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Graft-versus-host disease (GVHD) is one of the main reasons affecting long-term survival and quality of life in post-transplant patients, and in March 2022, the European Medicines Agency's Commission on Human Medical Products recommended the approval of rusotinib for the treatment of patients with acute or chronic GVHD.
Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and has become a major factor affecting the long-term survival and quality of life of patients after transplantation.
In March 2022, the European Medicines Agency's Committee on Human Medical Products recommended ruxolitinib (Jakafi) for the treatment of acute or chronic graft-versus-host disease (GVHD) patients aged 12 years and older who do not respond adequately to corticosteroids or other systemic therapy.
Specifically, data from REACH2 showed that at day 28, the overall response rate (ORR) of rusotinib was 62.3%, compared to 39.4% for BAT. Among patients who still responded to treatment on day 56, the ORRs in the rusotinib and control groups were 40% and 22%, respectively.
The results of the REACH3 study showed that at week 24, rusotinib showed better ORR in patients with steroid-refractory or dependent chronic GVHD, with orR in the rusotinib group and 25.6% in the control group, respectively. In the rusotinib group and the control group, 76.4% and 60.4% of patients observed the optimal overall response rate (BOR) at any time prior to week 24, respectively.
REACH2 study data
REACH2 recruited patients with GVHD aged 12 years and older and randomly divided the patients into two groups on a 1:1 ratio. Patients in the rusotinib group (n =154) 10 mg of rusotinib orally twice a day. The control group (n =155) accepted the BAT selected by the researchers, which may include: antiplatelet globulin, in vitro phototherapy, interstitial cells, low-dose methotrexate, mycophenolates, everolimus (Afinitor) or sirolimus (Rapamune), etanercept (Enbrel), or infliximab (Remicade).
The primary endpoint of the trial was the overall response rate at day 28 and the key secondary endpoint was the overall response rate at day 56. Other secondary endpoints included duration of remission, BOR, failure-free survival (FFS), overall survival (OS), and cumulative glucocorticoid use prior to day 56. The study also assessed safety.
34% of patients in the rusotinib group had a complete response to treatment (CR), compared with 19% in the control group. It has been proven that in patients with grade II acute GVHD at baseline, the response rate with rusotinib was 75%, the response rate with BAT was 51%, and in patients with grade III disease, the response rate was 56% and 38%, respectively. In patients with grade IV acute disease at baseline, the response rate with rusotinib was 53% and with BAT was 23%.
REACH3 experimental data
REACH3 recruits patients 12 years of age and older who have undergone allogeneic stem cell transplantation and have moderate or severe glucocorticoid refractory or dependent chronic GVHD.
Patients were randomized on a 1:1 ratio and received 10 mg of rusotinib (n = 165) twice daily, or therapies of the investigator's choice (n = 164), which may include in vitro phototherapy, low-dose methotrexate, mycophenolate, mTOR inhibitors, infliximab (Remsimab), rituximab (Rituxan), pentostatin (Nipent), Imatinib (Gleevec, Gleevec, Gleevec) or ibnotinib (Imbruvica, Ibrutix).
The primary endpoint for REACH3 was the overall response rate at week 24, and the 2 key secondary endpoints included FFS and week 24 response to the modified Lee symptom scale. Other endpoints included subgroup analysis of the overall response rate, response in individual organs, BOR at any time prior to week 24, DOR, changes in glucocorticoid dose over time, OS, changes in quality of life, and safety.
Data are cut to May 8, 2020, with a median follow-up of 57.3 weeks. Other data published in the New England Journal of Medicine showed that 6.7 percent of patients treated with rusotinib received CR and 3.0 percent of patients treated with BAT received CR.
Compared with the control group, the rusotinib group had a longer FFS, with median FFS of 5.7 months and 18.6 months, respectively. Within 12 months, the rusotinib group had a higher probability of sustained remission at 68.5% compared to 40.3% in the control group.
61 patients who switched from the control group to the study group also experienced a response, with BOR at the data cut-off rate of 78.7 percent; this included 4 cases of CR and 44 cases of PR.
No mature OS data were found at the data cut-off, and the 12-month OS in the rusotinib group was expected to be 81.4% and the control group to be 83.8%.
History of rusotinib approval (ruxolitinib, Jakafi)
Rusotinib is an oral inhibitor of Janus kinase 1 and Janus kinase 2 (JAK1/JAK2).
In 2011, the FDA approved rusotinib for the treatment of patients with medium- and high-risk myelofibrosis.
In December 2014, the FDA approved rusotinib for hydroxyurea intolerant or drug-resistant patients with polycythemia vera.
In June 2016, the FDA granted rusotinib a Breakthrough Drug (BTD) for the treatment of acute graft-versus-host disease (GVHD).