eligibility

 Inclusion Criteria:

 1. Age >18 years and less than age 45 years at time of pretransplant evaluation and,

 2. Ability to give informed consent.

 And either A or B A)An established clinical diagnosis of severe CD with disease onset
 before 16 years old (at least 71 genetic loci predispose to pediatric CD, Limbergen, JV.
 Annu. Rev. Genom. Human Genet. 2009; 10:89-116) that has failed therapy with prednisone, 5
 ASA products and has failed an anti-TNF therapy. Failure is defined as a CDAI (appendix A)
 250-400 or a Craig Severity Score that is > 17 (appendix C).

 B)Relapse after an autologous HSCT with a CDAI (appendix A) 250-400 or a Craig Severity
 Score that is > 17 (appendix C).

 Exclusion Criteria:

 1. HIV positive.

 2. History of coronary artery disease, or congestive heart failure.

 3. Uncontrolled diabetes mellitus or any other illness that in the opinion of the
 investigators would jeopardize the ability of the patient to tolerate aggressive
 chemotherapy.

 4. 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

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

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

 7. FEV 1/FVC < 50% of predicted, DLCO < 50% of predicted.

 8. Resting LVEF < 50%.

 9. Bilirubin > 2.0 mg/dl, transferase (AST) > 2x upper limit of normal, unless the
 abnormalities are secondary to Crohn's disease.

 10. Serum creatinine > 2.0 mg/dl.

 11. Platelet count less than 100,000/ul, ANC less than 1500/ul.

 12. Patients presenting with intestinal perforation or toxic megacolon, or a suppurative
 problem that will require urgent surgery. In addition, the patient may not have any
 active infection. The presence of intestinal stomas does not exclude the patient from
 study.

 13. Pre-study peripheral blood counts must include a platelet count greater than
 100,000/ul and an absolute neutrophil count greater than 1500/ul.

 14. Creatinine clearance more than 20% below lower limit of normal for age and sex.

 15. Short gut syndrome.

 Donor eligibility

 Inclusion criteria

 1. Donor must be an HLA 6 out of 6 matched sibling

 Exclusion criteria of HLA matched sibling donor

 1. Physiologic age > 50 years old or <18 years old

 2. HIV positive

 3. Active ischemic heart disease or heart failure

 4. Acute or chronic active hepatitis

 5. Uncontrolled diabetes mellitus or any other illness that in the opinion of the
 investigators would jeopardize the ability of the donor to tolerate stem cell
 collection

 6. 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 (but not limited to) head and neck cancer, or stage I or II breast cancer will
 be considered on an individual basis.

 7. Positive pregnancy test

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

 9. Major hematological abnormalities such as platelet count less than 100,000/ul, ANC
 less than 1000/ul

 10. Donor has history of Crohn's or ulcerative colitis