Evaluation of Ruxolitinib for Steroid-Refractory Chronic Graft-vs-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

Wu, Huitao; Shi, Jimin; Luo, Yi; Tan, Yamin; Zhang, Mingming; Lai, Xiaoyu; Yu, Jian; Liu, Lizhen; Fu, Haidong; Huang, He; Zhao, Yanmin

doi:10.1001/jamanetworkopen.2020.34750

Cited by 30 publications

(23 citation statements)

References 24 publications

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“…Furthermore, recipients of MHC II KO BM supplemented with WT T cells (supplemental Figure 8E-F) demonstrated improved behavior in the FST at day 35 (supplemental Figure 8G) compared with recipients of WT BM plus T cells. Notably, MHC II deficiency did not diminish brain Ifng messenger RNA levels (supplemental Figure 8H), indicating that IFN-γ signaling functions upstream of and may be required for 55 MHC II expression by donor BMDMs to promote CNS cGVHD behavioral perturbations.…”

Section: Resultsmentioning

confidence: 97%

Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice

Adams

Carter-Cusack

Shaikh

et al. 2022

Blood

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Graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality after allogeneic stem cell transplantation for haematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients, however, the mechanisms driving chronic GVHD in the CNS are yet to be elucidated. Our studies of murine chronic GVHD revealed behavioural deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the chronic GVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with IFN-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived TNF. In contrast, infiltration of pro-inflammatory MHC class II+ donor bone marrow-derived macrophages (BMDM) was identified as a distinguishing feature of chronic CNS GVHD. Donor BMDM, which comprised up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout bone marrow grafts exhibited attenuated neuroinflammation and behaviour comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS chronic GVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.

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Section: Resultsmentioning

confidence: 97%

Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice

Adams

Carter-Cusack

Shaikh

et al. 2022

Blood

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“…Other studies have reported similar relapse rates. 23 , 25 , 32 Choi et al and Carniti et al demonstrated that ruxolitinib treatment reduced GVHD and preserved the beneficial of GVT effect in murine models. 8 , 9 More prospective clinical trials are needed to determine whether ruxolitinib reduces the risk of relapse in patients compared with other immunosuppressants.…”

Section: Discussionmentioning

confidence: 99%

Ruxolitinib for Treatment of Steroid-Refractory Graft-versus-Host Disease: Real-World Data from Chinese Patients

Zhang¹,

Liang²,

Yang³

et al. 2021

DDDT

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Background: Graft-versus-host disease (GVHD) is a main complication following allogeneic hematopoietic stem cell transplantation and is a leading cause of non-relapse-related death. Unsatisfactory response to standard first-line therapy with glucocorticoids is a predictor of a poor prognosis in patients with GVHD. Ruxolitinib is a selective Janus kinases 1/2 inhibitor which has been shown to control acute (a) and chronic (c) GVHD while maintaining graft-versus-tumor effects.Objective: This study aims to evaluate the efficacy and safety of ruxolitinib in the treatment of steroid-refractory GVHD (SR-GVHD) in a population of Chinese patients. Methods: We report the results of 55 patients, including 23 patients with aGVHD and 32 patients with cGVHD, who were treated with ruxolitinib as salvage therapy between August, 2017 and December, 2020. Results: In patients with aGVHD, the overall response rate (ORR) was 86.9%, and the 1-year overall survival (OS) was 82.6% (95% CI, 67.1-98.1%). The 1-year OS was significantly improved in responders than in non-responders (90.0% vs 33.3%, P=0.004). In patients with cGVHD, the ORR was 78.1%, and the 1-year OS was 81.3% (95% CI, 67.8-94.8%). There was no significant difference in the 1-year OS between responders and nonresponders (84.0% vs 71.4%, P=0.327). Cytopenia, cytomegalovirus-reactivation and infections were common adverse events, particularly in patients with aGVHD. Conclusion: Our real-world data from Chinese patients further confirm that ruxolitinib is a safe and effective treatment for SR-GVHD.

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“…Furthermore, early azithromycin administration in patients undergoing allogeneic HSCT is associated with worse airflow decline–free survival [ 48 ]. A recent case series found that ruxolitinib in patients with steroid refractory cGVHD had an overall response rate of 70.7%; however, the response is less favorable in patients with lung involvement [ 52 ]. A randomized clinical trial of ruxolitinib in treatment of cGVHD is currently underway (NCT03112603).…”

Section: Late Post-transplantation Period (>100 Days Post-transplant)mentioning

confidence: 99%

Pulmonary Complications in Hematopoietic Stem Cell Transplant Recipients—A Clinician Primer

Astashchanka

Ryan

Lin

et al. 2021

JCM

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Hematopoietic stem cell transplants (HSCT) are becoming more widespread as a result of optimization of conditioning regimens and prevention of short-term complications with prophylactic antibiotics and antifungals. However, pulmonary complications post-HSCT remain a leading cause of morbidity and mortality and are a challenge to clinicians in both diagnosis and treatment. This comprehensive review provides a primer for non-pulmonary healthcare providers, synthesizing the current evidence behind common infectious and non-infectious post-transplant pulmonary complications based on time (peri-engraftment, early post-transplantation, and late post-transplantation). Utilizing the combination of timing of presentation, clinical symptoms, histopathology, and radiographic findings should increase rates of early diagnosis, treatment, and prognostication of these severe illness states.

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Evaluation of Ruxolitinib for Steroid-Refractory Chronic Graft-vs-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

Cited by 30 publications

References 24 publications

Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice

Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice

Ruxolitinib for Treatment of Steroid-Refractory Graft-versus-Host Disease: Real-World Data from Chinese Patients

Pulmonary Complications in Hematopoietic Stem Cell Transplant Recipients—A Clinician Primer

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