JAK1/2 inhibitor ruxolitinib promotes the expansion and suppressive action of polymorphonuclear myeloid-derived suppressor cells via the JAK/STAT and ROS-MAPK/NF-κB signalling pathways in acute graft-versus-host disease.

Objectives: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, demonstrates efficacy for treating steroid-resistant acute graft-versus-host disease (SR-aGVHD) following allogeneic stem cell transplantation (allo-HSCT). Myeloid-derived suppressor cells (MDSCs) have a protective effect on aGVHD via suppressing T cell function. However, the precise features and mechanism of JAK inhibitor-mediated immune modulation on MDSCs subsets remain poorly understood. Methods: A total of 74 SR-aGVHD patients treated with allo-HSCT and ruxolitinib were enrolled in the present study. The alterations of MDSC and regulatory T cell (Treg) populations were monitored during ruxolitinib treatment in responders and nonresponders. A mouse model of aGVHD was used to evaluate the immunosuppressive activity of MDSCs and related signalling pathways in response to ruxolitinib administration in vivo and in vitro. Results: Patients with SR-aGVHD who received ruxolitinib treatment achieved satisfactory outcomes. Elevation proportions of MDSCs before treatment, especially polymorphonuclear-MDSCs (PMN-MDSCs) were better to reflect the response to ruxolitinib than those in Tregs. In the mouse model of aGVHD, the administration of ruxolitinib resulted in the expansion and functional enhancement of PMN-MDSCs and the effects could be partially reversed by an anti-Gr-1 antibody in vivo. Ruxolitinib treatment significantly elevated the suppressive function of PMN-MDSCs through reactive oxygen species (ROS) production by Nox2 upregulation as well as bypassing the activated MAPK/NF-κB signalling pathway. Additionally, ex vivo experiments demonstrated that ruxolitinib prevented the differentiation of mature myeloid cells and promoted the accumulation of MDSCs by inhibiting STAT5. Conclusions: Ruxolitinib enhances PMN-MDSCs functions through JAK/STAT and ROS-MAPK/NF-κB signalling pathways. Monitoring frequencies and functions of MDSCs can help evaluate treatment responses to ruxolitinib.

Comparison of autologous and allogeneic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Objectives: To analyze the outcomes of patients who received autologous stem cell transplantation (auto-SCT), matched sibling donor stem cell transplantation (MSD-SCT) and haploidentical stem cell transplantation (haplo-SCT) and provide the basis for the choice of transplantation method in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Methods: We retrospectively investigated the outcomes of 119 adult patients with Ph+ ALL in our center. The overall survival (OS) rate, leukemia-free survival (LFS) rate, cumulative incidence of relapse (CIR) rate, non-relapse mortality (NRM) rate and the impact of achievement of complete molecular response (CMR) within 3 months and sustaining CMR up to transplantation (s3CMR) on transplantation method were explored. Results: The estimated OS, LFS, CIR and NRM rates at 3 years were not significantly different among three groups (p = 0.960, 0.917, 0.375 and 0.096, respectively). For the 65 patients who achieved s3CMR, there was no significant difference in OS (84.5% vs 72.5% vs 100%, p = 0.374), LFS (75.2% vs 64.5% vs 83.3%, p = 0.668), CIR (17.2% vs 8.1% vs 16.7%, p = 0.583) and NRM (3.1% vs 23.4% vs 0%, p = 0.055) among auto-SCT group, MSD-SCT group and haplo-SCT group. However, in patients who did not achieve s3CMR, auto-SCT recipients tended to have higher CIR (60% vs 33.2% vs 24.0%, p = 0.013) than the allo-HSCT group. Conclusions: Auto-SCT with maintenance therapy after HSCT appears to be an attractive treatment option for patients with Ph+ ALL especially for those whose s3CMR was kept up to transplantation. For non-s3CMR patients, allogeneic transplantation may be more effective from lower relapse.