Zübeyde Nur Özkurt

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.

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.

Factors affecting stem cell mobilization for autologous hematopoietic stem cell transplantation.

High‐dose chemotherapy with autologous stem cell transplantation (ASCT) is curative treatment in various hematologic malignancies. Mobilization and collection of peripheral blood stem cell is the essential part of ASCT. The aim of this study was to evaluate the effectiveness of various mobilization regimens, determine the risk factors associated with mobilization failure (MF). We also investigated whether iron overload, which has an adverse impact on various aspects of HSCT including overall survival had any impact on mobilization kinetics. A total of 118 consecutive patients were included in this study. The rate of MF was 11.8 % with the first mobilization regimen. Frequency of MF was higher in lymphoma (P < 0.001) patients and in those receiving G‐CSF alone (P= 0.01). Peripheral CD34+ cell count (P < 0.001), bone marrow cellularity (P < 0.001), reticulin fibrosis (P < 0.05) were significantly lower whereas serum ferritin levels (P = 0.06) tended to be higher in patients with MF. CD34+ cell count of the first apheresis product was positively correlated with the white blood cell count (P < 0.05; r = 0.232), platelet count (P = 0.01; r = 0.233), peripheral CD34+ cell count (P < 0.001; r = 0.704) and the grade of bone marrow reticulin fibrosis (P < 0.001; r = 0.366). Serum ferritin levels were negatively correlated with maximum peripheral CD34+ cell count (P = 0.02; r = −0.216) and the CD34+ cell count in the first product (P = 0.05; r = −0.183). Platelet count (P = 0.03; β = 0.262), peripheral CD34+ cell count (P = 0.02; β=0.279) were the two variables which remained to be significant in multivariate analysis. Predicting the poor mobilizers with the platelet count for instance may reduce the risk of MF by using more effective regimens in advance. J. Clin. Apheresis, 2010.

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.

Relationship of left ventricular mass to insulin sensitivity and body mass index in healthy individuals.

Objective— The objective of this study was to investigate the contribution of insulin resistance, hyperinsulinaemia and obesity, independently of other major factors, to changes in left ventricular mass a cardiovascular risk indicator, in a healthy population without co-morbid states such as diabetes or hypertension. Methods and results— This cross-sectional relational study was perfomed in 153 healthy subjects, comprising 76 men and 77 women with ages ranging from 23 to 67 years. All of them were normotensive and had a normal oral glucose tolerance test, none had cardiovascular disease and none were taking any medication. Weight, height and waist circumference were measured and BMI was calculated.A blood sample was drawn in the fasting state: plasma glucose, insulin, serum total and high density lipoprotein (HDL), low density lipoprotein cholesterol and triglycerides were measured. Insulin resistance was determined by the ‘Homeostasis Assessment Model’ (HOMA-IR). Subjects were studied by echocardiography. The left ventricular mass was calculated by using the anatomically validated formula of Devereux et al. Results— Left ventricular mass significantly and positively correlated with BMI, age, systolic and diastolic blood pressure and fasting blood glucose. The correlation of left ventricular mass with fasting blood glucose was not maintained after controlling for BMI. BMI, fasting blood glucose, HOMAIR, systolic and diastolic blood pressure showed significant differences with higher values for people with left ventricular hypertrophy.The logistic regression analysis showed a strong association between left ventricular hypertrophy and BMI (p < 0.05). Conclusion— Insulin resistance and fasting insulin is not associated with left ventricular hypertrophy in healthy people, independent of obesity. Obesity appears to be an independent risk factor for left ventricular hypertrophy.

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.

Hepatitus B virus reactivation in HBV-DNA negative and positive patients with hematological malignancies

Abstract Reactivation of hepatitis B virus (HBV) is a frequent complication of chemotherapy (CT) in patients with HBsAg carriers. In this prospective study, we documented CT induced HBV reactivation risk in patients with hematological malignancies. HBV reactivation risk is influenced by baseline viral load. Therefore, we divided our study population into two groups according to HBV-DNA status. HBV-DNA negative patients (n=18) were treated with nucleoside analogues once HBV reactivation was observed. HBV-DNA positive patients (n=12) commenced lamivudine before the initiation of the CT. In HBV-DNA negative patients HBV reactivation was found in 10 patients (55·5%). HBV reactivation was significantly more frequent in chronic lymphocytic leukemia (CLL) patients (P=0·008) and in patients receiving rituximab containing chemotherapy regimens (P=0·06). Eight patients (80·0%) responded to antiviral treatment after HBV reactivation. Two CLL patients experienced a flare-up after the withdrawal of antiviral therapy. In HBV-DNA positive patients, HBV reactivation was observed in four patients (33·3%) during lamivudine treatment and in two patients after lamivudine withdrawal. This study demonstrated the increased risk of CT-induced HBV reactivation in CLL patients, for the first time.

Extranodal multifocal Rosai-Dorfman disease: response to 2-chlorodeoxyadenosine treatment

Rosai–Dorfman disease (RDD) or “sinus histiocytosis with massive lymphadenopathy” is a rare lymphoproliferative disorder of unknown etiology. The disease usually presents with painless lymphadenopathy with occasional extranodal involvement in various organs. We report a case of a 36-year-old man with a history of non-Hodgkin lymphoma (NHL), who recently presented with inguinal lymphadenopathy. Following the diagnosis of RDD on lymph node biopsy, he developed symptoms of spinal cord compression due to a mass lesion discovered at T6-7 vertebral level. 18F-Fluorodeoxyglucose (18FDG) positron emission tomography (PET-CT) revealed extensive disease with lung, renal and bone involvement. The patient received a short course of steroid therapy for cord compression findings and 2-chlorodeoxyadenosine (2-CdA) treatment was initiated for long-term disease control. He had a dramatic sustained response to treatment with six courses of 2-CdA. These results suggest that 2-CdA can be an effective treatment of choice and positron emission tomography with 18FDG can be used for determining the extent of disease and for follow-up in RDD.

Free light chain: a novel predictor of adverse outcome in chronic lymphocytic leukemia

Objectives: Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. This retrospective study is planned to assess the prognostic value of serum free light chain (sFLC) levels and FLC ratio (FLCR) in CLL. Methods: Quantitative levels of sFLC were measured nephelometrically in sera collected at diagnosis. The expressions of ZAP70 and CD38 were quantified by flow cytometry. Chromosomal abnormalities were determined by interphase fluorescence in situ hybridization (FISH). Results: In a cohort of 101 patients with a median follow‐up of 29 (1–234) months, sFLC levels were found to be high in 55 patients (54.5%). An abnormal FLCR was found in 30 patients (29.7%). FISH‐based genetic risk groups did not differ significantly with respect to sFLC and FLCR (P > 0.05). Median time to first treatment was shorter in patients with high sFLC levels (P = 0.02). Median overall survival (OS) was shorter in patients with high sFLC levels (P = 0.01) and abnormal FLCR (P = 0.05). In patients with early stage disease, median OS was shorter in high sFLC (P = 0.03) and abnormal FLCR groups (P = 0.048). A relationship was observed between abnormal sFLC levels and CD38 positivity on logistic regression analysis (P = 0.003; OR: 4.44; 95% CI: 1.66–11.8). Conclusions: This study highlighted the adverse prognostic impact of high sFLC levels and abnormal FLCR with regard to survival in CLL, even in early stage patients. Prospective studies are warranted to validate the adverse impact of sFLC and FLCR on clinical outcome.

Donor lymphocyte infusion for leukemia relapse after hematopoietic stem cell transplantation

Leukemia relapse is a serious therapeutic challenge following hematopoietic stem cell transplantation (HSCT). In this retrospective study, 23 patients [15 (65.2%) AML, 8 (34.8%) ALL] who received DLI+/-reinduction chemotherapy for post-transplant relapse were reviewed. The overall response rate of DLI was 66.7% for AML and 50% for ALL. A total of 15 patients (65.2%) developed acute graft versus host disease (GVHD). Response rates were higher in patients with GVHD (80% versus 25%; p=0.01; OR: 12.0). The probability of OS was better in patients who respond to DLI (p=0.04). Further strategies are required to improve the anti-tumor properties of alloreactive donor lymphocytes and to obtain durable responses with DLI in patients with relapsed acute leukemia after allogeneic HSCT.