Hematopoietic Stem Cell Transplant as a Therapy for Severe, anti-TNF-α Resistant Inflammatory Bowel Disease Christopher Sweat, MD Resident, PGY1 University of Washington Dept. of Surgery July 10, 2014

Patient XH  2½ year old male with severe early onset inflammatory bowel disease, unresponsive to Remicaid and steroids.

Course Initially mild, intermittent bloody diarrhea starting at 7 months of age Progressively worsening and painful since fall 2013, at which time he was diagnosed with allergic colitis. By April 2014, was having 20+ painful, bloody bowel movements per day. Diagnosed with inflammatory bowel disease.

Course, cont. Started on sulfasalazine, high dose corticosteroids, and Remicade. Initial significant improvement, with complete remission of symptoms. After several weeks, tapered off steroids, and symptoms returned in full. Given additional doses of Remicade, but no response.

Course, cont. 6/20, endoscopic biopsies performed – Severe lymphocytic inflammation extending from the rectosigmoid past the transverse colon, with severe crypt abscess formation – Mild lymphocytic inflammation of gastric antrum – Severe ulcerative or indeterminate colitis. 7/2, total colectomy with Brooke ileostomy

Course, cont. Pathology 7/7/14- severe chronic colitis limited to the mucosa and submucosa, not extending into the distal ileus, most consistent with ulcerative colitis. Discharged home on 7/9/14.

Conventional Therapies Salicylates Antibiotics Steroids TNF-α inhibitors – Infliximab – Adalibumab

Stem cell transplant in IBD In the 1980s, it was found that several patients being treated for leukemia would achieve complete remission of their coexisting autoimmune diseases after receiving bone marrow transplants, (including SLE, IBD, and systemic sclerosis.)

HCST in IBD Long term case series of 11 patients being treated for AML and CML, , 4 with UC, 7 with Crohn’s. All received allogeneic SCT from matched donors. All but one achieved complete and lasting remission of their IBD, with one exception – 1 pt with Crohn’s had incomplete myeloablation resulting in immune chimerism- had some recurrence, but it was very mild.

Allogeneic Stem Cell Transplant Stem cells from a matched donor, again enriched via CD34 + selection. Total Myeloablation/Immunoablation Post-transplant Immunosupression to prevent GVHD.

Advantages 1.Possibility of long-term, complete remission. Multiple small studies have shown complete and lasting remission of IBD symptoms- longest follow up was 15 years.

Disadvantages 1.Requires post-transplant immunosuppression to prevent GVHD 2.More danger of sepsis and a more prolonged recovery of cell counts 2/2 the need for complete myeloablation. Incomplete myeloablation in one case led to chimerism and return of symptoms 1.5 years post transplant.

HSCT in IBD, cont. Starting in the early 2000s, RCT studies explored the possibility of autologous stem cell transplants as a way to treat severe, medication resistant IBD- specifically Crohn’s- and were partially successful. While complete remission was only rarely achieved, (only ~20% after 5 years) short term outcomes were excellent- 91% completely symptom free for first year. More importantly, when symptoms did return, previously treatment intractable Crohn’s would actually respond to conventional medications.

Autologous Stem Cell Transplant 1.Patient’s own stem cells are mobilized using cyclophosphamide 2g/m 2 and Filgrastim, (G- CSF) 10 μg/kg/day. 2.Enriched via CD34 + selection 3.Stem cells are reinfused after partial immunosupression using cyclophosphamide 200 mg/kg in conjunction with antithymocyte globulin.

Advantages of Autologous SCT 1- Autologous Cells- no risk of GVHD 2-Nonmyeloablative- bone marrow is suppressed rather than ablated, leading to a faster recovery, less neutropenia, and overall less risk of infection 3- Significantly more responsive to conventional therapies even after recurrence.

Disadvantages of Autologous SCT Remission is temporary – Rates in one RCT 91% remission at 1 year post HSCT, 63% at 2 years, 57% at 3 years, 39% at 4, and 19% at 5. Infection risk 2/2 immune compromise (less than allograft due to suppression rather than destruction of marrow, but still present)

Conclusions Allogenic HSCT is a potentially curative method of treatment for severe, anti-TNFα resistant IBD, though it’s use is limited due to the high risks of myeloablation and post-transplant GVHD. Though not curative, autologous SCT may provide short term relief of symptoms and, more importantly, lead to the patient having a better response to conventional IBD treatment regimens. Regardless, it’s effectiveness provides interesting insite into the disease.

References Lopez-Cubero S., et al. Course of Crohn’s Disease after allogeneic marrow transplantation (1998) Ditschkowski M., et al. Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation (2003) Elding H, et al. Refinement in localization and identification of gene regions associated with Crohn's Disease (2013) Burt R., Craig R., et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long term follow-up (2010) Snowden J.A., Ansari A., et al. Autologous stem cell transplantation in severe treatment-resistant Crohn's disease: long-term follow-up of UK patients treated on compassionate basis. (May 5, 2014) Sostegni R., Daperno M., et al. Review Article: Crohn’s Disease: monitoring disease activity. Kriván G., Szabó D., et al. Successful autologous haemopoietic stem cell transplantation in severe, therapy-resistant childhood-onset Crohn's disease. Report on the first case in Hungary (May 18, 2014) McGovern D. Crohn Disease and NOD2/CARD15.

Supplement: Crohn’s/ NOD2 Very complex genetic and immunologic basis – Over 70 loci identified – Incidence: 3-7/100,000 diagnoses per year. – 15x more likely if 1 st degree relative affected, 30x with an affected sibling, and a 67% concordance rate in identical twins. Genetic relation definitively shown in 2001 with discovery of the NOD2 gene. – Risk for Crohn’s goes up 2x if heterozygous for mutant NOD2, 20x if homozygous. – Has a leucine rich sequence that interacts with bacterial compounds- exact purpose unclear, but suggests autoimmune