Zinaida Perić

Features of Epstein-Barr Virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation

This single centre study assessed the incidence, kinetics and predictive factors of Epstein-Barr Virus (EBV) reactivation and EBV-related lymphoproliferative diseases (LPDs) in 175 consecutive patients who received a reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT). The cumulative incidence of EBV reactivation at 6 months after allo-HSCT defined as an EBV PCR load above 1000 copies of EBV DNA/105 cells was 15%, and none of these patients experienced any sign or symptom of LPD. A total of 17 patients, who had EBV DNA levels exceeding 1000 copies/105 cells on two or more occasions, were pre-emptively treated with rituximab. With a median follow-up of 655 (range, 92–1542) days post allo-HSCT, there was no statistically significant difference in term of outcome between those patients who experienced an EBV reactivation and those who did not. In multivariate analysis, the use of antithymocyte globulin as part of the RIC regimen was the only independent risk factor associated with EBV reactivation (relative risk=4.9; 95% confidence interval, 1.1–21.0; P=0.03). We conclude that patients undergoing RIC allo-HSCT using anti-thymocyte globulin as part of the preparative regimen are at higher risk for EBV reactivation. However, this did not impact on outcome, as quantitative monitoring of EBV viral load by PCR and preemptive rituximab therapy allowed for significantly reducing the risk of EBV-related LPD.

Features of EBV reactivation after reduced intensity conditioning unrelated umbilical cord blood transplantation

This single centre study assessed the incidence, kinetics and predictive factors of EBV reactivation and EBV-related lymphoproliferative diseases (LPD) in 33 consecutive patients who received a reduced intensity conditioning (RIC) before umbilical cord blood transplantation (UCBT). During the first 6 months after UCBT, weekly all patients were DNA-PCR screened in the peripheral blood for EBV reactivation and were clinically monitored for clinical features attributable to EBV. The cumulative incidences of EBV reactivation (defined as an EBV load >1000 EBV copies per 105 cells measured at least once during follow-up) at 6 months and 2 years after UCBT were 9 (95% confidence interval (CI), 2–22%) and 17% (95% CI, 6–33%), respectively. In 28 patients (85%), the EBV load remained negative at all times, and none of these patients experienced any sign of LPD. Five patients (15%) experienced at least one EBV reactivation episode. EBV reactivation was observed at a median of 132 days (range, 85–438) after UCBT. Two patients developed EBV-related LPD (cumulative incidence, 6% at 3 years). With a median follow-up of 468 days (range, 92–1277) post UCBT, the OS was 62% at 3 years. Five patients died of disease progression and seven patients died of transplant-related complications, including one case of EBV-related LPD. Univariate analysis did not identify any significant risk factor associated with EBV reactivation. We conclude that patients undergoing RIC UCBT are at risk for EBV reactivation, with the need for close EBV monitoring and the use of preemptive rituximab treatment as some cases may progress to life-threatening LPD.

Late Complications and Quality of Life after Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation

Late complications (LC) and quality of life (QOL) were analyzed in 110 adult patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) and were alive for more than 2 years after allo-SCT. Overall survival of these patients was 93% (95% confidence interval [CI], 88% to 99%) and 81% (95% CI, 71% to 94%) at 5 and 10 years, respectively. The primary cause of death was a recurrence of primary malignancy. With a median follow-up of 4.6 years (range, 2 to 12.1), chronic graft-versus-host disease (cGVHD) was the most prevalent late effect, with a cumulative incidence of 66% (95% CI, 57% to 74%) at 10 years. Cardiovascular complications were the most prevalent LC with a cumulative incidence of 47% (95% CI, 35% to 59%), followed by pulmonary complications with a cumulative incidence of 33% (95% CI, 21% to 46%) and renal impairment with a cumulative incidence of 34% (95% CI, 25% to 43%) at 10 years. Secondary malignancies occurred with a cumulative incidence of 11% (95% CI, 5% to 20%) at 10 years. In this series, 61 patients (55%) responded to QOL survey. With the use of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and Functional Assessment of Cancer Therapy-Bone Marrow Transplant questionnaires, most of the patients reported good to excellent QOL and patients with cGVHD had significantly lower QOL than patients without cGVHD. In conclusion, QOL after RIC is comparable to that seen after myeloablative conditioning, while the natural history of LC after RIC appears to be different from that described in the standard myeloablative setting, warranting further research in this field.

High incidence of aseptic hip necrosis in Hodgkin lymphoma patients treated with escalated BEACOPP receiving methylprednisolone

Escalated BEACOPP (eBEACOPP) is an effective but fairly toxic regimen for the treatment of Hodgkin lymphoma (HL). Avascular necrosis (AVN) of femoral head was previously reported to increase in patients treated with eBEACOPP, but so far, no systematic analysis of its frequency has been published.

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.

Author reply: Letters to the Editor

Galia M. Whole-body MRI, FDG-PET/CT, and bone marrow biopsy, for the assessment of bone marrow involvement in patients with newly diagnosed lymphoma. J Magn Reson Imaging 2017; 45: 1082–9. 6 Murphey MD, Foreman KL, KlassenFischer MK, Fox MG, Chung EM, Kransdorf MJ. From the radiologic pathology archives imaging of osteonecrosis: radiologic-pathologic correlation. Radiographics 2014; 34: 1003–28. 7 Galia M, Albano D, Tarella C, Patti C, Sconfienza LM, Mulè A et al. Whole body magnetic resonance in indolent lymphomas under watchful waiting: the time is now. Eur Radiol 2018; 28: 1187–93. 8 Koren L, Ginesin E, Melamed Y, Norman D, Levin D, Peled E. Hyperbaric oxygen for stage I and II femoral head osteonecrosis. Orthopedics 2015; 38: e200–5.

Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study evaluated clinical and morphological practices of TA-TMA diagnosis in EBMT centers. Two questionnaires, one for transplant physician and one for morphologist, and also a set of electronic blood slides from 10 patients with TA-TMA and 10 control patients with various erythrocyte abnormalities, were implemented for evaluation. Seventeen EBMT centers participated in the study. Regarding criteria used for TA-TMA diagnosis, centers reported as follows: 41% of centers used the International Working Group (IWG) criteria, 41% used “overall TA-TMA” criteria and 18% used physician’s decision. The threshold of schistocytes to establish TA-TMA diagnosis in the participating centers was significantly associated with morphological results of test cases evaluations (p = 0.002). The mean number of schistocytes reported from blood slide analyses were 4.3 ± 4.5% for TA-TMA cases (range 0–19.6%, coefficient of variation (CV) 0.7) and 1.3 ± 1.6% for control cases (range 0–8.3%, CV 0.8). Half of the centers reported schistocyte levels below 4% for 7/10 TA-TMA cases. The intracenter variability was low, indicating differences in the institutional practices of morphological evaluation. In conclusion, the survey identified the need for the standardization of TA-TMA morphological diagnosis.

Variability of nutritional practices in peritransplant period after allogeneic hematopoietic stem cell transplantation: a survey by the Complications and Quality of Life Working Party of the EBMT.

Recommendations on screening and nutritional support for patients undergoing hematopoietic stem cell transplantation (HSCT) have been presented by international nutritional societies, but nutritional practices remain poorly standardized. Following the general policy of the European Society for Blood and Marrow Transplantation (EBMT) to standardize transplantation procedures, the Complications and Quality of Life Working Party and Nursing Research Group carried out a survey among all EBMT centers about their current nutritional practices. The aim of this study was to better understand current practices, differences from available guidelines, and possible barriers for recommended nutritional therapy. Responses from 90 centers (19%) from 23 countries were received. We observed a marked variability in nutritional care between EBMT centers and a substantial lack of standardized operating procedures in screening patients for malnutrition and management of gastrointestinal GVHD. Furthermore, our study confirmed neutropenic diet as standard of care in most centers as well a preference for parenteral nutritional support over enteral. On the basis of these findings, future EBMT efforts will focus on better implementation of international nutritional guidelines into clinical practice.

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.