Allogeneic Stem Cell Transplant Offers Cure for Intractable Childhood Enteropathy

Early onset inflammatory bowel disease and other intractable enteropathies of childhood (IEOC) comprise a heterogenous range of genetically defined and undefined conditions, associated with immune dysregulation. These disorders have an extremely poor prognosis and are associated with poor quality of life and a high mortality from the complications of parental nutrition +/- prolonged immunosuppressive therapy. Given emerging data that many of these patients have an underlying genetic disorder of immune regulation, we have developed a UK National Commissioning Group programme of allogeneic stem cell transplant (SCT) for IEOC. We now report initial data on this novel indication for SCT.

26 patients were treated with 27 SCTs at two centres between 1999 and 2013. All patients had onset of symptoms before 7 years of age and were either TPN dependent (n=13) or had enteropathy refractory to at least 3 immunosuppressive agents (n=13) prior to transplant. Patients with overt primary immunodeficiency were excluded. 8 of 26 patients had a confirmed pathogenic mutation identified (IPEX, XIAP, IL10, IL10Rα) and 18/26 remain genetically undefined. 11 patients (42%) had previously undergone gut resections +/- defunctioning stoma formation and 63% had suffered life threatening complications prior to transplant (sepsis, lymphoproliferative disease, vasculitis).

22 SCTs were performed with fully HLA matched donors (8 family, 14 unrelated), and 5 with 9/10 mismatched donors. With exception of 2 sibling donor grafts conditioned, all patients received reduced toxicity conditioning, the majority with alemtuzumab 1mg/kg, fludarabine 150mg/m² + either treosulphan 42g/m² (n=12) or melphalan 140mg/m² (n=10). Transplant related mortality was 23% (n=6) from GVHD, conditioning toxicity, viral infections and pulmonary hypertension. One patient died from diabetic ketoacidosis unrelated to SCT following a successful transplant.  96% of patients engrafted, but one patient required a second graft following rejection. The majority of patients (22/26) had full donor chimerism at last follow-up, and the remaining 4 patients have stable mixed chimerism with 73-94% donor chimerism within the lymphoid lineage. 8 patients (30%) developed significant aGVHD but the incidence of cGVHD was low (n=1, 4%).

At a median follow-up of 51 months, 19 patients are alive, 17 of whom have had sustained improvement in their enteropathy. 8 surviving patients (89%) on TPN pre-transplant have now discontinued and 14 (78%) are off all immunosuppression.

Our data demonstrate that reduced toxicity conditioned SCT can cure the majority of patients with IEOC even in the absence of a defined genetic defect. We believe that given the severity of this condition, SCT offers patients major improvement in quality of life at an acceptable risk of toxicity and that further studies of this approach in well-defined patients are warranted.