Ruxolitinib refractoriness in severe aGvHD: The 2026 definition

The updated working definition of ruxolitinib refractoriness in severe acute graft-versus-host disease (aGvHD) was published by Malard et al. in Bone Marrow Transplantation. The 2026 definition is a revision of the 2020 framework to reflect evolving clinical practice, particularly in high-risk gastrointestinal (GI) aGvHD. Rapid disease worsening, escalating severity at presentation, and increasing availability of third-line therapies make earlier declaration of refractoriness both clinically rational and necessary to avoid irreversible organ damage.

Key data: The 2026 definition introduces a risk-adapted approach with three refractoriness criteria: 1) aGvHD progression after 5 days of ruxolitinib; 2) lack of improvement in aGvHD after ≥7 days in high-risk patients (defined by Stage III–IV GI aGvHD, Stage IV skin or liver aGvHD, Eastern Cooperative Oncology Group [ECOG] performance status 3–4, and/or impaired nutritional status) and 14 days in standard-risk patients; and 3) loss of response at any time after initial improvement. The 2026 definition also includes a more detailed definition of Stage IV disease worsening, including emergence of additional Stage IV GI aGvHD symptoms (severe abdominal pain, ileus and/or hematochezia).

Key learning: A risk-adapted definition of ruxolitinib refractoriness in aGvHD, with shorter time-to-declare thresholds in high-risk patients, may better align trial eligibility with clinical urgency and support earlier escalation to third-line therapies in patients with the most severe aGvHD presentations.