Patients with steroid-refractory acute graft-versus-host disease (GVHD) following hematopoietic cell transplant (HCT) experienced durable clinical responses by 28 days and had promising overall survival (OS) rates following treatment with ruxolitinib, according to findings from the phase II REACH1 trial published in Blood. The study also found that grade III/IV GVHD and longer prior corticosteroid exposure were significant predictors of reduced OS in this ruxolitinib-treated patient population.
Lead investigator Madan Jagasia, MD, of the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, told ASH Clinical News that he feels ruxolitinib should be initiated once a patient fulfills the criteria for steroid-refractory GVHD. He emphasized that timely initiation of ruxolitinib therapy in patients with steroid-refractory GVHD is an important factor to improve outcomes in this patient population. “That’s not to say you should start ruxolitinib before a patient is steroid-refractory,” Dr. Jagasia explained, “but once they are, don’t waste too much time hoping they will get better, because they won’t.”
Patients with grades II to IV steroid-refractory acute GVHD (n=71; median age = 58 years) following HCT were recruited from 26 medical centers across the U.S. Steroid-refractory GVHD was defined by at least one of the following:
- progressive GVHD after 3 days of primary treatment or no improvement of GVHD after 7 days of primary therapy with ≥2 mg/kg/day methylprednisolone or equivalent
- new organ GVHD following lower-dose corticosteroids (≥1 mg/kg/day methylprednisolone) for skin or skin plus upper gastrointestinal GVHD
- inability to tolerate corticosteroid taper
At time of enrollment, 48 patients (68%) had grade III/IV acute GVHD. The median duration of exposure to corticosteroids prior to enrollment was 15 days. For patients with grades II or III/IV acute GVHD, the median duration of exposure to corticosteroids prior to enrollment was 17 and 12 days, respectively.
Oral ruxolitinib at a starting dose of 5 mg twice daily was administered to all patients. The study protocol allowed for an increase of this dose to 10 mg twice daily after 3 days if new cytopenias were not present. In patients who achieved a complete response (CR) or very good partial response (VGPR) and discontinued a corticosteroid regimen for at least 8 weeks, ruxolitinib could be tapered after day 180.
Concomitant corticosteroids, either intravenous methylprednisolone 2.0 mg/kg/day or oral prednisone 2.5 mg/kg/day, were administered on day 1. These medications were tapered as tolerated. Patients who experienced flares of GVHD during corticosteroid taper continued on ruxolitinib.
The median follow-up period of the study at time of analysis was 156 days. For all patients, the median duration of ruxolitinib therapy was 46 days, whereas the median average total daily dose of the drug was 10.3 mg/day.
Grade III/IV GVHD and longer prior corticosteroid exposure were significant predictors of reduced OS.
The 28-day overall response rate (ORR) primary endpoint was defined as the percentage of patients who demonstrated a CR, VGPR, or partial response (PR). A total of 39 patients (55%) achieved the primary ORR endpoint by day 28 (95% CI 43-67%). The rates of CR, VGPR, and PR were 27%, 10%, and 18%, respectively.
In addition, approximately 73% of patients had an ORR at any time (95% CI 61–83%), which included CR in 56% of patients. Overall, the median time to a first response was 7 days. More than half (61%) of patients had a first response on or prior to day 14.
A post hoc model found a significant association between grade II versus grade III/IV acute GVHD with day 28 response (odds ratio = 0.15; 95% CI 0.04-0.55; p=0.0042), suggesting acute GVHD grade at therapy onset could be an independent predictor of response.
Across all patients, the 6-month OS was 51% (95% CI 39-62%) and the 12-month OS was 43% (95% CI 30.0-54.6). The median OS was 7.6 months (95% CI 3.1 months to not evaluable). The OS rate was significantly higher for day 28 responders versus nonresponders (p<0.0001) as well as for other responders (p=0.0016). Responders to therapy by day 28 had a relatively high probability of survival at 6 months (73%; 95% CI 56%-85%) and 12 months (66%; 95% CI 48-79%).
According to Dr. Jagasia, most patients who die after response to ruxolitinib have lower gastrointestinal involvement by GVHD, which results in diarrhea and protein loss leading to further severe complications.
At long-term follow-up (median = 323 days for surviving patients), a total of 4 patients developed chronic GVHD after ruxolitinib discontinuation. All patients experienced at least 1 treatment-emergent adverse event (AE), and 75% of patients experienced at least 1 AE attributed to the study drug. The most frequently reported hematologic AEs included:
- anemia (65%)
- thrombocytopenia (62%)
- neutropenia (48%)
According to the study authors, the nonrandomized design and heterogenous definition of steroid-refractory acute GVHD were limitations of the study. Also, the lack of data maturity limits information about long-term survival outcomes and rates of chronic GVHD.
Dr. Jagasia told ASH Clinical News that the next step in this research will be to identify a biomarker or profile that will predict response to ruxolitinib. He suggests that studies could pair ruxolitinib with the MAGIC (Mount Sinai Acute GVHD International Consortium) biomarkers to ask “whether ruxolitinib should be started up front at the onset of GVHD instead of waiting for the disease to become steroid refractory.”
Study authors report relationships with Incyte Corporation, which sponsored this trial.
Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label, phase 2 trial. Blood. 2020 Mar 5. [Epub ahead of print]