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Factors Affecting the Incidence of Severe (Stage 2-4) Gastrointestinal (GI) Graft-Versus-Host Disease (GVHD) in Adult Patients (pts) Undergoing Allogeneic Hematopoietic Transplant (Allo-HCT) for Hematologic Malignancy
Patients and Methods: This analysis includes 376 adult pts who underwent a first allo-HCT at Mayo Clinic Arizona between 2003 and 2013. All pts received FK-based GVHD prophylaxis, combined with either mycophenolate mofetil (MMF) or methotrexate (MTX); a subset of pts, mostly those with unrelated donors, also received rabbit ATG (Thymoglobulin). The use of MMF vs. MTX was based on physician discretion and program guidelines. Univariate and multivariate statistical analyses were performed to evaluate the impact of pt- and transplant-specific factors on the incidence of stage 2-4 GI GVHD.
Results: The median age was 52 (18-76), and median follow-up for surviving pts is 22 months. Fifty seven pts (15.2%) developed stage 2-4 GI GVHD at a median of 43 days (range 10-303) after allo-HCT. In univariate analysis, there was no difference in incidence of stage 2-4 GI GVHD based on age, CIBMTR risk status, HCT-CI score, donor type, use of ATG, or sex match. Conditioning regimens were divided into 3 groups: myeloablative (high dose busulfan- and high-dose TBI-based), melphalan (Mel)-based (fludarabine/BCNU/Mel, Flu-Mel, and BEAM), and RIC/NMA (Flu-TBI200, low-dose busulfan + fludarabine, FCR, etc). Pts who received RIC/NMA conditioning had significantly less stage 2-4 GI GVHD (cumulative incidence [CI] at 6 months 2.9%) compared to pts who received either myeloablative (CI 9.0%) or Mel-based (CI 15.1%) regimens (P = .017). Pts who received MMF had a significantly higher incidence of stage 2-4 GI GVHD (CI at 6 months 17.8%) compared to pts who received MTX (9.1% at 6 months; P = .008). In a multivariate Cox proportional hazards analysis adjusted for the factors listed above, both the use of MMF (vs. MTX) for GVHD prophylaxis (HR 2.33 [95% CI, 1.04 – 5.4]; P = .04, and type of conditioning regimen (RIC/NMA vs. myeloablative: HR 0.17 [95% CI .03 - .68]; P = .01; RIC/NMA vs. Mel-based: HR .20 [95% CI, .03 - .70]; P = .009 retained significance for development of stage 2-4 GI GVHD.
Conclusions: These data indicate that use of myeloablative or Mel-based conditioning regimens, as well as the use of MMF (vs. MTX) for GVHD prophylaxis (in combination with FK ± ATG) are both associated with significantly higher rates of severe GI acute GVHD. The results suggest caution in the use of MMF as a secondary agent for routine GVHD prophylaxis, and emphasize the increased risk of severe GI GVHD associated with myeloablative or Mel-based conditioning.