6th Annual BMRP Investigator Meeting - Abstract
Immunoablation and Hematopoietic Stem Cell Therapy for Refractory Crohn's Disease; Six Year Follow-up; Initiation of Randomized Study
Robert M. Craig1,a, Yu Oyama1, Kathleen Quigley1, Laisvyde Statkute1, Dzemila Spahovic1, Amy Halverson1, Mary Brush1, Larissa Verda1, Willem J. S. de Villiers2, Borko Jovanovic1 and Richard K. Burt1
1Department of Medicine, Northwestern University (Chicago, Illinois, U.S.A.); 2University of Kentucky Medical Center (Lexington, U.S.A.)
Objective: To report on the clinical course following autologous hematopoietic stem cell transplantation (HSCT) with lymphoablation in a cohort of refractory Crohn’s disease (CD), in terms of clinical remissions, relapses, and requirement for surgery.
Design: Open label, non-randomized, cohort study; initiation of controlled study comparing HSCT vs. delayed HSCT.
Setting: A tertiary care medical center.
Patients: Patients with severe CD who have failed standard therapy including infliximab, whose Crohn’s Disease Activity Index (CDAI) was > 250, and/or Crohn’s Severity Index (CSI) was > 16 were accessed for therapy.
Intervention: Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m2) and G-CSF (10 ug/kg/day), enriched ex vivo by CD34+ selection, and re-infused after immune conditioning with cyclophosphamide (200 mg/kg) and either equine anti-thymocyte globulin (ATG) (90 mg/kg) or rabbit ATG, 6 mg/kg.
Main outcome measures: Primary outcomes of safety, clinical variables, small bowel radiography, and colonoscopy were followed annually post HSCT. The subjects were also analyzed in terms of relapses and remissions. Secondary considerations included T regulatory (Treg) cells and genetic studies.
Results: 21 subjects have undergone the therapy successfully. HSCT had no treatment related mortality. Usually, diarrhea and abdominal pain resolved prior to hospital discharge. Perianal fistulae, colonic strictures, and perianal disease were slower to resolve. CDAI and Crohn’s sefverity index (CSI) improved over baseline at each interval. Following HSCT, a robust rise in CD4+CD25+(bright) T-cells was observed. Genetic studies showed heterozygotic NOD2 or TLR5 variants in only 4 subjects. 9 subjects have had relapse, 5 of whom required surgery. Three others required surgery for ileal stricture or colovesicle fistula, unrelated to relapse. 18 subjects are in clinical remission defined as having a CDAI < 150, a CSI < 12, and no corticosteroid therapy (1- 6yrs; 3- 5yrs; 4- 4yrs; 4- 3yrs; 4- 2yrs; 2- 6mos. 3 remain in relapse. One subject has been enlisted in the controlled study (HSCT arm) and is doing well. Two others have been accepted for study.
Conclusion: The experience in the first 21 patients who received this radical therapy continues to be encouraging, although relapses have occurred.
aPrincipal Investigator