Final Results of a Prospective Observational Study Using Budesonide, Added to Ptcy-Based Gvhd Prophylaxis, for Prevention of Acute GI Gvhd after Allogeneic Transplantation

Background: Post-transplantation cyclophosphamide (PTCy) has been shown to decrease incidence of GVHD compared with standard GVHD prophylaxis in allogeneic hematopoietic stem cell transplantation (AHSCT). However, despite the use of PTCy, a significant proportion of AHSCT recipients still experience severe GI acute GVHD (aGVHD). Oral budesonide (B), a potent topical glucocorticoid, has been used as treatment for upper GI GVHD. Its formulation was developed to release the active drug in the ileum and colon to exert a local effect, thus effectively preventing immunologic reaction against intestinal tissues with negligible systemic glucocorticoid activity due to rapid first pass metabolism. We hypothesized that B, added to the PTCy platform would be effective in preventing severe aGVHD of the GI tract. Here, we present results of a prospective observational study using B added to PTCy, tacrolimus (T) and mycophenolate mofetil (M) for prevention of GI aGVHD after AHSCT. Methods: Patients were included if they were >/= 18 years of age and received their first AHSCT using B in combination with a PTCy-based GVHD prophylaxis regimen. Fludarabine-based conditioning regimens were used in all patients. GVHD prophylaxis consisted of PTCy (50 mg/kg on D+3 and +4), T (goal 8 ng/ml), M (15 mg/kg TID) and budesonide (3 mg PO TID) starting on D+5 and continued until D+90 followed by a weekly taper if no GVHD occurred. T was continued for at least 6 months for HLA-matched and 9 months for HLA-mismatched AHSCT, followed by a taper. Serum GVHD biomarkers (REG3α and ST2) were measured within 7 days post-engraftment and at GI symptom onset, and combined results were reported per the MAGIC algorithm probability (MAP). Results: Eighty patients with a median age of 53 years (range 19-74) were treated including 74 patients with a hematologic malignancy and 6 patients with severe aplastic anemia (AA). Donors were matched sibling, haploidentical and unrelated in 17 (21.3%), 58 (72.5%) and 5 (6.3%) patients, respectively. Fludarabine plus melphalan and either TBI or thiotepa was used in 62 patients (77.5%) including 43 (53.8%) and 19 (23.8%) patients who received melphalan 100 mg/m2 and 140 mg/m2, respectively. ATG was used in all 6 patients with severe AA. Sixty-one patients (76.3%) received unmanipulated PB graft. All patients achieved engraftment of donor cells with a median time to neutrophil engraftment of 16 days and 21 days for platelet engraftment. All patients achieved full donor chimerism by D+100. Cumulative incidence (CI) of GI aGVHD at 100 days and 1-year post-transplant was 5.19% (95%CI 1.68-11.74) and 11.09% (95%CI 5.15-19.58), respectively. Of 8 patients with GI aGVHD, 6 patients had maximum stage 1, 2 patients had stage 2, and none of the patients experienced stage 3-4 GI aGVHD. One patient had isolated upper GI GVHD. CI of aGVHD all grades, grade II-IV and III-IV at 100 days were 7.76% (96%CI 3.17-15.07), 3.83% (95%CI 1.02-9.82), 1.32% (95%CI 0.11-6.32), respectively. CI of chronic GVHD was 4.68% (95%CI 1.24-11.84) and 10.07% (95%CI 3.42-20.90) at 1 and 2 years, respectively. CI of NRM at D+100 and 1-year post-transplant were 2.6% and 17%, respectively. With a median follow-up duration of 15 months, OS, PFS, GRFS, CI of relapse at D+100 were 96.15%, 92.20%, 90.89% and 5.2%, respectively, and at 1-year, 80.95%, 73.39%, 70.52% and 9.62%, respectively. A significant increase in mean GVHD biomarker MAP at symptom onset from baseline was noted in patients with GI aGVHD (0.298 vs. 0.157, p=0.011). AuROC of intermediate/high-risk MAP at symptom onset in predicting NRM within 6 months was 0.694. Median absolute lymphocytes (ALC), CD3+, CD3+CD4+, CD3+CD8+, CD19+, and CD3-CD56+ at D+180 were 1,114, 390, 171, 220, 46 and 195, respectively. The cumulative incidence of systemic immunosuppressive therapy discontinuation was 63.31% (95%CI 49.69-82.98) at 1 year. Eight patients (10%) had newly diagnosed diabetes mellitus (DM), 5 patients (6.25%) with preexisting DM required additional anti-hyperglycemic drugs within 100 days, and 8 patients (10%) developed adrenal insufficiency. CI of grade 2-3 infections was 32% within the first 100 days. Conclusions: Addition of B to the PTCy-based GVHD prophylaxis (Cy-TMB) is feasible and appears to be very effective in preventing severe GI aGVHD without compromising immunologic recovery and transplant outcomes.