Autologous Hematopoietic Stem Cell Transplantation for Crohn's Disease Treatment

The treatment of Crohn's disease has proven to be quite efficacious in the majority of
patients with the timely use of combination therapies for remission induction
(corticosteroids and/or biologics) and maintenance of disease control (immunosuppressives
and/or biologics). However, a proportion of patients fail to achieve complete and long term
disease control and often require multiple intestinal surgeries with a risk of developing
short bowel syndrome. Lymphoablation followed by hematopoietic stem cell transplantation to
rescue the immune system has been proposed as an alternative strategy to induce long term
disease control in this high risk population. It has been demonstrated that despite the
potential toxicity and morbidity associated with the procedure, the benefit-risk ratio is
favorable. Hence, we propose to offer HSCT to selected CD patients, and to study mechanisms
of reducing T cell autoreactivity which will hopefully lead to more focused therapeutic
approaches in the future.

Inclusion Criteria:

1. Age between 7 and 50 years (patients aged 50 - 70 can participate up to the principal
investigators discretion).

2. Confirmed diagnosis of active Crohn's disease:

1. Diagnosis of Crohn's disease based on typical radiological appearances and or
typical histology at least 6 months prior to screening.

2. Active disease at the time of registration to the trial, defined as

i)Crohn's Disease Activity Index (CDAI) > 250, and ii)Two of the following:

1. elevated C-Reactive Protein (CRP)

2. endoscopic evidence of active disease confirmed by histology

3. clear evidence of active small bowel Crohn's disease on Computed tomography (CT)
or Magnetic Resonance (MR) enterography.

3. Unsatisfactory course despite 3 immunosuppressive agents (usually azathioprine,
methotrexate and infliximab, adalimumab and/or certolizumab) in addition to
corticosteroids. Patients should have relapsing disease (i.e. 1 exacerbation/year)
despite thiopurines, methotrexate and/or infliximab/adalimumab/certolizumab
maintenance therapy or clear demonstration of intolerance / toxicity to these drugs.

4. Current problems unsuitable for surgery or patient at risk for developing short bowel
syndrome.

5. Informed consent:

1. Prepared to undergo additional study procedures as per trial schedule

2. Patient has undergone intensive counseling about risks

Exclusion Criteria:

1. Pregnancy or unwillingness to use adequate contraception during the study, in women
of childbearing age. Unwillingness of using appropriate contraceptive measures in
males.

2. Concomitant severe disease

1. renal: creatinine clearance < 30 mL/min (measured or estimated)

2. cardiac: clinical evidence of refractory congestive heart failure; left
ventricular ejection fraction < 40% by multigated radionuclide angiography
(MUGA) or cardiac echo; chronic atrial fibrillation necessitating oral
anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with
hemodynamic consequences as evaluated by an experienced echo cardiographer.

3. pulmonary: diffusion capacity <40%

4. psychiatric disorders including active drug or alcohol abuse

5. concurrent or recent history of malignant disease (excluding non-melanoma skin
cancer)

6. uncontrolled hypertension, defined as resting systolic blood pressure ≥ 140
and/or resting diastolic pressure ≥ 90 despite at least 2 anti-hypertensive
agents.

7. uncontrolled acute or chronic infection with HIV, Human T-Lymphotropic virus
(HTLV-1 or 2), hepatitis viruses or any other infection the investigators
consider a contraindication to participation.

8. other chronic disease causing significant organ failure.

3. Infection or risk thereof:

1. Current clinical relevant abscess or significant active infection.

2. Perianal fistula without free drainage. Perianal fistulas is not an exclusion
provided there is natural free drainage or a seton suture(s)have been placed.

3. History of tuberculosis or currently at risk for tuberculosis

4. Quantiferon Gold test result or other investigations that the investigators
regard as evidence of active tuberculosis.

5. Abnormal chest X-ray (CXR) consistent with active infection or neoplasm.

4. Significant malnutrition: Body Mass Index (BMI) ≤ 18, serum albumin < 20g/l.

5. Previous poor compliance.

6. Concurrent enrollment in any other protocol using an investigational drug or
hematopoietic growth factor up to four weeks before study entry.