5th Annual BMRP Investigator Meeting - Abstract
Autologous Hematopoietic Stem Cell Transplantation (HSCT)for Severe Crohn’s Disease (CD), 4 Year Follow-up
Robert Craig1,2,a, Yu Oyama1 and Richard Burt1
1Division of Immunotherapy and 2Division of Gastroenterology, Department of Medicine, Northwestern University Medical School (Chicago, Illinois, U.S.A.)
Purpose: Autologous hematopoietic stem cell transplantation (HSCT) with lymphoablation is being studied in an effort to ascertain its value in inducing a clinical remission in refractory Crohn’s disease (CD).
Methods: Patients with severe CD who have failed standard therapy (5-ASA, antibiotics, corticosteroids, immunosuppression, and infliximab), whose CDAI was > 250, and/or CCSI was > 16 were accessed for therapy. 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 reinfused after immune conditioning with cyclophosphamide (200 mg/kg) and anti-thymocyte globulin (90 mg/kg). Clinical variables, small bowel radiography, colonoscopy and T-cell subsets were followed annually following the HSCT. ASCA and genetic studies were also performed.
Results: 19 subjects have undergone the therapy successfully. HSCT had no in-patient mortality, and was complicated only by 24-48 hours of culture negative fever. Usually, diarrhea and abdominal pain resolved prior to hospital discharge. Perianal fistulae and perianal disease were slower to resolve, but gradually improved over months to years. Abdominal masses and colonic strictures have resolved. Two patients had progression of their small intestinal strictures following the transplantation and required surgical resection. One of these had a relapse associated with the second stricturing event, which required re-institution of prednisone and 6-MP therapy. Three patients have had major relapses, 2 at one year and 1 at 2 years, requiring re-institution of immunotherapy, one requiring Humira. Two of these required total proctocolectomy, but did well subsequently. A fifth patient had a minor relapse at 1 year requiring re-institution of infliximab, which induced remission (which was ineffective pre-transplant). A sixth patient had a minor relapse at 2 years with fistula formation and inflammation in her proximal jejunum, who required meselamine and budesonide. A seventh patient had a minor relapse at 3 1/2 years requiring prednisone therapy. Following HSCT, a robust rise in CD4+CD25+(bright) T-cells was observed. There was a smaller rise in these T-cells in those who eventually relapsed.
Genetic studies: ASCA was found in most but the titers did not correlate with disease activity or severity, and the levels remained elevated when the subjects entered clinical remission. In most subjects, serum albumins, hemoglobins, weights, sedimentation rates, and CRPs have improved or normalized. Defining clinical remission as absence of CD symptoms off systemic corticosteroid therapy, 13 subjects are in clinical remission at various times post HSCT. The patient with the longest follow up, at 5 years post HSCT, remains in clinical remission off all CD medication.
Conclusion: The experience in the first 19 patients who have received this radical therapy continues to be encouraging, although it is far from perfect therapy, and 7 have had major recurrences of the disease and/or have required surgery. A randomized study is in progress.
aPrincipal Investigator