Cumulative incidence and organ involvement for classic cGVHD and ocGVHD:
The cumulative incidence of all grades of cGVHD through one-year post-transplant on ABA2 was 43.1% for 8/8 placebo patients, 49.7% for 8/8 ABA patients, and 63.7% for 7/8 ABA patients (Fig. 1A, p = 0.54 for the 8/8 placebo versus 8/8 ABA comparison, and p = 0.19 for the 8/8 ABA versus 7/8 ABA comparison). Of the 92 patients diagnosed with cGVHD within one-year of HCT, 35 developed ocGVHD (Table 1). As shown in Table 1, the ocGVHD and classic cGVHD groups were balanced for baseline characteristics, except for older age at transplant for patients with ocGVHD compared to classic cGVHD (mean 54.5 vs 37.1 years respectively, p = 0.02). The most common organs involved in both classic cGVHD and ocGVHD are shown in Table 2A-B. The most common organs in classic cGVHD, when analyzed at the time of presentation, were the mouth (82%), eyes (39%), liver (39%) and skin (37%). The most common organs involved in ocGVHD when analyzed at the time of presentation were the skin (86%), mouth (80%) and GI tract (54%) (Table 2A). The most common organs in classic cGVHD, when analyzed at the time of maximum disease severity, were the mouth (84%), eyes (49%), skin (39%) and liver (39%). The three most common organs involved in ocGVHD when analyzed at the time of maximum disease severity were the skin (91%), mouth (83%) and GI tract (60%) (Table 2B). At the time of ocGVHD diagnosis, 97% (34/35) of patients had diagnostic features of cGVHD (oral 88.6%, eyes 3%, skin 6%, GU 3%, GI 3%). Three percent (1/35) had myositis, a distinctive feature of cGVHD (Supplemental Table 1)8. Within the 8/8 cohort (8/8 ABA and 8/8 placebo), there was no difference in the cumulative incidence of classic cGVHD (29.7% 8/8 placebo vs 30.4% 8/8 ABA, p = 0.98, Fig. 1B) or ocGVHD (13.4% 8/8 placebo vs 19.3% 8/8 ABA, p = 0.34, Fig. 1C). Within the ABA cohort (8/8 ABA and 7/8 ABA), there was no difference in the cumulative incidence of classic cGVHD (30.4% 8/8 ABA vs. 35.5% 7/8 ABA, p = 0.61, Fig. 1B) or ocGVHD (19.3% 8/8 ABA vs. 28.2% 7/8 ABA, p = 0.30, Fig. 1C). Additionally, there was no significant difference in the cGVHD global severity score at cGVHD diagnosis or at maximum cGVHD presentation within the 8/8 placebo versus 8/8 ABA cohorts or within the 7/8 versus 8/8 ABA cohorts (Table 3). Because of the similarities between the incidence and severity of classic cGVHD and ocGVHD in the 8/8 placebo, 8/8 ABA and 7/8 ABA cohorts, these cohorts were combined for most of the downstream analyses.
Distinguishing disease characteristics between classic cGVHD and ocGVHD:
As shown in Fig. 2, patients with ocGVHD had significantly more severe cGVHD at initial diagnosis and at maximum severity within the first year post-HCT compared to those who developed classic cGVHD. The distribution of affected organs was also different for the two cGVHD subtypes (Table 2). Notably, the acute GVHD components of disease made a substantial impact on the severity of cGVHD in many ocGVHD patients. Thus, for patients with moderate-severe ocGVHD, more than a third of these patients would have been reclassified as having mild cGVHD if only their chronic organ involvement was scored. The severity of disease at presentation for these patients was driven by the acute GVHD aspects of their disease (Fig. 3). In addition, 48.6% of patients with ocGVHD were diagnosed with progressive onset compared to 1.8% of classic cGVHD patients (p = < 0.0001 Table 1). Given that the type of onset of cGVHD (i.e. progressive versus quiescent versus de novo) has been shown to have potential prognostic implications, with evidence that progressive onset cGVHD is significantly associated with worse survival and increased NRM,25,34 these data suggest a link between onset characteristics and down-stream survival effects of ocGVHD.
OcGVHD is associated with decreased survival versus classic cGVHD:
As shown in Fig. 4 and Table 4, compared to patients with classic cGVHD, patients with ocGVHD had significantly decreased survival. Thus, OS was significantly lower for patients with ocGVHD versus classic GVHD (p = 0.003, Fig. 4A). This was reflected in the estimated probability of OS in ocGVHD compared with classic cGVHD at 1 year (83% vs 100%, respectively) and 2 years (64% vs 92% respectively) (Table 4). DFS was also decreased in patients with ocGVHD versus classic GVHD (Fig. 4B, p = 0.014), with a similar trend compared to OS. Thus, the 1-year estimated DFS was 83% for ocGVHD versus 100% for classic cGVHD, while 2-year DFS was 65% for ocGVHD and 84% for classic cGVHD. For NRM, there was a trend for increased NRM in patients with ocGVHD versus classic cGVHD (Fig. 4C, p = 0.068), with ocGVHD patients experiencing earlier NRM than those with classic cGVHD. Indeed, for the 15 patients who experienced NRM (8 with ocGVHD, 7 with classic cGVHD), those with ocGVHD had shorter survival after cGVHD diagnosis compared to those with classic cGVHD (86 days versus 465 days, p = 0.007). NRM at 1-year was 17% for those with ocGVHD versus 0% for patients with classic cGVHD, while 2-year NRM was 26% for ocGVHD and 8% for classic cGVHD. Of note, for patients with ocGVHD, many of the deaths (58%) were GVHD-related (Supplemental Table 2), further highlighting the impact that ocGVHD made to patient outcomes. Indeed, the majority of NRM recorded in cGVHD patients on ABA2 occurred in those who had severe cGVHD at diagnosis, and 87% of deaths in ocGVHD patients occurred in those who had severe acute GVHD manifestations in the GI tract and liver (Supplemental Table 3). Time-to-relapse was similar for patients with classic cGVHD and ocGVHD (Fig. 4D) but with a trend towards increased later relapses apparent in ocGVHD patients. Together, the pattern of mortality risk for patients with ocGVHD versus classic cGVHD suggests a more significant difference in early versus late mortality with ocGVHD, consistent with the acute attributes of this GVHD subtype.
To determine whether there were any notable differences between the placebo and ABA patients with regard to ocGVHD, we performed a sub-analysis of the 8/8 cohort for OS and DFS, comparing outcomes between classic cGVHD and ocGVHD amongst 8/8 Placebo versus 8/8 ABA patients. Although, as shown in Supplemental Table 4, the global severity of both classic cGVHD and ocGVHD was similar for 8/8 Placebo versus 8/8 ABA, there were survival differences between these two cohorts. Thus, in the 8/8 Placebo group, patients who developed ocGVHD demonstrated significantly lower OS and DFS compared to those with classic cGVHD (p = 0.004 and 0.003, respectively, Supplemental Table 5). In contrast, in the 8/8 ABA group, OS and DFS were similar (p = 0.74 and 0.698 respectively) suggesting that ABA’s protective effect on acute GVHD had a positive impact on ocGVHD outcomes.