Deferasirox in children with transfusion-dependent thalassemia or sickle cell anemia: A large cohort real-life experience from Turkey (REACH-THEM).

OBJECTIVES: To evaluate the long-term efficacy and safety of deferasirox therapy in a large observational cohort of children with transfusion-dependent thalassemia (TDT) and sickle cell anemia (SCA) in Turkey. METHODS: This was a multicenter, prospective cohort study including TDT and SCA patients aged 2-18 years with iron overload (≥100 mL/kg of pRBC or a serum ferritin [SF] level >1000 µg/L) receiving deferasirox. Patients were followed for up to 3 years according to standard practice. RESULTS: A total of 439 patients were evaluated (415 [94.5%] TDT, 143 [32.6%] between 2 and 6 years). Serum ferritin levels consistently and significantly decreased across 3 years of deferasirox therapy from a median of 1775.5 to 1250.5 µg/L (P < 0.001). Serum ferritin decreases were noted in TDT (1804.9 to 1241 µg/L), SCA (1655.5 to 1260 µg/L), and across age groups of 2-6 years (1971.5 to 1499 µg/L), 7-12 years (1688.5 to 1159.8 µg/L), and 13-18 years (1496.5 to 1107 µg/L). Serum ferritin decreases were also noted for all deferasirox dose groups but only significant in patients with doses ≥30 mg/kg/d (n = 120, -579.6 median reduction, P < 0.001). Only 9 (2%) patients had adverse events suspected to be related to deferasirox. Serum creatinine slightly increased but remained within the normal range. CONCLUSIONS: Deferasirox has long-term efficacy and safety in children with TDT and SCA, although higher doses (≥30 mg/kg/d) may be required to achieve iron balance.

Impact of Prophylaxis on Bone Mineral Metabolism in Children With Hemophilia.

In this study, we aimed to investigate changes in calcium (Ca) metabolism in hemophilia patients (PWH). We also aimed to investigate the importance of diagnosis and treatment of factors impairing calcium metabolism and the significance of early diagnosis and prophylaxis with respect to these subjects. For all patients, serum calcium, phosphorus, alkaline phosphatase, 25 hydroxy vitamin D (25-OHD), parathormone (PTH), and calcitonin levels were evaluated. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry. Low BMD scores and 25-OHD deficiency were observed in 29 (74.4%) and 34 (87.2%) patients, respectively. Prophylaxis of PWH did not differ significantly in terms of 25-OHD levels and BMD scores. Patients in the prophylaxis group had significantly higher PTH levels (P=0.042). A negative correlation was found between PTH measurements and Z-score (P=0.008). In summary, our findings, with a small number of PWH in our study group, suggest that biochemical markers of bone turnover may be used to detect bone loss. Follow-up through annual BMD measurements coupled with appropriate exercise programs could be recommended.

Factors associated with bone marrow stem cell yield for pediatric allogeneic stem cell transplantation: The impact of donor characteristics.

The aim of this study was to investigate the effects of donor characteristics on CD34+ cell yield in BM harvest. Between April 2010 and November 2013, consecutive donors who underwent BM harvesting in our BM transplantation unit were retrospectively investigated. Donors were classified into two groups: those who donated BM without mobilization (steady-state BM donors) and those who received G-CSF for stem cell mobilization (G-CSF-primed BM donors). Donor characteristics (age, gender, race, body weight, BMI, and laboratory factors including donor's leukocyte, platelet, and monocyte) and their relationship with total nuclear cell and CD34+ cell numbers has been evaluated. A total of 64 healthy related donors (29 males/35 females, median age 11.2 years; 49 [76.6%] younger than 18 and 36 [56.3%] younger than 12 years) were included in the study. The median CD34+ cell yield in the harvest was 0.12×106 /L (0.02-0.21) in SS-BM donors and 0.18×106 /L (0.09-0.67) in GP-BM donors (P=.03). Median of CD34+ cell count given to recipients was 2.6×106 /recipient body weight (1.3-19.3) in SS-BM yields and 3.8×106 /recipient body weight (1.1-10.2) in GP-BM yields, respectively. Multiple regression analysis showed that donor height and pre-G-CSF platelet were the most important parameters to obtain a sufficient BM harvest. Our data suggest that the shorter donors and the donors with higher thrombocyte counts may offer more hematopoietic stem cell. The height and thrombocyte count of the donors should be taken into consideration before planning the targeted CD34+ cell count especially for pediatric donors.

Effects of stem cell transplantation on bone mineral density and vitamin D status in children with thalassemia major.

HSCT is a curative treatment in TM, but conditioning and immunosuppressive treatment may affect bone metabolism. In this retrospective study, we aimed to compare BMD, vitamin D status, and growth in children with TM who underwent HSCT to those in children with TD TM. Twenty-three children with TM who underwent HSCT (mean age 7.1 years [1.03-14.7]) and 24 children with TD thalassemia (mean age 9.8 years [1.6-14]) were recruited. Lumbar spine BMD of TD thalassemia patients was higher than those in patients who had HSCT at both baseline and second-year assessments (P=.009, P<.001, respectively). However, BMD Z scores or serum 25-OH vitamin D levels were not different in two groups. Being >10 years of age was a significant risk factor for low BMD, height, and weight Z score for both groups. Patients who underwent HSCT with Pesaro risk class II or III had higher risk for low BMD compared to those risk class I patients (P=.044). In conclusion, children with TM who were >10 years at HSCT are at risk for low BMD and growth retardation. HSCT had no effect on BMD deficit in children with TM.

Assessment of left ventricular functions and myocardial iron load with tissue Doppler and speckle tracking echocardiography and T2* MRI in patients with ß-thalassemia major.

BACKGROUND: The purpose of this study is to determine early myocardial dysfunction in ß-thalassemia major (BTM) patients. Where the myocardial dysfunction cannot be detected by conventional echocardiography, it could be detected by tissue Doppler imaging (TDI) or speckle tracking echocardiography (STE). METHODS: In this study, we analyzed 60 individuals, 30 of whom were BTM patients and the other 30 of whom were the control group. T2* magnetic resonance imaging (MRI) was used to measure cardiac iron deposition. The myocardial functions were evaluated by conventional echocardiography, TDI and STE. RESULTS: When basal lateral left ventricular and basal septal wall TDI values were compared between the patient group and control group, only isovolumic contraction time values were significantly longer in the patients. The global circumferential strain was significantly lower in the patients. When evaluated as segmental, longitudinal strain values of basal inferoseptum and circumferential strain values of anteroseptum, anterior, and inferolateral segments were significantly lower in the patients. In the patients, global longitudinal and circumferential strains in the group who had pathological T2* values were significantly lower than the group who did not. In addition, circumferential strain values in anteroseptum, anterolateral, inferior, and inferoseptum segments were significantly lower in the patients with T2* values<20 ms than those with T2* values≥20 ms. CONCLUSION: Although T2* MRI is the most sensitive test detecting myocardial iron load, TDI and STE can be used for screening myocardial dysfunction. The abnormal strain values, especially circumferential, may be detected as the first finding of abnormal iron load and related to T2* values.

Comparison of prophylactic use of intravenous immunoglobulin versus Pentaglobin® in pediatric patients after hematopoietic stem cell transplantation.

There are few studies evaluating the use of IgM-enriched IVIG (Pentaglobin(®) ) in HSCT recipients. This study aimed to compare the efficacy of prophylactic use of IVIG versus prophylactic use of Pentaglobin(®) within the first 100 days after allogeneic HSCT. We performed a prospective, randomized study of the use of prophylactic IVIG versus prophylactic use of Pentaglobin(®) in patients after allogeneic HSCT. The first dose of IVIG or Pentaglobin(®) was given before conditioning regimen and after transplant was given on day +1, +8, +15, and +22. And then, it was given if IgG level was below 400 mg/dL. Twenty-seven patients in IVIG group and 32 patients in Pentaglobin(®) group were included in the study. There were no significant differences in the duration of neutropenia, hospitalization, fever, and in the number of pyrexial episode, septicemia, bacteremia, local infection, CMV infection, acute GVHD, VOD, and adverse events between the IVIG group and Pentaglobin(®) group. Randomized placebo-controlled trials are needed to conclude that utilization of IVIG or Pentaglobin(®) has no beneficial effect in HSCT.

Risk factors, complications and outcome of cholelithiasis in children: A retrospective, single-centre review.

AIM: The aim of this study was to evaluate the clinical presentation, risk factors, complications, treatment and outcomes of cholelithiasis in children. METHODS: Children with cholelithiasis were reviewed for demographic information, predisposing factors, presenting symptoms, laboratory findings, complications, treatment and outcome, retrospectively. RESULTS: A total of 254 children with cholelithiasis (mean age: 8.9 ± 5.2 years) were recruited to the study. Girls (52.8%) were significantly older than boys (P < 0.001). Symptomatic patients (59%) were significantly older than asymptomatic patients (P = 0.002). Abdominal pain was the most frequent symptom. No risk factors were identified in 56.6% of the patients. Ceftriaxone (20%) was the most commonly associated risk factor. At presentation, at least one of the following complications was seen in 14.1% of patients: cholecystitis (10.9%), obstructive jaundice (2.7%), pancreatitis (1.96%) and cholangitis (1.2%). There was no relationship between gallstone size and symptoms, aetiological factors and complications. The cholelithiasis dissolution rate was higher in younger children (P = 0.032), in those with biliary sludge (P < 0.0001) and ceftriaxone-related cholelithiasis (P < 0.001). Haemolytic anaemia (P = 0.001) and older age (P = 0.002) were associated with stable stones. Ursodeoxycholic acid was administered to 94.4% of patients at presentation. Twenty-nine patients underwent cholecystectomy, and seven patients underwent endoscopic retrograde cholangiopancreotography. Patients who were symptomatic at presentation had significantly more frequent symptoms at follow-up (P < 0.001) CONCLUSIONS: Dissolution rate of cholelithiasis was higher in younger children, biliary sludge formation and ceftriaxone-related cholelithiasis but lower in older children and haemolytic anaemia-related cholelithiasis.

The Effect of Granulocyte Colony-Stimulating Factor on Immune-Modulatory Cytokines in the Bone Marrow Microenvironment and Mesenchymal Stem Cells of Healthy Donors.

Granulocyte colony stimulating factor (G-CSF) is sometimes administered to donors before bone marrow (BM) harvest. G-CSF-primed (G-BM) and unprimed BM (U-BM)-derived mesenchymal stem cells (MSC) were obtained from 16 healthy donors and were expanded in vitro. Their proliferative characteristics, morphology, and differentiation capacity were examined. Supernatants of the second passage of MSCs were evaluated for transforming growth factor ß1, hepatocyte growth factor, and prostaglandin E2 (PGE2) levels and compared with controls. The analyses of cytokines in the G-BM- and U-BM-derived MSCs supernatants revealed that PGE2 levels were significantly lower in the G-CSF-primed samples. These cytokines were also measured in BM plasma. The level of hepatocyte growth factor in G-BM plasma was significantly increased. The current study is the first to show the effects of G-CSF on the BM microenvironment of healthy human donors. The preliminary data suggest that G-BM- and U-BM-derived MSCs have similar morphologic/phenotypic properties and differentiation capacity but differ in their secretory capacity. Significant changes in cytokine levels of BM plasma in G-CSF-primed donors were also demonstrated. These findings suggest that BM MSCs and changes in the BM microenvironment may contribute to the effects of G-CSF on inflammation and immunomodulation.

Pulmonary arterial hypertension in a child with stage-IV neuroblastoma after autologous hematopoietic stem cell transplantation and review of the literature.

PH is a rare condition with high mortality rate after pediatric HSCT. As clinical presentation is non-specific and may mimic other conditions, a high degree of suspicion is required for diagnosis. Here, we present a patient with stage-IV neuroblastoma who developed PAH after autologous HSCT. After exclusion of other causes of PH, we regarded that this condition was secondary to HSCT.

Secondary antifungal prophylaxis in pediatric hematopoietic stem cell transplants.

Invasive fungal infections (IFIs) constitute a leading cause of morbidity and infection-related mortality among hematopoietic stem cell transplant (HSCT) recipients. With the use of secondary prophylaxis, a history of IFI is not an absolute contraindication to allo-HSCT. However, still, IFI recurrence remains a risk factor for transplant-related mortality. In this study, of the 105 children undergoing HSCT between April 2010 and February 2013, 10 patients who had IFI history before transplantation and had undergone allo-HSCT were evaluated retrospectively to investigate results of secondary prophylaxis. In conclusion, our study shows that amphotericin B and caspofungin was successful as secondary antifungal prophylaxis agents with no relapse of IFI. In addition, after engraftment, secondary prophylaxis was continued with voriconazole orally in 4 patients that yielded good results.

Clinical outcomes and graft characteristics in pediatric hematopoietic stem cell transplantation: Effect of granulocyte-colony stimulating factor priming.

In this study, we aimed to determine the effect(s) of G-CSF priming on graft and transplantation parameters and compare these findings with those obtained without priming. A total of 64 pediatric patients transplanted from HLA-matched family donors were enrolled in the study. Twenty-nine patients received G-CSF primed marrow (G-BM group) and 35 patients received steady state bone marrow (S-BM group). Number of total nucleated cells (TNC) and CD34(+) cells, CFU-GM colony number, neutrophil and platelet engraftment times, total length of stay in hospital, overall and disease free survival, and occasions of acute and chronic GvHD has been compared between these two groups. Granulocyte colony stimulating factor primed bone marrow (G-BM) yielded higher numbers of CD34(+) cells, TNCs, and CFU-GM colony numbers compared to those obtained in S-BM. The neutrophil engraftment time, platelet engraftment time, length of stay in hospital, overall survival and disease free survival were not different between G-BM and S-BM groups. Also the cumulative incidence of grades II-IV acute and chronic GvHD were similar. It was observed that the use of G-CSF did not increase the risk of acute or chronic GvHD. We concluded that use of G-CSF for stem cell mobilization is an effective and safe method in children.

Evaluation of Cardiac Markers in Children Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: Early life-threatening cardiotoxicity and cardiac death have been reported after hematopoietic stem cell transplantation (HSCT). The purpose of the current study was to evaluate cardiac toxicity of conventional chemotherapy followed by HSCT with cardiac markers: heart-type fatty acid binding protein (H-FABP), glycogen phosphorylase BB (GPBB), high sensitive C reactive protein (hsCRP) cardiac troponin I, (cTnI), creatine kinase MB (CK-MB mass) and myoglobin. METHODS: A total of 20 children who underwent HSCT for malignant and non-malignant diseases were included in this study. Blood samples were collected from all patients in 0th, 7th and 21st day for evaluating these cardiac biomarkers. The patients' echocardiography was assessment before and after one-month of HSCT. RESULTS: Serum 21st H-FABP level was significantly higher when compared with the 0th day H-FABP level (P < 0.05) . 7th day hsCRP level was significantly higher than 0th and 21st day levels (P < 0.05). Interestingly, 7th day GPBB level was significantly lower than 0th and 21st day levels (P < 0.05). Myoglobin, CK-MB mass and cTnI biomarkers remained within the reference range in all patients. CONCLUSIONS: This study showed that H-FABP and hsCRP both seem to be promising markers for evaluation of cardiotoxicity in HSCT process and probably superior to GPBB, cTnI, CK-MB mass and myoglobin.

Evaluation of cardiotoxicity by tissue Doppler imaging in childhood leukemia survivors treated with low-dose anthracycline.

Improvement in long-term survival in patients with acute childhood leukemia has led to the need for monitorization of chemotherapy-related morbidity and mortality. This study included 60 patients with acute lymphoblastic leukemia that were in remission for at least 2 years and 30 healthy controls. Systolic and diastolic function of myocardium was evaluated using conventional echocardiography and tissue Doppler imaging of the left ventricle, interventricular septum and right ventricle. Median age of patients was 11.7 years (range 10-14.9 years), and the median duration of remission was 4 years (range 2.5-5 years). All patients were treated with a low cumulative dose of adriamycin (100 mg/m(2)) according to the St. Jude Total-XIIIA protocol. The ejection fraction (EF) and fractional shortening were normal in the patient and control groups, even though EF values were significantly lower in the patients (69.5 ± 2.3 vs. 72.7 ± 3 %, P < 0.01). Myocardial systole (S m), early diastole (E m) and late diastole (A m) velocities in all segments of the myocardium were significantly lower in the patient group (P < 0.01 for all segments). Cardiotoxicity was noted in all segments of the myocardium in the patient group, despite the fact that they were all treated with a low cumulative dose of adriamycin. Based on these findings, we think that there is no safe dose for anthracyclines and periodic echocardiographic evaluation of both the left and right ventricles must be performed in all patients treated with anthracyclines, even at low doses.

Assessment of Nutritional Status in Children With Cancer and Effectiveness of Oral Nutritional Supplements.

Malnutrition is a common consequence of cancer in children, but the most effective methods of nutrition intervention are under debate. We aimed to evaluate the nutritional status of children diagnosed with cancer, and to investigate the effect of oral nutritional supplements on anthropometric measurements, biochemical parameters, and outcome. A randomized clinical study of 45 newly diagnosed cancer patients was performed. Anthropometric and biochemical data and related factors were assessed at 0, 3, and 6 months after diagnosis. On initial anthropometric assessment, prevalence of malnutrition by weight or height was found to be lower as compared with body mass index (BMI), or weight for height (WFH), or arm anthropometry. Twenty-six of the patients (55%) received oral nutritional supplement. During the second 3 months after diagnosis, there was a statistically significant decrease in number of the patients with WFH <90th percentile and BMI <5th percentile (P = .003 and P = .04, respectively). Infectious complications occurred more frequently in malnourished patients during first 3 months, and survival of children who were malnourished at the 6th month was significantly lower than that of well-nourished children (P = .003). On laboratory assessment, serum prealbumin levels of the all subjects were below normal ranges, but no relation was found for serum prealbumin or albumin levels in patients who were malnourished or not at diagnosis. Nutritional intervention is necessary to promote normal development and increase functional status as a child receives intensive treatment. Protein- and energy-dense oral nutritional supplements are effective for preventing weight loss in malnourished children.

Direct Antiglobulin Test Positivity in Children With Acute Lymphoblastic Leukemia at Diagnosis.

Direct antiglobulin test positivity had been reported in the course of some lymphoproliferative neoplasms. However, there are a few case reports describing direct antiglobulin test (DAT) positivity in children with acute lymphoblastic leukemia (ALL). We herein report 8 patients who had positive DAT among 95 newly diagnosed children with ALL. None of these patients had evidence of hemolysis during the follow-up. An antibody was detected in 2 of 8 patients with positive DAT. These 2 children also had positive indirect antiglobulin test (IAT); an autoantibody that was reactive at 4°C, and an alloantibody (anti E) that was reactive at 37°C was detected. We believe DAT positivity in ALL without significant hemolysis is not a rare disorder, and a need for further prospective studies is apparent.

Successful Off-Label Use of Recombinant Factor VIIa and Coil Embolization in an Adolescent with Massive Hemoptysis Due to Invasive Pulmonary Aspergillosis.

Invasive fungal infections have turned out to be a significant cause of morbidity and mortality in pediatric patients with malignant disorders. Massive hemoptysis, a rare complication of invasive pulmonary aspergillosis, may threaten the lives of patients, usually during the resolution of neutropenia. In this report, we describe a patient with massive hemoptysis due to invasive pulmonary aspergillosis whose bleeding was controlled successfully with off-label use of recombinant factor VIIa and subsequent coil embolization of the right pulmonary artery.

Neurological complications after allogeneic hematopoietic stem cell transplantation in children, a single center experience.

In this study, we retrospectively examined the data of children who underwent allo-HSCT from HLA-matched family donors. We analyzed the incidence, etiological factors, clinical characteristics, possible reasons, risk factors, and follow-up of neurologic complications. BU-based conditioning regimens were used in most of the cases (n = 62). The median duration of follow-up for the 89 patients was 20 months (range 1-41 months). Eleven percent of transplanted children developed one or more neurological symptoms after HSCT with a median observation time of two months (range -6 days to 18 months). The median age of the four girls and six boys with neurological complication was 13 yr (range 5.3-17.6 yr). Cylosporine A neurotoxicity was diagnosed in five children, four of them were PRES. The rest of complications were BU and lorazepam toxicity, an intracranial hemorrhage, a sinovenous thrombosis, and a transient ischemic attack during extracorpereal photopheresis. No difference was found between groups of neurological complication according to age, gender, diagnosis, hospitalization time, neutrophil and platelet engraftment time, stem cell source, and conditioning regimen, acute and chronic GVHD or VOD. Neurological complication was the cause of death in one patient (1.1%).

Massive splenic infarction and portal vein thrombosis in children with chronic myeloid leukemia.

Massive splenic infarction and portal vein thrombosis (PVT) due to chronic myeloid leukemia (CML) is extremely rare. We describe 2 children who were presented with massive splenic infarction and PVT in the course of CML. Massive splenic infarction and PVT treated with splenectomy in one and with medical treatment in another in whom PVT resolved by cytoreductive treatment, led to downsizing of spleen or splenectomy. Splenic infarct and PVT should be considered in CML patients with long-lasting severe abdominal pain despite appropriate medical attempts. Splenectomy should be spared for persistent symptoms and complications.

Do two different stem cell grafts: G-CSF stimulated and unstimulated bone marrow differ according to hematopoietic colony forming capacity?

The study was designed to compare colony forming capacity of granulocyte-colony stimulating factor (G-CSF) stimulated bone marrow (G-BM) with standard unstimulated bone marrow (U-BM) of healthy donors of pediatric patients. CFU-Assay results of 26 healthy donors of pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) were analyzed retrospectively. 13 of donors received 10 µg/kg per day of G-CSF as a single injection for 3 consecutive days and other 13 of donors had unstimulated BM. Colony forming capacity of hematopoietic stem cells evaluated with Colony Forming Unit-Assay (CFU-Assay) with in semi-solid agar culture medium after 14-18 days of culture period. CFU-Assay results of G-BM and U-BM (expressed as means) were; Burst Forming Unit-Erythroid (BFU-E): 15.20 × 10(4)/kg and 8.38 × 10(4)/kg, Colony Forming Unit-Granulocyte Macrophage (CFU-GM): 10.35 × 10(4)/kg and 5.67 × 10(4)/kg, Colony Forming Unit-Erythroid (CFU-E): 0.59 × 10(4)/kg and 0.33 × 10(4)/kg, CFU-Granulocyte Erythroid Macrophage Megakaryocyte (CFU-GEMM): 0.52 × 10(4)/kg and 0.53 × 10(4)/kg respectively. BFU-E and CFU-GM capacity of G-BM was increased and statistically significantly different than standard U-BM (p ⩽ 0.01). In conclusion, increased colony forming capacity of hematopoietic stem cells of G-BM when compared with standard unstimulated BM could be a major advantage for transplantation.

Use of plerixafor for peripheral blood stem cell mobilization failure in children.

BACKGROUND: Peripheral blood stem cell mobilization is usually performed following chemotherapy plus G-CSF in children. This standard approach may not be successful in some heavily pretreated patients undergoing mobilization. Plerixafor (AMD3100) has been used in adults as a second line mobilizing agent. Our aim is to analyze our experiences with plerixafor in children. METHODS: We retrospectively evaluated three children who received plerixafor as a second line stem cell mobilizing agent in our department in the 2010-2012 period. Data including age, sex, diagnosis, previous chemotherapy, radiotherapy details, previous harvest attempts, adverse reaction, and harvest outcome were analyzed. RESULTS: We used plerixafor in combination with G-CSF and chemotherapy or with only G-CSF seven times in three patients. All three patients were treated with different multiple chemotherapy regimens prior to stem cell harvest and failed earlier mobilization with chemotherapy plus G-CSF. The diagnoses were relapsed Hodgkin lymphoma in two and recurrent Ewing's sarcoma in one patient. We used plerixafor in combination with G-CSF and chemotherapy or with only G-CSF seven times in three patients. The harvest was successful in four of seven attempts. No adverse reaction was observed in the patients. CONCLUSION: The success rate is four out of seven attempts (57%) in our group. Although the data regarding the use of plerixafor in children is scarce, our experience also supports its use in poor mobilizer children. The use of plerixafor in children results in effective increases in peripheral stem cell counts and reduces the risk of mobilization failure.