[Evolving treatment strategies for chronic graft-versus-host disease].

Chronic graft-versus-host disease (GVHD) affects various organs and causes significant morbidity and mortality after allogeneic hematopoietic cell transplantation. The 2005 National Institutes of Health consensus criteria for chronic GVHD have set international standards for endpoints and designing and reporting of clinical trials; these criteria were revised in 2014 to incorporate accumulated evidence and controversies. In addition, preclinical studies of chronic GVHD have identified treatment targets such as regulatory T cells, B-cell signaling, Th17 cells, Tc17 cells, follicular helper T cells, follicular regulatory T cells, and fibrosis-promoting factors. These efforts led to the approval of ibrutinib, belumosudil, and ruxolitinib by the U.S. Food and Drug Administration for treating chronic GVHD after failure of one or more lines of systemic therapy, and an increasing number of investigational agents that target different biological pathways of chronic GVHD are under development in clinical trials. To address challenges in a rapidly evolving field, a third National Institutes of Health consensus project was held in 2020, in which investigators, patient advocacy organizations, and pharmaceutical companies aimed to define basic and clinical research roadmaps that may lead to significant change in chronic GVHD management over the next 5 years.

[Treatment of graft-versus-host disease].

Graft-versus-host disease (GVHD) is one of the most important complications after an allogeneic hematopoietic stem cell transplantation (allo-SCT). The current National Institutes of Health's (NIH) consensus is that clinical manifestations, and not the time to symptomatic onset after transplantation, determine whether the clinical syndrome of GVHD is considered acute or chronic. In the past decade, peripheral blood stem cell transplantation from an unrelated donor can be performed in Japan. Furthermore, poor-risk patients without human leukocyte antigen (HLA)-matched donor can receive allo-SCT from HLA haploidentical donor. Therefore, severe or steroid-refractory GVHD would be increased. Corticosteroid, at a dose of 2 mg/kg, is a standard first-line therapy for acute GVHD. If there is no improvement after the first-line therapy, second-line therapy should be administered immediately. Although anti-thymocyte globulin and mesenchymal stem cells are covered by health insurance in Japan, another treatment options should be determined for steroid-refractory acute GVHD. Furthermore, severe chronic GVHD increases patients' mortality and decreases their quality of life. A number of novel drugs targeting specific biological pathways for GVHD are under development. Currently, more than 60 clinical trials are carried out for the treatment of steroid-refractory GVHD worldwide for drug approval. The accumulation of novel evidence for GVHD treatment is expected to be established.

Occurrence and Severity of Donor Lymphocyte Infusion-Associated Chronic Graft-versus-Host Disease Influence the Clinical Outcomes in Relapsed Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation.

The aim of this study was to investigate the occurrence and severity of chemotherapy plus donor lymphocyte infusion (Chemo-DLI)-associated chronic graft-versus-host disease (cGVHD) in a consecutive cohort of patients with acute leukemia who experienced relapse after allogeneic hematopoietic stem cell transplantation (n = 104). The 5-year cumulative incidence of complete remission after Chemo-DLI was 81.0% (95% CI, 73.3% to 88.7%) and 84.6% (95% CI, 74.5% to 94.7%) in the moderate and severe cGVHD groups, respectively, which was significantly higher than that of the mild cGVHD group at 40.9% (95% CI, 29.3% to 52.5%) and non-cGVHD group at 29.2% (95% CI 23.1% to 35.3%). The cumulative incidence of nonrelapse mortality was comparable between patients with and without cGVHD. The 5-year probabilities of progression-free survival after Chemo-DLI were 42.9% (95% CI, 26.2% to 70.2%) and 34.6% (95% CI, 15.3% to 78.2%) in the moderate and severe cGVHD groups, respectively, which were both significantly higher than those of the mild cGVHD group at 9.1% (95% CI, 2.4% to 34.1%) and non-cGVHD group at 8.3% (95% CI 3.3% to 21.3%). The 5-year probabilities of overall survival after Chemo-DLI were 56.7% (95% CI, 38.9% to 82.7%) and 43.1% (95% CI, 22.1% to 84.0%) in the moderate and severe cGVHD groups, respectively, which were both significantly higher than those of the mild cGVHD group at 9.1% (95% CI 1.8% to 47.1%) and non-cGVHD group at 14.9% (95% CI, 7.3% to 30.2%). Our observations highlight the close relationship between cGVHD and immune-mediated graft-versus-leukemia (GVL) effect in patients with relapse receiving Chemo-DLI; however, mild cGVHD may not be associated with a sufficiently strong GVL effect to induce remission and improve survival.

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Research Methodology and Study Design Working Group Report.

The increasing numbers of hematopoietic cell transplantations (HCTs) performed each year, the changing demographics of HCT recipients, the introduction of new transplantation strategies, incremental improvement in survival, and the growing population of HCT survivors demand a comprehensive approach to examining the health and well-being of patients throughout life after HCT. This report summarizes strategies for the conduct of research on late effects after transplantation, including consideration of the study design and analytic approaches; methodologic challenges in handling complex phenotype data; an appreciation of the changing trends in the practice of transplantation; and the availability of biospecimens to support laboratory-based research. It is hoped that these concepts will promote continued research and facilitate the development of new approaches to address fundamental questions in transplantation outcomes.

Reprint of: Long-Term Survivorship after Hematopoietic Cell Transplantation: Roadmap for Research and Care.

The number of survivors after hematopoietic cell transplantation (HCT) is expected to dramatically increase over the next decade. Significant and unique challenges confront survivors for decades after their underlying indication (malignancy or marrow failure) has been cured by HCT. The National Institutes of Health (NIH) Late Effects Consensus Conference in June 2016 brought together international experts in the field to plan the next phase of survivorship efforts. Working groups laid out the roadmap for collaborative research and health care delivery. Potentially lethal late effects (cardiac/vascular, subsequent neoplasms, and infectious), patient-centered outcomes, health care delivery, and research methodology are highlighted here. Important recommendations from the NIH Consensus Conference provide fresh perspectives for the future. As HCT evolves into a safer and higher-volume procedure, this marks a time for concerted action to ensure that no survivor is left behind.

Long-Term Survivorship after Hematopoietic Cell Transplantation: Roadmap for Research and Care.

The number of survivors after hematopoietic cell transplantation (HCT) is expected to dramatically increase over the next decade. Significant and unique challenges confront survivors for decades after their underlying indication (malignancy or marrow failure) has been cured by HCT. The National Institutes of Health (NIH) Late Effects Consensus Conference in June 2016 brought together international experts in the field to plan the next phase of survivorship efforts. Working groups laid out the roadmap for collaborative research and health care delivery. Potentially lethal late effects (cardiac/vascular, subsequent neoplasms, and infectious), patient-centered outcomes, health care delivery, and research methodology are highlighted here. Important recommendations from the NIH Consensus Conference provide fresh perspectives for the future. As HCT evolves into a safer and higher-volume procedure, this marks a time for concerted action to ensure that no survivor is left behind.

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report.

A number of studies have shown that autologous and allogeneic hematopoietic cell transplantation (HCT) contribute to an increased incidence of cardiovascular disease (CVD) and worsening of cardiovascular risk factors that could contribute to further CVD over time. These observations, combined with a notable increase in the number of survivors after HCT in recent years, highlight the need for studies aimed at modifying risk or preventing these outcomes by changing specific approaches and/or post-HCT interventions. To address these issues, the National Heart, Lung and Blood Institute and National Cancer Institute co-sponsored an international initiative on late effects after HCT. This report summarizes the major gaps in knowledge along with detailed recommendations regarding study priorities from the Cardiovascular Disease and Associated Risk Factors Committee, a multidisciplinary panel of international experts. The committee calls for specific studies aimed at understanding and preventing arterial disease and cardiac dysfunction (heart failure, valvular disease, and arrhythmias), as well as decreasing cardiovascular risk factors (hypertension, hyperglycemia, dyslipidemia, and sarcopenic obesity) after HCT.

Long-Term Morbidity and Mortality in Children with Chronic Graft-versus-Host Disease Classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation.

We report the long-term morbidity and mortality of 105 pediatric patients who developed chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). According to the consensus criteria of the National Institutes of Health, the global severity of cGVHD was mild in 26 patients (25%), moderate in 30 patients (29%), and severe in 49 patients (47%). Patients with severe cGVHD had a significantly lower cumulative incidence of cGVHD remission and higher probability of continuing cGVHD at 8 years from cGVHD diagnosis compared with those with mild or moderate cGVHD. The 10-year cumulative incidence of nonrelapse mortality in severe cGVHD patients was significantly higher and the probability of disease-free survival was significantly lower than those among patients with mild and moderate cGVHD. Of the 59 patients who survived for more than 5 years, 20 (34%) (4 with moderate and 16 with severe cGVHD) had persistent functional impairment caused by cGVHD with a Karnofsky/Lansky performance score of 90% in 3 patients, 80% in 4 patients, and below 70% in 13 patients at the time of relapse, death, or last follow-up. Better therapeutic strategies are needed to lower the incidence of severe cGVHD, considering the longer life expectancy of pediatric HSCT survivors.

Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force.

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.

Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia.

Chronic graft-versus-host disease (cGVHD) is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia (n = 280). The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria. A total of 169 patients suffered from cGVHD. The patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD (total, 66.0% vs. 53.7%, P = 0.031; moderate to severe, 42.4% vs. 30.1%, P = 0.036) than the patients who had 1 to 2 loci mismatched. The patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD (49.2% vs. 32.9%, P = 0.024) compared with the patients who had other donors. The patients who had grades III to IV acute GVHD (aGVHD) had higher 8-year incidence of cGVHD (total, 88.0% vs. 50.4%, P < 0.001; moderate to severe, 68.0% vs. 27.0%, P < 0.001) compared with the patients without aGVHD. In multivariate analysis, grades III to IV aGVHD was the only independent risk factor for cGVHD. Thus, further interventions should be considered in patients with severe aGVHD to prevent cGVHD.