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8h
ROCK2 inhibition in steroid-refractory chronic GvHD: real-world outcomes, risk stratification, and corticosteroid-sparing evidence

Chronic graft-versus-host disease (cGvHD) is a leading cause of late morbidity and non-relapse mortality following allogeneic hematopoietic stem cell transplantation. Steroid-refractory cGvHD carries poor prognosis, demanding effective targeted salvage strategies.

A selective ROCK2 inhibitor with immunomodulatory and antifibrotic properties demonstrated durable efficacy in a multicenter Canadian real-world study of 46 heavily pretreated steroid-refractory cGvHD patients: best overall response rate 52%, 12-month failure-free and overall survival 64.3% and 91.1%, respectively. Corticosteroid discontinuation was achieved in 73% by 12 months. A prognostic risk model stratifying by prior acute GvHD and organ involvement (≥4 organs) identified distinct 12-month failure-free survival rates of 100%, 75.8%, and 30% for zero, one, and two risk factors (HR 3.91; p=0.003), informing patient selection and therapeutic sequencing.

Hematologists, transplant physicians, and immunologists managing steroid-refractory cGvHD will benefit from peer discussion of ROCK2 inhibitor evidence, risk-stratified patient selection, combination therapy, and corticosteroid-sparing strategies.

How do you use organ involvement, prior acute GvHD history, and prior JAK inhibitor exposure to guide patient selection and sequencing when initiating ROCK2 inhibitor therapy in steroid-refractory cGvHD? What clinical response milestones guide your decisions to continue, adjust, or discontinue targeted therapy in steroid-refractory cGvHD, and how do you approach non-responders?

  • 8h
    In steroid refractory patients, tend to use ROCK2 but challenge due to authorization restrictions and usually first utilizing Ruxolitinib as well as ibrutnib and axatilimab. Choice based on multiple factors including drug interaction.
  • 1w
    Belumosudil is a ROCK2 inhibitor FDA-approved for cGvHD after failure of at least two prior lines of systemic therapy, so its formal positioning is third-line or later.
    It is a category 2A option under the NCCN Hematopoietic Cell Transplantation guidelines, alongside ibrutinib and axatilimab.
    Ruxolitinib remains the category 1 (preferred) agent for steroid-refractory cGvHD based on REACH3, so most patients reach belumosudil after ruxolitinib exposure.
    [3Selection is individualized: the NCCN explicitly states there is insufficient evidence to prefer one agent, and choice should be based on organ involvement, prior treatment effect, toxicity profile, drug interactions, accessibility, and tolerability.
  • 2w
    Would use ROCK2 earlier in the process in steroid refractory. More likely to use overall.
    Non-responders are a challenge and often require combination therapy
  • 3w
    consider a ROCK2 inhibitor for patients with steroid-refractory chronic GvHD based on the extent of organ involvement, prior acute GvHD, previous treatments (including JAK inhibitors), overall health, and treatment goals. I monitor improvements in symptoms, organ function, steroid reduction, and quality of life to assess response. If patients respond, I continue therapy while tapering corticosteroids when possible. For non-responders or those with disease progression, I reassess the diagnosis, evaluate alternative targeted therapies or clinical trials, and individualize the next treatment approach.
  • 3w
    The ROCK agents focus more on fibrotic disease. So, organ involvement and pattern of GVHD may make this agents more attractive in certain patterns of GVHD. Non steroid responders may show a more fibrotic vs inflammatory pattern and that is , perhaps, the main decision point on what to use 2nd line

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