Steroid-refractory chronic graft-versus-host disease: treatment options and patient management

Wolff, Daniel; Fatobene, Giancarlo; Rocha, Vanderson; Flowers, Mary E.D.

doi:10.1038/s41409-021-01389-5

Cited by 51 publications

(39 citation statements)

References 101 publications

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“…First-line treatment of chronic GVHD remains corticosteroids [ 21 ], with second-line options including targeting activation with calcineurin inhibitors, anti-proliferative reagents including mycophenolate mofetil, mammalian target of rapamycin (mTOR) inhibitors, adenosine analogues including pentostatin, proteasome inhibitors, tyrosine kinase inhibitors including ibrutinib or extra-corporal photopheresis [ 22 , 26 ].…”

Section: Allogeneic Haematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Insights into mechanisms of graft-versus-host disease through humanised mouse models

et al. 2022

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Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic haematopoietic stem cell transplantation (HSCT) for the treatment of haematological cancers and other blood-related disorders. GVHD is an inflammatory disorder, where the transplanted donor immune cells can mediate an immune response against the recipient and attack host tissues. Despite over 60 years of research, broad-range immune suppression is still used to prevent or treat GVHD, leading to an increased risk of cancer relapse and infection. Therefore, further insights into the disease mechanisms and development of predictive and prognostic biomarkers are key to improving outcomes and reducing GVHD development following allogeneic HSCT. An important preclinical tool to examine the pathophysiology of GVHD, and to understand the key mechanisms that lead to GVHD development, are preclinical humanised mouse models. Such models of GVHD are now well-established and can provide valuable insights into disease development. This review will focus on models where human peripheral blood mononuclear cells are injected into immune-deficient non-obese diabetic (NOD)-scid-interleukin-2(IL-2)Rγ mutant (NOD-scid-IL2Rγnull) mice. Humanised mouse models of GVHD can mimic the clinical setting for GVHD development, with disease progression and tissues impacted like that observed in humans. This review will highlight key findings from preclinical humanised mouse models regarding the role of donor human immune cells, the function of cytokines and cell signalling molecules and their impact on specific target tissues and GVHD development. Further, specific therapeutic strategies tested in these preclinical models reveal key molecular pathways important in reducing the burden of GVHD following allogeneic HSCT.

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Section: Allogeneic Haematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Insights into mechanisms of graft-versus-host disease through humanised mouse models

et al. 2022

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“…Within the NIH 2020 initiative a summary has been provided about the major advances in understanding of the aetiopathology of cGvHD and future efforts (11,102,103). The field is moving toward clinical studies targeting prevention strategies that decrease the risk of morbid cGvHD such as moderate-tosevere cGvHD without an increased risk of relapse or infection.…”

Section: Prognostic Factors Associated With Higher Nrm And/or Poorer Osmentioning

confidence: 99%

“…A comprehensive review on the management of cGvHD in children was provided by Jacobsohn (106), but since that publication major advances, as outlined in detail within this manuscript, have been made and an update is pending. Recently, an individualised and patient-centred cGVHD management offering continuing care embedded in a multidisciplinary team has been described (103,141). To fill this gap regarding paediatric cGVHD patients was the central aim of this manuscript.…”

Section: Personalised Management Of Paediatric Cgvhdmentioning

confidence: 99%

Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan

Sobkowiak-Sobierajska

Lindemans

Sýkora

et al. 2022

Front. Pediatr.

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Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.

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“…The skin is the most commonly affected site, with manifestations that can be observed in up to 75% of chronic GVHD patients, but clinical features may affect multiple organs or body areas with varying presentation, depending on the patient [ 27 , 28 ]. Corticosteroids with or without calcineurin inhibitors compose first-line treatment, but the prognosis is poor if the patient is steroid-refractory [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Advances in Allogeneic Cancer Cell Therapy and Future Perspectives on “Off-the-Shelf” T Cell Therapy Using iPSC Technology and Gene Editing

Furukawa

Hamano

Shirane

et al. 2022

Cells

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The concept of allogeneic cell therapy was first presented over 60 years ago with hematopoietic stem cell transplantation. However, complications such as graft versus host disease (GVHD) and regimen-related toxicities remained as major obstacles. To maximize the effect of graft versus leukemia, while minimizing the effect of GVHD, donor lymphocyte infusion was utilized. This idea, which was used against viral infections, postulated that adoptive transfer of virus-specific cytotoxic T lymphocytes could reconstitute specific immunity and eliminate virus infected cells and led to the idea of banking third party cytotoxic T cells (CTLs). T cell exhaustion sometimes became a problem and difficulty arose in creating robust CTLs. However, the introduction of induced pluripotent stem cells (iPSCs) lessens such problems, and by using iPSC technology, unlimited numbers of allogeneic rejuvenated CTLs with robust and proliferative cytotoxic activity can be created. Despite this revolutionary concept, several concerns still exist, such as immunorejection by recipient cells and safety issues of gene editing. In this review, we describe approaches to a feasible “off-the-shelf” therapy that can be distributed rapidly worldwide. We also offer perspectives on the future of allogeneic cell cancer immunotherapy.

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Steroid-refractory chronic graft-versus-host disease: treatment options and patient management

Cited by 51 publications

References 101 publications

Insights into mechanisms of graft-versus-host disease through humanised mouse models

Insights into mechanisms of graft-versus-host disease through humanised mouse models

Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan

Advances in Allogeneic Cancer Cell Therapy and Future Perspectives on “Off-the-Shelf” T Cell Therapy Using iPSC Technology and Gene Editing

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