Utilizing JAK Inhibition to Treat Acute GVHD

Aaron C. Logan, MD, PhD:I think the REACH1 data and the FDA approval of ruxolitinib are practice changing, primarily because it appropriately makes ruxolitinib the standard of care for salvage therapy for patients who have steroid-refractory or steroid-dependent acute GVHD [graft-versus-host disease]. Prior to this, there was no gold standard. There was no approved agent for the treatment of refractory acute GVHD; and different centers, and even different providers within individual centers would pick between multiple agents hoping to see a response. Now I think we have justification to use ruxolitinib in a fairly standardized manner, but with some awareness that ruxolitinib is associated with some significant potential adverse effects that can affect patient outcomes.

The main toxicities of ruxolitinib when used in this setting are the incidence of cytopenias, which can be quite severe. Ruxolitinib, as a JAK1 and JAK2 inhibitor, is myelosuppressive. A substantial proportion of patients on the REACH1 study, when ruxolitinib was used as standard of care, experienced neutropenia, anemia, and/or thrombocytopenia that can be clinically relevant.

Some patients actually need to have the dose of ruxolitinib reduced, or even have the drug held due to the incidence of neutropenia or severe thrombocytopenia. Some patients may develop infections due to ruxolitinib-induced neutropenia, and this is something that we have identified as a potential adverse event of clinical interest because it can affect patient outcomes.

One thing that providers should be very aware of is that the renal clearance of ruxolitinib is very important. Patients who have impaired renal function, particularly those who become infected or septic and have prerenal azotemia or renal failure associated with sepsis, can develop severe myelosuppression associated with the use of ruxolitinib that can lead to worsening of their clinical status. And so, this is something that providers should be aware of when they’re using this agent, and they should be willing to hold the drug when necessary to let the patient get through the infection. Then, they can bring it back for management of the GVHD at the clinically appropriate time.

The REACH1 study started the dose of ruxolitinib at 5 mg twice daily and allowed escalation to 10 mg twice a day in patients who did not have clinically significant cytopenias. The REACH2 study is actually starting the dose directly at 10 mg twice a day. My clinical practice is generally to start at 10 mg twice a day, except in patients who have vulnerable grafts, meaning they already have low blood counts, or have borderline renal function. In those patients, I will start at 5 mg twice a day, or sometimes even a lower dose, and I’m sensitive to how they react. If they develop significant cytopenias or renal dysfunction, I’ll drop to an even lower dose, such as 5 mg once a day.

Transcript edited for clarity.