Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease

Zeiser, Robert; Polverelli, Nicola; Ram, Ron; Hashmi, Shahrukh K.; Chakraverty, Ronjon; Middeke, Jan Moritz; Musso, Maurizio; Giebel, Sebastian; Uzay, Ant; Langmuir, Peter; Hollaender, Norbert; Gowda, Maanasa; Stefanelli, Tommaso; Lee, Stephanie J.; Teshima, Takanori; Locatelli, Franco

doi:10.1056/nejmoa2033122

Cited by 227 publications

(193 citation statements)

References 39 publications

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“…At this time, only Ibrutinib and Belumosudil (KD025) are FDA-approved drugs for chronic GVHD patients failing corticosteroids or >1 line of prior therapy [4,5]. Ruxolitinib is being evaluated by the FDA as consideration for approval based on the recently published REACH3 study (NCT03112603) [6]. New treatments are critically needed to reduce GVHD prevalence and severity in an effort to improve HSCT patient outcomes, as well as reduce toxicities associated with long-term drug therapy.…”

Section: Introductionmentioning

confidence: 99%

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Hefazi

Bolivar-Wagers

Blazar

2021

IJMS

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Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation using regulatory T cells (Tregs) offers an exciting option to prevent and/or treat GVHD as these cells naturally function to maintain immune homeostasis, can induce tolerance following HSCT, and have a tissue reparative function. Studies to date have established a clinical safety profile for polyclonal Tregs. Functional enhancement through genetic engineering offers the possibility of improved potency, specificity, and persistence. In this review, we provide the most up to date preclinical and clinical data on Treg cell therapy with a particular focus on GVHD. We discuss the different Treg subtypes and highlight the pharmacological and genetic approaches under investigation to enhance the application of Tregs in allo-HSCT. Lastly, we discuss the remaining challenges for optimal clinical translation and provide insights as to future directions of the field.

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Section: Introductionmentioning

confidence: 99%

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Hefazi

Bolivar-Wagers

Blazar

2021

IJMS

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“…Treatment can include both inhaled and systemic steroids with other immunosuppressive medications, though very few studies demonstrated significant clinical benefit (51). For patients whose symptoms are steroid refractory, treatment can include Janus-associated kinase 1/2 inhibitors such as ruxolitinib (80,81). Studies have been published reporting 59%-68% overall response rate with a tolerable safety profile (80,82).…”

Section: Bronchiolitis Obliteransmentioning

confidence: 99%

“…Studies have been published reporting 59%-68% overall response rate with a tolerable safety profile (80,82). Most common toxicities included reactivation thrombocytopenia and anemia; some studies have reported increased CMV reactivation, though this is not consistently demonstrated across all studies (80)(81)(82)(83). However, these studies evaluated those 12 years of age or older; studies evaluating effectiveness/dosing in children younger than 12 and dosing are ongoing (81,83).…”

Section: Bronchiolitis Obliteransmentioning

confidence: 99%

Pulmonary Complications After Pediatric Stem Cell Transplant

et al. 2021

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The number of disorders that benefit from hematopoietic stem cell transplantation (HSCT) has increased, causing the overall number of HSCT to increase accordingly. Disorders treated by HSCT include malignancy, benign hematologic disorders, bone marrow failure syndromes, and certain genetic diagnoses. Thus, understanding the complications, diagnostic workup of complications, and subsequent treatments has become increasingly important. One such category of complications includes the pulmonary system. While the overall incidence of pulmonary complications has decreased, the morbidity and mortality of these complications remain high. Therefore, having a clear differential diagnosis and diagnostic workup is imperative. Pulmonary complications can be subdivided by time of onset and whether the complication is infectious or non-infectious. While most infectious complications have clear diagnostic criteria and treatment courses, the non-infectious complications are more varied and not always well understood. This review article discusses pulmonary complications of HSCT recipients and outlines current knowledge, gaps in knowledge, and current treatment of each complication. This article includes some adult studies, as there is a significant paucity of pediatric data.

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“…The REACH3 study evaluated ruxolitinib in SR-cGVHD and was presented at the 2020 annual meeting of the American Society of Hematology (32). It was an open-label, randomized phase III trial comparing ruxolitinb to BAT.…”

Section: Studies In Refractory Gvhdmentioning

confidence: 99%

“…Insights into the pathogenesis of GVHD demonstrate a necessary role for signaling through the JAK/ STAT pathway, particularly STAT1 and STAT3 (24)(25)(26)(27). This is supported by clinical efficacy of JAK inhibitors in the treatment of acute and chronic GVHD (28)(29)(30)(31)(32). The FDA approval of ruxolitinib, a JAK1/2 inhibitor, represents a major advance in the treatment of SR-aGVHD (31).…”

Section: Introductionmentioning

confidence: 99%

Janus Kinase Inhibitors and Cell Therapy

Assal

Mapara

2021

Front. Immunol.

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Cellular therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) and immune-effector cell therapy (IECT) continue to have a critical role in the treatment of patients with high risk malignancies and hematologic conditions. These therapies are also associated with inflammatory conditions such as graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) which contribute significantly to the morbidity and mortality associated with these therapies. Recent advances in our understanding of the immunological mechanisms that underly GVHD and CRS highlight an important role for Janus kinases (JAK). JAK pathways are important for the signaling of several cytokines and are involved in the activation and proliferation of several immune cell subsets. In this review, we provide an overview of the preclinical and clinical evidence supporting the use of JAK inhibitors for acute and chronic GVHD and CRS.

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Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease

Cited by 227 publications

References 39 publications

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Pulmonary Complications After Pediatric Stem Cell Transplant

Janus Kinase Inhibitors and Cell Therapy

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