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.

Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

Pro-oxidative/antioxidative imbalance: a key indicator of adverse outcome in hematopoietic stem cell transplantation.

INTRODUCTION: Pretransplantation iron overload (IO) is considered as a predictor of adverse outcome in hematopoietic stem cell transplantation (HSCT). Peroxidative tissue injury caused by IO leads to progressive organ dysfunction. METHODS: This is a retro-prospective study which explores the possible relationship between IO, oxidative stress and transplant outcome. Serum samples of 149 consecutive HSCT candidates were subjected to analysis of iron parameters, including nontransferrin bound iron (NTBI) and pro-oxidant/antioxidant status. RESULTS: Serum ferritin was found to be positively correlated with NTBI and negatively correlated with glutathione peroxidase (GPx) and superoxide dismutase (SOD). An inverse correlation of NTBI with SOD, total antioxidant potential (TAP) and malonyldialdehide (MDA) was also demonstrated. An adverse impact of serum ferritin level on early posttransplant complications including pulmonary toxicity, fungal infections and sinusoidal obstruction syndrome (SOS) was shown. A significant impact of NTBI on +30 day (P = 0.027) and +100 day survival (P = 0.028) was shown in auto-transplanted patients. MDA levels had a significant impact on +30 day and +100 day survival in autologous (P = 0.047; P = 0.026) and allogeneic (P = 0.053; P = 0.059) groups. GPx (P = 0.016) and MDA (P = 0.021) were identified as independent prognostic parameters for overall survival in allo-transplanted patients. CONCLUSION: Pretransplantation IO might be a major contributor to adverse outcome in HSCT recipients through an impaired pro-oxidative/antioxidative homeostasis. The reversible nature of IO and oxidative stress suggests that early preventive strategies might have a potential to improve transplant outcome.

The impact of bone marrow fibrosis on the outcome of hematopoietic stem cell transplantation.

We retrospectively analyzed the data of 175 patients who underwent autologous (n = 69) or allogeneic hematopoietic stem cell transplantation (HCT) (n = 106) including 19 (27.5%) and 38 (35.8%) recipients who had bone marrow fibrosis (BMF) prior to transplantation, respectively. We investigated the effects of BMF on engraftment, graft-versus-host disease (GVHD), early posttransplant complications, and survival. Pretransplantation BMF did not delay engraftment and showed no impact either on early posttransplant complications or on the development of acute and/or chronic GVHD. Probability of 1-year overall survival (OS) and progression-free survival (PFS) of autologous HCT recipients were similar, namely 76.7% versus 88.6% (P > .005) and 26.33% versus 16.5% (P > .05) among patients with versus without fibrosis, respectively. In allogeneic HCT recipients, the probability of 1-year OS was 35.2% among patients with versus 48.9% among those without fibrosis (P = .004) PFS at 1 year was inferior among allogeneic HCT recipients with BMF: 27.8% versus 51.2% (P = .0008). Cox regression analysis revealed BMF to be independently associated with age, Sorror comorbidity index, primary disease, and disease status during HCT (P = .045).

Iron overload: predictor of adverse outcome in hematopoietic stem cell transplantation.

INTRODUCTION: Iron overload is an important problem in candidates for and survivors of hematopoietic stem cell transplantation (HSCT), and affects long-term outcome and survival. The objective of the present study was to determine the effect of iron overload on early toxic or infectious complications and survival. PATIENTS AND METHODS: We retrospectively reviewed the medical records for 250 adult patients (162 men and 88 women; median [range] age, 34 [16-71] years who underwent HSCT between September 2003 and August 2008. The HSCT grafts were autologous in 102 patients, and allogeneic in 148. RESULTS: Follow-up was 315 (1-1809) days. Mean (SD) pre-HSCT serum ferritin concentration was 1402.6 (5016.2) ng/mL in the entire group, 647.6 (1204.3 ng/mL in autologous recipients, and 1410.6 (2410.4) ng/mL in allogeneic recipients. Twenty-eight autologous graft recipients (27.4%) and 102 allogeneic recipients (68.9%) demonstrated serum ferritin concentrations of 500 ng/mL or greater, and were classified as the high-ferritin group. High ferritin concentrations were significantly associated with toxic or infectious complications including mucositis, fungal infections, pneumonia, and sinusoidal obstruction syndrome in the early post-HSCT setting. A significant effect of pre-HSCT ferritin concentration on overall survival and transplant-related mortality was observed. The effect of pre-HSCT ferritin on survival was independent of the comorbidity index at Cox regression analysis. In the entire study population, the probability of survival was significantly lower when ferritin concentration was greater than 500 ng/mL. CONCLUSION: Transplant-related mortality has decreased substantially with the development of supportive treatments. Pretransplantation risk assessment and risk-adapted strategies such as decreasing iron overload might further improve transplant-related complications.

Risk factors for fungal pulmonary infections in hematopoietic stem cell transplantation recipients: the role of iron overload.

Fungal pulmonary infections (FPIs) are frequent causes of mortality in hematopoietic stem cell transplantation (HSCT) recipients. Determination of the specific risk factors may improve the prognosis. The aim of this study was to evaluate the risk factors of FPIs due to HSCT. Patient history, physical examination, chest X-rays and the consultation records of the pulmonary disease department which were a part of the routine evaluation before and at first, third, sixth, ninth and twelfth months of HSCT were retrieved in 148 adult HSCT recipients. Results of the high-resolution computed tomography, fiber-optic bronchoscopy and the microbiological data were also included. FPI was diagnosed in 22 patients (14.9%). Multivariate analysis showed that increased ferritin levels (>1000 ng/ml; OR: 3.42, 95% CI 1.03-11.42, P=0.045) and the development of sinusoidal obstruction syndrome (SOS; OR: 5.09, 95% CI 1.53-16.90, P=0.008) were significant risk factors for FPIs. The sensitivity and specificity of ferritin >1000 ng/ml for the prediction of FPIs were 67 and 70%, respectively. There was a positive correlation between the increased risk of FPIs and pretransplantation ferritin levels (r=0.413, P<0.001) and increased ferritin levels and SOS (r=0.331, P<0.001). Increased pretransplantation ferritin levels and development of SOS are predictive factors of FPIs during HSCT.

Abnormal protein bands in patients with multiple myeloma after haematopoietic stem cell transplantation: does it have a prognostic significance?

Abnormal protein bands (APB) unrelated to the original monoclonal protein occasionally appear in serum immunofixation samples from patients with multiple myeloma (MM) following haematopoietic stem cell transplantation (HCT). To investigate the significance of APB, medical records and serum immunofixation patterns of 53 MM patients, who had undergone HCT (49 autologous and 4 allogeneic) at the stem cell transplantation unit of Gazi University Faculty of Medicine, were reviewed. Patients were staged according to Durie-Salmon and International staging systems (ISS) and disease response was determined according to European Bone Marrow Transplantation (EBMT) criteria. Fourteen (26.4%) of the 53 patients developed APBs after HCT. The median time for the appearance and duration of APB was 3 (range 1-24) and 5.5 (range 1.5-14) months, respectively. Probability of overall survival (OS) at the end of the follow-up was 77 and 61.4% in patients with and without APB, respectively (p = 0.334). The median duration of follow-up (767 days (range, 220-2905) vs. 726 days (range, 120-1780) p = 0.545) was not different in patients with and without APB. Probability of progression free survival (PFS) at the end of follow-up was 28.8% in patients with and 27.7% in patients without APB (p = 0.835). PFS (910 days (range 180-2905) vs. 730 days (range 90-1765) p = 0.835) was longer in patients with APB, though without statistical significance. Thus, the occurrence of APB post-transplantation is not associated with any adverse long-term consequences and does not require treatment modification.

Impact of ABO-incompatible donor on early and late outcome of hematopoietic stem cell transplantation.

ABO incompatibility is not a barrier to allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of an ABO mismatch on the outcome of the HSCT remains controversial. We analyzed whether ABO incompatibility leads to an increased risk of early/late complications, mortality, or increased transfusion requirements. The 147 consecutive allogeneic HSCTs includes 80 ABO-identical and 25 major, 30 minor, and 12 bidirectional ABO-mismatched grafts. The four groups were balanced with respect to disease status at transplantation. Transplantation-related mortality was significantly greater (P < .01) and overall survival significantly shorter (P = 0.2) among HSCT recipients with minor ABO-mismatched grafts. The relapse rate, progression-free survival, and transfusion requirements until discharge were not different between ABO-identical and ABO-mismatched groups. Pure red cell aplasia (PRCA); (P < .0001) and delayed red blood cell (RBC) engraftment (P < .001) were more frequent in HSCT recipients with major mismatched donors. Delayed RBC engraftment was associated with posttransplantation hyperferritininemia and increased mortality risk (P = .05). The greater frequency of sinusoidal obstruction syndrome and graft-versus-host disease (GVHD) in patients with minor mismatched transplants, did not show statistical significance. In contrast severe GVHD was significantly more frequent among minor mismatched patients (P = .04). ABO-mismatched HSCT might have an unfavorable impact on transplant outcomes. Selection of ABO-compatible donors when possible, strategies to prevent and treat PRCA, modifications in transfusion practice, and effective iron chelation are among the measures that can improve transplant outcomes.

Cardiac systolic function in patients receiving hematopoetic stem cell transplantation: risk factors for posttransplantation cardiac toxicity.

One hundred eleven patients who received 125 hematopoetic stem cell transplantations (HSCT) with myeloablative conditioning regimens were retrospectively evaluated for the development of cardiac toxicity (CT). The aims of this study were to assess the frequency of cardiac complications in patients receiving HSCT and to investigate the value of pretransplantation variables to predict posttransplantation CT. Severe grade III-IV CT was not observed in this cohort, in whom pretransplantation eligibility criteria excluded the patients with a left ventricular ejection fraction (LVEF) of 50% or less. Grade I-II CT was seen in 13.4% patients. Patients with a history of previous mediastinal radiotherapy, high doses of anthracycyclines, and a longer interval between diagnosis and treatment were found to have higher risk of developing CT. Pretransplantation ferritin levels and the type of HSCT did not seem to have an effect on posttransplantation cardiac complications. Our results indicated that CT was managable in patients with a LVEF of at least 50%.

The role of liver biopsy in the workup of liver dysfunction late after SCT: is the role of iron overload underestimated?

Abnormalities in liver function tests are common in hematopoietic SCT (HSCT) recipients. We retrospectively investigated the role of liver biopsy in determining the cause of elevated liver enzymes and its impact on the management of patients in the post-HSCT setting. A total of 24 consecutive liver biopsies were obtained from 20 patients from September 2003 to December 2007. A definite histopathologic diagnosis was obtained in 91.7% of the biopsies. Iron overload (IO) was found in 75% and GVHD in 54.2% of the patients. The initial clinical diagnosis of GVHD was confirmed in 56.5% and refuted in 43.5% of the allogeneic HSCT recipients. The median number of post transplant transfusions, percent transferrin saturation and ferritin levels were found to be higher in patients who had histologically proven hepatic IO (p1=0.007, p2=0.003 and p3=0.009, respectively). Regression analysis showed a significant correlation between serum ferritin levels and histological grade of iron in the hepatocytes. Our data suggest that hepatic IO is a frequent finding in the post-HSCT setting, which contributes to hepatic dysfunction and it should be considered in the differential diagnosis, particularly in patients with high serum ferritin levels.

Effects of sympatholytic therapy with moxonidine on serum adiponectin levels in hypertensive women.

We examined whether moxonidine influences lipid profile, insulin resistance, adiponectin levels, renal function and microalbuminuria in women with essential hypertension in a study of 55 non-diabetic hypertensive patients and 53 normotensive women. Hypertensive patients received moxonidine for 12 weeks. At baseline the hypertensive group had significantly higher mean blood pressure, low-density lipoprotein cholesterol, triglycerides, total cholesterol, fasting glucose, urinary albumin excretion and homeostasis model assessment of insulin resistance (HOMA-IR), together with significantly lower mean high-density lipoprotein cholesterol, creatinine clearance and serum adiponectin than the normotensive group. Moxonidine significantly decreased blood pressure, fasting glucose, triglycerides, total cholesterol, HOMA-IR and albumin excretion, but significantly increased serum adiponectin. The change in adiponectin level was negatively correlated with the change in HOMA-IR. Moxonidine treatment may improve unfavourable metabolic status related to insulin resistance by increasing adiponectin levels in patients with essential hypertension. Since it can improve adiponectin levels, it may be used in the antihypertensive treatment of patients at high risk of diabetes and cardiovascular disease.

Adiponectin and insulin resistance in obesity-related diseases.

The relationship between insulin resistance and serum adiponectin levels in 400 subjects with different obesity-related diseases was studied. Lean subjects with body mass index (BMI) < 25 kg/m(2) were placed in one group and the other five groups of overweight/obese subjects with BMI >or= 25 kg/m(2) were grouped according to disease profile. The homeostasis model assessment insulin resistance (HOMA-IR) index and adiponectin levels were similar in the lean, metabolically normal (MNO) and hypertensive groups, but were different when the dyslipidaemic group was compared with the lean and MNO groups. The type 2 diabetic (DMO) and hypertensive, type 2 diabetic (DMHTO) groups were significantly different from other groups with respect to HOMA-IR index and adiponectin levels. Adiponectin levels were lower in the DMHTO than the DMO group. In multiple regression analysis, adiponectin levels correlated with group categorization independently of age, sex, BMI and HOMA-IR. Hypoadiponectinaemia may play a role in the development of complications of obesity.

Treatment of sinusoidal obstruction syndrome with defibrotide: a single-center experience.

Sinusoidal obstruction syndrome (SOS) is a frequent, troubling, and potentially fatal complication of hematopoietic stem cell transplantation. Despite promising results with defibrotide (DF), no treatment has been established as standard. DF is a single-stranded polydeoxyribonucleotide, obtained from controlled depolymerization of porcine intestinal mucosal cells. It has antithrombotic, antiischemic, antiinflammatory, and thrombolytic properties without significant side effects. We retrospectively evaluated the charts of 80 consecutive patients, with 89 hematopoietic stem cell transplants for hematologic malignancies. The results of early initiation of DF treatment in 14 patients with SOS are presented in this study. Fourteen patients, 8 males and 6 females % median age 40.5 years (range, 16-46 years) were diagnosed to have SOS. Disease severity was classified as severe in 6 (42.85%), moderate in 4 (28.57%), and mild in 4 (28.57%) patients. We treated 14 patients with DF for a median of 21.5 days (range, 4-39 days). All 14 patients received DF after the diagnosis of SOS. Three patients with severe and all of the patients with mild to moderate SOS responded to treatment with complete resolution of SOS-related signs and symptoms. All patients responding to DF were alive at 100 days posttransplantation. There was no significant drug-related side effect among patients treated with DF. With an overall response rate of 78.56% and a 50% complete response rate in severe SOS cases and minimal side effects, we suggest that DF is the best available agent to treat SOS.

Frequencies of serum antibodies to Helicobacter pylori CagA and VacA in a Turkish population with various gastroduodenal diseases.

Infection with Helicobacter pylori (H. pylori) strains secreting cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) proteins is associated with more severe gastroduodenal pathologies. However, this association varies among geographical regions and ethnic groups. We investigated the frequencies of antibodies to CagA and VacA proteins in 131 H. pylori-infected dyspeptic patients [40 duodenal ulcer (DU), 19 gastric ulcer (GU), 28 gastric cancer (GC), and 44 non-ulcer dyspepsia (NUD)] across 30 H. pylori-infected and endoscopically normal asymptomatic subjects (AS). Anti-CagA and anti-VacA antibodies were detected by Western blotting. The positivity rates of anti-CagA and anti-VacA antibodies were higher in patients with DU (92.5 and 75%), GU (89.5 and 84.2%) and GC (96.4 and 85.7%) than patients with NUD (70.5 and 50%) and AS (50 and 23.3%) (p < 0.05). CagA+ VacA+ phenotype was more frequent in patients with DU, GU and GC than patients with NUD and AS (75, 84.2, 85.7 vs. 47.7 and 20%, respectively) (p < 0.01). Our results showed that there is a significantly positive association between the presence of anti-CagA and anti-VacA antibodies and DU, GU and GC in our region.

Hemoglobin Lepore Boston in a Turkish Family.

An abnormal hemoglobin was detected in a Balkan immigrant Turkish family. Erythrocyte morphology was similar to ß-thalassemia trait. Molecular analysis showed that the abnormal hemoglobin was Hemoglobin LeporeBoston. All affected family members were in heterozygote state and asymptomatic.