REACH5: Ruxolitinib Active, Well-Tolerated for Chronic GVHD in Children

Franco Locatelli, MD, PhD

Credit: Wikipedia

An interim analysis of the single-arm, multicenter, Phase 2 REACH5 study provided updated insight into the use of ruxolitinib in treatment-naive or corticosteroid-refractory pediatric patients with chronic graft-versus-host disease (GVHD).¹

Results from the REACH5 study showed the efficacy and tolerability for this pediatric patient population, with an overall response rate of 40%, at Cycle 7 Day 1 of treatment administration in 28-day cycles for approximately 3 years.

“Pending final analysis, this study suggests that ruxolitinib is active and well-tolerated in both treatment-naive and corticosteroid-refractory patients aged 2 years to younger than 18 years with chronic GVHD, thereby supporting its use in this patient population,” wrote the investigative team, led by Franco Locatelli, MD, PhD, department of pediatric hematology and oncology, IRCCS Ospedale Pediatrico.

Allogenic hematopoietic stem cell translation (HSCT) is a curative therapy for a rising number of children and adolescents with a variety of malignant and non-malignant hematological diseases.² It has been linked to improved transplant procedures and a reduction in early mortality.

However, long-term outcome success can be hindered by chronic GVHD, which can be severe and represents the most common complication post-HSCT.

National Institutes for Health (NIH) consensus criteria for cGvHD diagnosis and grading for use in clinical trials in 2005, and revised in 2014, represented a major advancement in the field of hematology.³ However, research into cGvHD in children and adolescents is relatively limited compared with evidence in adults.

For REACH5, Locatelli and colleagues analyzed markers of activity, pharmacokinetics, and safety of ruxolitinib added to corticosteroids in pediatric patients with moderate-to-severe chronic GVHD.¹ The study population was recruited from 21 hospitals or clinics across 14 countries in Asia, Europe, and Canada.

Eligible patients were aged 18 days to <18 years, had undergone allogeneic HCST, and had been diagnosed with relevant moderate-to-sever GVHD, as per the 2014 consensus criteria from the National Institutes of Health.

Oral ruxolitinib dosing was administered according to age at the beginning of treatment. Patients aged ≥12–<18 years received twice-daily 10 mg ruxolitinib, those aged ≥6–<12 years received twice-daily 5 mg ruxolitinib, and those aged ≥2–<6 years received twice-daily 4 mg/m2.

Administration was performed in 28-day cycles for approximately 36 months, together with guideline-recommended supportive treatment. The primary active endpoint was the overall response rate at Cycle 7 Day 1. This prespecified interim analysis was scheduled to occur after all patients had completed 1 year of treatment or discontinued treatment.

During the study period, between May 2020 and September 2021, 48 patients were screened and 45 were enrolled to receive >1 dose of oral ruxolitinib. The median age was 11 years, 16 (36%) patients were female, and 29 (64%) were male. Of the population, 21 (47%) were White, 1 (2%) were Black or African American, and 23 (51%) were Asian.

Notably, 17 (38%) patients were treatment-naive and 28 (62%) were corticosteroid-refractory.

At the data cutoff in October 2022, after a median ruxolitinib exposure of 55.1 weeks, the overall response rate at Cycle 7 Day 1 was 40% (n = 18; 90% CI, 27.7–53.3). Responses were achieved in 7 (41%) treatment-naive patients and 11 (39%) corticosteroid-refractory patients.

Ruxolitinib’s safety in the pediatric patient population remained consistent with the profile in adults. The most common treatment-related adverse events (TEAEs) of Grade 3 or worse were neutropenia (n = 8 [18%]) and thrombocytopenia (n = 6 [13%]).

Meanwhile, 7 (16%) patients had Grade 3 or worse serious TEAEs, with the most common being hyponatremia (n = 2 [4%]). A total of 3 (7%) patients died within 30 days of treatment discontinuation, due to Aspergillus infection, septic shock, and acute respiratory distress syndrome, respectively. None were deemed to be related to oral ruxolitinib.

“Final analysis of this study will provide further information on the long-term benefits of ruxolitinib in children with chronic GVHD,” Locatelli and colleagues added.

References

1. _{Locatelli F, Antmen B, Kang HJ, Koh K, Takahashi Y, Kupesiz A. Ruxolitinib in treatment-naive or corticosteroid-refractory paediatric patients with chronic graft-versus-host disease. The Lancet Haematology. July 10, 2024. Accessed July 12, 2024. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(24)00099-1/abstract.}
2. _{Sobkowiak-Sobierajska A, Lindemans C, Sykora T, et al. Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan. Front Pediatr. 2022;10:808103. Published 2022 Feb 18. doi:10.3389/fped.2022.808103}
3. _{Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001}