S245: ruxolitinib in pediatric patients with treatment-naive or steroid-refractory chronic graft versus host disease: primary findings from the phase ii reach5 study

Topic: 22. Stem cell transplantation - Clinical Background: Chronic graft-versus-host disease (cGvHD) is a major complication of allogeneic stem cell transplantation and ≈ 50% of patients (pts) become steroid-refractory (SR) or steroid-dependent. In the phase 3 REACH3 randomized study (Zeiser et al., N Engl J Med, 2021), ruxolitinib (RUX) demonstrated a superior overall response rate (ORR) vs. best available therapy in pts ≥12 years with SR cGvHD. Aims: We present the first data from REACH5 (NCT03774082), a phase 2 open-label, single-arm, multicenter study of RUX added to corticosteroids (CS) in pediatric pts with moderate to severe cGvHD. Methods: Pts with moderate to severe treatment-naive or SR cGvHD were grouped according to age (Group 1: ≥12 to <18 years, Group 2: ≥6 to <12 years, and Group 3: ≥2 to <6 years). All pts received RUX plus CS ± calcineurin inhibitor for up to 3 years (39 cycles of 28 days/week 156); RUX starting dose was 10 mg twice daily [BID] in Group 1, 5 mg BID in Group 2, and 4 mg/m2 BID in Group 3). The primary efficacy endpoint was ORR at cycle 7 day 1 (C7D1); key secondary endpoints included best overall response (BOR) up to C7D1, failure-free survival, overall survival, and evaluation of safety. CS taper was permitted 2 weeks after the achievement of complete or partial response; following successful CS taper, RUX taper could commence after C7D1. Data were analyzed once all pts had completed 1 year of treatment or discontinued earlier (data cut-off 19 October 2022). Results: Overall, 45 pediatric pts were treated with RUX; 64.4% were male and the median age was 11.0 years (range, 2.0–17.8). At screening, 37.8% of pts had moderate cGvHD and 62.2% had severe cGvHD; 62.2% were SR and 37.8% were treatment-naive. Median time from cGvHD diagnosis to start of study treatment was 49 days (range,1–2999). At data cut-off, the treatment phase was ongoing for 15 pts and 30 pts had discontinued treatment; the most common reasons for discontinuation were physician’s decision (15.6%), adverse event (AE; 13.3%) and lack of efficacy (13.3%). Among all pts, the ORR at C7D1 was 40% (18/45; 90% confidence interval [CI] 27.7, 53.3) and the BOR rate up to C7D1 was 82.2% (37/45; 90% CI 70.2, 90.8) (Table). ORR at C7D1 in treatment-naive and SR pts were 41.2% and 39.3%, respectively. Of pts receiving CS at baseline (40/45; 88.9%), 42.5% (17/40) stopped or completely tapered CS and 75.0% (30/40) had a ≥50% reduction from baseline at least once by C7D1. Among all pts, the CS-free ORR at data cut-off was 37.8% (17/45; 90% CI 25.7, 51.1). The median duration of RUX exposure was 55.1 weeks (range 2.1–112.1). In total, 97.8% (44/45) of pts had an AE (any grade) and 64.4% had a ≥3 grade AE. Most frequently reported AEs were anemia (22.2% any grade; 20.0% ≥3 grade), COVID-19 (17.8% any grade; 4.4% ≥3 grade) and decreased neutrophil count (17.8% any grade; 17.8% ≥3 grade). Overall, 73.3% (33/45) of pts had an infection. Viral infections occurred in 40.0% (18/45) of pts, including 17.8% (8/45) SARS-CoV-2 infections; bacterial and fungal infections occurred in 2.2% and 11.1% of pts, respectively. Overall, 10 (22.2%) pts died during the study. Three (6.7%) pts died whilst receiving RUX or within 30 days of the last study dose; causes of death were aspergillus pneumonia, septic shock and acute respiratory distress syndrome (1 pt each). Summary/Conclusion: In pediatric pts with cGvHD, RUX treatment led to high ORR at C7D1 and a high BOR up to C7D1, across age groups. ORR was similar in treatment-naive and SR pts at C7D1. The safety profile was consistent with expectations for RUX and this pt population. This study was sponsored by Novartis Pharmaceuticals.Keywords: Graft-versus-host disease (GVHD), Pediatric, Chronic graft-versus-host, Ruxolitinib