National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report

Williams, Kirsten M.; Inamoto, Yoshihiro; Im, Annie; Hamilton, Betty K.; Koreth, John; Arora, Mukta; Pusic, Iskra; Mays, Jacqueline W.; Carpenter, Paul A.; Luznik, Leo; Reddy, Pavan; Ritz, Jérôme; Greinix, Hildegard; Paczesny, Sophie; Blazar, Bruce R.; Pidala, Joseph; Cutler, Corey; Wolff, Daniel; Schultz, Kirk R.; Pavletić, Steven Z.; Lee, Stephanie J.; Martin, Paul J.; Socié, Gèrard; Sarantopoulos, Stefanie

doi:10.1016/j.jtct.2021.02.035

Cited by 29 publications

(27 citation statements)

References 142 publications

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“…Concepts surrounding primary prevention, early diagnosis, and preemptive therapy of cGVHD have been explored in the 2020 NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft versus Host Disease and should inform trial development in the future. 36-38 Lastly, another major proposal from this 2020 NIH Consensus Project involved supporting innovative trials testing lower-dose or steroid-free approaches with targeted agents. 39 Prior phase II data with the use of rituximab with or without corticosteroids in the frontline setting pointed toward overall high response rates.…”

Section: Discussionmentioning

confidence: 99%

A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease

et al. 2022

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Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal and transient responses in a significant number of patients. Safety and feasibility of anti-CD20 directed B-cell therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n=12). We now report the mature results of the phase II expansion of the trial (n=38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The combined therapy was generally well tolerated, with some anticipated infusion reactions to ofatumumab, and common toxicities of glucocorticoids. Total B-cell depletion following therapy was profound, with marginal recovery within first 12 months from initial therapy. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR=complete + partial response[CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial IS agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial is registered at www.clinicaltrials.gov as NCT01680965.

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Section: Discussionmentioning

confidence: 99%

A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease

et al. 2022

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“…To address the challenges in a rapidly changing field, a third NIH consensus project was held in November 2020. Investigators aimed to define basic and clinical research directions that may lead to significant changes in cGvHD management over the next five years [34][35][36][37][38] . Four working groups have discussed etiology/prevention, diagnosis/preemptive therapy, initial and subsequent lines of systemic treatment, and highly morbid forms of cGvHD, including sclerotic form, bronchiolitis obliterans, ocular GvHD, and gastrointestinal GvHD.…”

Section: Update On the Treatments Of Cgvhdmentioning

confidence: 99%

“…Four working groups have discussed etiology/prevention, diagnosis/preemptive therapy, initial and subsequent lines of systemic treatment, and highly morbid forms of cGvHD, including sclerotic form, bronchiolitis obliterans, ocular GvHD, and gastrointestinal GvHD. Initial and second insults have been proposed as etiologies of cGvHD, and many emerging targets have been suggested for current and future preventive and therapeutic strategies 34 . Although further research on prognostic or predictive biomarkers of cGvHD is required, preemptive therapy might be possible in the near future 35,36 .…”

Section: Update On the Treatments Of Cgvhdmentioning

confidence: 99%

Novel Treatment for Graft-versus-Host Disease

2021

BCT

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Allogeneic hematopoietic cell transplantation is a curative therapy for a variety of hematological diseases, but its success is hampered by acute and chronic graft-versus-host disease (GvHD). In the last five years, multiple novel therapeutic approaches for GvHD have entered the arena. The National Institutes of Health consensus criteria for chronic GvHD have set standards for designing and reporting clinical trials, and preclinical experiments of chronic GvHD have revealed the central roles of regulatory T cells, B-cell signaling, Th17 cells, Tc17 cells, follicular helper T cells, follicular regulatory T cells, and fibrosis-promoting factors. These scientific efforts and the resulting clinical studies led to the approval of ibrutinib, belumosudil and ruxolitinib for the treatment of refractory chronic GvHD. Recently, large randomized phase III trials showed that ruxolitinib was superior to the best available therapy for glucocorticoid-refractory acute GvHD (REACH2 trial) and glucocorticoid-refractory chronic GvHD (REACH3 trial). Furthermore, novel regenerative approaches, including IL-22, R-spondin, and glucogon-like peptide-2, and cellular therapies, such as the transfer of mesenchymal stem cells and regulatory T cells, are under intensive investigation. GvHD prevention using abatacept, dipeptidyl peptidase 4 inhibition, and post-transplant cyclophosphamide are also promising strategies that require further evaluation. In this article, we summarize the emerging knowledge of acute GvHD, chronic GvHD, and preclinical and clinical data of mesenchymal stem cells as GvHD therapy. In the next five years, basic and clinical studies will further advance the field, and dramatic changes in GvHD management will be encountered.

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“…Standard GVHD prophylaxis for HLA-matched transplants comprises a calcineurin inhibitor plus a short course of methotrexate or mycophenolate mofetil (MMF) with or without additional antithymocyte globulin (ATG) in transplants from unrelated donors; ATG has recently been also recommended for use in HLA-identical sibling transplantation [31]. The aim of these prophylactic treatments is to reduce the risk of aGVHD, one of the major risk factors for cGVHD which continue to manifest in approximately half of the patients [32]. Nevertheless, several approaches have resulted in decreased rates of cGVHD, including the use of ATG as part of GVHD prophylaxis [33][34][35][36] and posttransplant cyclophosphamide in combination with a calcineurin inhibitor (with or without MMF), even in the peripheral blood stem cell transplantation setting and naïve T-depleted grafts [37].…”

Section: Introductionmentioning

confidence: 99%

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

Wolff

Fatobene

Rocha

et al. 2021

Bone Marrow Transplant

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Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles.

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National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report

Cited by 29 publications

References 142 publications

A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease

A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease

Novel Treatment for Graft-versus-Host Disease

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

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