A Multicenter Randomized Controlled Trial of Low-Dose Ruxolitinib for Gvhd Prophylaxis in Haploidentical Hematopoietic Stem Cell Transplantation

Background

Haploidentical (Haplo) donors are widely used for hematopoietic stem cell transplantation (HSCT) in high-risk acute leukemia due to their strong graft-versus-leukemia effect. Our previous study indicated that haploidentical HSCT yielded comparable efficacy to HLA-matched sibling transplantation but with a higher incidence of acute graft-versus-host disease (GVHD). Acute GVHD (aGVHD) is a major obstacle in allogeneic HSCT and a leading cause of post-transplant mortality. Ruxolitinib, a JAK1/2 inhibitor, is approved for treating steroid-refractory acute and chronic GVHD. Our preliminary research showed that ruxolitinib reduced aGVHD incidence to 10% in CNI-intolerant patients. This study investigates whether adding low-dose ruxolitinib to cyclosporine and short-course methotrexate (MTX) can prevent aGVHD without increasing relapse rates post haplo-HSCT.

Method

Between March 2021 and December 2023, a multi-center, open-label, randomized, phase 3 clinical trial was conducted at five sites in China (clinicaltrials.gov NCT04838704). Eligible patients (hematological malignancies, aged 12+ years, received haplo-HSCT after myeloablative conditioning) were randomly assigned to experimental (n = 103) or control groups (n = 103). All patients received a myeloablative busulfan/cyclophosphamide-based conditioning regimen with anti-thymocyte globulin. The control group received cyclosporine, MTX, and mycophenolate mofetil (MMF). Cyclosporine was given from day -7 pre-transplant until day +90 post-transplant, tapered by day +180. MTX was administered on days +1, +3, +6, and +9. MMF was started on day -9, maintained for 60 days, and tapered by day +90. The experimental group received ruxolitinib and cyclosporine/MTX, without MMF. Ruxolitinib was initiated on day +1 post-transplant at 5 mg BID (>50 kg) or 5 mg QD (<50 kg), maintained for 60 days, tapered till day +90. The primary endpoint was the cumulative incidence of grade II-IV aGVHD by day 100. Secondary endpoints included engraftment, chronic GVHD (cGVHD), relapse, non-relapse mortality (NRM), overall survival (OS), and GVHD-free, relapse-free survival (GRFS).

Results

A total of 206 patients were included. The median follow-up was 676 days (range, 229-1115) for the ruxolitinib group and 672 days (range, 202-1197) for the control group. Baseline characteristics were similar between the two groups.

The incidence of grade 2-4 aGVHD at 100 days was significantly lower in the ruxolitinib group at 7.8% (95% CI, 2.5%-12.8%) compared to 36.9% (95% CI, 26.9%-45.6%; P < 0.001) in the control group (hazard ratio, 2.375; 95% CI, 1.057-5.338; P = 0.036). At 180 days, the incidence of grade 2-4 aGVHD was 12.6% (95% CI, 6.0%-18.8%) in the ruxolitinib group, significantly lower than 38.8% (95% CI, 28.7%-47.6%) in the control group (P < 0.001). The cumulative incidence of cGVHD was similar between the groups (42.2% vs. 51.4%, P = 0.17). However, moderate to severe cGVHD was significantly lower in the ruxolitinib group (3.3% [95% CI, 0.0%-7.0%] vs. 19.6% [95% CI, 10.4%-27.9%], P < 0.001).

Regarding engraftment, the ruxolitinib group experienced slightly slower neutrophil engraftment, with a median day of 12 (range, 9-21) compared to 11 (range, 5-26) in the control group (P = 0.002). However, there was no significant difference in platelet engraftment rates between the two groups, with a median day of 13 (range, 6-28) for the ruxolitinib group and 12 (range, 6-65) for the control group (P = 0.71). NRM was 0% in the ruxolitinib group and 6.3% in the control group (P = 0.014). The CIR was similar between the two groups (14.5% vs. 10.5%, P = 0.43). OS was 83.7% in the ruxolitinib group and 84.2% in the control group (P = 0.57). The ruxolitinib group had a significantly higher GRFS compared to the control group (81.4% vs. 52.8%, P < 0.001).

Conclusion

Adding low-dose ruxolitinib to the standard prophylactic regimen for haplo-HSCT significantly reduced grade II-IV aGVHD incidence at 100 and 180 days. cGVHD incidence was similar, but moderate to severe cGVHD was lower in the ruxolitinib group. Neutrophil engraftment was slightly delayed, but platelet engraftment rates were comparable. NRM was significantly lower in the ruxolitinib group, with similar OS. Ruxolitinib enhanced GVHD prophylaxis without increasing disease relapse, improving overall outcomes in haplo-HSCT.