Lana Desnica

High frequency of cutaneous manifestations including vitiligo and alopecia areata in a prospective cohort of patients with chronic graft-vs-host disease.

Aim To determine the frequency and the characteristics of cutaneous manifestations, especially vitiligo and alopecia areata, in patients with chronic graft-vs-host disease (cGVHD). Methods 50 patients with cGVHD were prospectively enrolled in the observational study protocol and evaluated by an experienced dermatologist. The evaluation was focused on the clinical spectrum of skin and adnexal involvement, and the cutaneous GVHD score was determined according to National Institutes of Health (NIH) Consensus criteria. The presence of vitiligo, alopecia, xerosis, nail changes, and dyspigmentation was also assessed. Results Out of 50 cGVHD patients, 28 (56%) had skin involvement, and 27 of them (96%) had hypo and/or hyperpigmentations. 11 patients (39%) had a mild cutaneous NIH cGVHD score, 22% moderate, and 39% severe. 15 (30%) patients had nail changes and 10 (20%) had vitiligo or alopecia areata. Univariate analysis showed that patients with vitiligo/alopecia areata received more lines of prior systemic immunosuppressive therapy (P = 0.043), had lower Karnofsky performance status (P = 0.028), and had a higher B-cell number (P = 0.005), platelet count (P = 0.022), and total protein (P = 0.024). Vitiligo and alopecia areata were associated with higher NIH skin score (P = 0.001), higher intensity of immunosuppressive treatment (P = 0.020), and total body irradiation conditioning (P = 0.040). Multivariate regression model showed that patients with higher NIH skin scoring were 3.67 times more likely to have alopecia and/or vitiligo (odds ratio 3.67; 95% confidence interval 1.26-10.73), controlled for all other factors in the model (age at study entry, number of B-cells, platelet count, and global NIH score). Conclusion These data indicate that vitiligo and alopecia areata occur more frequently in cGVHD than previously reported.

High prevalence of small- and large-fiber neuropathy in a prospective cohort of patients with moderate to severe chronic GvHD

High prevalence of small- and large-fiber neuropathy in a prospective cohort of patients with moderate to severe chronic GvHD

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.

Chronic graft-vs-host disease in 2016: a major challenge and an opportunity.

Despite major advances in the treatment of hematological diseases over the last decades, allogeneic hematopoietic stem cell transplantation (alloHSCT) still remains the only curative option for many of them. According to the recent survey of the European Society of Blood and Marrow Transplantation (EBMT), nearly 15 000 alloHSCT are currently performed each year across Europe and EBMT-affiliated countries (1).

Amniotic membrane transplantation—a new approach to crossing the HLA barriers in the treatment of refractory ocular graft-versus-host disease

Ocular chronic graft-versus-host disease (oGVHD) occurs in 40-60% of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) [1]. Severe forms of oGVHD can be devastating since they restrict daily activities and severely deteriorate quality of life. The most common clinical manifestations of oGVHD include dry eye syndrome and conjunctival inflammation. Available therapies include a variety of topical and systemic approaches with respect to the severity of the condition. However, there is a lack of effective treatment for steroid refractory disease as well as a paucity of controlled trials in the management of oGVHD. New strategies include autologous tear drops and scleral lenses with some encouraging results [2, 3]. Despite all available therapies, some cases still progress to severe ocular ulcerations and occasionally result in corneal perforation requiring emergency keratoplasty. Moreover, catastrophic consequences with enucleation of the eye and permanent visual impairment have also been described [4]. Amniotic membrane (AM) is an avascular fetal membrane collected from placental tissue during elective cesarean sections, from donors screened for transmissible infectious diseases. As it lacks HLA-A, HLA-B and HLADR antigens, AM is universally tolerated and can be used without fear of rejection. Amniotic membrane transplantation (AMT) is an established technique in the treatment of non-healing skin wounds and severe burns [5]. In ophthalmology, AMT was first developed for severe ocular manifestations of acute Stevens-Johnson syndrome [6]. Today it is being efficiently used for the treatment of various types of keratitis, neurotrophic keratopathy, non-healing corneal ulcers and corneal perforations [7]. The application of AM is simple and well tolerated among recipients, with no serious complications following the procedure [8]. AM typically dissolves over a period of 1–2 weeks; thus, more than one application may be necessary during the acute phase of the disease. Topical medications can be used concurrently, as medication penetration has not been found to be an issue. Two types of AM—cryopreserved and dehydrated are approved for distribution as tissue allografts and are commercially available. In our institution, AMT is used for the treatment of severe oGVHD refractory to all available local and systemic therapy. Herein we report clinical course and outcomes of first four consecutive patients who underwent the AMT procedure as salvage therapy for oGVHD. AM-s were manufactured in the institutional tissue bank according to a standardized protocol with the institutional review board approval. The description of the AMT technique is available in Supplementary Information 1. The characteristics of patients and AMT are depicted in Table 1. First patient was a 26-year-old male who underwent a related allo-HSCT for lymphoblastic transformation of chronic myeloid leukemia (CML) and received three donor lymphocytes infusions (DLI) due to molecular relapse. Six months later, he developed severe chronic GVHD of the mouth and eye that gradually progressed despite corticosteroid treatment and topical therapy, and finally led to * Zinaida Peric zinaida.peric@mef.hr

Early human cytomegalovirus reactivation is associated with lower incidence of relapse of myeloproliferative disorders after allogeneic hematopoietic stem cell transplantation

Conflicting results have been reported regarding the association between early cytomegalovirus (CMV) reactivation and relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This prompted us to evaluate the impact of CMV reactivation on outcomes of 155 consecutive adult patients transplanted in our institution. In our study, CMV reactivation did not affect cumulative incidence (CI) of relapse in patients with lymphoproliferative disorders. However, the CI of relapse in patients with myeloproliferative disorders (AML and MPN) was 37% (95% CI, 21–53) in patients without CMV reactivation as opposed to 17% (95% CI, 9–28) in patients with CMV reactivation (p = 0.03). An important correlation between CMV reactivation and relapse was found in patients with MPN; the CI of relapse was 50% (95% CI, 12–80) in patients without CMV reactivation as opposed to only 7% (95% CI, 0–27) in patients with CMV reactivation (p = 0.02). A substantial reduction of relapse in myeloproliferative disorders associated with CMV reactivation was confirmed by multivariate analysis (HR 2.73; 95% CI, 1.09–6.82, p = 0.03) using time-dependent covariates for high-risk disease, older age, RIC conditioning, ATG, grade II–IV acute, and chronic GVHD. To our knowledge, we are the first to show an association of CMV reactivation with relapse reduction in MPN patients. This putative virus vs myeloproliferation effect warrants further research.

Glycoprotein YKL-40: a novel biomarker of chronic graft-vs-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.

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.