Ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, bested control therapies among patients with moderate or severe chronic graft-versus-host disease (GVHD) whose disease did not adequately respond to glucocorticoids, an analysis of the results from the REACH3 trial found.
“REACH3 is a phase III randomized trial that showed the superiority of ruxolitinib over common second-line therapeutic options, including ibrutinib and extracorporeal photopheresis, for treatment of glucocorticoid-refractory or -dependent chronic GVHD,” Robert Zeiser, MD, from the department of Medicine I, Faculty of Medicine, Medical Center, University of Freiburg, in Germany, and colleagues reported in The New England Journal of Medicine. “Ruxolitinib led to a higher overall response than control therapy at week 24 (49.7% versus 25.6%), regardless of the organs involved, and a higher best overall response (76.4% versus 60.4%), a longer duration of response, and longer failure-free survival.”
As Zeiser and colleagues pointed out, GVHD “is a serious complication of allogeneic stem-cell transplantation that limits the success of the procedure.” About 30%-70% of patients who undergo allogeneic stem-cell transplantation experience chronic GVHD “and [it] is a leading cause of complications and of nonrelapse-associated death.” Moreover, they noted that “patients with chronic GVHD have impaired physical, social, psychological, and general quality of life, which worsened with disease severity.”
While glucocorticoids are the usual first-line treatment for GVHD, about 50% of patients are “glucocorticoid-refractory or glucocorticoid-dependent, greatly increasing the risk of poor outcomes.” Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is currently the only treatment approved in the U.S. and Canada as a second-line treatment for GVHD, but, as the study authors pointed out, there is no definitive second-line treatment backed by large, randomized-controlled trials, and treatment is dependent on treatment center protocol.
“Although guidelines provide several treatment options, including extracorporeal photopheresis and mycophenolate mofetil, enrolling patients into clinical trials is recommended,” Zeiser and colleagues wrote.
REACH3 randomized 329 patients to either ruxolitinib, 10 mg, twice daily (n=165), or a therapy of the investigator’s choice (n=164). The investigators could choose from a list of 10 therapies that included extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, a mammalian target of rapamycin (mTOR) inhibitor (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, or ibrutinib.
The patients included in the trial were age 12 or older with moderate or severe glucocorticoid-refractory or glucocorticoid-dependent GVHD. Those who had a partial or complete response to JAK inhibitors prior to the trial or those who discontinued JAK therapy at least 8 weeks prior to the trial were included, but those “treated previously with 2 or more systemic therapies for chronic GVHD in addition to glucocorticoids with or without calcineurin inhibitors were ineligible,” Zeiser and colleagues wrote. “Patients were excluded if they had a relapse of the primary cancer or had graft loss within 6 months before treatment initiation or if they had an active, uncontrolled infection.”
The trial’s primary endpoint was complete or partial response at week 24, with failure-free survival and improved score on the modified Lee Symptoms Scale at week 24 as the key secondary endpoints. Failure-free survival was “defined as time to recurrence of underlying disease, start of new systemic treatment for chronic GVHD, or death, whichever came first,” the study authors noted.
Most of the patients in the trial were men and the median age of the patients was 49 (range 12-76 years). Less than half of the patients (42.9%) had moderate chronic GVHD; more than half (56.5%) had severe chronic GVHD; and the majority (71.4%) had glucocorticoid-refractory chronic GVHD, with 28.6% having glucocorticoid-dependent disease.
“Control therapy was primarily extracorporeal photopheresis (34.8%), mycophenolate mofetil (22.2%), and ibrutinib (17.1%),” Zeiser and colleagues wrote. “Approximately half the patients received calcineurin inhibitors during the trial.”
Among the trial’s results at 24 weeks:
- The patients in the ruxolitinib group had a greater overall response rate at week 24 than in the controls—49.7% versus 25.6%; odds ratio, 2.99; P<0.001—regardless of organs involved.
- There was a 76.4% overall response in the ruxolitinib group versus 60.4% in the controls (P=0.001).
- A complete response was seen in 11 patients (6.7%) in the ruxolitinib group versus 5 patients (3.0%) in the control groups.
- There was a longer median failure-free survival in the ruxolitinib group at >18.6 months versus 5.7 months in the control group (HR 0.37; 95% CI, 0.27-0.51; P<0.001).
- The modified Lee Symptom Scale score was higher in the ruxolitinib group than in the control group—24.2% versus 11.0%; odds ratio, 2.62 (95% CI, 1.42 to 4.82); risk ratio, 2.19 (95% CI, 1.31 to 3.65); P=0.001).
- There was a decrease in glucocorticoid dose in both groups, although it was slightly greater in the ruxolitinib group.
- Best overall response was seen in 76.4% of the patients in the ruxolitinib group versus 60.4% in the controls.
- 97.6% of patients in the ruxolitinib group versus 91.8% of the controls experienced adverse events of any grade.
- ≥10% of patients had adverse events of grade 3 or higher and included thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively).
- Cytomegalovirus infection and reactivation was similar in both groups.
- 37.6% of patients treated with ruxolitinib experienced adverse events that led to dose modifications compared with 16.4% of controls.
“The absence of a strong end point, such as glucocorticoid-free remission, and the presence of confounders, including concomitant treatments, make determination of the effect on glucocorticoid dose over time with ruxolitinib as compared with commonly used therapies difficult,” Zeiser and colleagues wrote. “However, patients treated with ruxolitinib had consistent reductions in glucocorticoid dose over time, suggesting a glucocorticoid sparing effect, a finding in line with previous observations.”
Study limitations include its open-label design.
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Ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, bested control therapies among patients with moderate or severe chronic graft-versus-host disease whose disease did not adequately respond to glucocorticoids, an analysis of the results from REACH3 trial found.
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The REACH3 trial showed that ruxolitinib was superior to common second-line therapeutic options, including ibrutinib and extracorporeal photopheresis, for treatment of glucocorticoid-refractory or -dependent chronic GVHD.
Candace Hoffmann, Managing Editor, BreakingMED™
The REACH 3 trial was funded by Novartis and Incyte.
Zeiser reports personal fees from Novartis, personal fees from Incyte, personal fees from MNK Mallinckrodt, outside the submitted work.
Cat ID: 118
Topic ID: 78,118,730,118,119,466,192,925
