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The development of ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease.

ABSTRACT: Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Despite the use of prophylactic immunosuppression including calcineurin inhibitors, antimetabolites, antithymocyte globulin, or posttransplant cyclophosphamide, patients still develop severe aGVHD. In particular, patients with glucocorticoid-refractory GVHD (SR-GVHD) have a dismal prognosis with a low 1-year post-allo-HCT survival rate. Most classical drugs used to prevent or treat aGVHD target 1 specific pathway such as calcineurin inhibitors or mammalian target of rapamycin inhibitors, or they interfere with fast-dividing activated cells (eg, methotrexate, mycophenolate, and cyclophosphamide). In contrast to these drugs, inhibition-of-signaling molecules, used by multiple immune cells and critical for signal transduction of multiple proinflammatory cytokines, could be more efficacious at blocking GVHD. Ruxolitinib blocks Janus kinases 1 and 2, which are required to mediate the downstream signaling of multiple cytokine receptors. Recently, a multicenter phase 3 clinical trial showed that ruxolitinib led to significant improvements in efficacy outcomes compared to best available therapy, which will lead to a paradigm shift in the treatment of SR-GVHD.

SUBMITTER: Zeiser R

PROVIDER: S-EPMC7422131 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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The development of ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease.

Zeiser Robert R Socié Gérard G

Blood advances 20200801 15

Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Despite the use of prophylactic immunosuppression including calcineurin inhibitors, antimetabolites, antithymocyte globulin, or posttransplant cyclophosphamide, patients still develop severe aGVHD. In particular, patients with glucocorticoid-refractory GVHD (SR-GVHD) have a dismal prognosis with a low 1-year post-allo-HCT survival rate. Most classical drugs u ...[more]

PMID: 32780849

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Project description:Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a lifesaving treatment for hematologic malignancies, but acute graft-versus-host-disease (aGVHD) is a potentially deadly adverse effect experienced by up to half of allo-HSCT recipients. Inadequate response to steroid therapy for aGVHD is associated with poor prognosis and high mortality, including among pediatric patients, who are the focus of this study. Ruxolitinib and remestemcel-L-rknd were evaluated for the treatment of steroid-refractory (SR) aGVHD in two separate single-arm trials. To effectively compare the safety and efficacy of these treatments without a head-to-head trial, a simulated treatment comparison (STC) was conducted. Methods: Regression techniques were used to adjust individual patient-level data from the remestemcel-L-rknd trial to mutually reported baseline characteristics from the ruxolitinib trial. Outcomes of interest included a 28-day overall response rate (ORR), a 28-day ORR in the grade III-IV aGVHD population, and adverse events (AEs). Results: In the full populations, the STC of risk ratios (RRs) found treatment with remestemcel-L-rknd to be associated with a numerical but not statistically significant improvement in the 28-day ORR versus ruxolitinib. In the grade III-IV aGVHD sub-group, the STC showed significantly improved 28-day ORR for remestemcel-L-rknd versus ruxolitinib (P=0.04). Remestemcel-L-rknd was also associated with improved safety outcomes (P<0.05) in 17 out of 30 AEs, including hematologic events, peripheral edema, muscular weakness, nausea, back pain, and fatigue. Conclusion: Remestemcel-L-rknd was associated with significant improvements in day 28 ORR compared with ruxolitinib in patients with severe (grade III-IV) SR aGVHD. Across all grades of SR aGVHD, remestemcel-L-rknd was associated with fewer all-grade treatment-emergent adverse events (TEAEs) (27/30) available for comparison, including the majority reaching statistical significance.

Project description:Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P<0.001), while the percentages of NK (CD16+CD56+) cells and regulatory T cells (CD4+CD127 ± CD25+) decreased (P<0.001, P<0.001). Among the B cell subsets, the proportion of total B cells approximately tripled from 3.69% to 11.16% (P<0.001). Moreover, we observed a significant increase in IL-10 levels after ruxolitinib treatment (P=0.025) and a remarkable decrease in levels of suppression of tumorigenicity 2 (ST2) from 229.90 ng/ml to 72.65 ng/ml. The median follow-up after the initiation of ruxolitinib treatment was 401 (6-1076) days. The estimated one-year overall survival rate of the whole group was 66.0% (54.4-77.6%, 95% CI), and the one-year overall survival rate of patients with mild and moderate cGVHD was 69.6% (57.4-81.8%, 95% CI), which was better than that of patients with severe cGVHD (31.3%, 0.0-66.2%, 95% CI) (P=0.002). Patients who achieved a CR and PR achieved better survival outcomes (84.5%, 73.9-95.1%, 95% CI) than those who showed NR to ruxolitinib treatments (16.7%, 0-34.3%, 95% CI) (P<0.001). At the final follow-up, cGVHD relapse occurred in six patients after they reduced or continued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.

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The development of ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease.

Publications

The development of ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease.

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