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First treatment for graft-versus-host disease is steroids, and in about half of people with chronic disease they do not work or cannot be reduced. Ruxolitinib is the only drug that has beaten the alternatives in a randomised trial here, and it has done so twice. About half of people respond; the common problems are low platelets and low haemoglobin.
Ruxolitinib is a JAK1 and JAK2 inhibitor. Its label states that it is indicated for steroid-refractory acute graft-versus-host disease in adult and paediatric patients 12 years and older, and for chronic graft-versus-host disease after failure of one or two lines of systemic therapy in the same age group. Those two indications rest on the two REACH trials, which are the only randomised phase 3 trials to have shown superiority over best available therapy in either setting.
REACH2, acute disease. 309 patients aged 12 or older with glucocorticoid-refractory acute GvHD were randomised to ruxolitinib 10 mg twice daily or the investigator's choice from a list of nine commonly used options. Overall response at day 28 was 62 per cent against 39 per cent (odds ratio 2.64, 95 per cent CI 1.65 to 4.22, P less than 0.001). Durable overall response at day 56 was 40 per cent against 22 per cent. Cumulative incidence of loss of response at six months was 10 per cent against 39 per cent. Median failure-free survival was 5.0 months against 1.0 month (hazard ratio 0.46, 95 per cent CI 0.35 to 0.60). Median overall survival was 11.1 months against 6.5 months, with a hazard ratio for death of 0.83 (95 per cent CI 0.60 to 1.15), which crosses one: the trial improved response and failure-free survival and did not demonstrate a survival difference. The commonest adverse events to day 28 were thrombocytopenia in 33 per cent against 18 per cent, anaemia in 30 per cent against 28 per cent and cytomegalovirus infection in 26 per cent against 21 per cent.
REACH3, chronic disease. The trial states in its own background that chronic GvHD becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50 per cent of patients, and that robust data from phase 3 randomised studies evaluating second-line therapy were lacking. 329 patients aged 12 or older with moderate or severe glucocorticoid-refractory or dependent chronic GvHD were randomised to ruxolitinib 10 mg twice daily or the investigator's choice from a list of ten options. Overall response at week 24 was 49.7 per cent against 25.6 per cent (odds ratio 2.99, P less than 0.001). Median failure-free survival was longer than 18.6 months against 5.7 months (hazard ratio 0.37, P less than 0.001). Symptom response on the modified Lee Symptom Scale was 24.2 per cent against 11.0 per cent (odds ratio 2.62, P = 0.001). Grade 3 or higher thrombocytopenia occurred in 15.2 per cent against 10.1 per cent and anaemia in 12.7 per cent against 7.6 per cent, and the incidence of cytomegalovirus infection and reactivation was similar in the two groups.
What that adds up to. In chronic disease, half of people treated had a measurable response at six months and a quarter felt meaningfully better on a scale they filled in themselves; the gap between those two numbers is itself worth knowing, because a response on the organ scores and a change a person notices are not the same thing. In acute disease the response rate was higher and the effect on survival was not established. The toxicity is predictable from the mechanism: JAK1 and JAK2 inhibition suppresses the cytokine signalling that drives both GvHD and normal haematopoiesis, so platelets and haemoglobin fall, and counts have to be watched and the dose adjusted.
Ruxolitinib does not cure chronic GvHD and it is not a short course. Treatment runs for months to years, tapering is slow, and relapse of GvHD on withdrawal is common. The reason it is graded strong here is narrow and specific: two randomised phase 3 trials against active comparators, both positive on their primary endpoints, with a label in both settings. Everything else offered for steroid-refractory chronic GvHD rests on weaker evidence, which is the subject of the next record.
Interferon-gamma and interleukin-6 signalling through JAK1 and JAK2 drives T cell differentiation, antigen presentation and tissue chemokine production in both acute and chronic GvHD. Blocking the kinases downstream of several cytokine receptors at once suppresses the alloreactive response more broadly than blocking a single cytokine, and also reduces regulatory T cell signalling and normal myelopoiesis, which is the source of the cytopenias.
Donor bone marrow stromal cells given to children whose acute graft-versus-host disease no longer responds to steroids, the first mesenchymal stromal cell therapy approved in the United States.
Query for this technology: (TITLE:"When steroids fail: ruxolitinib for steroid-refractory GvHD" OR ABSTRACT:"When steroids fail: ruxolitinib for steroid-refractory GvHD" OR TITLE:"REACH2" OR ABSTRACT:"REACH2" OR TITLE:"REACH3" OR ABSTRACT:"REACH3" OR TITLE:"steroid-refractory GvHD" OR ABSTRACT:"steroid-refractory GvHD") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about When steroids fail: ruxolitinib for steroid-refractory GvHD, not a curated reading list.
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