RESUMO
BACKGROUND: Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit-risk balance. METHODS: This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient's response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. RESULTS: Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1-87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9-48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). CONCLUSIONS: Belumosudil treatment demonstrated a favorable benefit-risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04930562.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Humanos , Acetamidas , Corticosteroides/uso terapêutico , Doença CrônicaRESUMO
Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74- NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.
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Transplante de Medula Óssea , Doença Enxerto-Hospedeiro , Células Matadoras Naturais , Transplante Homólogo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Animais , Camundongos , Humanos , Transplante de Medula Óssea/efeitos adversos , Doença Crônica , Masculino , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Modelos Animais de Doenças , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Camundongos Endogâmicos C57BL , Reconstituição Imune , Síndrome de Bronquiolite ObliteranteRESUMO
(1) The aim of the study was to analyze the salivary concentrations of lysozyme, lactoferrin, and sIgA antibodies in adult patients in the late period after allogeneic stem cell transplantation (alloHSCT). The relationship between these concentrations and the salivary secretion rate and the time elapsed after alloHSCT was investigated. The relationship between the concentrations of lysozyme, lactoferrin, and sIgA and the titer of the cariogenic bacteria S. mutans and L. acidophilus was assessed. (2) The study included 54 individuals, aged 19 to 67 (SD = 40.06 ± 11.82; Me = 39.5), who were 3 to 96 months after alloHSCT. The concentrations of lysozyme, lactoferrin, and sIgA were assessed in mixed whole resting saliva (WRS) and mixed whole stimulated saliva (WSS). (3) The majority of patients had very low or low concentrations of the studied salivary components (WRS-lysozyme: 52, lactoferrin: 36, sIgA: 49 patients; WSS-lysozyme: 51, lactoferrin: 25, sIgA: 51 patients). The levels of lactoferrin in both WRS and WSS were statistically significantly higher in the alloHSCT group than in the control group (CG) (alloHSCT patients-WRS: M = 40.18 µg/mL; WSS: M = 27.33 µg/mL; CG-WRS: M = 17.58 µg/mL; WSS: 10.69 µg/mL). No statistically significant correlations were observed between lysozyme, lactoferrin, and sIgA concentrations and the time after alloHSCT. In the group of patients after alloHSCT a negative correlation was found between the resting salivary flow rate and the concentration of lactoferrin and sIgA. The stimulated salivary flow rate correlated negatively with lactoferrin and sIgA concentrations. Additionally, the number of S. mutans colonies correlated positively with the concentration of lysozyme and sIgA. (4) The concentrations of non-specific and specific immunological factors in the saliva of patients after alloHSCT may differ when compared to healthy adults; however, the abovementioned differences did not change with the time after transplantation.
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Transplante de Células-Tronco Hematopoéticas , Muramidase , Adulto , Humanos , Muramidase/metabolismo , Lactoferrina/metabolismo , Saliva/metabolismo , Imunoglobulina A Secretora/metabolismo , Proteínas e Peptídeos SalivaresRESUMO
Dysbiosis of the gut microbiota has been reported to increase early complications after allogeneic haematopoietic stem cell transplantation (allo-HSCT). However, it remains unclear whether gut microbial alterations persist during late complications, such as chronic graft-versus-host disease (cGVHD) or secondary cancers. Here, we analysed the gut microbiota of 59 patients who survived for 1-21.7 years (median, 6.4 years) after allo-HSCT. Long-term survivors showed lower gut microbial diversity than the age- and sex-matched healthy controls. This decreased diversity was reflected in the reduced abundance of the butyrate-producing bacteria. Patients with a history of grade 3 acute graft-versus-host disease (aGVHD) exhibited higher Veillonella abundance than patients with a history of grade 1-2 or non-aGVHD cases. The abundance of Faecalibacterium showed no decrease only in limited cGVHD cases. Additionally, the microbial structure in the secondary cancer group was significantly different (p < 0.05) from that in the non-secondary cancer group. This study is the first to show that microbial dysbiosis is present over a 10-year lifetime after discharge following allo-HSCT. Our results suggest that these prolonged gut microbial alterations may be associated with the development and exacerbation of late complications in post-transplant survivors.
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Síndrome de Bronquiolite Obliterante , Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Disbiose/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Alta do Paciente , Doença Enxerto-Hospedeiro/microbiologiaRESUMO
OBJECTIVES: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a newly discovered immune checkpoint (IC) that exhibits immunosuppressive function in the regulation of immune system. Activation of TIGIT signaling has emerged as a promising approach for autoimmune disease immunotherapy, such as systemic lupus erythematosus (SLE). METHODS: We generated a chimeric protein, TIGIT-immunoglobulin (Ig), by fusing the extracellular domain of murine TIGIT to the Fc region of mouse IgG2a, which was used to investigated the effect of activating the TIGIT signaling in murine lupus models (MRL/lpr and chronic graft-versus-host disease mice). Treated mice were harvested, and samples of serum, kidney, and spleen were collected for outcome evaluation. In vitro treatment of TIGIT-Ig in B cells was used for exploring the roles of TIGIT in toll-like receptor 7 (TLR7)-mediated B cell differentiation and antibody production. RESULTS: TIGIT-Ig treatment delayed disease progression in both lupus models, accompanied by a decrease in the production of anti-double stranded DNA antibodies (anti-dsDNA), proteinuria, proteinuria/creatinine, and Ig kidney deposition. Additionally, the group treated with TIGIT-Ig displayed a decreased proportion of T helper cell (Th)1 cells, T follicular helper (Tfh) cells, and B-cell subsets, including germinal center B cells (GC B), plasmablasts, and plasma cells, compared to the group treated with control IgG. Interestingly, we also observed an increased proportion of Tregs in the spleen of the TIGIT-Ig group. We have discovered a new way in which activating the TIGIT pathway can regulate B-cell differentiation through the SPI-B-PAX5-XBP1 pathway, resulting in a reduction in autoantibodies. CONCLUSION: Together, TIGIT may be a promising IC target for SLE treatment.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Animais , Camundongos , Nefrite Lúpica/terapia , Camundongos Endogâmicos MRL lpr , Autoanticorpos , Receptores Imunológicos/genética , Proteinúria , Diferenciação Celular , Modelos Animais de DoençasRESUMO
BACKGROUND: Approximately 30-70% of patients who have undergone allogeneic (allo) hematopoietic stem cell transplantation (HSCT) eventually experience chronic graft-versus-host disease (cGVHD). Patients who develop steroid-refractory (SR)-cGVHD are the most severely impacted due to significant disease and financial burden. There remains an unmet need for safe, efficacious, and accessible treatments for these patients. The objective of this study was to determine the cost effectiveness of ruxolitinib for treatment of SR-cGvHD from the Singapore healthcare system perspective. METHODS: Based on data from the REACH3 randomized open-label trial, a semi-Markov model was developed to evaluate cost-effectiveness of ruxolitinib compared with investigators' choice of best alternative therapy (BAT) for treatment of patients > 12 years of age with SR-cGVHD in Singapore over a 40-year time horizon. The model only considered direct medical-care costs related to the treatment of SR-cGVHD and reported them in Singapore Dollars (SGD). Half-cycle correction was applied to all costs and outcomes, which were discounted at 3%. Probabilistic sensitivity analysis (PSA), one-way sensitivity analysis (OWSA), and scenario analysis were conducted to explore the drivers of uncertainty in the model. RESULTS: In the deterministic base case, more life years (LY; 10.28 vs. 9.42) and quality-adjusted life years (QALYs; 7.31 vs. 6.51) were gained with ruxolitinib than BAT at higher costs (SGD 303,214 vs. SGD 302,673) leading to an incremental cost-effectiveness ratio (ICER) of SGD 677/QALY. At a willingness-to-pay threshold of SGD 75,000/QALY gained, PSA found that ruxolitinib had a 78.52% probability of being cost-effective. Findings were sensitive to variations in non-responder utilities in the BAT arm and duration of BAT treatment in the OWSA, or comparison to either methotrexate (MTX) or mycophenolic acid as a single comparator in the scenario analysis. ICERs remained lower than SGD 75,000/QALY in all other tested variations and scenarios. CONCLUSION: Ruxolitinib is likely to be cost-effective from Singapore healthcare system's perspective for patients with SR-cGVHD, which is promising in the management of patients with unmet clinical needs.
RESUMO
OBJECTIVE: Chronic graft-versus-host disease (cGVHD) is the main cause of late non-relapse mortality following hematopoietic cell transplantation. Oral mucosal (om-) cGVHD is common, but diagnosis and assessment rely on clinical interpretation and patient-reported symptoms. We investigated immunohistopathological profiles with respect to om-cGVHD severity disease duration. MATERIAL AND METHODS: Ninety-four transplant patients and 15 healthy controls (n = 212 biopsies) were investigated by quantitative immunohistochemistry for T cells (CD4, CD8, and CD5), B cells (CD19 and CD20), macrophages (CD68), and Langerhans cells (CD1a). RESULTS: We found significant increases in T (CD4, CD8) and monocytic (CD68) cells in om-cGVHD, and a notable absence of B (CD19 and CD20) cells. Histopathological activity correlated with increased CD4, CD8 and CD68. However, CD4 was associated with mild om-cGVHD, whereas CD8 and CD68 were found to be elevated in severe om-cGVHD. CD8 and CD68 levels were raised at disease onset, but during late phase, the predominant CD68 population was accompanied by CD4. CONCLUSION: Oral cGVHD is a heterogenous clinical disorder, but our knowledge of the underlying biology remains limited. We highlight the importance of CD4, CD8 and CD68 immune profiling, together with histological grading for the staging of oral cGVHD, to broaden our understanding of the biology and individual disease course.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfócitos T , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mucosa Bucal/patologia , Doença CrônicaRESUMO
Chronic graft-versus-host disease (cGVHD) presents with dermal inflammation and fibrosis. We investigated the characteristics of extracellular vesicles (EVs) obtained from cGVHD patients, and their potential effects on human dermal fibroblast (NHDF) cells. The anti-inflammatory and anti-fibrotic effects of placental EVs were also explored given their known anti-inflammatory properties. Fourteen cGVHD patients' EVs contained higher levels of fibrosis-related proteins, TGFß and α-smooth muscle actin (αSMA), compared to EVs from thirteen healthy subjects. The exposure of NHDF cells to the patients' EVs increased the NHDF cells' TGFß and αSMA expressions. Placental EVs derived from placental-expanded cells (PLX) (Pluri Inc.) and human villous trophoblast (HVT) cells expressing the mesenchymal markers CD29, CD73, and CD105, penetrated into both the epidermal keratinocytes (HACATs) and NHDF cells. Stimulation of the HACAT cells with cytokine TNFα/INFγ (0.01-0.1 ng/µL) reduced cell proliferation, while the addition of placental EVs attenuated this effect, increasing and normalizing cell proliferation. The treatment of NHDF cells with a combination of TGFß and placental HVT EVs reduced the stimulatory effects of TGFß on αSMA production by over 40% (p = 0.0286). In summary, EVs from patients with cGVHD can serve as a biomarker for the cGVHD state. Placental EVs may be used to regulate dermal inflammation and fibrosis, warranting further investigation of their therapeutic potential.
Assuntos
Vesículas Extracelulares , Doença Enxerto-Hospedeiro , Humanos , Feminino , Gravidez , Placenta/metabolismo , Vesículas Extracelulares/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Inflamação/metabolismo , Fibrose , Doença Enxerto-Hospedeiro/patologiaRESUMO
Chronic graft versus host disease (cGVHD) is an important transplant complication that affects the quality of life of the recipient by causing organ damage after hematopoietic stem cell transplantation. Prospective controlled studies conducted to date for the treatment of the disease are limited. The results obtained in current studies are not sufficient to establish a standard treatment algorithm. Therefore, clinical experience and adequate clinical observations of the transplant team come to the fore for the treatment strategy to be established. Rational use of available instruments is possible, provided that we understand the mechanisms of the disease and use validated diagnostic and response criteria. In this study, we tried to create a practical workflow by evaluating current literature data.
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Doença Enxerto-Hospedeiro/terapia , Doença Crônica , Humanos , Estudos ProspectivosRESUMO
Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplant, which is known to be mediated by cytotoxic T-cell effectors and dysregulated inflammatory cytokines. Similarly, the lung injury observed in severe COVID-19 cases appears to be related to a massive production of pro-inflammatory cytokines. The selective JAK1/2 inhibitor ruxolitinib has shown promising results in the context of GVHD, and different trials are currently underway in patients with severe COVID-19; nevertheless, no clinical observation of safety or efficacy of treatment with ruxolitinib in this context has been published yet. We describe a first case of severe COVID-19 developed after hematopoietic stem cell transplantation in a patient with a concomitant chronic GVHD (cGVHD), in which a treatment with ruxolitinib was administered with good tolerance and positive outcome.
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COVID-19/complicações , COVID-19/patologia , Doença Enxerto-Hospedeiro/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pirazóis/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Pirimidinas , SARS-CoV-2RESUMO
Anti-thymocyte globulin (ATG) is an established approach to decrease chronic GVHD (cGVHD), yet the exact mechanism is uncertain. To better understand the mechanism of action of ATG in preventing cGVHD, we evaluated the day 100 immune reconstitution of known cGVHD cellular biomarkers using patients from the randomized Canadian Bone Marrow Transplant Group (CBMTG) 0801 trial, which demonstrated a significant impact of ATG on cGVHD. In a separate companion biology study, we evaluated the impact of ATG prophylaxis on cGVHD cellular markers at day 100 in 40 CBMTG 0801 patients. Analysis focused on previously identified cGVHD cellular biomarkers, including naive helper T (Th) cells, recent thymic emigrant (RTE) Th cells, CD21low B cells, CD56bright NKreg cells, and Treg cells ST2, osteopontin, soluble B-cell activating factor (sBAFF), Interleukin-2 receptor alpha (sCD25), T-cell immunoglobulin and mucin domain-3 (TIM-3), matrix metallopeptidase 3, ICAM-1, C-X-C motif chemokine 10 (CXCL10), and soluble aminopeptidase N. The ATG-treated group had a >10-fold decrease in both RTE naive Th and naive Th cells (P < .0001) and a 10-fold increase in CD56bright NKreg cells (P < .0001). Treg cells, conventional Th cells, CD21low B cells, and all plasma markers were not affected. In the populations most affected by ATG, changes in naive Th cells were associated with the later development of cGVHD. This analysis suggests that ATG primarily impacts on cGVHD through suppression of naive Th cell expansion after transplantation. These associations need to be validated in additional studies.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Soro Antilinfocitário/uso terapêutico , Canadá , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Condicionamento Pré-TransplanteRESUMO
An open-label phase 2 study of topical dexamethasone versus tacrolimus solutions in new-onset oral chronic graft-versus-host disease (cGVHD) revealed the superior efficacy of dexamethasone. The objective of this study was to report long-term patterns of topical therapy utilization and clinical outcomes in this cohort after completing the 30-day trial. A retrospective record review was performed from the date of study completion to January 2017. Topical therapies, systemic immunosuppressive therapies, objective measurements (National Institutes of Health severity score, oral mucosal scores), patient- reported outcomes (dryness, sensitivity, pain), and adverse events were recorded for oral cGVHD-related outpatient visits. Follow-up (FU) periods were defined as FU1 (0-1 month), FU2 (1-3 months), FU3 (3-6 months), FU4 (6-12 months), FU5 (12-18 months), and FU6 (18-24 months). Forty patients (52.5% males, median age, 56 years) completed the clinical trial and were included in the analysis. Topical therapies used were dexamethasone, tacrolimus, clobetasol, or a combination of these agents. At FU1, all 40 patients were receiving topical therapy, which decreased to 54.5% (12 out of 22) at FU6. Clinician-reported oral mucosal scores (0-12) and patient-reported sensitivity scores (0-10) decreased over time from FU1 (median mucosal score, 3; sensitivity, 3) to FU6 (mucosal score, 1; sensitivity, 2). Intralesional steroid therapy was provided to 6 patients for management of refractory oral ulcerations, all within the first year of follow-up. Patients with de novo symptomatic oral cGVHD may require long-term care with topical immunomodulatory therapy for up to 2 years, if not longer. Topical steroid and tacrolimus therapies are safe and effective in managing symptomatic oral cGVHD. Second-line topical therapy for refractory oral cGVHD requires further investigation.
Assuntos
Doença Enxerto-Hospedeiro , Doenças da Boca , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/uso terapêuticoRESUMO
Graft-versus-host disease (GVHD) can manifest as acute or chronic complications in patients after hematopoietic cell transplantation (HCT). Oral chronic GVHD (cGVHD) occurs in approximately 70% of HCT recipients and includes lichenoid-like mucosal reactions, restricted mouth opening, and salivary gland dysfunction. However, the underlying histopathological presentation remains to be validated in large cohorts. We characterized the histopathological features of oral mucosal cGVHD and devised a scoring model in a large patient cohort (n = 112). Oral mucosal biopsy sections (n = 303) with and without oral cGVHD were identified from archived and current HCT recipients with additional healthy controls. Histological screening was performed on hematoxylin and eosin-stained and periodic acid-Schiff-stained sections. A points-based grading tool (0 to 19, grade 0 to IV) was established based on intraepithelial lymphocytes and band-like inflammatory infiltrate, atrophic epithelium with basal cell liquefaction degeneration, including apoptosis, as well as separation of epithelium and pseudo-rete ridges. Validation involved 62 biopsy specimens, including post-HCT (n = 47) and healthy (n = 15) specimens. Remaining biopsy specimens (n = 199) were blindly graded by 3 observers. Histological severity was correlated with clinical diagnostic and distinctive features, demonstrating a spectrum of individual patient severity, including frequent signs of subclinical GVHD in healthy mucosa. However, oral cGVHD presented with significantly higher (P < .001) scores compared with HCT controls, with moderate to high positive likelihood ratios for inflammatory infiltrate, exocytosis, and basal membrane alterations. The grade II-IV biopsy specimens demonstrated a histopathological diagnosis of active mucosal lichenoid-like cGVHD, highlighting the importance of correlating clinical presentation with the dynamic histopathological processes for improved patient stratification. In addition, this tool could be used for assessing treatments, pathological processes, and immune cellular content to provide further insight into this debilitating disease.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doenças da Boca , Doença Crônica , Estudos de Coortes , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Doenças da Boca/etiologia , Mucosa BucalRESUMO
Ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, has recently been proposed for steroid-refractory chronic graft-versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), particularly in severe skin cGVHD. Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome (BOS) or restrictive lung disease (RLD) from skin sclerosis. To date, no treatment has shown a benefit on lung function in this context. We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of 70 patients diagnosed with sclerotic-type skin cGVHD between March 2015 and April 2018. Among these patients, 36 received ruxolitinib. To handle confounding by indication bias, exposure groups were matched on the propensity score to receive ruxolitinib, incorporating age, myeloablative conditioning, total body irradiation, BOS, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and tobacco use at the time of cohort entry, as well as the time from transplantation. The 1:1 matching used a greedy-matching algorithm with replacement, with a caliper of 0.10. FVC and FEV1 trajectories during follow-up were compared in the matched samples, using linear mixed-effects models. The median duration of follow-up of the 46 matched patients was 58 months (interquartile range, 32 to 84 months). Ten patients had an RLD (6 exposed, 4 unexposed), and 13 patients were diagnosed with BOS (8 exposed, 5 unexposed). FEV1 decreased significantly over time independent of exposure to ruxolitinib (P < .0001). The FEV1 trajectory was similar in the exposed patients and the unexposed patients (Pâ¯=â¯.11). In conclusion, ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in allogeneic HSCT recipients with sclerotic-type skin cGVHD.
Assuntos
Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Bronquiolite Obliterante/tratamento farmacológico , Bronquiolite Obliterante/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pulmão , Nitrilas , Pirazóis , Pirimidinas , Estudos RetrospectivosRESUMO
The present study was conducted to investigate cellular and molecular features of chronic graft-versus-host disease fibroblasts (GVHD-Fbs) and to assess the effectiveness of nilotinib as a fibrosis modulator. Growth kinetics, phenotype, and differentiation of cultured skin biopsy-derived GVHD-Fbs were compared with normal fibroblasts from both a dermal cell line (n-Fbs) and healthy individuals undergoing cosmetic surgery (n-skin-Fbs). Collagen genes (COL1α1/COL1α2) and p-SMAD2 expression were assessed by real-time PCR and immunofluorescence. The in vivo effects of nilotinib on chronic GVHD (cGVHD)-affected skin were investigated by immunohistochemistry; the relationship to TGF-ß plasma levels was assessed. Although the morphology, phenotype, and differentiation of cultured GVHD-Fbs were comparable to normal fibroblasts, growth was slower and senescence was reached earlier. The expression of COL1α1 and COL1α2 mRNAs was respectively 4 and 1.6 times higher in cGVHD-Fbs (P = .02); the addition of TGF-ß increased n-Fbs, but not GVHD-Fbs, collagen gene expression. Compared with the baseline, the addition of 1 µM nilotinib induced 86.5% and 49% reduction in COL1α1 and COL1α2 expression in cultured GVHD-Fbs, respectively (P< .01). In vivo immunohistochemistry analysis of skin biopsy specimens from patients with cGVHD showed strong baseline staining for COL1α1 and COL1α2, which decreased sharply after 180 days of nilotinib; immunofluorescence revealed TGF-ß inhibition and p-Smad2 reduction at the intracellular level. Of note, nilotinib treatment was associated with normalization of TGF-ß levels both in culture supernatants and in plasma. In general, the data show that cGVHD fibroblasts promote fibrosis through abnormal collagen production induced by hyperactive TGF-ß signaling. TGF-ß inhibition at the intracellular and systemic level represents an essential antifibrotic mechanism of nilotinib in a clinical setting.
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Doença Enxerto-Hospedeiro , Fator de Crescimento Transformador beta , Células Cultivadas , Colágeno , Fibroblastos , Fibrose , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Humanos , Pirimidinas , Pele/patologiaRESUMO
We retrospectively analyzed the safety and efficacy of cyclophosphamide (cyclo) for salvage treatment of chronic graft-versus-host disease (cGvHD) and cGvHD-associated (glomerulo-)nephritis at our center between 01/2010 and 11/2019. We identified 13 patients (pts) receiving cyclo for treatment of moderate (3/13) and severe (6/13) steroid-refractory cGvHD, cGvHD-associated (glomerulo-)nephritis (3/13), or vasculitis-like CNS manifestation of cGvHD (1/13). Cyclo was started on median day 509 (range 42-8193) after cGvHD onset; the median duration of application was 153 days (range 14-486) with 2/13 currently continuing treatment. The National Institute of Health organ grading and the intensity of immunosuppression (IS) were assessed at cyclo start and repeated after 3, 6, and 12 months. Response assessment was stopped at the start of any additional new IS. The median time of follow up was 407 days (range 86-1534). Best response was 1/13 CR, 6/13 PR, 4/13 SD, 1/13 MR, and 1/13 PD (ORR 54%). Significant and durable response was observed especially in cGvHD-associated (glomerulo-)nephritis (3/3). Infectious complications > CTCAE grade III were observed in 3/12 pts. During cyclo therapy, none of the pts suffered from recurrence of underlying malignancy. Overall, cyclo was relatively well tolerated and showed responses in heavily pretreated patients but requires further evaluation within clinical trials.
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Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/terapia , Imunossupressores/uso terapêutico , Terapia de Salvação/métodos , Adulto , Idoso , Doença Crônica , Estudos de Coortes , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo/métodosRESUMO
cGVHD is a significant cause of morbidity and mortality after transplant. Ibrutinib has been studied as treatment for cGVHD in the adult population. Pediatric dosing and safety of ibrutinib are unknown. We conducted a retrospective review on the use of ibrutinib in 22 children with cGVHD at Cincinnati Children's Hospital Medical Center. All patients received a dose of 250 mg/m2 orally, once daily. Responses were measured at 6 months after drug initiation using the 2014 NIH consensus panel response criteria. Twenty-two patients of median age 13.5 years received ibrutinib. cGVHD grades were severe (n = 15), moderate (n = 6), and mild (n = 1). Eight patients stopped ibrutinib prior to 3 months due to adverse events or death and could not be evaluated for 6-month response. Of the 14 evaluable patients, 12 achieved a partial response at 6 months and two patients had progressive disease. Seven evaluable patients with lung involvement had stable lung function at 6 months. One patient had EBV reactivation, and one patient developed pneumococcal sepsis despite appropriate prophylaxis while on ibrutinib therapy. No fungal infections occurred while on ibrutinib. Adverse events leading to discontinuation included recurrent fevers without a source, extensive bruising, oral bleeding, gastrointestinal distress, lower GI bleeding, dizziness, elevated transaminases, and pneumococcal sepsis. Ibrutinib administration of 250 mg/m2 oral daily shows promising responses in pediatric cGVHD. Pediatric-focused pharmacokinetic-directed studies are needed to establish optimal dosing and define efficacy in children.
Assuntos
Adenina/análogos & derivados , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Piperidinas/uso terapêutico , Adenina/uso terapêutico , Administração Oral , Adolescente , Criança , Pré-Escolar , Doença Crônica , Esquema de Medicação , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: A new protocol has been developed on the Amicus Separator that enables the device to perform online extracorporeal photopheresis (ECP) procedures when used in conjunction with the Phelix photoactivation device and associated disposable kit. The objective of this study was to evaluate the safety and performance of the Amicus ECP System in adult subjects with steroid-refractory or dependent chronic graft vs host disease (cGVHD). STUDY DESIGN AND METHODS: Eight subjects with mild to severe cGVHD underwent 31 procedures. Subject safety evaluations were performed pre and post procedure and adverse events (AEs) were recorded during treatment and 24 hours after the last procedure. In vitro evaluations of the treated cells included hematology counts and lymphocyte apoptosis, viability and proliferation as measures for ECP procedure validation. RESULTS: For n = 23 evaluable procedures, median (range) procedure time was 88 (78-110) minutes, during which 2.9 (0.6-4.7) × 109 TNCs (approximately 90% MNCs) were treated and reinfused to the subjects. All subject safety evaluations (vitals, cell counts, plasma hemoglobin and bacterial and endotoxin testing) were within expected ranges. All device or procedure related AEs were mild in nature. After 24 hours in culture, 86 (52-98)% of treated lymphocytes were apoptotic compared to 27 (15-51)% in controls. Inhibition of lymphocyte proliferation was >91% in all procedures. CONCLUSION: ECP procedures were safely completed in adult subjects with SR-cGVHD treated using the new online Amicus ECP system.
Assuntos
Doença Enxerto-Hospedeiro/terapia , Fotoferese/métodos , Esteroides/uso terapêutico , Adulto , Idoso , Apoptose , Proliferação de Células , Sobrevivência Celular , Feminino , Taxa de Filtração Glomerular , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Técnicas In Vitro , Internet , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Fotoquímica , Projetos Piloto , Risco , Resultado do TratamentoRESUMO
Little is known about the anatomic distribution of cutaneous chronic graft-versus-host disease (cGVHD). Using data from the cGVHD Consortium Improving Outcomes Assessment Study, we describe the frequency and extent of erythema and superficial and deep sclerosis in 8 anatomic sites in patients with incident disease (ie, new cGVHD diagnosis within 3 months of study entry) receiving systemic therapy. Of 339 patients with incident disease, 182 (54%) had skin involvement. When an extremity was involved, the same type of disease was present contralaterally in 92% of cases, revealing a high level of symmetry. As anticipated, erythema was the most common incident feature; however, sclerotic skin involvement at the time of cGVHD diagnosis was more common than has been suggested by previous studies. Erythema occurred in 155 (85%) and sclerosis in 53 (29%) of the patients with skin involvement (46% and 16%, respectively, of the entire cohort of 339 incident cGVHD cases). Erythema was least common on the lower extremities (nâ¯=â¯71; 39% of patients with skin involvement). Moveable sclerosis was rare on the head, neck, and scalp (nâ¯=â¯4; 2%). Deep sclerosis did not occur in this region, and instead was most likely to occur on the upper extremities (nâ¯=â¯14; 8%) and lower extremities (nâ¯=â¯14; 8%). More than one-half of patients with erythema (nâ¯=â¯107; 58.7%) had diffuse involvement (4 or more of 8 sites involved), compared with less than one-third of those with sclerosis (nâ¯=â¯16; 30.2%).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Neoplasias , Dermatopatias , Adulto , Aloenxertos , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/patologia , Neoplasias/terapia , Estudos Prospectivos , Dermatopatias/epidemiologia , Dermatopatias/etiologia , Dermatopatias/patologiaRESUMO
INTRODUCTION: Different forms of graft-versus-host disease (GVHD) remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The prognosis for steroid-refractory chronic GVHD (cGVHD) remains poor. Our aim was to evaluate extracorporeal photopheresis (ECP) treatment in cGVHD patients with different organ involvement to detect subgroups of patients with the best response. MATERIAL AND METHODS: Thirty-four patients who underwent HSCT and developed moderate (n = 7) or severe (n = 27) steroid-refractory or steroid-dependent cGVHD treated with ECP were included in the analysis. A matched cGVHD control patient group untreated with ECP was collected for comparison. RESULTS: Compared to the control group and the stable/progressive disease (SD/PD) patients, individuals with complete/partial remission have higher overall survival and lower transplant-related mortality. Furthermore, patients with complete and partial remission (CR/PR) had significantly higher levels of albumin and platelets after ECP treatment compared to patients with stable or progressive cGVHD (SD/PD). Corticosteroid treatment and other immunosuppressive agents could successfully be tapered in the CR/PR group compared to the SD/PD patients. In this study patients with skin cGVHD are those with the highest rate of CR/PR after ECP treatment. CONCLUSIONS: Our results suggest that ECP treatment is safe and effective for patients with predominantly skin, oral and liver cGVHD.