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

National Cancer Institute’s First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Summary and Recommendations from the Organizing Committee

The National Cancer Institute’s First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation was organized and convened to identify, prioritize, and coordinate future research activities related to relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Each of the Workshop’s 6 Working Committees has published individual reports of ongoing basic, translational, and clinical research and recommended areas for future research related to the areas of relapse biology, epidemiology, prevention, and treatment. This document summarizes each committee’s recommendations and suggests 3 major initiatives for a coordinated research effort to address the problem of relapse after allo-HSCT: (1) to establish multicenter correlative and clinical trial networks for basic/translational, epidemiologic, and clinical research; (2) to establish a network of biorepositories for the collection of samples before and after allo-HSCT to aid in laboratory and clinical studies; and (3) to further refine, implement, and study the Workshop-proposed definitions for disease-specific response and relapse and recommendations for monitoring of minimal residual disease. These recommendations, in coordination with ongoing research initiatives and transplantation organizations, provide a research framework to rapidly and efficiently address the significant problem of relapse after allo-HSCT

Pulmonary Symptoms Measured by the National Institutes of Health Lung Score Predict Overall Survival, Nonrelapse Mortality, and Patient-Reported Outcomes In Chronic Graft-Versus-Host Disease

The 2005 NIH Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with non-relapse mortality (NRM), overall survival (OS) and patient reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplant characteristics and non-lung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (p=0.02), overall survival (p=0.02), patient-reported symptoms (p<0.001) and functional status (p<0.001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM, although some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0–3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality

An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this “NOTCH2-BCR axis” in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8, each critical to B-cell differentiation and fate. All-trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4-to-IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5, but not BLIMP1 (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity