Crohn's Allogeneic Transplant Study
Condition: Crohn Disease
MeSH terms: Crohn Disease
Intervention: Allogeneic Bone Marrow Transplantation; Cyclophosphamide; Fludarabine Phosphate; Laboratory Biomarker Analysis; Mycophenolate Mofetil; Mycophenolic Acid; Quality-of-Life Assessment; Tacrolimus; Total-Body Irradiation
Intervention description: Undergo allogeneic BMT; Given IV; Given IV; Correlative studies; Given PO; Given PO; Ancillary studies; Given IV or PO; Undergo TBI
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Crohn's Disease; Allogeneic bone marrow transplantation; Hematopoietic cell transplantation

Summary:

      This phase II trial studies how well giving a donor bone marrow transplant (BMT) works in
      treating patients with refractory Crohn's Disease. We will select patients with severe
      Crohn's Disease and active inflammation despite the best medical and surgical treatments.
      These patients must be healthy enough to undergo a transplantation procedure. They cannot
      have an active infection, and their heart, lungs, kidneys, and liver cannot be failing. The
      transplant procedure starts with chemotherapy and a small dose of radiation, to weaken a
      patient's immune system so that it will accept bone marrow cells from another person. After
      that other person's bone marrow cells are given to the patient, immune suppressive medicines
      are given to prevent the new cells from being rejected and to stop those cells from damaging
      the patient. After the new donor cells start to work, blood counts will rise and the new
      immune system will start to grow. During this time, there is a risk of infection. Antibiotics
      and anti-viral drugs will be given to prevent infection. When the new donor cells are
      well-established, immune suppressive medicines are discontinued. We will examine parts of the
      intestine that were inflamed before the start of the transplant procedure, to be sure the
      Crohn's Disease has disappeared after the transplant. Patients will be formally evaluated for
      Crohn's activity at around 100 days after transplant, and yearly after that for 5 years.
    

Eligibility criteria:

        Inclusion Criteria:

          -  A diagnosis of CD established by referring physician(s) and confirmed by our review of
             the clinical presentation, clinical course, endoscopic and imaging findings, and
             histology of mucosal tissue specimens

          -  An adverse prognosis, documented by persistent signs and symptoms of CD that have
             failed to respond satisfactorily to medical and surgical therapies in the past,
             including but not limited to systemic immune suppressive drugs and biopharmaceuticals;
             to be considered as refractory to medical and surgical therapy, there must be
             clinical, endoscopic, and histologic evidence of active inflammatory Crohn's Disease
             that has either persisted or recurred despite exhaustive treatment with available
             pharmaceutical and surgical therapies; exhaustive treatment is defined as prior
             exposure to the following, without durable improvement:

               -  Systemic glucocorticoids at or above a prednisone equivalent of 40 mg/day for at
                  least 2 weeks, or until drug toxicity or intolerance develops

               -  Methotrexate (25 mg per week for at least 3 months, or until drug toxicity or
                  intolerance develops) and/or a thiopurine antimetabolite (either 2.5 mg/kg
                  azathioprine or 1.5 mg/kg 6-mercaptopurine in patients homozygous wild-type for
                  the thiopurine-S-methyltransferase [TPMT] gene, or either 1.5 mg/kg azathioprine
                  or 1 mg/kg 6-mercaptopurine in patients heterozygous for TPMT, or doses of these
                  drugs capable of producing a 6-thioguanine nucleotide level of 230-400 without
                  producing a 6-methylmercaptopurine nucleotide level above 5700 for at least 3
                  months, or until drug allergy, intolerance or toxicity develops); if a patient is
                  homozygous mutant for the TPMT gene, thiopurines would be contraindicated and
                  their use would not be a requirement for enrollment in this protocol

               -  Use of at least two anti-tumor necrosis factor (TNF)-alpha therapies, that is,
                  infliximab (at least 5 mg/kg every 8 weeks for at least 3 months, or until drug
                  allergy, toxicity or intolerance or anti-infliximab antibodies develop) and/or
                  adalimumab (at least 40 mg subcutaneously [SQ] every 2 weeks for at least 3
                  months, or until drug allergy, toxicity or intolerance develops) and/or
                  certolizumab pegol (at least 400 mg SQ every 4 weeks for at least 3 months, or
                  until drug allergy, toxicity or intolerance develops)

               -  Due to the serious risk of progressive multifocal leukoencephalopathy (PML) and
                  the reluctance of some patients to agree to therapy that carries such risk, prior
                  exposure to natalizumab is not required to meet the definition of exhaustive
                  pharmaceutical treatment; neither will use of natalizumab among patients who are
                  John Cunningham (JC) virus antibody seronegative be an exclusionary criterion

               -  Exhaustive surgical treatment will be defined as indicated operations for
                  complications of Crohn's Disease up to the point where the risks of surgery (for
                  example, mortality or post-operative morbidity such as short bowel syndrome or
                  extensive adhesions with high risk for inadvertent enterotomy) are deemed by
                  patients and their physicians to be unacceptably high; indicated operations for
                  complications of Crohn's Disease include, but are not limited to, surgical
                  resection of involved intestine, stricturoplasty, drainage, curettage, or
                  adhesiolysis of tissues affected by Crohn's disease

               -  Exposure of patients to investigational drug therapies for Crohn's Disease, that
                  is, to drugs that are not Food and Drug Administration (FDA) approved for this
                  indication, will not be a criterion for either inclusion or exclusion

          -  Endoscopic and histologic evidence of active intestinal inflammation consistent with
             CD; in the event that the involved mucosa cannot be readily reached by endoscopic
             biopsy, an imaging test that shows typical changes of CD in the intestinal tract will
             suffice as evidence of active intestinal inflammation; the presence of intestinal
             stomas does not exclude the patient from study

          -  Severe CD as defined by one of the following:

               -  CDAI >= 250

               -  Need for total parenteral nutrition to maintain weight

               -  Recurrent intestinal inflammation caused by CD following surgical resection

          -  Identification of a HLA-matched hematopoietic cell donor without a history of a
             disorder that can be transmitted by hematopoietic cells, including but not limited to
             inflammatory bowel disease, and without nucleotide-binding oligomerization domain
             containing 2 (NOD2) mutations in the case of a HLA matched sibling

          -  DONORS will be a HLA-identical sibling or HLA-matched unrelated donor; unrelated
             donors are required to be matched by high resolution allele level typing for HLA-A, B,
             C and DRB1 and intermediate resolution Sequence Specific Oligonucleotide Probes
             (SSOP), identifying alleles in groups of related families historically defined as
             antigens for DQB1; an unrelated donor is considered matched if patient and donor share
             HLA-A, B, C alleles with identical sequences at exons 2 and 3, DRB1 alleles with
             identical sequences at exon 2, and DQB1 results that include the same allele groups

          -  DONORS will have the ability to understand and the willingness to sign a written
             informed consent document for bone marrow harvest.

        Exclusion Criteria:

          -  A current complication of CD that would jeopardize survival after hematopoietic cell
             transplantation, including but not limited to the following:

               -  Abscess, phlegmon, necrotizing skin lesion, or inflammatory fistula

               -  Intestinal fibrotic stricture and intestinal obstruction

               -  Uncontrolled mucosal, organ, or systemic infection with a bacterial, viral,
                  fungal, or parasitic organism

               -  Sclerosing cholangitis

          -  History of progressive multifocal leukoencephalopathy

          -  Organ dysfunction or disease that would jeopardize survival after hematopoietic cell
             transplantation, including but not limited to the following:

               -  Renal insufficiency as defined by an estimated glomerular filtration rate (GFR) <
                  60 mL/minute

               -  Cardiac dysfunction as defined by symptomatic coronary artery disease, congestive
                  heart failure, valvular heart disease, cardiomyopathy, uncontrolled
                  arrhythmia(s), or left ventricular ejection fraction < 50%

               -  Pulmonary dysfunction that poses a risk of mortality after transplant, defined as
                  pulmonary disease-moderate, using pre-transplant pulmonary function testing per
                  the Fred Hutchinson Cancer Research Center (FHCRC) Standard Practice Manual

               -  Necroinflammatory or fibrotic liver disease with evidence of liver dysfunction,
                  including but not limited to jaundice, hepatic encephalopathy, or portal
                  hypertension

               -  Marrow dysfunction that poses a risk of peri-transplant mortality, defined as an
                  absolute neutrophil count or lymphocyte count below the lower limit of normal, or
                  a platelet count below 50,000/mm^3

               -  Poorly controlled hypertension despite appropriate therapy, defined as a
                  diastolic blood pressure greater than 90 mm Hg while on therapy

               -  Neurologic dysfunction that affects activities of daily living and medical care

               -  Poorly controlled diabetes mellitus, defined as persistent hyperglycemia despite
                  therapy or recurrent hypoglycemia while on therapy

               -  Extreme protein-calorie malnutrition defined by body mass index < 18 kg/m^2 and
                  unintentional weight loss (3 kg in the last month or 6 kg in the last 6 months)

          -  Pregnancy

          -  Fertile men or women unwilling to use contraceptive techniques during and for 12
             months following transplant

          -  History of smoking either tobacco or other herbal products in the last 3 months

          -  Human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus
             (HCV) seropositivity

          -  Patients whose life expectancy is severely limited by illness other than CD

          -  Untreated psychiatric illness, including drug/alcohol abuse, that would compromise
             compliance

          -  Inability to give voluntary informed consent or obtain a parent or guardian's informed
             consent

          -  Demonstrated lack of compliance with prior medical care

          -  History of a malignancy, excluding adequately treated squamous cell skin cancer, basal
             cell carcinoma, and carcinoma in situ

          -  Hematopoietic cell transplant-co-morbidity Index greater than 2

          -  DONOR: Identical twin

          -  DONOR: Pregnant or lactating females

          -  DONOR: HIV seropositivity or presence of HBV deoxyribonucleic acid (DNA) or HCV
             ribonucleic acid (RNA) in the serum

          -  DONOR: Current serious systemic illness including uncontrolled infections

          -  DONOR: Malignancy within 10 years prior to donation of marrow, excluding adequately
             treated squamous cell skin cancer and basal cell carcinoma; treatment must have been
             completed (with the exception of hormonal therapy for breast cancer) with
             cure/remission status verified for at least 10 years at time of marrow harvest

          -  DONOR: History of or symptoms consistent with inflammatory bowel disease or a serious
             autoimmune disorder

          -  DONOR: Homozygous NOD2 mutation

          -  DONOR: History of a serious disease or disorder that could be adoptively transferred
             by infusion of donor hematopoietic cells

          -  DONOR: Failure to meet institutional criteria for donation as described in the
             Standard Practice Guidelines