Low-dose ruxolitinib for graft-versus-host disease prevention in haploidentical haematopoietic stem-cell transplantation: a multicentre, open-label, randomised, controlled, phase 3 trial.
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BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haploidentical haematopoietic stem-cell transplantation (HSCT). Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor with established activity in steroid-refractory GVHD, has shown promise for prophylaxis in early studies, but there is little evidence from randomised trials in the haploidentical HSCT setting. We investigated whether, within a backbone of antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, replacing mycophenolate mofetil with low-dose ruxolitinib could reduce acute GVHD after haploidentical HSCT. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial conducted at five centres in China, eligible patients were aged 12-70 years, had haematological malignancies for which allogeneic HSCT was indicated, had a Karnofsky performance status of at least 70 or a Lansky score of at least 70 for patients younger than 16 years, and were undergoing their first myeloablative haploidentical HSCT. Patients were randomly assigned (1:1) to receive antithymocyte globulin, a calcineurin inhibitor, short-course methotrexate, and low-dose ruxolitinib, or standard prophylaxis with antithymocyte globulin, a calcineurin inhibitor, short-course methotrexate, and mycophenolate mofetil. Randomisation was stratified by centre and patient age (<40 years vs ≥40 years) using computer-generated permuted blocks with random block sizes. Oral ruxolitinib was started on day 1 at 5 mg twice daily for patients weighing at least 50 kg and 5 mg once daily for those weighing less than 50 kg, continued up to day 60, and then tapered to day 90 in the absence of grade II-IV acute GVHD. The primary endpoint was the cumulative incidence of grade II-IV acute GVHD by day 100. Efficacy and safety were analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of the assigned prophylaxis, excluding those with major protocol deviations. This trial is registered with ClinicalTrials.gov, NCT04838704, and is complete. FINDINGS: Between April 1, 2021, and Dec 28, 2023, 215 patients were randomly assigned, of whom 206 were included in the modified intention-to-treat population (103 in the ruxolitinib prophylaxis group and 103 in the standard prophylaxis group). The median recipient age was 40 years (IQR 24-48), 98 (48%) patients were female and 108 (52%) were male, and all participants were Chinese. Among surviving patients, the median follow-up was 26·4 months (IQR 20·0-33·3). By day 100, grade II-IV acute GVHD occurred in seven (cumulative incidence of 6·8% [95% CI 1·9-11·7]) of 103 patients in the ruxolitinib prophylaxis group and 38 (36·9% [27·5-46·3]) of 103 patients in the standard prophylaxis group (subdistribution hazard ratio 0·15, 95% CI 0·07-0·34; p<0·0001). The most common grade 3-4 adverse events in the ruxolitinib prophylaxis group and the standard prophylaxis group were thrombocytopenia (17 [17%] vs 11 [11%]), neutropenia (14 [14%] vs 9 [9%]), anaemia (12 [12%] vs 9 [9%]), and cystitis (7 [7%] vs 10 [10%]). Serious adverse events occurred in 31 (30%) patients in the ruxolitinib prophylaxis group and 36 (35%) patients in the standard prophylaxis group. No fatal adverse events occurred in the ruxolitinib prophylaxis group. Three deaths occurred in the standard prophylaxis group: pulmonary infection (n=1), sepsis, bacteraemia, or fungaemia (n=1) and transplant-associated thrombotic microangiopathy (n=1). No deaths were considered related to the assigned study drug. INTERPRETATION: Low-dose ruxolitinib, used in place of mycophenolate mofetil within a backbone of prophylactic antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, reduced grade II-IV acute GVHD by day 100 after haploidentical HSCT and had manageable toxicity. These findings support further evaluation of targeted JAK1/2 inhibition as part of GVHD prophylaxis. FUNDING: National Natural Science Foundation of China.