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Background: Chemotherapy sensitivity, defined simply as at least a partial response to chemotherapy, is an important outcome predictor for non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity allogeneic hematopoietic stem cell transplantation (allo-HCT). The authors hypothesized that further differentiation of chemotherapy sensitivity by specific response, complete remission (CR) versus partial remission (PR) versus stable disease (SD) versus progression of disease (PD), correlates with post-transplant outcomes.Methods: The impact of pretransplant and early (28 days) post-transplant disease response on transplant outcomes was analyzed in 63 NHL patients treated with reduced-intensity allo-HCT.Results: The 3-year event-free survival (EFS) and overall survival (OS) (median potential follow-up after reduced-intensity allo-HCT = 58 months) for all patients was 37% and 47%, respectively. The 3-year EFS based on pretransplant response was: CR = 50%; PR = 66%; SD = 18%; no patient with PD pretransplant reached 3-year follow-up. The 3-year OS based on pretransplant response was: CR = 63%; PR = 69%; SD = 45%. The 3-year EFS based on post-transplant response was: CR = 57%; PR = 32%; SD = 33%; no patient with PD post-transplant reached 3-year follow-up. The 3-year OS based on post-transplant response was: CR = 65%; PR = 43%; SD = 50%. In multivariate analyses, pretransplant response was the best predictor of EFS (P < .0001). Pretransplant response (P < .0001) and age (P = .0035) were jointly associated with OS.Conclusions: These data suggest that NHL patients with pretransplant SD, generally considered inappropriate candidates, may benefit from reduced-intensity allo-HCT, and patients with pretransplant PD should only receive this therapy in clinical trials. [ABSTRACT FROM AUTHOR]

Competing Interests: We report no financial or personal relationships related to the submitted work. ERV declares (outside of the submitted work) consulting and speaking fees from Boehringer Ingelheim; consulting fees from GSK and AbbVie; and institutional support received for performing systemic sclerosis studies for Kadmon, Boehringer Ingelheim, Horizon, and Prometheus. BRB declares (outside of the submitted work) consulting fees from GentiBio; patents planned, issued, or pending for chimeric antigen receptor (CAR) T cells as therapeutic interventions for autoimmunity and alloimmunity, September 28, 2016 (publication number 20180264038), drug-resistant immune cells and methods of use thereof (application 62/672868, May 17, 2018), regulatory T cells and their use in immunotherapy and suppression of the autoimmune response, therapeutic methods involving modulating inflammasome activation of myeloid-derived suppressor cells, and methods and compositions for increasing the suppressive function of regulatory T-cells. SZP declares (outside of the submitted work) research support from the Center for Cancer Research at the National Cancer Institute through the US National Institutes of Health's Intramural Research Program. JV declares no relevant financial disclosures outside of the submitted work.

The intestinal microbiome has been mechanistically linked with health and many disease processes. Cancer is no exception. Both in solid tumors and hematologic malignancies, there is increasing evidence supporting the involvement of the intestinal microbiome in tumor development, disease progression, response to treatment, and treatment toxicity. Consistent with microbiome mediation of the immune system and the potent effect of the immune system on cancer, the most compelling evidence has been obtained in the setting of cancer immunotherapy. Here, we review the current state of knowledge about microbiome effects in myelodysplastic syndromes, identify gaps and challenges in related research, and provide insights for future work., Competing Interests: Declaration of competing interest A.R. has received consulting fees from Seres Therapeutics and serves as a member of an Emmes Data and Safety Monitoring Board, both outside of the scope of the present review., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Myelodysplastic syndromes/neoplasms (MDS) and related diseases are highly heterogeneous myeloid stem cell cancers that predominantly affect the elderly. The only curative treatment is allogeneic hematopoietic cell transplantation (HCT). Given the prevalence of age-related comorbidities, HCT in patients aged 65 years or older requires a highly personalized approach. This review summarizes disease risk stratification, treatment modalities, and outcomes for patients with MDS and related disorders, and discusses specific considerations and challenges for elderly patients undergoing HCT, including geriatric assessment, timing, conditioning treatment, donor and graft selection, and graft-versus-host disease prophylaxis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Purpose: Whether and how the oral microbiome and its changes in allogeneic hematopoietic cell transplantation (alloHCT) recipients may contribute to oral chronic GVHD (cGVHD) pathogenesis is unknown. In addition, although the oral and colonic microbiota are distinct in healthy adults, whether oral microbes may ectopically colonize the gut in alloHCT patients is unknown., Experimental Design: To address these knowledge gaps, longitudinal oral and fecal samples were collected prospectively in the multicenter Close Assessment and Testing for Chronic GVHD study (NCT04188912). Through shotgun metagenomic sequencing of the samples collected at baseline, oral cGVHD onset, first post-cGVHD onset visit, and 1-year post-HCT time points in patients with oral cGVHD (cases; N = 29) or without any cGVHD (controls; N = 51), we examined whether (i) oral and/or gut microbiomes and their longitudinal trajectories differ between cases and controls and (ii) oral and gut microbiomes overlap in alloHCT recipients, especially those developing cGVHD., Results: A total of 195 samples were analyzed. The onset of oral cGVHD was characterized by an expansion of Streptococcus salivarius and Veillonella parvula in the oral microbiome. High levels of oral/gut microbiota overlap were observed, particularly in patients with oral cGVHD, suggesting ectopic colonization of the gut by oral bacteria., Conclusions: The unusual coalescence of two distant niches in these patients may result in short- or long-term consequences for the host, a novel avenue for future research. In addition, this study suggests a contribution of the oral microbiome to oral cGVHD pathogenesis., (©2024 American Association for Cancer Research.)

Although lifestyle interventions have shown promise in oncology and for cancer survivorship, their potential to improve outcomes in allogeneic hematopoietic cell transplantation (allo-HCT) and chronic graft-versus-host disease (cGVHD) patients remains to be fully explored. Given the high rates of cardiovascular disease, metabolic syndrome, and secondary malignancy in this patient population, lifestyle modifications can serve as a vital frontline defense against chronic diseases. Current research has illuminated the potential supportive role of lifestyle interventions in the solid cancer patient population, which is encouraging future lifestyle medicine research for patients with hematologic malignancies and allo-HCT recipients. Recent studies have indicated the pernicious effects of poor lifestyle choices on the course of cGVHD development and survival. The intersection between certain pillars of lifestyle medicine (ie, nutrition and exercise) and allo-HCT patient outcomes has been more well documented than that of other pillars (ie, social relationships and spirituality). Ongoing randomized trials studying the effects of exercise and nutrition on clinical outcomes in cGVHD and allo-HCT patients may provide important future evidence of the role of lifestyle medicine in this patient population. In this review, we describe the current landscape of lifestyle medicine in allo-HCT and cGVHD, its potential, and propose ways to further develop this evolving field of medicine., (Copyright © 2024. Published by Elsevier Inc.)

Abstract: Chronic graft-versus-host disease (cGVHD) remains a significant problem for patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although in vivo lymphodepletion for cGVHD prophylaxis has been explored in the myeloablative setting, its effects after reduced-intensity conditioning (RIC) are not well described. Patients (N = 83) with hematologic malignancies underwent targeted lymphodepletion chemotherapy followed by a RIC allo-HSCT using peripheral blood stem cells from unrelated donors. Patients were randomized to 2 GVHD prophylaxis arms: alemtuzumab and cyclosporine (AC; n = 44) or tacrolimus, methotrexate, and sirolimus (TMS; n = 39), with the primary end point of cumulative incidence of severe cGVHD. The incidence of severe cGVHD was lower with AC vs TMS prophylaxis at 1- and 5-years (0% vs 10.3% and 4.5% vs 28.5%; overall, P = .0002), as well as any grade (P = .003) and moderate-severe (P < .0001) cGVHD. AC was associated with higher rates of grade 3 to 4 infections (P = .02) and relapse (52% vs 21%; P = .003) with no difference in 5-year GVHD-free-, relapse-free-, or overall survival. AC severely depleted naïve T-cell reconstitution, resulting in reduced T-cell receptor repertoire diversity, smaller populations of CD4Treg and CD8Tscm, but a higher ratio of Treg to naïve T-cells at 6 months. In summary, an alemtuzumab-based regimen successfully reduced the rate and severity of cGVHD after RIC allo-HSCT and resulted in a distinct immunomodulatory profile, which may have reduced cGVHD incidence and severity. However, increased infections and relapse resulted in a lack of survival benefit after long-term follow-up. This trial was registered at www.ClinicalTrials.gov as #NCT00520130., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Chronic graft-versus-host disease (GVHD) is an immune-mediated disorder that causes significant late morbidity and mortality following allogeneic hematopoietic cell transplantation. The "Close Assessment and Testing for Chronic GVHD (CATCH)" study is a multi-center Chronic GVHD Consortium prospective, longitudinal cohort study designed to enroll patients before hematopoietic cell transplantation and follow them closely to capture the development of chronic GVHD and to identify clinical and biologic biomarkers of chronic GVHD onset. Data are collected pre-transplant and every two months through one-year post-transplant with chart review thereafter. Evaluations include clinician assessment of chronic GVHD and its manifestations, patient-reported outcomes, multiple biospecimens (blood, saliva, tears, buccal mucosa and fecal samples, biopsies of skin and mouth), laboratory testing, and medical record abstraction. This report describes the rationale, design, and methods of the CATCH study, and invites collaboration with other investigators to leverage this resource. trial registration: This study is registered at www.clinicaltrials.gov as NCT04188912., Competing Interests: JP has been a consultant and advisory board member for Syndax, CTI Biopharma, Amgen, Regeneron, Incyte. He has received clinical trial support from Novartis, Amgen, Takeda, Janssen, Johnson and Johnson, Pharmacyclics, Abbvie, CTI Biopharma, and Bristol Myers Squibb. SZP received research support from the Center for Cancer Research at the National Cancer Institute through the National Institutes of Health Intramural Research Program, which includes Clinical Research Development Agreements with Celgene, Actelion, Eli Lilly, Pharmacyclics and Kadmon Corporation. NF Incyte Advisory Board SJL has received consulting fees from Mallinckrodt, Equillium, Kadmon, Novartis and Incyte; research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Sanofi, Syndax and Takeda, and drug supply from Janssen. She is on Incyte and Sanofi clinical trial steering committees. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Abstract: Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Background: Chronic graft-versus-host disease (cGVHD) is a debilitating late complication of hematopoietic stem cell transplantation. It is often accompanied by extensive symptom burden. No validated cGVHD patient-reported outcome (PRO) measure exists to evaluate cGVHD symptom bother in children and adolescents younger than 18 years. This paper presents the study protocol for a multi-center, two-phase protocol to develop a psychometrically valid pediatric cGVHD Symptom Scale (PCSS) and a companion caregiver-proxy measure to capture the symptom burden experienced by children with cGVHD. In the first phase of the study, our aim is to evaluate the comprehension, clarity and ease of response of the PCSS through cognitive interviewing and to iteratively refine the measure to optimize content validity. In the second phase of the study, we will quantitatively examine the measurement properties of the PCSS in children and their caregiver-proxies., Methods and Analysis: Eligible participants are children/adolescents ages 5-17 with cGVHD who are receiving systemic immunosuppressive treatment or have recently tapered to discontinuation. In the first phase, we are enrolling 60 child and caregiver-proxy dyads in three child age strata (5-7, 8-12, and 13-17 years old). Semi-scripted cognitive debriefing interviews are conducted to assess comprehension, clarity, and ease of response of each PCSS item with the child alone, and then jointly with the caregiver-proxy to explore discordant ratings. In phase two, an age-stratified cohort of 120 child-caregiver dyads will be enrolled to evaluate test-retest reliability, construct validity, and responsiveness. Anchors for known-groups validity include the PedsQL module and clinical variables, including cGVHD clinician-rated severity scores. In participants ages 13-17, we will also compare responses on the PCSS with those from the Lee cGVHD Symptom Scale, to gauge the youngest age at which adolescent respondents can comprehend this adult measure., Discussion: This study will yield a well-validated, counterpart measure to the Lee cGVHD Symptom Scale for use in children with cGVHD and their caregiver-proxies. This new patient-reported outcome measure can be integrated into clinical trials and care delivery for pediatric transplant survivors to improve the precision and accuracy with which their cGVHD symptom experience is captured., Clinical Trial Registration: www.ClinicalTrials.gov, NCT04044365., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mitchell, Hunter, Fry, Pavletic, Widemann and Wiener.)

Cutaneous sclerotic chronic graft-versus-host disease (cGVHD) is a common and highly morbid complication of allogeneic hematopoietic stem cell transplantation. Our goals were to identify signals active in the skin of patients with sclerotic cGVHD in an effort to better understand how to treat this manifestation and to explore the heterogeneity of the disease. We identified genes that are significantly upregulated in the skin of patients with sclerotic cGVHD (n = 17) compared with those in the skin of patients who underwent allogeneic hematopoietic stem cell transplantation without cutaneous cGVHD (n = 9) by bulk RNA sequencing. Sclerotic cGVHD was most associated with T helper 1, phagocytic, and fibrotic pathways. In addition, different transcriptomic groups of affected patients were discovered: those with fibrotic and inflammatory/T helper 1 gene expression (the fibroinflammatory group) and those with predominantly fibrotic/TGFβ-associated expression (the fibrotic group). Further study will help elucidate whether these gene expression findings can be used to tailor treatment decisions. Multiple proteins encoded by highly induced genes in the skin ( SFRP4 , SERPINE2 , COMP ) were also highly induced in the plasma of patients with sclerotic cGVHD (n = 16) compared with those in plasma of control patients who underwent allogeneic hematopoietic stem cell transplantation without sclerotic cGVHD (n = 17), suggesting these TGFβ and Wnt pathway mediators as candidate blood biomarkers of the disease.

Patients with chronic graft-versus-host disease (cGVHD) are at heightened risk for components of metabolic syndrome (MetS), yet the prevalence and impact of MetS in the cGVHD patient population remain unknown. Adult patients (n = 229) with cGVHD enrolled in the cross-sectional NIH cGVHD Natural History Study (NCT00092235) were evaluated for MetS at enrollment and for variables associated with MetS. A majority (54.1%, 124/229) of the cohort met the diagnostic criteria for MetS. Patients with higher body mass index and lower performance status scores were more likely to have MetS (P < 0.0001; P = 0.026; respectively). Higher circulating erythrocyte sedimentation rate, C-reactive protein, and creatinine concentrations, along with lower estimated glomerular filtration rate, were associated with MetS (P < 0.001; P < 0.004; P = 0.02; P = 0.002; respectively). Patients with MetS compared to patients without MetS had no statistical differences in survival or NRM (5-year OS: 64% [95% CI: 54.8-71.8%] vs. 75.1% [95% CI: 65.6-82.3%]; respectively; overall P = 0.20; 5-year NRM: 21.7% [95% CI: 13.6-30.9%] vs. 10.1% [95% CI: 4.4-18.7%]; respectively; overall P = 0.12). Additionally, there was no difference in cGVHD severity between the two groups. Given the high prevalence of MetS in this cohort, clinicians should screen for its presence before it develops into comorbidities that complicate the course of cGVHD treatment., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Chronic graft-versus-host disease (cGvHD) is a devastating complication of hematopoietic stem cell transplantation (HSCT). Effective early detection may improve the outcome of cGvHD. The potential utility of circulating cell-free DNA (cfDNA), a sensitive marker for tissue injury, in HSCT and cGvHD remains to be established. Here, cfDNA of prospectively collected plasma samples from HSCT recipients (including both cGvHD and non-cGvHD) and healthy control (HC) subjects were evaluated. Deconvolution methods utilizing tissue-specific DNA methylation signatures were used to determine cfDNA tissue-of-origin. cfDNA levels were significantly higher in HSCT recipients than HC and significantly higher in cGvHD than non-cGvHD. cGvHD was characterized by a high level of cfDNA from innate immune cells, heart, and liver. Non-hematologic tissue-derived cfDNA was significantly higher in cGvHD than non-cGvHD. cfDNA temporal dynamics and tissue-of-origin composition have distinctive features in patients with cGvHD, supporting further exploration of the utility of cfDNA in the study of cGvHD., Competing Interests: The authors declare no competing interest., (© 2023.)

Kidney complications have been studied in allogeneic hematopoietic stem cell transplant patients but not specifically among chronic graft-versus-host disease (cGVHD) patients. Participants (n = 365) enrolled in the cross-sectional cGVHD natural history study (NCT00092235) were assessed for kidney dysfunction and overall survival. Kidney dysfunction was analyzed for associations in univariate and multivariable analyses. Kidney dysfunction (eGFR < 60) was found in 64 patients, and 29 patients had moderate-severe kidney dysfunction (eGFR < 45). Patients with kidney dysfunction were more likely treated with cyclosporine at evaluation or to have received it for GVHD prophylaxis, or prior treatment of GVHD. Patients with kidney dysfunction were less severely affected by cGVHD of skin, mouth, and joints/fascia. In multivariable modeling, history of cyclosporine use (OR = 2.19, 95% CI 1.13-4.25), angiotensin receptor blocker use (OR = 5.57, 95% CI 1.49-20.84), proteinuria (OR = 2.39, 95% CI 1.19-4.79), lower CRP (OR = 0.95, 95% CI 0.91-0.99), lower C3 (OR = 0.98, 95% CI 0.97-0.99), and lower hemoglobin (OR = 0.70, 95% CI 0.58-0.84) were jointly associated with kidney dysfunction. Overall survival was lower in those with moderate-severe kidney dysfunction (p = 0.015), demonstrating the importance of addressing kidney dysfunction in this population. The association of kidney dysfunction with less severe cGVHD suggests an etiology unrelated to cGVHD but potentially a consequence of drug-related toxicities., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Chronic graft-versus-host disease (cGvHD) remains a prominent barrier to allogeneic hematopoietic stem cell transplantion as the leading cause of nonrelapse mortality and significant morbidity. Tremendous progress has been achieved in both the understanding of pathophysiology and the development of new therapies for cGvHD. Although our field has historically approached treatment from an empiric position, research performed at the bedside and bench has elucidated some of the complex pathophysiology of cGvHD. From the clinical perspective, there is significant variability of disease manifestations between individual patients, pointing to diverse biological underpinnings. Capitalizing on progress made to date, the field is now focused on establishing personalized approaches to treatment. The intent of this article is to concisely review recent knowledge gained and formulate a path toward patient-specific cGvHD therapy., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Approximately 90% of patients with myelodysplastic syndromes (MDSs) have somatic mutations that are known or suspected to be oncogenic in the malignant cells. The genetic risk stratification of MDSs has evolved substantially with the introduction of the clinical molecular international prognostic scoring system, which establishes next-generation sequencing at diagnosis as a standard of care. Furthermore, the International Consensus Classification of myeloid neoplasms and acute leukemias has refined the MDS diagnostic criteria with the introduction of a new MDS/acute myeloid leukemia category. Monitoring measurable residual disease (MRD) has historically been used to define remission status, improve relapse prediction, and determine the efficacy of antileukemic drugs in patients with acute and chronic leukemias. However, in contrast to leukemias, assessment of MRD, including tracking of patient-specific mutations, has not yet been formally defined as a biomarker for MDS. This article summarizes current evidence and challenges and provides a conceptual framework for incorporating MRD into the treatment of MDS and future clinical trials., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.

Chronic graft versus host disease (cGVHD) affects patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). This orphan disease poses a challenge for clinicians and researchers. The purpose of the cGVHD Dictionary is to provide a standardized structure for cGVHD databases on an international level, reconciling differences in data retrieval and facilitate database merging. It is derived from several consensus meetings of the EUROGRAFT consortium (European Cooperation in Science and Technology-COST Action CA17138) followed by a consensus process involving European Society for Blood and Marrow Transplantation (EBMT), US GvHD consortium and Center for International Bone Marrow Transplant Registry (CIBMTR). Databases used for the dictionary were: the National Institutes of Health (NIH) database, the Center for International Blood and Marrow Transplant Research, Applying Biomarkers to Minimize Long Term Effects of Childhood/Adolescent Cancer Treatment - Pediatric Blood and Marrow Transplant Consortium database, EBMT registry, the German-Austrian-Swiss GvHD registry, Italian Blood and Marrow Transplantation Society registry and Regensburg-Göttingen-Newcastle HSCT dataset. A four-part cGVHD Dictionary was formed based on the databases, consensus, and evidence in the literature. The Dictionary is divided into: (1) Patient characteristics, (2) Transplant characteristics, (3) cGVHD characteristics and (4) patient-reported quality of life, symptom burden and functional indicators., (© 2022. The Author(s).)

Chronic graft-versus-host disease (cGVHD) of the lung, or bronchiolitis obliterans syndrome (BOS), is a high-risk disease manifestation associated with poor outcomes. Currently available treatments have demonstrated limited clinical efficacy in this setting. Belumosudil is a novel oral selective rho-associated coiled-coil-containing protein kinase-2 inhibitor that was recently approved by the US Food and Drug Administration in the treatment of cGVHD. We identified 59 subjects with BOS who were enrolled and treated in 2 prospective clinical trials of belumosudil. Patients with BOS had a percentage predicted forced expiratory volume in 1 second (FEV1) of ≤79% at enrollment and clinician attribution of lung disease owing to cGVHD. The National Institutes of Health (NIH) cGVHD lung scores at enrollment were 1 (n = 30, 59%), 2 (n = 23, 39%), or 3 (n = 6, 10%). According to NIH response criteria, the best overall response rate (ORR) for lung cGVHD was 32% (partial response: 17%; complete response: 15%). Response rates were inversely proportional to baseline NIH GVHD lung score at enrollment (lung score 1: ORR 50%; lung score 2: ORR 17%, lung score 3: ORR 0%) (P = .006). In multivariable analysis, male sex, lower baseline NIH cGVHD lung score, and partial response to previous line of cGVHD therapy before enrollment were associated with higher rates of lung-specific response. No significant correlation was identified between pulmonary function evaluations and measures of patient symptoms (NIH lung symptom score or Lee Symptom Scale score for lung). In conclusion, belumosudil treatment was associated with lung-specific clinical responses for subjects with BOS, which were more commonly observed in less advanced disease. Optimization of treatment response evaluations remains a challenge in patients with BOS., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Chronic graft-versus-host disease (GVHD) is a major cause of late morbidity and non-relapse mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Its biology, however, remains poorly understood, making the studies of its biology and immunomodulatory therapies a difficult task. Such research is often hampered by lymphopenia which is common in these patients and precludes studies of critical cellular subsets across the spectrum of severity of disease. This study explores the potential of leukapheresis to safely acquire and efficiently store immune cells for immunology research in chronic GVHD., Methods: This is a cross-sectional study in which 132 consecutively accrued patients undergo optional research leukapheresis and a one-week comprehensive outpatient evaluation. Baseline clinical and laboratory data and efficiency of the procedure were reported., Results: Ninety-four of 132 patients (71%) achieved the goal collection of 2 × 10^9 PBMNCs with a mean volume processed of 4.6 L. Only mild decreases in hemoglobin, platelet, lymphocyte and monocytes were observed. All adverse events were mild (grade 1) and had resolved by the time of discharge from the apheresis unit., Conclusion: This study demonstrates feasibility, safety, and efficiency of research leukapheresis in a frail patient population. Results presented promote leukapheresis as a standard research practice option in studies of chronic GVHD in humans which may expedite advances in our understanding of this complex multisystem disease., (© 2022. The Author(s).)

Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality. The study was registered with a ClinicalTrials.gov identifier NCT00092235., (Published by Elsevier Inc.)

Chronic graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) owing to both the disease itself and the immunosuppressive agents used for treatment. Response criteria endorsed by the National Institutes of Health (NIH) Consensus Conference on Clinical Trials in chronic GVHD include both clinician-documented measures and patient-reported outcomes (PROs) since both are considered clinical benefits by the Food and Drug Administration. The correlation between clinically assessed responses in organs and PRO improvements in organ-specific symptoms has not been investigated in depth. We used data from 2 published studies of belumosudil, an oral rho-associated coiled-coil-containing protein kinase-2 (ROCK2) inhibitor, for chronic GVHD to test the correlation between clinical and PRO outcomes. Participants completed PROs at enrollment and every 1 to 2 cycles according to the study design. Individual organ responses (complete plus partial response) and clinically meaningful changes in PROs were defined according to published methods. Generalized estimating equation methods were used to correlate changes in PROs associated with clinical responses according to NIH criteria, accounting for missing information and repeated measures. Data from all doses in both trials were included without stratification. The liver and genital tract were not included owing to a lack of site-specific PROs. Our pooled analysis of clinical and PRO data included 170 patients enrolled in 2 belumosudil studies (NCT02841995, n = 54; NCT03640481, n = 132) for whom we had baseline PROs, at least 1 follow-up PRO, and at least 1 response assessment. There was a strong positive correlation between complete and partial organ and overall responses and changes in PRO symptom scores, as well as clinically meaningful improvements. For all organs except joints, esophagus, and lower gastrointestinal tract, there was at least 1 PRO statistically correlated with NIH organ response. These data support the use of PROs for response assessment to document clinically meaningful benefit in chronic GVHD clinical trials., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Objective: Autologous haematopoietic cell transplantation (AHSCT) improves immunologic dysfunction in patients with SLE. However, the curative potential of this therapy remains uncertain. This study reports outcomes in SLE patients receiving a lymphodepleting, reduced intensity regimen for AHSCT in SLE., Methods: Eight patients with SLE refractory to treatment, including i.v. cyclophosphamide (CYC), were enrolled. Five had LN and three CNS involvement as primary indications for transplant. Haematopoietic cell mobilization with CYC, G-CSF and rituximab was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of concurrent administration of CYC, fludarabine and rituximab. All immunosuppressive medications were discontinued at the start of mobilization and CS were rapidly tapered after the transplant., Results: Five of eight patients achieved a complete response, including a decline in the SLEDAI to zero, which was sustained in four patients for a median of 165 months (range 138-191). One patient achieved a partial response, which was followed by relapse at month 18. Two patients with nephritis and underlying comorbidities in most organs had early deaths from infection and multiorgan failure. AHSCT resulted in profound lymphodepletion, followed by expansion of Treg cells and repopulation of naive T and B cells. Patients with a complete response showed a sustained suppression of the SLE-associated IFN-induced gene signature, marked depletion of memory and plasmablast B cells and resultant sustained elimination of anti-dsDNA antibody., Conclusion: Durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory SLE following lymphodepleting AHSCT., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00076752., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by a US Government employee and is in the public domain in the US.)

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., Competing Interests: Declaration of Competing Interest G.D.E.C. received consultancy fees from Miltenyi Biotech. M.S. received consultancy fees from Chugai/Roche, Hexal/Sandoz, Gilead, AbbVie, Janssen-Cilag, Boehringer/Ingelheim, onkowissen.de, EUSA-Pharma, Novartis, AstraZeneca, Amgen, Medac, and Lilly, travel support from Chugai/Roche, Boehringer/Ingelheim, Celgene, Medac, UCB, Mylan, and honoraria from BMS, Novartis, AbbVie, AstraZeneca, Chugai/Roche, Janssen-Cilag, Gilead, Boehringer/Ingelheim. O.P. received honoraria or travel support from Astellas, Gilead, Jazz, MSD, Neovii Biotech, Novartis, Pfizer and Therakos, received research support from Gilead, Incyte, Jazz, Neovii Biotech and Takeda, and is a member of advisory boards to Jazz, Gilead, MSD, Omeros, Priothera, Shionogi and SOBI. BDS has received consultancy fees from Janssen, Legend Biotech, Kite/Gilead, Celgene, BMS, and Incyte, and is a member of advisory board to In8bio. W.T.K. received grant support and consulting fees from Biogen and NControl Therapeutics, Inc. M. B.-H. received speaker fees from Alexion and Sanofi and received a grant for an advanced training course from Norvatis. R.Z. received speaker fees from Novartis, Incyte and Mallinckrodt. K.A. received travel support from Alexion, Bayer, Biogenldec, MerckSerono, Novartis, Teva (until 2014) and received honoraria from Biogenldec. Y.I. served on advisory boards for Novartis, Janssen, and Meiji Seika Pharma. S.J.L. received consultant fees from Mallinckrodt, Equillium, Kadmon; research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, Takeda; drug supply from Janssen; she is on an Incyte Steering Committee. S.P. received research support from the Center for Cancer Research at the National Cancer Institute through the National Institutes of Health Intramural Research Program, which includes Clinical Research Development Agreements with Celgene, Actelion, Eli Lilly, Pharmacyclics and Kadmon Corporation. D.W. received research grant support from Novartis and honoraria from Novartis, Mallinckrodt, Behring, Takeda, Neovii, Gilead and Pfizer., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Pulmonary chronic graft-versus-host disease (PcGVHD) is a devastating complication of allogeneic hematopoietic stem cell transplant (HCT). The 2014 National Institutes of Health cGVHD consensus criteria (NIH criteria) only captures bronchiolitis obliterans syndrome (BOS). In this study, we adapted the 2019 International Society for Heart and Lung Transplantation (ISHLT) criteria of chronic lung allograft dysfunction (CLAD) to define novel phenotypes of PcGVHD and compared the performance of this criteria with the NIH criteria to identify patients with high-risk PcGVHD. We reviewed consecutive patients in a cGVHD natural history protocol (#NCT00092235) and adapted the 2019 CLAD criteria (the adapted criteria) to define PcGVHD as post-HCT forced expiratory volume at 1 second < 80% predicted value, with 4 phenotypes: obstructive, restrictive, mixed obstructive/restrictive, and undefined. An independent adjudication committee evaluated subjects for diagnosis and phenotyping. We identified 166 (47.4%) patients who met the adapted criteria, including obstruction (n = 12, 3.4%), restriction (n = 67, 19.1%), mixed obstruction/restriction (n = 47, 13.4%), and undefined (n = 40, 11.4%). In these patients, less than half (n = 78) met the NIH criteria for BOS (NIH+); the rest (n = 88) did not (NIH-). The NIH- subjects showed increased risk of death compared with those without PcGVHD (hazard ratio = 1.88, 95% confidence interval = 1.20-2.95; P = .006) that was similar to NIH+ subjects (P = .678). Our study demonstrated the potential of the adapted criteria in identifying patients with high-risk PcGVHD that have been missed by the NIH criteria. The adapted criteria could become a valuable tool to better phenotype and study lung disease in cGVHD., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Bronchiolitis obliterans syndrome (BOS) is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation (HCT). Montelukast interrupts cysteinyl leukotriene (CysLT) activity and may diminish the activation and homing of cells to bronchioles and subsequent fibrosis. We performed a prospective phase II trial to test whether montelukast altered lung decline for patients with BOS after HCT. In this single-arm, open-label, multi-institutional study, the primary endpoints were stability or improvement (<15% decline) in forced expiratory volume in 1 second (FEV1) and a <1-point decline in the slope of FEV1 after 6 months of treatment. Secondary endpoints included symptom and functional responses and immune correlates investigating the role of leukotrienes in BOS progression. The study enrolled 25 patients with moderate to severe lung disease after 3 months of stable cGVHD therapy. Montelukast was well tolerated, and no patient required escalation of BOS-directed therapy. At the primary endpoint, all 23 evaluable patients met the criteria for treatment success using FEV1% predicted, and all but 1 patient had stable or improved FEV1 slope. In those with a >5% improvement in FEV1, clinically meaningful improvements were seen in the Lee scores of breathing, energy, and mood. Improvements in the Human Activity Profile and 6-minute-walk test were observed in those with a <5% decline in FEV1. Overall survival was 87% at 2 years. Immune correlates showed elevated leukotriene receptor levels on blood eosinophils and monocytes versus healthy controls, elevated urine leukotrienes in 45% of the cohort, and CysLT receptors in bronchoalveolar lavage subsets and a predominance of Th2 cells, all pretreatment. These data suggest that montelukast may safely halt the progression of BOS after HCT, and that leukotrienes may play a role in the biology of BOS., (Copyright © 2022. Published by Elsevier Inc.)

Chronic graft-versus-host disease (cGVHD) is an important systemic complication of allogeneic haematopoietic stem cell transplantation with heterogeneous, multi-organ involvement that can lead to increased morbidity and mortality. Despite significant advances in understanding the complex pathophysiology driving the disease, curative treatment options remain suboptimal. The past decade, however, has seen much growth in collaborative research efforts and standardization of criteria for clinical trials that have led to discovery of several new second-line therapies in cGVHD. The key to successful cGVHD control and management includes a comprehensive and sustained multidisciplinary effort with emphasis on ancillary and supportive care for these patients. The focus of this review is to summarize the new developments in systemic, organ-specific, and topical treatments in the management of cGVHD that emerged since the 2014 NIH consensus conference., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Chronic graft-versus-host disease (cGVHD) targets include the oral mucosa and salivary glands after allogeneic hematopoietic stem cell transplant (HSCT). Without incisional biopsy, no diagnostic test exists to confirm oral cGVHD. Consequently, therapy is often withheld until severe manifestations develop. This proteomic study examined saliva and human salivary gland for a biomarker profile at first onset of oral cGVHD prior to initiation of topical steroid therapy. Whole saliva collected at onset of biopsy-proven oral GVHD was assessed using liquid chromatography-coupled tandem mass spectrometry with identification of 569 proteins, of which 77 significantly changed in abundance. ZG16B, a secretory lectin protein, was reduced 2-fold in oral cGVHD saliva (p <0.05), and significantly decreased in salivary gland secretory cells affected by cGVHD. Single-cell RNA-seq analysis of healthy MSG localized ZG16B expression to two discrete acinar cell populations. Reduced ZG16B expression may indicate specific cGVHD activity and possibly general salivary gland dysfunction., Competing Interests: No competing interests from the authors., (© 2021.)

Limited information is available regarding clinical and biological properties of fatigue in patients with chronic graft-versus-host disease (cGvHD). Patients with moderate-to-severe cGvHD per NIH criteria were enrolled on a cross-sectional study and categorized as "fatigued" if SF-36 vitality score was <40. Clinical and laboratory parameters of fatigued (n = 109) and nonfatigued patients (n = 72) were compared. In univariate analysis, walk velocity, NIH joint-fascia score, human activity profile, and SF-36 physical and mental health self-report scales were correlates of fatigue. No cGvHD biomarkers were associated with fatigue. NIH joint score, Lee sleep and depression questions, and PG-SGA activities and function score jointly predicted fatigue. Though higher rates of depression and insomnia were reported in the fatigued group, antidepressant or sleep aid use did not differ between groups. Survival ratio was not significantly different by fatigue status. Pathophysiology of fatigue in patients with cGvHD is complex and may involve mechanisms unrelated to disease activity. Patients with cGvHD experiencing fatigue had higher rates of untreated depression and insomnia, highlighting the need to focus clinical management of these conditions to improve health-related quality of life., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Subsequent cancer (SC) is a significant cause of morbidity and mortality in long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) and treatment-related immunosuppression have been recognized as risk factors for SC. This study sought to investigate the incidence and risk factors for SC in patients with established cGVHD, assessed separately for onset of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)-categorized into nonmelanoma skin cancer (NMSC)-and all cancers other than NMSC. Two hundred and four patients were enrolled in the prospective cross-sectional cGVHD Natural History Study and underwent comprehensive clinical evaluation. Patients were followed-up with an annual survey. The cumulative incidences of NMSC and cancers other than NMSC with competing risks were estimated separately, and transplantation- and cGVHD-related factors were assessed for association with outcomes using Gray's test and multivariable Cox models. The time period for all analyses began at 2 years postevaluation to restrict analyses to patients presumed to not have had SC present at evaluation. Nineteen patients were diagnosed with NMSC and 19 were diagnosed with cancers other than NMSC, with 10-year cumulative incidences of 15.5% (95% confidence interval, 9.0% to 27.6%) and 13.8% (95% CI, 8.2% to 20.8%), respectively. Age at transplantation (hazard ratio [HR], 1.94; 95% CI, 1.23 to 3.06) and higher C-reactive protein level at evaluation (HR, 9.49; 95% CI, 1.26 to 71.58) were jointly associated with NMSC, and gastrointestinal cGVHD at evaluation (HR, 0.26; 95% CI, 0.09 to 0.78) was associated with reduced risk of NMSC. T cell depletion at transplantation (HR, 3.09; 95% CI, 1.17 to 8.20), lymphoma as an indication for transplantation (HR, 3.96; 95% CI, 1.56 to 10.05), and oral cGVHD severity at evaluation (HR, 4.36; 95% CI, 1.52 to 12.46) were jointly associated with cancers other than NMSC. This study estimates the incidence of SC in a population of allo-HSCT recipients with severe cGVHD and identifies correlations with the subsequent development of SC. These factors seem to differ between NMSC and cancers other than NMSC. Further longitudinal investigations accounting for dynamic and cumulative processes are needed to improve our understanding and management of SC., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)