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GVHD: Current and Future
My Thoughts on Current and Future Prophylactic and Therapeutic Strategies for GVHD

Released: April 27, 2021

Expiration: April 26, 2022

Corey Cutler
Corey Cutler, MD, MPH, FRCPC
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We are entering a new phase in graft-vs-host disease (GVHD) prevention and treatment. Having several new compounds for therapy of steroid-resistant or advanced disease is crucial, but more important are the advances that we are making in preventing both acute and chronic GVHD and bringing these new therapies to the frontline setting rather than waiting for patients to become resistant or refractory to steroids.

There are currently several randomized, controlled trials that will inform the future of how we manage both acute and chronic GVHD. In acute GVHD, the JAK1/2 inhibitor ruxolitinib is the current standard of care in frontline steroid-resistant settings with which future therapeutics will need to be compared. We are now approaching upfront therapy with renewed enthusiasm. Newer JAK inhibitors and agents that prevent T-cell trafficking to target sites of disease or T-cell activation are currently being tested. If these agents are active, they will certainly move into the prevention or steroid-naive setting where we are currently testing additional strategies such as costimulation blockade.

We also are using novel prophylactic strategies for graft manipulation. Having recently learned that pan–T-cell depletion is not likely to be an effective strategy based on randomized trials, we are now considering selective depletion of T-cell subsets, which might prove more useful. Also, antithymocyte globulin continues to be explored as a prophylactic agent in North America, whereas it is a standard of care in much of Europe.

Clinical Trials in the Acute GVHD Setting
Ongoing clinical trials are exploring strategies that will minimize steroid exposure. One important study is the multicenter, randomized phase II BMT CTN 1501 trial. This trial enrolled 127 patients with newly diagnosed and untreated, standard-risk acute GVHD and compared sirolimus with prednisone as monotherapy. Sirolimus was given at a loading dose of 6 mg orally once daily for patients aged older than 12 years and 5 mg/m2 orally once daily for patients aged 12 years or younger. This was followed with a maintenance dose targeting a serum trough level of 10-14 ng/mL until acute GVHD resolution and then 5-10 ng/mL after resolution up to Day 56. Prednisone was administered at 2 mg/kg/day and that dose was maintained for at least 3 days. The primary endpoint was combined complete response (CR) and partial response (PR) rates, and the secondary endpoint was CR/PR with a prednisone dose of ≤0.25 mg/kg/day. In this setting, sirolimus had efficacy approximately equivalent to corticosteroids. The Day 28 CR/PR rate for sirolimus was 64.8% compared with 73.0% for prednisone. The Day 28 CR/PR rate with ≤0.25 mg/kg/day of prednisone was 66.7% for sirolimus vs 31.7% for prednisone (P <.001). This trial is ushering in a new strategy of steroid-free regimens for the treatment of acute GVHD.

Ongoing Clinical Trials in the Chronic GVHD Setting
Regarding chronic GVHD, we now have several compounds with marked efficacy. Ibrutinib was approved in 2017, and we anticipate that before the end of 2021, 2 additional agents will be approved for steroid-resistant chronic GVHD.

In the multicenter, open-label, randomized phase III REACH3 TRIAL, ruxolitinib was compared with best available therapy (BAT) in patients (N = 329) with severe steroid-refractory/dependent chronic GVHD and evidence of myeloid engraftment, with absolute neutrophil count >1000/mm3 and platelets >25,000/mm3. The investigator’s choice of therapies included extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, everolimus, sirolimus, infliximab, rituximab, pentostatin, imatinib, or ibrutinib. The primary endpoint for the REACH3 trial was the overall response rate (ORR) at 6 months, and key secondary endpoints were failure-free survival (FFS) and modified Lee symptom score (mLSS) at 6 months. Patients received either ruxolitinib 10 mg twice daily or BAT in the primary efficacy period of 6 months, and treatment could be administered for up to 3 years. Patients receiving ruxolitinib had an ORR of 49.7% compared with 25.6% in the BAT arm (odds ratio: 2.99; 95% CI: 1.86-4.80; P <.0001). Of the responders in the ruxolitinib arm, 6.7% had a CR and 43.0% had a PR vs 3.0% and 22.6%, respectively, in the BAT arm. Median FFS for the ruxolitinib arm was not reached vs 5.7 months for the BAT arm (HR: 0.370; 95% CI: 0.268-0.510; P <.0001). Among the patients treated with ruxolitinib, 24% had an improvement in symptoms by mLSS compared with only 11% of those treated with BAT (odds ratio: 2.62; 95% CI: 1.42-4.82; P = .0011) Together, these data show that ruxolitinib is superior to the current standard of care in this setting, and we anticipate approval in 2021.

Another promising agent is the ROCK2 inhibitor belumosudil, formerly known as KD025. In the multicenter, open-label, randomized phase II ROCKstar trial, belumosudil 200 mg was administered daily or twice daily to patients (N = 132) with chronic GVHD after allogeneic stem cell transplantation and 2-5 lines of systemic therapy. The primary endpoint was ORR, and key secondary endpoints were safety, duration of response, FFS, and overall survival. The ORR for those receiving belumosudil once daily was 73% and 77% for twice-daily belumosudil, and responses were observed across all subgroups. Median duration of response was 50 weeks, and 60% of patients maintained a response for more than 20 weeks. Overall survival was 90% (95% CI: 82%-93%), and FFS was approximately 58% at 12 months. The most common adverse events were fatigue (38%), diarrhea (33%), and nausea (28%). With these results, we anticipate approval in 2021 for this agent as well.

Another drug of interest currently being tested in chronic GVHD is axatilimab, a CSF1R antagonist being investigated in a phase I trial in patients with chronic GVHD and a history of ≥2 lines of systemic therapy. In addition to agents for steroid-refractory disease, we are considering some of the newer compounds to the upfront setting to test them against the use of corticosteroids to minimize steroid toxicity. Strategies are also being developed to prevent chronic GVHD near the time of transplantation, as with the posttransplant cyclophosphamide regimen, or with novel agents that are given prophylactically in the posttransplant setting before the clinical appearance of chronic GVHD.

Conclusion
We have come a long way with our supportive care of patients with acute and chronic GVHD. Recognizing that the complete management of GVHD includes supportive care of individual organs with local immunosuppressive and supportive measures, I look forward to the continued evolution of GVHD management with new treatment strategies in prophylaxis and the acute and chronic settings.

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