Ruxolitinib Significantly Improves Outcomes in Acute Graft-Versus-Host-Disease

Ruxolitinib (Jakafi) improved upon the overall response rate (ORR), as well as multiple other efficacy measures in patients with steroid-refractory acute graft-versus-host-disease (GVHD compared with best available therapy (BAT), meeting the primary end point of the phase III REACH 2 trial (NCT02913261), Novartis announced in a press release.¹

“These new data from REACH2 showing superiority of Jakavi over current standard-of-care therapies add to a growing body of evidence on how targeting the JAK pathway can be an effective strategy in this difficult-to-treat condition,” said Robert Zeiser, professor, University Hospital Freiburg, Department of Haematology, Oncology and Stem Cell Transplantation, in a statement.

In the study, ruxolitinib induced a significantly greater ORR in comparison with best available therapy (BAT) in patients with steroid-refractory acute graft-versus-host-disease (GVHD) in the REACH2 trial, the first phase III study of ruxolitinib for this setting, according to the results published in The New England Journal of Medicine.²

The ORR at day 28 was 62% versus 39% in the ruxolitinib versus control arm, respectively (odds ratio [OR], 2.64; 95% CI, 1.65-4.22; P <.001). Overall, 34% of patients in the ruxolitinib arm and 19% in the control arm achieved a complete response.

“This trial showed that, among patients with grade II to IV glucocorticoid-refractory acute GVHD, ruxolitinib therapy led a significantly higher overall response than control therapy at day 28 and a higher durable overall response at day 56,” the study authors wrote.

The primary end point of ORR at day 28 was achieved with ruxolitinib treatment for acute GVHD. Secondary end points included overall durability at day 56, duration of response, best overall response, failure-free survival, overall survival (OS), and cumulative glucocorticoid use until day 56.

Durable overall response at day 56 was significantly higher in the ruxolitinib arm (40%) compared with BAT (22%; OR, 2.38; 95% CI, 1.43-3.94; P <.001). The best overall response at day 28, of either a complete or partial response, was achieved in 82% of the ruxolitinib arm and 61% of the BAT arm (OR, 3.07; 95% CI, 1.80-5.25).

The cumulative incidence of loss of response at 6 months was 10% (95% CI, 4-17) with ruxolitinib versus 10% (95% CI, 26-52) with BAT. Thirty-two patients (21%) versus 21 (14%) had discontinued glucocorticoids by day 56 in the ruxolitinib versus BAT arms, respectively.

Failure-free survival was significantly prolonged in the ruxolitinib group. The median failure-free survival was 5.0 months versus 1.0 months in the ruxolitinib versus BAT arms, respectively (HR, 0.46; 95% CI, 0.35-0.60).

The cumulative incidence of relapse or progression of disease at 18 months was 13% with ruxolitinib versus 19% with BAT, and the cumulative incidence of non-relapse-related death at 18 months was 49% versus 51%, respectively.

The median OS in the ruxolitinib arm was 11.1 months versus 6.5 months in the control arm. (HR, 0.83; 95% CI, 0.60-1.15).

“The safety profile of ruxolitinib in this trial was consistent with the known safety profile of ruxolitinib and was as expected in patients with glucocorticoid-refractory acute GVHD,” authors wrote.

Overall, 111 of the 154 patients in the ruxolitinib arm (72%) discontinued treatment compared with 132 of 155 patients (85%) in the control arm. The most common reason for discontinuation was lack of efficacy, which occurred in 21% in the ruxolitinib arm and 44% in the control arm.

The most common adverse events (AEs) of any grade up to day 28 were thrombocytopenia, anemia, and cytomegalovirus infection. Grade 3 infection up to day 28 were observed in 22% of patients treated with ruxolitinib and 19% with BAT. The median time to first grade 3 infection was 0.8 months with ruxolitinib and 0.7 months with BAT. The median time to the first event was not reached in the ruxolitinib arm but was 6.0 months in the BAT arm.

The most common grade 3 or greater AEs in the ruxolitinib arm versus the control arm were thrombocytopenia (27% vs. 15%), anemia (22% vs. 19%), and platelet count decrease (14% vs. 13%), neutropenia (13% vs. 9%).

Serious AEs up to day 28 were observed in 38% of patients on ruxolitinib compared with 34% in the control arm. AEs led to dose modifications in 38% of patients in the ruxolitinib versus 9% with BAT, and treatment was discontinued due to AEs in 11% versus 5%, respectively.

Overall, 47% and 51% of patients receiving ruxolitinib or BAT died by the cutoff date, which included 28% and 24% during the randomization period, respectively. Most deaths were related to acute GVHD, but the most commonly reported causes were underlying disease progression, multiple organ dysfunction syndrome, and septic shock.

The multicenter, open-label REACH2 study randomized patients 1:1 to receive either ruxolitinib or the investigator’s choice of therapy from a list of 9 commonly used treatment options. Ruxolitinib was given orally at 10 mg twice daily and was modified for AEs per provided guidance if necessary.

The therapeutic options in the control arm included anti-thymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, a mammalian target of rapamycin inhibitor of either everolimus or sirolimus, etanercept, or infliximab. Crossover to ruxolitinib was permitted beginning on day 28 if the patients did not have a response or had lost response and did not have signs of chronic GVHD after receiving additional systemic therapy.

To be eligible, patients had to be at least 12 years or older and received previous allogeneic stem cell transplant. They had to be refractory to glucocorticoids and have myeloid and platelet engraftment. Patients were excluded from the study if their tumor relapsed after transplant in the last 6 months, had a relapsed primary cancer after transplant, or received more than 1 prior treatment for glucocorticoid-refractory acute GVHD.

Ruxolitinib was approved by the FDA in 2019 as treatment of adult and pediatric patients aged 12 years or older with steroid-refractory acute GvHD, based on the earlier phase II REACH-1 trial. The phase III REACH-2 study is ongoing and aim to enroll 310 patients. Full results from the study are expected in the second half of 2020.¹

_Reference:

1. _{Novartis announces data showing Jakavi® (ruxolitinib) more effective than best available therapy in acute graft-versus-host disease [news release]. Basel, Switzerland: Novartis; April 22, 2020. https://bit.ly/2VtEIyG. Accessed April 23, 2020.}
2. _{Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease [Published Online April 22, 2020]. NEJM. DOI: 10.1056/NEJMoa1917635.}