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S. Nikiforow et al.
AB
Figure 2. Treatment-related mortality for patients with isolated UGI aGvHD versus aGvHD without UGI symptoms. Cumulative incidence curves of TRM from time of aGvHD onset for patients with isolated UGI symptoms and subsets of patients with other grades of aGvHD without any UGI symptoms. A. Transplantation from a matched-related donor. B. Transplantation from a well-matched or partially-matched unrelated donor. UGI: upper gastrointestinal. aGvHD: acute graft-versus-host disease.
pathology reports submitted to the CIBMTR. Given the limiting numbers and reliability of biopsy-confirmed results, all subsequent analyses were conducted on the clinical grades reported. The timing of onset of UGI or any individual organ involvement was not captured in the CIBMTR database.
A notable feature of this cohort was the use of systemic steroids recorded in 79.8% of patients with maximum Grade I (skin-only) disease. In patients with iUGI or UGI symptoms plus Stage I or II skin disease (both Grade II) systemic steroids were received in 95.4% and 91.6% of cases, respectively (Table 1). Further data on timing and doses of therapeutic modalities/doses and response to therapy were not available.
Prognostic impact of isolated upper GI acute GvHD
Acute GvHD populations analyzed. In order to determine the optimal placement of iUGI aGvHD within the aGvHD grading system, we performed pairwise comparisons between patients with aGvHD starting from the time of transplantation: specifically, those with iUGI aGvHD versus those with Grades I, II (Stage 3 skin, Stage 1 liver or Stage 1 LGI), or III/IV aGvHD without UGI manifesta- tions (Online Supplementary Figure S1). Notable differences in baseline characteristics included a higher percentage of patients without aGvHD receiving MRD grafts (59%) and a higher prevalence of partially-matched URD grafts among patients with Grades III/IV aGvHD (20%) versus those without aGvHD (10%), although significant differ- ences in demographics were addressed via the respective statistical models (Table 2).
Overall Survival. There were no significant differences in survival between patients with iUGI aGvHD and those with Grades I or II aGvHD without UGI symptoms in uni- variate or multivariable analyses (Table 3A, Figure 1). As anticipated, patients with iUGI aGvHD had better sur- vival than those with Grade III/IV aGvHD (MRD Hazard ratio (HR) 2.06, P<0.0001; URD HR 2.28, P<0.0001).
Covariates with significant impacts on survival and other transplant-related outcomes in these analyses are reported in Online Supplementary Table S2.
Disease-free survival and relapse. There were no signifi- cant differences in DFS between patients with iUGI aGvHD and those with Grades I or II aGvHD, although there was a trend towards improved DFS in those with Grade I aGvHD after URD HSCT (P=0.016) (Table 3A). Patients experiencing Grade III/IV aGvHD demonstrated worse DFS (MRD HR 1.66, P=0.0015; URD HR 1.66, P<0.0001). There was no significant difference in relapse incidence between patients with iUGI aGvHD and those with other grades of aGvHD.
Treatment-related mortality and chronic GvHD. TRM was similar for patients with iUGI aGvHD, and those with Grades I or II aGvHD. Patients with Grade III/IV aGvHD had more TRM (MRD HR 3.39, P<0.0001; URD HR 3.91, P<0.0001) (Table 3A, Figure 2). The incidence of cGvHD after iUGI symptoms was similar to the incidence with Grades I or II aGvHD in MRD recipients. After URD HSCT, those with iUGI aGvHD had less frequent cGvHD than patients with Grade I (HR 1.38, P=0.016) and Grade II aGvHD (HR 1.59, P=0.0004).
Secondary analysis including patients without acute GvHD. In secondary analyses starting at the time of transplanta- tion, pairwise comparisons were performed between patients without aGvHD and those with iUGI and Grades I, II and III/IV, recognizing that some patients in the “No aGvHD” group experienced early deaths related to TRM before the possible onset of aGVHD. In analyses for OS, DFS, TRM, and cGvHD incidence, outcomes after iUGI aGvHD were not significantly different from those of patients with no aGvHD (Table 3B). In comparison, patients with Grade II aGvHD without UGI symptoms trended towards worse TRM (MRD P=0.0074, URD P=0.038), and those with Grade I or II aGvHD had increased cGvHD than those without aGvHD (MRD and URD, all P-values ≤ 0.0002). Additionally, patients with
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