Prognostic Factors and Outcomes of Severe Gastrointestinal Graft Versus Host Disease after Allogeneic Hematopoietic Cell Transplantation

Introduction: Treatment of severe GI GVHD poses a challenge, as little progress has been made in developing better treatments and survival remains poor. One problem is that it is difficult to know the ultimate severity of GVHD and the outcome at the onset of symptoms. We analyzed patients with peak stage 3–4 GI GVHD to identify factors within 2 weeks of the onset of GVHD that predicted the eventual outcome. This information could be useful in initial patient management and to inform the design of clinical trials. Patients and methods: We reviewed the records of 117 consecutive patients transplanted between 2000–2005 who developed stages 3–4 GI GVHD. Data were collected for more than 20 parameters, including stool volume, abdominal pain, melena, upper GI symptoms, serum albumin, number of GVHD treatments, visual findings at endoscopy and histopathologic grade of GI biopsies. Clinical parameters were measured as the peak value during each 14 day period starting from 2 weeks before the diagnosis of GI GVHD to the resolution of symptoms, loss of follow-up or patient death. Patients had been treated with myeloablative or reduced intensity conditioning regimens and received either marrow or growth factor-mobilized blood cells from related or unrelated HLA-matched donors. All patients received prophylactic pharmacologic immunosuppression for GVHD. Results: Median onset of symptoms was day 28 (range 4 – 113); 11 (9.6%) patients presented after day 80. Mean daily stool volume at diagnosis was 1494 ±1450 mL/day. At onset of GI symptoms, 75% of patients had ≥ stage 1 skin GVHD and 65% had ≥ stage 1 liver GVHD. At onset, 78% had upper GI symptoms (nausea and vomiting); less than 50% of patients presented with severe abdominal pain. Within the first 2 weeks after the diagnosis of GI GVHD, 52 (44.8%), 45 (38.7%), 7 (6.2%) and 12 (10.3%) patients had a peak GI stage of 4, 3, 2 and 1 respectively. All patients received high dose prednisone/prednisolone as initial treatment; 67 received 2nd line therapy; and 32 received three or more lines of treatment. Steroid refractoriness was defined as worsening GI symptoms after 3 days of high-dose steroid therapy, or non-response after 7 days, or only partial response after 14 days of therapy. Patients who developed stage 3 or 4 GI GVHD while receiving high dose prednisone for skin or liver GVHD were also considered steroid refractory. Non-relapse mortality was 71% and 41% at 1 year after transplant in patients with steroid-refractory and steroid-responsive GVHD, respectively. Overall survival was 30% at 1 year after HCT and 26% at 2 years. Thirteen patients relapsed, and all but 1 died subsequently. Adult patients who had steroid-refractory GVHD within 2 weeks of onset had a 1-year survival of 16% compared to 88% among steroid refractory pediatric patients. During the 14 day periods immediately before or after the onset of GI symptoms, these risk factors for overall mortality were identified by multivariable analysis: All patients, no endoscopy result considered (N=117) Factor Hazard Ratio p-value Adult age 3.2 .007 Jaundice (bilirubin >3.1 mg/dL) 1.97 .006 Albumin ≤1.6 g/dL 1.91 .01 Steroid refractory 1.76 .02 In a subgroup of patients who underwent endoscopy (N=73), a finding of ulcerated mucosa was predictive of mortality (HR 2.52, p=0.02). Conclusions: Within 2 weeks of GI symptom onset, mortality in patients with GVHD can be predicted by age, jaundice, hypoalbuminemia, response to prednisone, and presence of ulcerated mucosa at endoscopy. More effective early treatment in GI GVHD patients at risk for mortality is likely to be more useful than salvage therapy for steroid-refractory patients.