aGvHD

TCT Meeting 2019 | Results from the REACH1 trial: ruxolitinib plus corticosteroids for the treatment of steroid-refractory acute graft-versus-host disease

On Saturday 23 February, an oral session was held and entitled: Graft Versus Host Disease II at the 2019 TCT Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR in Houston, Texas, USA. During this session, an oral abstract was presented by Madan Jagasia from Vanderbilt University Medical Center, Nashville, TN, USA. The title of the talk was: Ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-versus-host disease: Results from the phase II REACH1 trial.

The REACH1 study is a single-cohort, pivotal phase II study (NCT02953678) evaluating ruxolitinib in combination with corticosteroids in patients with steroid-refractory acute graft-versus-host disease (SR aGvHD). Ruxolitinib is an oral, Janus-associated kinase 1 and 2 inhibitor (JAK1, JAK2). The implications of JAK 1 and 2 inhibition, lead to decreased signaling of inflammatory mediators associated with graft-versus-host disease (GvHD), such as tumor necrosis factor and interleukins.

The primary outcome measure was overall response rate at day 28. Multiple secondary endpoints include 6-month duration of response, relapse of primary disease, non-relapse mortality, overall survival rates, and safety.

Patients and methods:
  • N = 71 patients
  • Median age = 58 years (range, 18–73)
  • All patients received ≥ 1 dose of ruxolitinib (69 of them received 5 mg ruxolitinib twice daily)
  • N = 60 patients discontinued therapy due to adverse events (n = 20 patients), physician decision (n = 20 patients), progression of GvHD (n = 6 patients), withdrawal by participant (n = 3 patients), relapse of primary disease (n = 2 patients), other (n = 2 patients)
  • Graft source:
    • PBSC: 80.3%
    • Bone marrow: 18.3%
    • Umbilical cord blood: 1.4%
  • N = 23 patients (32.4%) had grade II aGvHD
  • N = 34 patients (47.9%) had grade III aGvHD
  • N = 14 patients (19.7%) had grade IV aGvHD
  • N = 36 patients (50.7%) had two or more organs involved
  • N = 19 patients (26.8%) had progression of aGvHD after 3 days of corticosteroid therapy
  • N = 30 patients (42.3%) did not respond after 7 days of corticosteroid administration
  • N = 8 patients (11.3%) had new organ involvement during steroid therapy at a dose of < 2 mg/kg
  • N = 14 patients (19.7%) were taper intolerant
Key findings:
  • Day-28 overall response rate: 54.9% (95% CI, 42.7–66.8)
  • Complete response: 19 patients (26.8%)
  • VGPR: 7 patients (9.9%)
  • PR: 13 patients (18.3%)
  • Response was observed in 52 patients (73.2%) at any time during treatment
  • Median duration of response was 345 days
  • Event-free probability estimates (95% CI) for day 28 responders at 3 and 6 months were 81.6% and 65.2%, respectively
  • Median overall survival: 232 days (95% CI, 93–not reached)
  • Four patients had relapsed
  • 8% (24/43) of patients had ≥50% reduction from baseline steroid use
  • Median steroid use: 156.3 mg/d at day 1 and 62.5mg/d at day 28
  • Treatment-emergent adverse events included anemia, hypokalemia, decreased platelet count, peripheral edema, and decreased neutrophil count
  • Cytomegalovirus infection (12.7%), sepsis (12.7%), and bacteremia (9.9%) were observed

Professor Jagasia concluded that the results of the REACH1 trial demonstrate that ruxolitinib can improve outcomes of allogeneic transplant recipients who develop SR aGvHD. Ruxolitinib therapy led to an overall response rate of 54.9% by day 28, best overall response rate at any time during treatment resulted in a percentage of 73.2% (complete response: 56.3%). Responses were rapid and durable.

The randomized pivotal phase III studies in SR aGvHD (REACH2) and SR chronic GvHD (REACH3) are both underway.

To listen to Professor Jagasia discussing this study at ASH 2018, click here.

Reference

1. Jagasia M. et al. Ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-versus-host disease: Results from the phase II REACH1 trial. TCT Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR 2019.

 

Expert Opinion

In an interview with the GvHD Hub, Professor Jagasia provided his opinion on the importance of the REACH1 trial:

"Today we know that only 50% of patients respond upfront to cortical steroids. The patients who are deemed as cortical steroid-refractory is an unmet need. There is no FDA approved strategy in that space. Overall, ruxolitinib is a big step forward for clinical practice and this is under review the FDA in the United States."

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