The success of allogeneic stem cell transplantation (allo-SCT) is limited by the development of graft-versus-host disease (GvHD), which occurs in up to 50% of patients, even with immunosuppressive prophylactic treatment. Despite a better understanding of the disease biology, acute GvHD (aGvHD) is still a significant cause of mortality and only half of patients respond to first-line treatment with corticosteroids.
The recent approval of ruxolitinib for use in treating adult and pediatric patients with steroid refractory GvHD has catered to an unmet need in GvHD therapy for treatment options beyond corticosteroids. As a result, Mohamad Mohty, chair of the GvHD Hub Steering Committee, and colleagues published an article in Blood to define the patient population that can now be considered ruxolitinib-refractory, in order to support the sequencing of therapies in patients with aGvHD.1
Use of ruxolitinib in the treatment of corticosteroid-refractory aGvHD
Following the results of the REACH1 trial (NCT02953678), ruxolitinib was approved for the treatment of corticosteroid-refractory adult and pediatric patients ≥ 12 years of age with aGvHD. This study showed an overall response rate (ORR) of 55%, with 27% of patients achieving a complete response after 28 days. For more details see the article on the GvHD Hub here.
Defining ruxolitinib-refractory aGvHD
In the REACH2 (NCT02913261) phase III randomized trial, ruxolitinib was compared with the best available therapy for treating patients with corticosteroid-refractory aGvHD. The summary of this trial can be found here on the GvHD Hub. Although the ORR at Day 28 was higher in the ruxolitinib group than in the control group, 38% of patients did not achieve a complete or partial response at this time point. At Day 56, the ORR was down to 40%, showing there is a need for novel therapies to treat patients who are refractory to ruxolitinib.
As ruxolitinib has become an established second-line standard salvage therapy for corticosteroid-refractory aGvHD, it is necessary to have a unified definition to aid the comparison of new third-line treatments. Mohty et al. suggest defining ruxolitinib-refractory aGvHD as
- progression of GvHD compared to baseline after at least 5–10 days of treatment with ruxolitinib, based either on objective increase in stage/grade, or new organ involvement;
- lack of improvement in GvHD (partial response or better) compared to baseline after at least 14 days of treatment with ruxolitinib; or
- loss of response, defined as objective worsening of GvHD determined by increase in stage, grade, or new organ involvement at any time after initial improvement.
This definition was created based on the information from the REACH1 and REACH2 trials along with retrospective studies showing that 10–14 days was the median time to initial response following the start of ruxolitinib treatment in patients with steroid-refractory aGvHD. A social media survey of hematologists was performed to assess how soon physicians would consider alternative treatment in patients treated with ruxolitinib that showed no improvement: 13% would consider it after only 7 days, while 12% and 40% said they would wait at least 10 days and 14 days, respectively. The remaining 35% would let at least 21 days pass before considering alternate treatment opinions.
The working definition should aid clinicians in identifying patients with ruxolitinib-refractory GvHD and will guide the design of treatment plans as well as study protocols for clinical trials investigating third-line therapies for this group. This current definition is a starting point but may need to be refined following the results from these clinical trials. In addition, the working definition may also serve as a basis for better defining the lack of improvement in intestinal symptoms compared with changes in skin or liver involvement that can happen within a week.