The objective of this study is to evaluate the safety and effectiveness of administering
high-dose chemotherapy followed by infusion of autologous CD34-selected peripheral blood stem
cells (PBSC) in pediatric and young adult patients with severe Crohn's disease.
Crohn's disease is considered to be an immune-mediated disease of the intestinal tract,
typically treated using immune modulating or immune suppressive therapies. These treatments
include local anti-inflammatory agents such as 5 aminosalicylic acid products, broad immune
suppression using corticosteroids, azathioprine, or methotrexate; cytokine suppression such
as antibody against TNFα; IL-12 and antibiotics such as ciprofloxacin and metronidazole that
work by decreasing the putative antigen exposure to the intestine. There is little in the
literature available on mortality data related to Crohn's Disease, but one series by Farmer
et al showed 6% mortality attributable to Crohn's disease. The mortality rate for selective
patients with refractory and severe disease is probably higher.
This protocol is based on the premise that the sustained inflammation of the GI tract that is
characteristic of Crohn's disease is the result of defective mucosal T cell tolerance. The
mucosal tolerance is normally maintained by CD4 + T cells characterized as T helper 3 (Th3)
and T regulatory 1 (TR1) T cell clones producing TGFβ and IL-10 respectively. There has been
much speculation on a possible infectious etiology of IBD implicating primarily mycobacterial
organisms, though despite extensive research no pathogenic organisms have definitively been
identified. In genetic cytokine knockout animal models of IBD, the typical nonpathogenic
enteric flora is sufficient to induce a chronic inflammatory reaction. Autoreactive T cells
appear to have broken through the mucosal tolerance with characteristic T helper 1 cytokine
profile secreting IL-1 and IFNγ.
In theory the most efficient approach to eradicate autoimmune T cell clones is through
replacement of the defective immune system with hematopoietic stem cells (HSC) from a healthy
allogeneic donor. However, the risks of morbidity and mortality associated with allogeneic
HSC transplantation currently do not appear to be justified even in treatment of refractory
cases of Crohn's disease. An alternative approach is to use autologous HSC from which
potential autoreactive T-cells have been eliminated, based on the hypothesis that from the
T-cell depleted autologous graft reconstitution of normal immunity will occur without
regeneration of autoimmune clones. Pilot trials in Crohn's and other autoimmune diseases have
confirmed the validity of this hypothesis. T-cells in the CD34 selected PBSC product are
significantly depleted. If active disease recurs despite intensive immunoablation, it is
likely that either CD34 selection did not adequately remove cells responsible for the
autoreactive state, or that the emerging genetically predisposed immune system was re-exposed
Unlike allogeneic transplants, the autologous transplant approach has greatly reduced
morbidity and mortality due to the absence of graft rejection and graft versus host disease
reactions. Currently, autologous HSCT demonstrate that transplant-related mortality is around
5% when transplanted for acute leukemia.
- Patients who have experienced significant morbidity and reduced quality of life
secondary to active CD are eligible. In general, CDAI should be >250 or PCDAI should
- Patients should be between the ages 5 to 25 years.
- Patients may be maintained on the optimal combination of medical therapy to stabilize
their disease before the administration of high dose cyclophosphamide.
- Hematopoietic: Platelet count greater than 100,000/mm3. Absolute neutrophil count
greater than 1500/mm3 at initial evaluation (unless secondary to 6MP therapy).
- Renal: Creatinine no greater than 2.0 mg/dL at initial evaluation.
- Cardiovascular: No history of coronary artery disease: no congestive heart failure,
resting LVEF at least 40% or shortening fraction at least 26% at initial evaluation.
- Pulmonary: FEV1/FVC at least 60% predicted for age; DLCO at least 60% predicted value
for age at initial evaluation.
- Fertile patients must agree to use appropriate contraceptive measures. These patients
will also be counseled regarding the potential risks of infertility following
cyclophosphamide therapy. They will be advised to discuss sperm banking or egg
harvesting from the ovary.
- Patients must have available full-time caregiver for entire course of treatment with
adequate social support.
- Patients <5 years of age or >26 years of age.
- Patients who have not been treated with adequate dosing of 6-MP, 5-aminosalicylate
products and metronidazole.
- Patients who sustained a decrement of 70 points on the CDAI or 15 points on the PCDAI,
and maintain a CDAI < 250 and PCDAI < 30 after at least one 4 month course of prior
anti-tumor necrosis factor alpha (infliximab).
- Patient has localized area of Crohn's disease of intestine which is surgically
- Patients with toxic megacolon, intestinal perforation
- DLCO < 60% of normal value for age
- Hepatic: Conjugated bilirubin greater than 2.0 mg/dL. Evidence of autoimmune chronic
active hepatitis or sclerosing cholangitis
- Patients with fever > 39o C or active infection within 1 week of stem cell
mobilization and/or admission for conditioning regimen
- Uncontrolled diabetes mellitus or other illness that would preclude study
- Pregnancy or nursing mother
- Massive splenomegaly
- Presence of increased anesthetic risk if central line will be inserted or other
procedure is expected to be performed under anesthesia.
- HIV/HTLV seropositive, Hep B surface antigen positive, or HCV RNA positive by PCR