Baseline characteristics of patients with SR-aGVHD

Demographics and clinical characteristics of patients with SR-aGVHD are shown by subgroups in Table 1. Of 309 patients, 154 (49.8%) patients were allocated to the ruxolitinib arm and categorized as receiving treatment early (n = 112 [72.7%]), late-and-very-late, (n = 42 [27.3%; late, n = 18, very late, n = 24]), or very late (n = 24 [15.6%]). The remaining 155 (50.2%) patients were randomized to BAT and categorized as receiving treatment early (n = 115 [74.2%]), late-and-very-late (n = 40 [25.8%; late, n = 18, very late, n = 22]), or very late (n = 22 [14.2%]). Mean time from diagnosis of initial aGVHD grade ≥II to randomization for treatment (ruxolitinib or BAT) of SR-aGVHD was 22.4, 37.5, and 42.0 days for the early, late-and-very-late, and very-late subgroups, respectively. Median ages were similar across subgroups, and most patients were men (Table 1).

Table 1 Baseline characteristics of patients with SR-aGVHD.

At randomization, most patients had grade II or III SR-aGVHD, with more patients having grade III than grade II SR-aGVHD across all treatment initiation subgroups (34.8%, 30.5%, and 30.4% had grade II SR-aGVHD in the early, late-and-very-late, and very-late subgroups, respectively, vs 42.3%, 48.8%, and 47.8% with grade III SR-aGVHD). Skin and lower GI tract organs were most frequently involved; (56.8%, 46.3%, and 43.5% had skin involvement in the early, late-and-very-late, and very-late subgroups, respectively; 67.0%, 72.0%, and 65.2% had lower GI tract involvement).

Patients with SR-aGVHD who received ≥1 dose of trial treatment (N = 302) were included in the safety analysis, which evaluated the impact of cytopenias (ruxolitinib, n = 152 [50.3%]; BAT, n = 150 [49.7%]).

Baseline characteristics of patients with SR-cGVHD

Demographics and clinical characteristics of the 329 patients with SR-cGVHD are shown in Table 2. Of these patients, 165 (50.2%) were randomized to ruxolitinib and categorized as receiving treatment early (n = 88 [53.3%]), late-and-very-late (n = 77 [46.7%; late, n = 30, very late, n = 47]), and very late (n = 47 [28.5%]). The remaining 164 (49.8%) patients were randomized to BAT and categorized as receiving treatment early (n = 85 [51.8%]), late-and-very-late (n = 79 [48.2%; late, n = 33, very late, n = 46]), and very late (n = 46 [28.0%]). Mean time from diagnosis of cGVHD to randomization of ruxolitinib or BAT was 175.7, 290.1, and 323.2 days for early, late-and-very-late, and very-late subgroups, respectively. Median ages for the early, late-and-very-late, and very-late subgroups were all 49.0 years. Most patients were men (59.5%, 62.8%, and 64.5% for the early, late-and-very-late, and very-late subgroups, respectively).

Table 2 Baseline characteristics of patients with SR-cGVHD.

Approximately half of patients with cGVHD (n = 180/329 [54.7%]) had experienced prior aGVHD. A numerically greater percentage of patients in the early treatment group had prior aGVHD compared with the other 2 groups (57.2%, 51.9%, and 48.4% of patients in the early, late-and-very-late, and very-late subgroups, respectively). At time of study entry, all but 1 patient (in the very-late subgroup) had moderate or severe SR-cGVHD.

Treatment initiation in patients with SR-aGVHD

Among patients with SR-aGVHD, Day 28 ORR was significantly higher with ruxolitinib treatment versus BAT in the early and late-and-very-late subgroups and numerically greater in the very-late treatment subgroup (Fig. 1a). A greater percentage of patients treated with ruxolitinib versus BAT achieved CR in all 3 time-to-treatment subgroups (Fig. 1a). BOR was also significantly higher with ruxolitinib treatment compared with BAT in the early and late-and-very-late subgroups and numerically greater in the very-late treatment subgroup (Fig. 1a). Median DOR was longer with ruxolitinib treatment versus BAT in the early (178.0 vs 101.0 days) and late-and-very-late treatment initiation subgroups (152.0 vs 88.0 days; Fig. 2a).

Fig. 1: Overall response rate and best overall response by treatment initiation subgroup.

a ORR: CR + PR at Day 28 (SR-aGVHD). b ORR: CR + PR at Week 24 (SR-cGVHD). Values at the top of graphs indicate OR (95% CI) for ruxolitinib vs BAT. BAT best available therapy, CR complete response, OR odds ratio, ORR overall response rate, PR partial response, SR-aGVHD steroid-refractory acute graft-versus-host disease, SR-cGVHD steroid-refractory chronic graft-versus-host disease.

Fig. 2: Duration of response in patients treated with ruxolitnib or BAT.

a DOR in patients with SR-aGVHD. b DOR in patients with SR-cGVHD. BAT best available therapy, DOR duration of response, IQR interquartile range, NE not evaluable, SR-aGVHD steroid-refractory acute graft-versus-host disease, SR-cGVHD steroid-refractory chronic graft-versus-host disease.

Responses among early, late, and very-late subgroups were compared in patients with SR-aGVHD treated with ruxolitinib. No significant differences between time-to-treatment subgroups were observed for ORR or BOR, although CR rates were numerically higher in early and late ruxolitinib initiation subgroups versus the very-late subgroup (Fig. 3a). Probability of loss of response was greater with late initiation and very late initiation of ruxolitinib versus early initiation (Fig. 3b).

Fig. 3: Time to ruxolitinib treatment initiation subgroup comparisons for responses and duration of response.

a ORR and BOR for patients with SR-aGVHD. b DOR for patients with SR-aGVHD. c ORR and BOR for patients with SR-cGVHD. d DOR for patients with SR-cGVHD. OR odds ratio, SR-aGVHD steroid-refractory acute graft-versus-host disease, SR-cGVHD steroid-refractory chronic graft-versus-host disease. a, c Values at the top of graphs indicate OR (95% CI) for early versus late or very late treatment initiation.

Treatment initiation in patients with SR-cGVHD

Among patients with SR-cGVHD, Week 24 ORR was significantly higher with ruxolitinib treatment versus BAT in all 3 time-to-treatment groups (Fig. 1b). BOR was significantly higher in the late-and-very-late and very-late ruxolitinib initiation subgroups with ruxolitinib treatment versus BAT, and numerically higher in the early subgroup (Fig. 1b).

Ruxolitinib treatment increased DOR compared with BAT in patients with SR-cGVHD. Median DOR ranged between 167.0–211.0 days in the BAT subgroups and was not reached in any ruxolitinib subgroup (Fig. 2b).

Responses among the early, late, and very-late subgroups were compared in patients with SR-cGVHD treated with ruxolitinib. No significant differences in ORR, BOR, or DOR were observed among ruxolitinib time-to-treatment subgroups (Fig. 3c, d).

Cytopenias in patients with SR-aGVHD

The ORRs for patients with SR-aGVHD were compared among patients stratified by low versus not-low WBC, ANC, PLT, or Hb count. ORRs at Day 28 among patients treated with ruxolitinib were similar between low and not-low WBC, ANC, PLT, or Hb subgroups individually (eg, low PLT, ORR 59.2% [95% CI 46.8–70.7] vs not-low PLT, ORR 66.7% [95% CI 55.3–76.8]). For the period of time that ORR was measured (until Day 28), the most frequent dose reduction was from 20 mg/d to 10 mg/d (44.4% of 135 patients with any cytopenia, vs 17.6% of 17 patients with no cytopenias; Supplementary Fig. 1), although the median dose of ruxolitinib (any cytopenia, 20.0 mg/d; no cytopenia, 20.0 mg/d; Q1–Q3 of median doses across all 152 patients with or without cytopenias, 17.85–20.0 mg/d) was approximately equal to the 20 mg/d starting dose in all subgroups regardless of cytopenia status. The presence of any cytopenia (low WBC, ANC, PLT, or Hb) did not diminish favorable response rates among patients treated with ruxolitinib (cytopenia subgroup, ORR 66.7% [95% CI 58.0–74.5] vs no cytopenia subgroup, ORR 35.3% [95% CI 14.2–61.7]; Fig. 4a). Response rate was numerically, but not significantly, higher for BAT than ruxolitinib in patients with no cytopenias (n = 6/17 [35.3%] treated with ruxolitinib; n = 7/15 [46.7%] treated with BAT). However, response rates were numerically or significantly higher in patients treated with ruxolitinib versus BAT for all cytopenia subgroups and for patients overall (Fig. 4a).

Fig. 4: Effect of cytopenias on responses in patients with SR-aGVHD treated with ruxolitinib or BAT.

a ORR at Day 28. b Durable response at Day 56, defined as the proportion of all patients who achieved a CR or PR at Day 28 and maintained a CR or PR at Day 56. c Median duration of response. ANC absolute neutrophil count, BAT best available therapy, CR complete response, Hb hemoglobin, IQR interquartile range, NE not evaluable, NR not reached, OR odds ratio, ORR overall response rate, PLT platelet count, PR partial response, SR-aGVHD steroid-refractory acute graft-versus-host disease, WBC white blood cell count. * Cytopenias were defined as low blood counts between baseline and Week 4; low blood cell counts were defined as: WBC, <5 × 109 cells/L; ANC, <1 × 109 cells/L; PLT, <30 × 109 cells/L; Hb, <8 g/dL.

Durable responses were observed across all subgroups (Fig. 4b). For the subgroup of patients with any cytopenia, median DOR was numerically longer for patients treated with ruxolitinib versus BAT (Fig. 4c). Mean PLT counts and Hb concentrations decreased over the first 4–12 weeks of treatment, then recovered, and were mostly similar between ruxolitinib and BAT treatment groups through Week 24 (Fig. 5). Mean WBC and ANC counts similarly decreased through Week 8 with both ruxolitinib and BAT and were generally lower in the ruxolitinib versus BAT group through Week 24 (Fig. 5).

Fig. 5

Hematologic laboratory values in patients with SR-aGVHD. ANC absolute neutrophil count, BAT best available therapy, Hb hemoglobin, PLT platelet count, SR-aGVHD steroid-refractory acute graft-versus-host disease, WBC white blood cell count.