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NEW YORK (Reuters Health) – When chronic graft-versus-host disease (GVHD) follows an allogeneic stem-cell transplant, and it’s either resistant to standard glucocorticoid therapy or dependent on glucocorticoids, ruxolitinib is better than other treatment options, according to results of the open-label REACH3 trial.
“The first drug shown to be superior to best available therapy in a randomized phase-3 trial as second line therapy for chronic GVHD is ruxolitinib,” chief author Dr. Rober Zeiser told Reuters Health by email. “This is reassuring for cGVHD patients.”
The control group included 164 patients who received any of 10 conventional therapies to fight a moderate or severe case of the deadly inflammatory response. The choice of control therapy was based on the judgment of investigators at the time of randomization.
The 24-week response rate was 25.6% in the control group and 49.7% for the 165 volunteers randomly assigned to receive 10 mg of ruxolitinib twice daily (P<0.001).
Median failure-free survival was 5.7 months in the control group versus 18.6 months with the drug (P<0.001).
The drug also produced a higher symptom response.
“I expected the difference to be less impressive,” said Dr. Zeiser, director of the Division of Tumor Immunology at Freiburg University Medical Center in Germany. For patients who can tolerate it and do not have a contraindication to ruxolitinib, it should become the new standard of care “until another phase-3 trial can show similar results for another drug.”
Thrombocytopenia of grade 3 or higher was significantly more common in the ruxolitinib group (15.2%) than in the control group (10.1%). Anemia of grade 3 or higher was also more common, surfacing in 12.7% and 7.6%, plavix side effects respectively.
Details of the study, known as REACH3, appear in the New England Journal of Medicine. The findings were also unveiled at December’s virtual American Society of Hematology Annual Meeting and Exposition. Novartis and Incyte, which sell the drug under the brand names Jakavi and Jakafi, funded the trial.
After first-line steroid treatment for GVHD is initiated, it becomes glucocorticoid refractory or glucocorticoid dependent in about half the cases. In glucocorticoid-dependent GVHD, the condition becomes worse every time doctors try to reduce the steroid dose, requiring an even higher dose and further increasing the risk of side effects such as diabetes, bone fractures, ulcers, infection and hypertension. At that point, treatment options become limited.
The new study was done at 149 centers in 28 countries.
The treatments covered at least six 28-day cycles. When patients in the control group could not maintain a complete or partial response, or the side effects were too bad, or if they had a flare of chronic GVHD, they could switch to ruxolitinib on or after the 24th week. Ultimately, 37% of them did.
The most common control treatments were extracorporeal photopheresis (ECP, used in 35% of cases), mycophenolate mofetil (used in 22%), and ibrutinib (used in 17%).
At week 24, 7% of ruxolitinib recipients had a complete response and 43% had a partial response. The respective rates in the control group were 3% and 23%.
“Among patients with a response at any time, the estimated probability of maintaining a response at 12 months was 68.5% in the ruxolitinib group as compared with 40.3% in the control group,” the researchers report.
However, there was no statistically significant difference in survival, at least at 12 months.
“We still follow these patients to understand what the long-term effect of the high response rate is,” said Dr. Zeiser.
Cancer relapse occurred within six months in 3% of both groups.
Although the side effects seen in the study were expected, the researchers saw a higher risk of fungal infections among the ruxolitinib recipients. Thus, “patients treated with ruxolitinib should receive prophylaxis against infection, and a low threshold for evaluation of new signs and symptoms should be adopted,” they say.
After a median follow-up of just over 57 weeks, half the ruxolitinib recipients had discontinued their treatment. In 14.5% of the cases it was because it wasn’t working, in 17% it was due to side effects and in 5.5% it was attributed to underlying disease. Three-quarters of volunteers receiving control therapies discontinued them.
Of the 10 other treatments available to the control group, ECP and mycophenolate mofetil produced the best response, but their overall response rates were about 30% compared with 49% in the ruxolitinib arm.
Last year, Dr. Zeiser and his colleagues published REACH2 data in the New England Journal showing that ruxolitinib was superior to other therapies for steroid-refractory acute GVHD, which is mediated by T cells and progresses rapidly, leading to death in about 80% of patients after one year.
Chronic GVHD progresses much more slowly, often taking months to develop, said Dr. Zeiser.
“Most patients with chronic GVHD don´t die but their quality of life is terrible,” he said. “They suffer from skin stiffness, local inflammation, wasting syndrome etc. The disease is mediated mainly by B cells, macrophages and fibroblasts.”
SOURCE: https://bit.ly/3hTPGaJ The New England Journal of Medicine, online July 14, 2021.
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