Metabolic syndrome and cardiovascular disease after haematopoietic cell transplantation (HCT) in adults: an EBMT cross-sectional non-interventional study.

Metabolic syndrome (MetS) is associated with cardiovascular disease in the general population and is also a potential cardiovascular risk factor in survivors of haematopoietic cell transplantation (HCT). We report an EBMT cross-sectional, multi-centre, non-interventional study of 453 adult HCT patients surviving a minimum of 2 years post-transplant attending routine follow-up HCT and/or late effects clinics in 9 centres. The overall prevalence of MetS was 37.5% rising to 53% in patients >50 years of age at follow-up. There were no differences in rates of MetS between autologous and allogeneic HCT survivors, nor any association with graft-versus-host disease (GvHD) or current immunosuppressant therapy. Notably, there was a significantly higher occurrence of cardiovascular events (CVE, defined as cerebrovascular accident, coronary heart disease or peripheral vascular disease) in those with MetS than in those without MetS (26.7% versus 9%, p < 0.001, OR 3.69, 95% CI 2.09-6.54, p < 0.001), and, as expected, MetS and CVE were age-related. Unexpectedly, CVE were associated with occurrence of second malignancy. Screening for and management of MetS should be integrated within routine HCT long-term follow-up care for both allogeneic and autologous HCT survivors. Further research is warranted, including randomised controlled trials of interventional strategies and mechanistic studies of cardiovascular risk in HCT survivors.

Management of growth failure and growth hormone deficiency after pediatric allogeneic HSCT: Endocrinologists are of importance for further guidelines and studies.

Growth failure (GF) is a frequent problem after pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Growth hormone deficiency (GHD) occurs in 20 to 85%, but published data on the efficacy of growth hormone treatment (GHT) are conflicting. Currently, there are no recommendations on screening for and treatment of GHD after HSCT. We aimed to describe the management of endocrine follow-up (FU)and details of GHT within European Society for Blood and Marrow Transplantation (EBMT) centers.In a retrospective questionnaire study, all EBMT centers performing pediatric HSCT were invited. Results were evaluated in correlation with the structure of endocrine aftercare (HSCT-clinicians and endocrinologists).The majority of centers (80%) reported endocrine FU by an endocrinologist - either within the HSCT-center or in a separate endocrine clinic. Fifty-four percent reported FU outside of the HSCT-center. As diagnostic tests the insulin-like growth factor IGF-I and insulin-like growth factor binding protein IGFBP3, insulin tolerance test and arginine stimulation test were most frequently used. Sixty-four percent of centers performed GHT and endocrinologists were more likely to prescribe GH (74%) compared to HSCT-clinicians (33%). The most frequent indication for GHT was GHD in 60%, with a distinct different approach of endocrinologists in comparison with HSCT-clinicians.Our study reveals substantial variation in practice and emphasizes the need for endocrine aftercare performed by dedicated endocrinologists in close collaboration with the HSCT-center. Our results indicate that the management of GHT depends on the structure of endocrine aftercare, which is important for the future development and distribution of studies and guidelines.

Inability to work and need for disability pension among long-term survivors of hematopoietic stem cell transplantation.

Return to work is critical goal following HSCT. However, late effects may impede return to normal activity after HSCT. In the case of inability to work, patients may need a work disability pension to ensure a reasonable livelihood. This study evaluated inability to work and need for disability pension among long-term survivors and analyzed possible determinants of need for social support. This retrospective, single-center study included all HSCT patients surviving ⩾5 years seen at the outpatient clinic between January 2013 and August 2015. There were 203 patients, median age at HSCT 35 years, and 50 years at time of study; median time between HSCT and study control was 12 years; 178 had allo-HSCT, 187 had a malignant disease. At time of study, 156 (77%) were working full or part-time, 47 (23%) were not working. In total, 76 (37%) survivors were receiving a work disability pension compared to 3.17% of the Swiss working population. Patients with a disability pension were significantly older at HSCT, were more often living alone, had more active physical and mental late effects, and higher score of fatigue compared to patients without. These findings underline the importance of screening for employment and the social consequences of non-employment in long-term survivors after HSCT.

Iron deficiency and thrombocytosis.

According to many textbooks, iron deficiency (ID) is associated with reactive thrombocytosis. In this study, we aimed to investigate the correlation between serum ferritin levels and platelet counts in a large cohort of healthy blood donors. We included all whole blood and apheresis donors aged 18 years or older with at least one ferritin measurement and one platelet count performed at the same visit between 1996 and 2014. A total of 130 345 blood counts and ferritin measurements obtained from 22 046 healthy donors were analysed. Overall, no correlation between serum ferritin and platelet count was observed (r = -0.03, ρ = 0.04 for males, and r = 0.01, ρ = -0.02 for females, respectively). Associations remained clinically negligible after adjusting for age, time since previous blood donation, number of donations and restricting the analysis to ferritin deciles. In this large, retrospective single-centre study, correlations between low ferritin and platelet count in a large and homogeneous cohort of healthy donors were negligible. Further studies in patients with more severe anaemia and patients with inflammation are warranted.

How do I manage hyperglycemia/post-transplant diabetes mellitus after allogeneic HSCT.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients frequently develop glucose intolerance and post-transplant diabetes mellitus (PTDM). The clinical importance of PTDM and its detrimental impact on HSCT outcomes are under-recognized. After allo-HSCT, various mechanisms can contribute to the development of PTDM. Here we review information about hyperglycemia and PTDM after allo-HSCT as well as PTDM after solid organ transplantation and describe ways to manage hyperglycemia/PTDM after allogeneic HSCT. Taking into consideration a lack of well-established evidence in the field of allo-HSCT, more studies should be conducted in the future, which will require closer multidisciplinary collaboration between hematologists, endocrinologists and nutritionists.

Paediatric reduced intensity conditioning: analysis of centre strategies on regimens and definitions by the EBMT Paediatric Diseases and Complications and Quality of Life WP.

The aim of this analysis was to explore the diversity of reduced intensity conditioning (RIC) in paediatric allo-SCT in daily practice across Europe. Data from the European Group for Blood and Marrow Transplantation (EBMT) Promise database from 1994 to 2008 were supplemented by a survey of EBMT centres performing paediatric allo-SCT on the current policy asking for the underlying diseases and for the drug combinations. Records from 161 centres from 30 countries were analysed and 139 various RIC regimens were reported. More centres applied RIC for malignant rather than for non-malignant diseases. In general, fludarabine (FLU)-based regimens predominated except for BU-based regimens in myeloid malignancies and haemoglobinopathies. Treosulfan (TREO) was mainly applied for unspecified malignant diseases and for haemophagocytic diseases. FLU-based regimens revealed the greatest number of different combinations. Correlating the number of regimens with the number of treating centres revealed the lowest variety in FLU and the highest variety in TBI and TREO. FLU/melphalane and FLU/CY were the most frequent combinations. This extreme heterogeneity in RIC may influence both the efficacy and the safety of the procedures, which requires further investigation. Optimization and standardization of RIC is the final goal to provide a platform for future prospective studies.

The impact of T-cell depletion techniques on the outcome after haploidentical hematopoietic SCT.

Several T-cell depletion (TCD) techniques are used for haploidentical hematopoietic SCT (HSCT), but direct comparisons are rare. We therefore studied the effect of in vitro TCD with graft engineering (CD34 selection or CD3/CD19 depletion, 74%) or in vivo TCD using alemtuzumab (26%) on outcome, immune reconstitution and infections after haploidentical HSCT. We performed a retrospective multicenter analysis of 72 haploidentical HSCT in Switzerland. Sixty-seven patients (93%) had neutrophil engraftment. The 1-year OS, TRM and relapse incidence were 48 (36-60)%, 20 (11-33)% and 42 (31-57)%, respectively, without differences among the TCD groups. In vivo TCD caused more profound lymphocyte suppression early after HSCT, whereas immune recovery beyond the second month was comparable between the two groups. Despite anti-infective prophylaxis, most patients experienced post-transplant infectious complications (94%). Patients with in vivo TCD had a higher incidence of CMV reactivations (54% vs 28%, P=0.015), but this did not result in a higher TRM. In conclusion, TCD by graft engineering or alemtuzumab are equally effective for haploidentical HSCT.

Pattern of care of blood donors with early-uncomplicated hereditary haemochromatosis in a Swiss blood donation centre.

BACKGROUND AND OBJECTIVES: We describe the recognition and pattern of care of voluntary blood donors with early-uncomplicated genetic haemochromatosis in our blood donation centre. MATERIALS AND METHODS: Asymptomatic volunteers with suspicion of hereditary haemochromatosis (HH) due to an elevated ferritin level on routine screening were referred for further investigation. Alternatively, we accepted subjects with prediagnosed HH on referral. In the case of early-uncomplicated genetic haemochromatosis, either standard whole blood donation (WBD) or double-erythrocytapheresis (DEC) was offered. RESULTS: A median of six procedures was needed to achieve a ferritin value below 100 ng/ml in the WBD group and of four in the DEC group (P = 0·5). The rate of donation side-effects was higher in the DEC group, while the costs it generated were equivalent to WBD. CONCLUSION: Compared with WBD, DEC had no beneficial effect on treatment number, length of treatment, side-effects or treatment budget in early-uncomplicated HH. Integrating donors with uncomplicated genetic haemochromatosis to blood donation programmes can supplement blood stores and provide the donors with a cost-effective and altruistic purpose of treatment.

Sicca symptoms and their impact on quality of life among very long-term survivors after hematopoietic SCT.

The objective of this prospective cross-sectional case-control study was to examine the prevalence of dryness symptoms and its impact on quality of life (QoL) among very long-term survivors after hematopoietic SCT (HSCT) in comparison with their respective sibling donors. Forty-four allogeneic HSCT recipients with a long-term survival (median: 17.5; range: 11-26 years) were included. Their respective, HLA-identical sibling donors served as controls. Clinical examinations included saliva flow rates (SFR) and the Schirmer's test. The presence of sicca symptoms of mouth, eyes and skin were inquired. The social functioning (SF)-36 questionnaire was applied. Recipients had lower (P<0.01) unstimulated and stimulated mean SFR than donors. Schirmer's test results <5 mm was found in 45% of the recipients in comparison with 27% of the donors (P = 0.07). Xerostomia (34 vs 4 subjects), xerophtalmia (23 vs 3) and dry skin (32 vs 12) were reported more often by the recipients than donors (P<0.001). Sicca symptoms and their objective findings correlated with QoL. The mean SF-36 scores of the donors were significantly higher than those of the recipients for physical component summary. In conclusion, sicca symptoms are common amongst long-term survivors of HSCT and affect remarkably the QoL.

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers.

Adoptive immunotherapy with allogeneic purified natural killer (NK) cell products might exert graft-versus-tumor alloreactivity with little risk of GVHD. In a prospective phase II study in two centers, we administered purified NK cell products to high-risk patients treated with haploidentical T-cell-depleted SCT. Sixteen patients received a total of 29 NK cell infusions on days +3, +40 and +100 after transplantation. Median doses (and ranges) of infused NK- and T-cells per product were 1.21 (0.3-3.8) × 10(7)/kg and 0.03 (0.004-0.72) × 10(5)/kg, respectively. With a median follow-up of 5.8 years 4/16 patients are alive. Cause of death was relapse in five, GVHD in three, graft failure in three, and transplant related neurotoxicity in one patient. Four patients developed acute GVHDgrade II, all receiving a total of 0.5 × 10(5) T cells/kg. Compared with historical controls, NK cell infusions had no apparent effect on the rates of graft failure or relapse. Adoptive transfer of allogeneic NK cells is safe and feasible, but further studies are needed to determine the optimal dose and timing of NK cell therapy. Moreover, NK cell activation/expansion may be required to attain clinical benefit, while careful consideration must be given to the number of T cells infused.

GVHD after allogeneic haematopoietic SCT for AML: angiogenesis, vascular endothelial growth factor and VEGF receptor expression in the BM.

There is increasing evidence suggesting that both angiogenesis and endothelial injury are involved in GVHD. To study the dynamics of angiogenesis, we examined 26 patients with AML who had undergone allogeneic haematopoietic SCT. All were in CR and had either acute GVHD (aGVHD) or chronic GVHD (cGVHD). We performed immunohistochemical studies of BM microvessel density (MVD) using Abs against vascular-endothelial (VE)-cadherin, CD34 and CD105, and expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. At the time of diagnosis, the MVD in AML patients was higher than that in the normal controls, and the MVD decreased after induction chemotherapy. Patients with aGVHD had a significantly higher MVD than patients without aGVHD. Conversely, patients with cGVHD did not have a significantly different MVD. In previous aGVHD, we also found more VEGF+ megakaryocytes. XY FISH in sex-mismatched patients showed that the BM blood vessels consisted mainly of recipient endothelial cells. Taken together, these results suggest that new vessel formation and the VEGF/VEGFR system are involved in aGVHD.

Diagnosis of acquired aplastic anemia.

Since the introduction of the concept of aplastic anemia (AA) by Paul Ehrlich in 1888 and despite the current better understanding of the underlying mechanisms involved in this disease, a clear delimitation among BM failure syndromes is still a matter of debate. The diagnosis of AA can be difficult basically due to the overlapping morphological characteristics with other BM failure disorders. This paper reviews critical data relevant to the diagnosis of acquired AA and recommends work out steps and main considerations to determine severity and characterization of the disease. The diagnostic challenge in the differentiation between AA and hypoplastic myelodysplastic syndromes is also addressed. The definition of the response criteria to treatment belongs to the diagnostic tasks and it is included in this review as well as an overview of novel tools for the diagnosis of AA.

Treatment of aplastic anaemia in elderly patients aged >60 years.

The treatment of aplastic anaemia (AA) in the elderly patient population is not always straightforward, as other factors apart from age per se and disease severity need to be considered in clinical management decisions. The presence of comorbidities needs to be evaluated carefully. In general, elderly patients have an inferior outcome following immunosuppressive therapy and haematopoietic SCT; hence patients need to be evaluated on an individual patient basis and their specific wishes respected, as quality of life is an extremely important outcome measure to consider. In this review we aim to provide some guidance on how to approach the options for treatment in the elderly patient.

[Neutropenia and fever of unknown origin]. / Neutropenie und Fieber unklarer Genese.

We report a case of a young man presenting with a severe neutropenia together with a mild anemia. The diagnostic work up of such a hematological anomaly is reviewed. It finally revealed a therapy-related acute myeloid leukemia, secondary to previous chemotherapy for a testicular tumor.

The EBMT activity survey: 1990-2010.

A total of 654 centers from 48 countries were contacted for the 2010 survey. In all, 634 centers reported a total of 33 362 hematopoietic SCT (HSCT) with 30 012 patients receiving their first transplant (12 276 allogeneic (41%) and 17 736 autologous (59%)). Main indications were leukemias: 9355 (31%; 93% allogeneic), lymphoid neoplasias specifically Non Hodgkin's lymphoma, Hodgkin's lymphoma and plasma cell disorders: 17 362 (58%; 12% allogeneic), solid tumors: 1585 (5%; 6% allogeneic) and non-malignant disorders: 1609 (6%; 88% allogeneic). There were more unrelated donors than HLA-identical sibling donors (53% versus 41%); the proportion of peripheral blood as stem cell source was 99% for autologous and 71% for allogeneic HSCT. Cord blood was primarily used in allogeneic transplants (6% of total) with three autologous cord blood HSCT being reported. The number of transplants has increased by 19% since 2005 (allogeneic 37% and autologous 9%) and continued to increase by about 1100 HSCT per year since 2000. Patterns of increase were distinct and different. The data show the development of transplantation in Europe since 1990, with the number of patients receiving a HSCT increasing from 4200 to over 30 000 annually. The most impressive trend seen is the steady increase of unrelated donor transplantation, in parallel to the availability of unrelated donors through donor registries.

Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy.

Although acquired uniparental disomy (aUPD) has been reported in relapse acute myeloid leukemia (AML), pretransplant aUPD involving chromosome 6 is poorly documented. Such events could be of interest because loss of heterozygosity (LOH) resulting from aUPD in leukemic cells may lead to erroneous results if HLA typing for hematopoietic stem cell donor searches is performed on blood samples drawn during blastic crisis. We report here six AML patients whose HLA typing was performed on DNA extracted from peripheral blood obtained at diagnosis. We observed LOH involving the entire HLA region (three patients), HLA-A, B, C (two patients) and HLA-A only (one patient). An array-comparative genomic hybridization showed that copy number was neutral for all loci, thus revealing partial aUPD of chromosome 6p21. When HLA typing was performed on remission blood samples both haplotypes were detected. A 3-4% LOH incidence was estimated in AML patients with high blast counts. Based on DNA mixing experiments, we determined by PCR sequence-specific oligonucleotide hybridization on microbeads arrays a detection threshold for HLA-A, B, DRB1 heterozygosity in blood samples with <80% blasts. Because aUPD may be partial, any homozygous HLA result should be confirmed by a second typing performed on buccal swabs or on blood samples from the patient in remission.

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation.

Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (eg, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri-, and posttransplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplantation experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation.

Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (for example, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplant experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This report provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.