Ruxolitinib in combination with low-dose steroids for intermediate- and high-risk aGvHD

The most common first-line treatment for acute graft-versus-host disease (aGvHD) is corticosteroids; however, approximately 50% of patients are refractory to first-line corticosteroid treatment and therefore have poor outcomes.¹ At the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, Liu presented results from a multicenter phase II trial (NCT04061876) investigating the use of ruxolitinib in combination with corticosteroids as a novel first-line treatment for aGvHD.¹

Study design¹

Patients with intermediate- or high-risk aGvHD, as determined by biomarker analysis (REG3a and ST2 were measured at Day 0 and following 4 weeks of treatment), were enrolled in the study (n = 198; Figure 1). Patients in the ruxolitinib group received a reduced dose of steroids every 5 days to achieve a dose of 0.1 mg/kg by Day 30, before being tapered off after 6 weeks. Ruxolitinib was given every day for 90 days and then tapered off.

Figure 1. Study design* 

aGvHD, acute graft-versus-host disease; allo-HSCT, allogeneic hematopoietic stem cell transplant; ORR, overall response rate.
*Adapted from Liu.¹

Results¹

Baseline patient characteristics are shown in Table 1. The majority of patients were male and the most common diagnosis was acute myeloid leukemia.

Table 1. Baseline patient characteristics*

The majority of patients in both treatment groups had Grade 2 GvHD, with skin and upper gastrointestinal tract being most common organs involved. GvHD characteristics at the time of patient diagnosis are shown in Figure 2.

Figure 2. A GvHD grade at diagnosis, B organ involvement at diagnosis, and C biomarker risk at diagnosis* 

GI, gastrointestinal; GvHD, graft-versus-host disease.
*Adapted from Liu.^1
†p = 0.517.
^‡p = 0.353.
^§p = 0.577.
^‖p = 0.678.

Efficacy

The median follow-up time was 601 days. The average time to response was 3 days (range, 1–7 days) and 8 days (range, 1–13 days) in the ruxolitinib and steroid only group, respectively; overall response rates (ORRs) are shown in Figure 3. The rate of failure-free survival was found to be significantly higher in the ruxolitinib group compared with the steroid only group (320 days vs 113 days; hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.35–3.31).

Figure 3. ORR at A Day 28 and B Day 56* 

ORR, overall response rate.
*Adapted from Liu.¹

At Day 28, older patients (50–65 years) had a significantly higher ORR in the ruxolitinib group compared with the steroid only group (100% vs 60%; p = 0.029). Patients with Grade 3–4 aGvHD also had a higher ORR with ruxolitinib compared with steroids (86.7% vs 33.3%; p = 0.031). The duration of steroid treatment was longer in patients in the steroid only group compared with the ruxolitinib group (48.7 days vs 29.4 days; p = 0.032). Two-year non-relapse mortality was comparable between groups. The Kaplan-Meier 48-month survival proportions were 69.1% and 76.5% for the ruxolitinib and steroid only group, respectively.

Safety

The rate of Grade 3 and 4 severe adverse events was similar between the groups, with 87.9% and 85% of patients experiencing a severe event in the ruxolitinib and steroid only group, respectively; however, Grade 4 events were more common in the steroid only group (50.5% vs 26.3%). Grade 3 and 4 thrombocytopenia occurred in 56.5% and 69.7% of patients treated with ruxolitinib and steroids alone, respectively. Rates of Grade 3 and 4 infections were higher in patients treated with steroids only, there was also no significant difference in the rates of cytomegalovirus and Epstein-Barr virus between treatment groups; the infection rates of both treatment groups are shown in Figure 4.

Figure 4. Rates of infection* 

*Adapted from Liu.¹

Conclusion¹ 

These data demonstrate that combination low-dose ruxolitinib + steroids can produce high response rates in patients with intermediate- and high-risk aGvHD, with similar safety signals steroid monotherapy. Failure-free survival was significantly higher in the ruxolitinib group compared with the steroids only group; furthermore, reduced cumulative use of steroids was shown to reduce the incidence of side effects and improve patient quality of life. Based on these findings, ruxolitinib with low-dose steroids represents a potential effective treatment option for patients with aGvHD.