ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH TREATMENT-REFRACTORY CROHNS DISEASE: A PHASE 2 STUDY
There is strong evidence for genetic susceptibility to Crohn's Disease (CD), with
environmental factors interacting with genetic polymorphisms. Some patients remain
refractory to the best available therapies. In patients with intestinal inflammation related
to other genetic disorders, allogeneic hematopoietic cell transplantation has led to
disappearance of inflammation, for example, in patients with IPEX (immune dysregulation,
polyendocrinopathy, enteropathy, X-linked) and with a mutation in the Interleukin-10
receptor, characterized by a severe, early onset, fistulating colitis for which
transplantation is the only therapy that offers benefit. Eleven patients with typical CD who
achieved allogeneic donor chimerism after transplant had resolution of signs and symptoms of
CD that was sustained for up to 15 years. These case series suggest that allogeneic
transplantation has substantial potential to cure CD.
HYPOTHESIS AND SPECIFIC AIMS:
The hypothesis is: Allogeneic hematopoietic cell transplantation (HCT) can achieve sustained
remissions in patients with refractory CD, and can be done safely. The specific aims are: 1)
To evaluate the safety and efficacy of allogeneic HCT as treatment for refractory CD. 2) To
evaluate treatment effect on CD activity/severity using the Crohn's Disease Activity Index
(CDAI) and the Simple Endoscopic Score for CD (SES-CD). 3) To evaluate safety by scoring
regimen-related toxicities, time to engraftment, infectious complications, acute and chronic
Graft-versus-Host Disease (GVHD), and treatment-related mortality. 4) To evaluate the effect
on quality of life.
This study is a prospective single-arm Phase II clinical trial that will enroll 12 patients.
PATIENT SELECTION: Patients will have documented CD (see eligibility criteria below); signs
and symptoms that have failed to respond satisfactorily to medical and surgical therapies;
active intestinal inflammation by endoscopy and histology, and CDAI >= 250 or need for total
parenteral nutrition or recurrent inflammation after resection. Donors will be an Human
Leukocyte Antigen (HLA)-matched sibling or unrelated donor.
ALLOGENEIC TRANSPLANT PROCEDURE: Patients will receive a reduced-intensity conditioning
regimen of cyclophosphamide, fludarabine and low-dose Total Body Irradiation (TBI), a
regimen that has been used successfully in patients receiving haploidentical allografts.
Marrow will be used as the graft source to reduce the risk of GVHD. GVHD prophylaxis will
consist of post-transplant high-dose cyclophosphamide followed by the combination of
tacrolimus and enteric coated mycophenolic acid. Supportive care includes the use of
N-acetyl cysteine infusions to reduce the risk of sinusoidal liver injury from
cyclophosphamide; prophylaxis with ursodiol to prevent cholestatic liver disease; and
antimicrobial drugs as prophylaxis and preemptive treatment for infections by bacteria,
fungi, herpes viruses, and Pneumocystis jiroveci. Tissue and blood samples will be archived
for future studies and evaluation of immune reconstitution at predefined intervals.
EFFICACY AND SAFETY ENDPOINTS: Safety and efficacy will be based on clinical assessments,
laboratory testing, and gastrointestinal endoscopy and histology at baseline, at day 100
post-transplant, and yearly for 5 years. The primary endpoint is event-free survival at 1
year, defined as alive and free of active CD by endoscopy and biopsy. Transplant-related
mortality is death occurring at any time after start of allogeneic HCT. Disease activity
will be evaluated using CDAI. Quality of Life will be measured using the Short Inflammatory
Bowel Disease Questionnaire.
RISKS AND POTENTIAL BENEFITS: The major risks include regimen-related toxicity, infections,
graft rejection, and GVHD. Autologous stem cells will be reserved in case of graft
rejection. Recent advances in transplant technique have substantially reduced the mortality
risk. Balancing these risks is the potential for allogeneic transplant to effect sustained
remissions and cures of CD.
I. The primary objective is to evaluate the safety and efficacy of HCT as treatment for
refractory Crohn's disease (CD).
I. To evaluate treatment effect on CD activity and severity.
II. To evaluate safety of allogeneic HCT as determined by regimen-related toxicities,
infectious complications, acute and chronic GVHD, treatment-related mortality, overall total
mortality, and time to engraftment.
III. To evaluate the effect of allogeneic HCT on quality of life (QOL) in patients with
severe refractory CD.
CONDITIONING THERAPY: Patients receive fludarabine phosphate intravenously (IV) over 30-60
minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients
undergo 200 cGy of total body irradiation on day -1.
TRANSPLANTATION: Patients undergo allogeneic BMT on day 0.
IMMUNOSUPPRESSIVE THERAPY: Patients receive high-dose cyclophosphamide IV over 1-2 hours on
days 3-4, tacrolimus IV continuously or orally twice daily on days 5-180 with taper to day
365, and mycophenolate acid enteric coated or mycophenolate mofetil orally three times daily
on days 0-35.
After completion of conditioning therapy and infusion of donor bone marrow cells, patients
are followed up at 1 month, 3 months, 12 months, and then yearly thereafter for up to 60
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Event-free survival (EFS)
Defined as alive and free of active Crohn's Disease (CD). Described graphically using a Kaplan-Meier estimate. Generated with confidence intervals using Greenwood's formula to calculate the standard error. Estimated with exact 90% confidence intervals.
At 1 year post-transplant
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
United States: Food and Drug Administration
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