JAK inhibitor success in steroid-refractory GVHD

Ruxolitinib treatment in patients with grade II to IV glucocorticoid-refractory acute GVHD results in a significantly higher overall response than control therapies, an international phase 3 study shows.

The positive results represent a major advance in managing the difficult-to-treat sequelae of allogeneic stem cell transplantation, according to the study investigators.

The REACH2 trial comprised 309 patients from 12 years of age, recruited from 105 treatment centres across 22 countries including Australia.

Patients were randomised to either oral ruxolitinib (10mg twice daily) or one of nine investigator-chosen control therapies such as antithymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, a mammalian target of rapamycin (mTOR) inhibitor (everolimus or sirolimus), etanercept or infliximab.

The study found patients treated with the JAK inhibitor had a significantly higher overall response at 28 days (62.3% v 39.4%; p<0.001) and at 56 days (39.6% v 21.9%; p<0.001).

The odds ratio for response to ruxolitinib compared to control was highest in patients with grade IV acute GVHD (OR 3.76).

The estimated loss of response after six months was 10% with ruxolitinib compared to 39% with control therapy and the median failure-free survival was 5.0 months with the JAK inhibitor versus 1.0 month for controls.

The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group.

Treatment discontinuation was high in both groups (72% v 85%) with the most common reason being lack of efficacy. Adverse events were also common in both groups (95% v 93%).

Thrombocytopenia was the most common adverse event and more common with ruxolitinib than other interventions (33% v 18% for any grade disease; 27% v 15% for grade III disease or higher).

An accompanying editorial in NEJM said ruxolitinib may work on JAK-mediated signalling in neutrophils, macrophages or dendritic cells.

“Although the mechanism of initial JAK–STAT (signal transducer and activator of transcription) signalling is relatively simple in theory, the downstream interactions and the cross talk are just beginning to be dissected further since these signaling cascades are complex, interact at various levels (enhancing or blocking responses), and differ among types of immune cells.”

“Given the effect of ruxolitinib in controlling glucocorticoid-refractory GVHD, it is interesting that the incidence of infectious complications or relapse was apparently not greater with ruxolitinib than with control therapy, but the total follow-up time was short,”

“Thus, as with all good research, these observations raise important questions and set the stage for further work in this area.”

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