Role of clinical markers of inflammation in assessing chronic graft versus host disease activity and severity

Chronic graft versus host disease (cGVHD) remains the major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We performed this study in a cohort of cGVHD patients highly enriched for those with established, severe and previously heavily treated disease. All patients were evaluated, and at a single time-point in their disease trajectory, the sera samples were well-annotated using a multidimensional battery of cGVHD descriptors. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. 189 adult patients with cGVHD (33% moderate and 66% severe according to NIH global scoring) were consecutively enrolled into a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of 4 prior systemic therapies for their cGVHD. This study identified a number of laboratory indicators of inflammation differing between patients with primarily established, moderate, or severe cGVHD and non-cGVHD transplanted controls, suggesting ongoing tissue inflammation in the patient cohort. We also identified several laboratory markers associated with the clinician's assessment of disease activity or severity. Lower albumin (p<0.0001), higher CRP (C-reactive protein; p=0.043), higher platelets (p=0.030) and higher number of PST (p<0.0001) were associated with active disease defined as clinician's intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (p=0.021) and higher number of PST (p<0.0001) were associated with more severe disease as defined by NIH global score. In the Cox proportional hazards model, better Karnofsky performance status (>= 80; p=0.0008; Hazard ratio=0.33; 95 CI: 0.17-0.63), higher FEV1 (>57; p=0.0028; Hazard ratio=0.35; 95% CI: 0.18-0.70) and higher absolute lymphocyte count (>0.65; p=0.017; Hazard ratio=0.43 (95% CI: 0.22-0.86) were associated with better survival. We developed a prognostic model and prediction equations for active and severe disease. Using this model (Table 10.), the equation for predicting disease activity was established. Based on this model, 71% of patients with active disease and 79 % of those with non-active disease would be correctly classified. Also, the equation for predicting disease severity was made and based on the developed equation, 76% of patients with severe disease and 74% of those with moderate disease would be correctly classified. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity

Amniotic membrane transplantation for severe ocular graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

Allogeneic stem cell transplantation (allo-SCT) offers cure to otherwise incurable hematologic malignancies, but can also lead to many infectious and immune complications, most importantly graft-versus-host disease (GVHD). Ocular GVHD (oGVHD) occurs in 40-60% of allo-SCT patients and can result in severe ocular surface disease causing vision impairment and deterioration of quality of life. Amniotic membrane transplantation (AMT) is an established technique in the treatment of various diseases of the ocular surface. This method could provide new options in the management of otherwise disabling severe oGVHD We describe a young female patient with myeloproliferative neoplasm who underwent allo-SCT from an unrelated donor and suffered from numerous post-transplant complications. In the early post-transplant period she developed acute skin and liver GVHD, requiring introduction of immunosupressive treatment with steroids. Steroid treatment was then complicated with miopathy, iatrogenic diabetes and many infections. She developed serious herpes virus (HSV) ophtalmitis followed by severe GVHD of the eye. Despite multiagent local therapy, oGVHD progressed to ocular ulcers with threatening corneal perforation. We hesitated from increasing systemic immunosupression due to severity of previous HSV reactivation. Therefore we decided to perform AMT which led to complete corneal healing and full clinical recovery. Moreover, there was no recurrence of severe oGVHD and the patient resumed her daily activities In conclusion, this case report serves as a foundation for further research of AMT possibilities. This procedure could become beneficial in the treatment of severe oGVHD, especially in patients at high risk for infectious complications and contraindication for systemic immunosuppression

Febrilne reakcije nakon infuzije krvotvornih matičnih stanica češće su ukoliko se ne primijeni premedikacija kortikosteroidima što rezultira većom upotrebom antibiotika rano nakon transplantacije

Background: There is no consensus as to the need for steroid premedication before fresh product hematopoietic stem cell (HSC) infusion. In case of febrile reaction post-HSC infusion, on-call staff frequently prescribe antibiotics empirically. Considering the recent data on the value of microbiota and its influence on GVHD incidence, we analysed the frequency of febrile reactions and the use of antibiotic after HSC infusion in 149 consecutive patients. Methods: In the time period between 1/2018 and 10/2019, 149 patients were subject to transplantation in our institution. Per institutional standard operating procedure (SOP), all the patients received premedication before hematopoietic stem cell infusion consisting of 20 mg chloropyramine-chlorid iv, and in case of ABO incompatible graft 1 mg/kg methylprednisolone iv. Retrospective data was collected by using patient charts. Survival probability was calculated by applying Kaplan-Meier method. Results: Fifty-two patients received steroids, 12 patients (23%) developing fever after graft infusion, 46 patients received no steroids, 26 of them (57%) developed fever (p<0.001). There was no difference in the number of patients having positive blood cultures. Nine (17%) and 16 (35%) patients received IV antibiotics in the “steroid” and no-steroid” group, respectively (p<0.05). There was no difference in survival between “steroid” and “no-steroid” group. Conclusions: Even with no difference in the frequency of febrile episodes caused by systemic infection, a significantly more patients not receiving steroid premedication develop fever and are treated with IV antibiotics, which could potentially have further implications on transplantation outcomes due to its influence on microbiota early post-transplant.Uvod: Trenutno ne postoji konsenzus o potrebi primjene premedikacije kortikosteroidima prije infuzije svježih krvotvornih matičnih stanica (KMS). U slučaju febrilne reakcije nakon infuzije KMS-a, dežurno osoblje često propiše antibiotike empirijski. Uzimajući u obzir nedavne podatke o vrijednosti mikrobiote i njezinom utjecaju na incidenciju GVHD-a, analizirali smo učestalost febrilnih reakcija i uporabu antibiotika nakon infuzije KMS-a u 149 uzastopna bolesnika. Metode: U razdoblju između 1/2018. i 10/2019. u našoj je ustanovi transplantirano ukupno 149 pacijenata. Prema institucionalnom standardnom operativnom postupku (SOP), svi su pacijenti primali premedikaciju prije infuzije krvotvornih matičnih stanica koja se sastojala od 20 mg kloropiramin-klorida iv, a u slučaju ABO inkompatibilnog presatka i 1 mg / kg metilprednizolona iv. Retrospektivno su prikupljeni podaci koristeći povijesti bolesti pacijenata. Vjerojatnost preživljavanja izračunata je Kaplan-Meierovom metodom. Rezultati: Pedeset i dva bolesnika su primila kortikosteroide, od njih je 12 bolesnika (23%) razvilo vrućicu nakon infuzije presatka, dok 46 bolesnika nije primilo kortikosteroide, a od njih je 26 (57%) razvilo vrućicu (p <0,001). Nije bilo razlike u broju bolesnika koji su imali pozitivne hemokulture. U skupini koja je primila kortikosteroide, 9 (17%) bolesnika je liječeno iv antibioticima, dok je u skupini koja nije primala kortikosteroide, 16 (35%) bolesnika liječeno iv antibioticima (p <0,05). Nije bilo razlike u preživljenju između te dvije skupine. Zaključci: Čak i bez razlike u učestalosti febrilnih epizoda uzrokovanih sistemskom infekcijom, znatno više pacijenata koji nisu dobili premedikaciju je razvilo vrućicu i liječilo se iv antibioticima, što bi potencijalno moglo imati daljnje implikacije na ishode transplantacije zbog utjecaja na mikrobiotu rano nakon transplantacije

Glycoprotein YKL-40: a novel biomarker of chronic graftvs- host disease activity and severity?

Aim To investigate whether increased YKL-40 levels positively correlate with graft-vs-host disease (cGVHD) activity and severity and if YKL-40 could serve as a disease biomarker. Methods This case-control study was conducted at the University Hospital Centre Zagreb from July 2013 to October 2015. 56 patients treated with hematopoietic stem cell transplantation (HSCT) were included: 35 patients with cGVHD and 21 without cGVHD. There was no difference between groups in age, sex, median time from transplant to study enrollment, intensity of conditioning, type of donor, or source of stem cells. Blood samples were collected at study enrollment and YKL-40 levels were measured with ELISA. Disease activity was estimated using Clinician’s Impression of Activity and Intensity of Immunosuppression scales and disease severity using Global National Institutes of Health (NIH) score. Results YKL-40 levels were significantly higher in cGVHD patients than in controls (P = 0.003). The difference remained significant when patients with myelofibrosis were excluded from the analysis (P = 0.017). YKL-40 level significantly positively correlated with disease severity (P < 0.001; correlation coefficient 0.455), and activity estimated using Clinician’s Impression of Activity (P = 0.016; correlation coefficient 0.412) but not using Intensity of Immunosuppression (P = 0.085; correlation coefficient 0.296). Conclusion YKL-40 could be considered a biomarker of cGVHD severity and activity. However, validation in a larger group of patients is warranted, as well as longitudinal testing of YKL-40 levels in patients at risk of developing cGVHD

Which questionnaires should we use to evaluate quality of life in patients with chronic graft-vs-host disease?

Aim To investigate the ability of two standard quality of life (QOL) questionnaires – The Short Form (36-item) Health Survey (SF-36) and The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire- Core 30 (EORTC QLQ C30) to evaluate QOL in patients with chronic graft-vs-host disease (cGVHD) graded according to National Institutes of Health (NIH) consensus criteria. Methods In this cross-sectional study, QOL was assessed in patients who underwent allogeneic stem cell transplantation (allo-SCT) at the University Hospital Centre Zagreb and were alive and in complete remission for more than one year after allo-SCT. Results The study included 58 patients, 38 patients with cGVHD and 20 controls, patients without cGVHD. Patients with cGVHD scored according to the NIH criteria had significantly lower scores of global health status and lower QOL on all SF-36 subscales and most of QLQ C30 functional subscales (P < 0.050 for all comparisons). Furthermore, patients with active cGVHD had significantly lower QOL scores than patients with inactive cGVHD, and this difference was most evident in physical functioning subscale of SF-36 (P = 0.0007) and social functioning subscale of QLQ C30 (P = 0.009). Conclusion cGVHD scored according to the NIH criteria is correlated with patient-reported QOL, particularly in the physical domains as detected by SF-36. QLQ C30 questionnaire adds more information on social functioning and should be used as a valuable tool in the evaluation of social domains in cGVHD patients

Retrospective analysis of the incidence and outcome of late acute and chronic graft-versus-host disease—an analysis from transplant centers across Europe

Introduction: Chronic graft-versus-host disease (cGvHD) is a serious late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: This multicenter analysis determined the cumulative incidence (CI) of cGvHD and late acute GvHD (laGvHD) and its impact on transplantation-related mortality (TRM), relapse (R), and overall survival (OS) in 317 patients [296 adults, 21 pediatrics (<12 years of age)] who underwent their first allo-HSCT in 2017. Results: The CI of laGvHD was 10.5% in adults and 4.8% in pediatrics, and the CI of cGvHD was 43.0% in all adult transplant patients and 50.2% in the adult at-risk cohort at the study end. The onset of cGvHD was de novo in 42.0% of patients, quiescent in 52.1%, and progressive in 5.9%. In adults, prophylactic use of antithymocyte globulin or posttransplant cyclophosphamide was associated with a significantly lower incidence of cGvHD (28.7%) vs. standard prophylaxis with calcineurin inhibitors (30.6%) and methotrexate/mycophenolate mofetil (58.4%) (all p < 0.01). TRM was significantly higher in patients with aGvHD (31.8%) vs. cGvHD (12.6%) and no GvHD (6.3%) (all p = 0.0001). OS in the adult at-risk cohort was significantly higher in patients with cGvHD (78.9%) vs. without (66.2%; p = 0.0022; HR 0.48) due to a significantly lower relapse rate (cGvHD: 14.5%; without cGvHD: 27.2%; p = 0.00016, HR 0.41). OS was also significantly higher in patients with mild (80.0%) and moderate (79.2%) cGvHD vs. without cGvHD (66.2%), excluding severe cGvHD (72.7%) (all p = 0.0214). Discussion: The negative impact of severe cGvHD on OS suggests a focus on prevention of severe forms is warranted to improve survival and quality of life

Vitamin D levels and their associations with survival and major disease outcomes in a large cohort of patients with chronic graft-vs-host disease

AIM: To identify the factors associated with vitamin D status in patients with chronic graft-vs-host disease (cGVHD) and evaluate the association between serum vitamin D (25(OH)D) levels and cGVHD characteristics and clinical outcomes defined by the National Institutes of Health (NIH) criteria. ----- METHODS: 310 cGVHD patients enrolled in the NIH cGVHD natural history study (clinicaltrials.gov: NCT00092235) were analyzed. Univariate analysis and multiple logistic regression were used to determine the associations between various parameters and 25(OH)D levels, dichotomized into categorical variables: ≤20 and >20 ng/mL, and as a continuous parameter. Multiple logistic regression was used to develop a predictive model for low vitamin D. Survival analysis and association between cGVHD outcomes and 25(OH)D as a continuous as well as categorical variable: ≤20 and >20 ng/mL; <50 and ≥50 ng/mL, and among three ordered categories: ≤20, 20-50, and ≥50 ng/mL, was performed. ----- RESULTS: 69 patients (22.3%) had serum 25(OH)D ≤20 ng/mL. Univariate analysis showed that supplement intake, nutritional status (severely malnourished, moderately malnourished, well-nourished), race (African-American, other), and estimated creatinine clearance (eCCr) were associated with 25(OH)D levels. A predictive model was developed based on supplement intake, nutritional status, race, and eCCr, accurately predicting 77.9% of patients with 25(OH)D ≤20 and 65.2% of those with 25(OH)D >20 ng/mL. No association was found between vitamin D and major cGVHD characteristics, but patients with 25(OH)D ≤20 ng/mL had somewhat decreased survival. ----- CONCLUSION: Nutritional status and adequate supplementation are important to maintain 25(OH)D >20 ng/mL in cGVHD patients. Intervention studies and more research is needed to reveal the underlying mechanism of vitamin D metabolism in cGVHD setting