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C rohn’s A llogeneic T ransplant S tudy (CATS) for patients with treatment-refractory disease

Broad Medical Research Program 11 th Annual Investigator Meeting March 7 – 8, 2013. C rohn’s A llogeneic T ransplant S tudy (CATS) for patients with treatment-refractory disease. George B. McDonald, M.D. Gastroenterology / Hepatology Section Fred Hutchinson Cancer Research Center

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C rohn’s A llogeneic T ransplant S tudy (CATS) for patients with treatment-refractory disease

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  1. Broad Medical Research Program 11th Annual Investigator Meeting March 7 – 8, 2013 Crohn’s Allogeneic Transplant Study (CATS) for patients with treatment-refractory disease George B. McDonald, M.D. Gastroenterology / Hepatology Section Fred Hutchinson Cancer Research Center and University of Washington School of Medicine

  2. www.CATS-FHCRC.org

  3. Some definitions…. •Hematopoietic cell transplantation: infusing blood-forming cells into a person •Different sources of blood-forming cells: bone marrow cells cells from the blood stream cells from an umbilical cord •Different kinds of donors of these cells: autologous (one’s own cells, given back) allogeneic (cells from someone else) syngeneic (from your identical twin)

  4. Some definitions…. •Hematopoietic cell transplantation: infusing blood-forming cells into a person •Different sources of blood-forming cells: bone marrow cells cells from the blood stream cells from an umbilical cord •Different kinds of donors of these cells: autologous (one’s own cells, given back) allogeneic (cells from someone else) syngeneic (from your identical twin)

  5. Rationale for allogeneic bone marrow transplantation as a cure for Crohn’s Disease •Crohn’s is a genetic disorder of immune regulation (see Elding et al, Am J Human Genetics 2013). •Allogeneic bone marrow transplantation can cure many genetic disorders of immune regulation (by giving patients a new, normal immune system). Thus, allogeneic bone marrow transplantation should be able to cure Crohn’s Disease by installing a new immune system.

  6. Examples of immune disorders with gut inflammation curable by allogeneic HCT • SCID • IPEX • IL10-receptor defect or IL-10 deficiency • CGD – chronic granulomatous disease • WAS – Wiskott Aldrich syndrome • CVID with severe autoimmune problems • XIAP – X-linked lymphoproliferative disease • XLA - X-linked Agammaglobulinemia • Trisomy 8 mosaicism (Behcet’s like) • NEMO (NF-k-B essential modulator) deficiency • STAT1 gain-of-function mutations

  7. Crohn’s Disease and hematopoietic cell transplantation Autologous transplant Northwestern University (Burt et al, Blood 2010) •9/24 elimination of CD to time of last follow-up (≤5 yrs) •15/24 recurrent CD before 5 yrs. ASTIC Trial (Hawkey et al, DDW 2012) Allogeneic transplant Seattle (Lopez Cubero et al, Gastroenterology 1998) •4/5 elimination of CD •1/5 graft rejection, recurrent CD Essen (Ditschkowski et al, Transplantation 2003) •7/7 elimination of CD

  8. CATS inclusion criteria A diagnosis of CD  An adverse prognosis, failed all therapies (including 2 anti-TNFa biologics) Active intestinal inflammation  Severe CD as defined by one of the following: CDAI ≥250 Need for TPN to maintain weight Recurrent intestinal inflammation after resection HLA-matched hematopoietic cell donor  Age from 18 through 60 years.

  9. Some CATS exclusion criteria Complication of CD that would jeopardize survival History of Progressive Multifocal Leukoencephalopathy Organ dysfunction that would jeopardize survival Life expectancy severely limited by illness other than CD History of a malignancy Hematopoietic Cell Transplant Co-morbidity Index >2

  10. Autologous stem cell collection Stimulation of peripheral blood cells with G-CSF Collection of CD34+ cells for storage Reduced intensity conditioning therapy Fludarabine Cyclophosphamide Total Body Irradiation

  11. Pre- and post-transplant prevention of complications N-acetyl cysteine (protects the liver) Ursodiol (protects the liver) Trimethoprim-sulfamethoxazole (prevents infection) Antibiotic (prevents bacterial infection) Antifungal (prevents fungal infection) Antiviral (prevents viral infection) Pre-emptive antiviral (for CMV, Adenovirus) Immune suppression (prevents rejection and GVHD)

  12. Graft-versus-Host Disease prophylaxis GVHD: damage caused by donor cells affects skin, gut, liver Prophylaxis drugs: Cyclophosphamidex 2 doses Tacrolimus Mycophenolic acid (enteric coated) Rationale for prophylaxis choices: No biologic advantage at all to having GVHD Prevent severe acute GVHD Prevent extensive chronic GVHD

  13. Assessment of Crohn’s Disease activity Timing: Baseline Day 80 One year Three years Five years Methods: Endoscopy with biopsy Imaging

  14. Statistical considerations Number of patients = 12 Primary endpoint: Event-free survival at one year (alive and free of Crohn’s Disease) Stop the study if Transplant Related Mortality >10%

  15. Ethical equipoise Life-long CD misery Cure of CD Long CD remission GVHD or death after HCT Death from CD Rx

  16. Progress to date Protocol approved, FDA IND application approved, posted www.clinicaltrials.gov Website, newspaper, M.D. letters, blogs 387 completed questionnaires from CATS website 112 patients met eligibility criteria, records requested 5 patients examined in Seattle ( all potentially eligible) + 3 patients arrive in March ‘13 18 complete records received

  17. Insurance coverage Screeningvisits show eligibility Allogeneic donor search Autologous stem cell collection Reduced intensity conditioning Allogeneic bone marrow Follow-up to 5 years

  18. Crohn’s Disease before and after allogeneic transplant — child with IL10R defect 3 months after before

  19. CATS Investigators and Research Staff George E. Georges, MD (Transplant Oncology) Laurie M. Burroughs, MD (Pediatric Transplant Oncology) Timothy L. Zisman, MD, MPH (Gastroenterology) David L. Suskind, MD (Pediatric Gastroenterology) Ashley Evans, M.D. (Fellow, Gastroenterology) Richard A. Nash, MD (Affiliate Investigator) James Lord, MD, PhD (Gastroenterology) Melissa P. Upton, MD (Pathology)  Katherine A. Guthrie, PhD (Statistics) Bernadette A. McLaughlin, RN (Research Nurse)* Christine Kane (Research coordinator)* * Supported by the BMRP

  20. Data and Safety Monitoring Board Keith Sullivan, M.D. (Chair) Division of Cellular Therapy, Department of Medicine Duke University, Durham Steve Pavletic, M.D. Medical Oncology Transplantation and Immunotherapy Service National Cancer Institute, Bethesda Athos Bousvaros, M.D., M.P.H. Inflammatory Bowel Disease Center Children’s Hospital, Boston Dermot McGovern, M.D., Ph.D., F.R.C.P. Translational Medicine Inflammatory Bowel and Immunobiology Research Institute Cedars Sinai Medical Center, Los Angeles

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