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CHANGES OF HEMOSTATIC FACTORS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA RECEIVING COMBINED CHEMOTHERAPY INCLUDING HIGH DOSE METHYLPREDNISOLONE AND L-ASPARAGINASE

In this study, protein C (PC), protein S (PS), heparin cofactor II (HCFII), prothrombin fragment 1+2 (PF 1,2), thrombin-antithrombin III complex (TAT), von Willebrand factor (vWF) and thrombomodulin (TM) were investigated in 19 patients with acute lymphoblastic leukemia, (ALL) receiving combined chemotherapy including L-asparaginase (L-ASP) and high dose methylprednisolone (HDMP). HDMP was administered in doses of 30 mg/kg/day for 7 days, and 20 mg/kg/day for another 7 days. In order to evaluate the effect of HDMP on the hemostatic system, the 8 patients studied here received HDMP (30 mg/kg/day) therapy for 4 days before the combined chemotherapy. These parameters were also studied in 12 healthy children as a control group. PC levels were normal in the patients while PS levels were decreased both before and after combined chemotherapies. Patients with ALL have laboratory signs of coagulation activation such as PF 1,2, TAT prior to initiation of chemotherapy. With combined chemotherapy, TAT levels were found to be normal while PF1,2 were not. TM levels were found to be increased both before and after therapies whereas HCFII and vWF levels were not different from those of the control group. The short course of HDMP therapy did not prominently influence these hemostatic parameters. These results indicate that both the malignant process and the drugs used in combined chemotherapy cause a decrease in natural inhibitors and an increase in procoagulant activity and endothelial injury. These hemostatic changes may contribute to a thrombotic tendency in the patients with ALL.

Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome

Dear Editor, We report a girl with AR-DOCK8 deficiency treated successfully with allogeneic bone marrow transplantation (BMT). She was born to consanguineous parents (cousins) originating from and living in eastern Turkey. The first two children of the family were not diagnosed as immunodeficient despite hypereosinophilia and high IgE levels. They had neonatal onset pruritic eczematous dermatitis, food allergies, recurrent and severe pneumonias (LRTI) when they died at five and six yr old, respectively. Sibling 6 (the propositus) who was born after three healthy children, presented with severe neurological disease: beginning nearly 6–8 months ago with mild ataxia and gradual deterioration with restlessness, spasticity, progressive hearing, speech and vision loss, hyperactive deep tendon reflexes, Babinsky and clonus. Radiological diagnosis of progressive multifocal leukoencephalopathy (PML) with serial MRI was supported by high JCV-DNA in serum and cerebrospinal fluid (2200 copies/mL). He also was diagnosed with hyper IgE syndrome (HIES) caused by the dermatitis of neonatal onset, severe food allergies, LRTIs and high peripheral blood eosinophilia and serum IgE. There were no pneumatoceles despite recurrent pulmonary infections and cold abscesses nor joint hypermobility. We treated him with i.v. immunoglobulin (IVIG) 400 mg/kg/day for 15 days with no clinical response. As the response to rh-interferon-gamma (rhIFN-c) stimulation is shown in Tyk-2 deficient patient (1), we gave rhIFN-c to this patient with PML using 50 lg/m, ·3/wk, by sc route. He died at the age of seven yr with sepsis in our intensive care unit. The last child (DOB: 25 October 2006) of this family also presented with neonatal rash. She developed severe eczema with lichenification since the first months of life. She had multiple food, environmental and drug allergies, including lentil anaphylaxis. At the age of 18 months, she underwent further investigations after the diagnosis of her brother s JCV infection. She presented with severe disseminated ichthyosiform eczema, ectropion of the eyelids, recurrent LRTI, oral, cutaneous and ungual candidiasis. Fortunately, her brain CT was normal and the serum and CSF did not reveal JCV infection as her brother. High levels of IgE (>10 000 IU/mL) and hypereosinophilia (>5000/lL) were persistent. Serum immunoglobulin levels (G: 1580, M: 71 and A: 8.7 mg/dL) were normal except for low IgA for age while lymphocyte phenotyping revealed CD4+ T cell lymphopenia (absolute: 250/lL) with CD3+ T cell 28%, CD19+B cell 60%, CD16+56+ NK cell 5% in the peripheral blood. Her serum anti-HBs, antipolio, anti-HSV, anti-CMV, anti-EBV, anti-IgM and anti-IgG antibodies and isohemagglutinins were absent. The girl was also clinically diagnosed as autosomal recessive-HIES and treatment was initiated with IVIG, itraconazole, sulfamethoxazoletrimethoprim and rhIFN-c for prophylaxis and immune modulation. She was not responding to topical steroids, emollients and oral antihistamines. Genomic DNA of the patient, parents and her brother who died with JCV infection were evaluated for the DOCK8 gene as the possible cause for the phenotype at the Department of Immunology and Molecular Pathology of Royal Free Hospital (London, UK). Engelhardt et al. identified a homozygous large deletion up to and including exon 25 of the DOCK8 gene (c.?_3121?del), deleting the first half of the gene (JACI 2009;124:1289, patients with codes of ARH016.6, ARH016.7) (2). It could not be understood where the exact beginning of the deletion was; the first deleted exon they detected was exon 3, but as they did not analyze exon 1 and 2, it was concluded that the deletion began before or at the start of the DOCK8 gene. Because of recurrent sibling deaths, she was considered for hematopoietic stem cell Pediatr Transplantation 2012: 16: 398–399 2012 John Wiley & Sons A/S.

Benefit of high-dose methylprednisolone in comparison with conventional-dose prednisolone during remission induction therapy in childhood acute lymphoblastic leukemia for long-term follow-up.

Eight-year event-free survival (EFS) was evaluated in 205 patients with acute lymphoblastic leukemia (ALL), to consider the efficacy of high-dose methylprednisolone (HDMP) given during remission induction chemotherapy between 1 and 29 days. The St Jude Total XI Study protocol was used after some minor modifications in this trial. Patients were randomized into two groups. Group A (n = 108) received conventional dose (60 mg/m2/day orally) prednisolone and group B (n = 97) received HDMP (Prednol-L, 900–600 mg/m2 orally) during remission induction chemotherapy. Complete remission was obtained in 95% of the 205 patients who were followed-up for 11 years; median follow-up was 72 months (range 60–129) and 8-year EFS rate was 60% overall (53% in group A, 66% in group B). The EFS rate of group B was significantly higher than of group A (P = 0.05). The 8-year EFS rate of groups A and B in the high-risk groups was 39% vs 63% (P = 0.002). When we compared 8-year EFS rate in groups A and B in the high-risk subgroup for both ages together ⩽2 or ⩾10 years, it was 44% vs 74%, respectively. Among patients in the high-risk subgroup with a WBC count ⩾50 × 109/l, the 8-year EFS was 38% in group A vs58% in group B. During the 11-year follow-up period, a total of 64 relapses occurred in 205 patients. In group A relapses were higher (39%) than in group B (23%) (P = 0.05). These results suggest that HDMP during remission-induction chemotherapy improves the EFS rate significantly for high-risk patients in terms of the chances of cure.

Two booster dose hepatitis B virus vaccination in patients with leukemia.

The aim of this study was to interpret the antibody response to hepatitis B (HB) vaccination following a two booster dose schedule in 94 acute lymphoblastic leukemia (ALL) patients. All patients were between 1-16 years of age with negative hepatitis B virus (HBV) serology and normal hepatic function. Fifty patients were vaccinated with Engerix B vaccine, and 44 patients were vaccinated with GenHevac B vaccine, with a schedule of 0, 1, 6 and 0, 1, 2, as well as booster doses, in 12 and 6 months respectively. A second booster was given as a fifth dose to 16 unresponsive patients in each vaccine group, 3 and 6 months after the first booster for Engerix B and GenHevac B vaccines respectively. Dosage was 20 microg HbsAg for all patients. Seroconversion rates with protective level antibody were 35.1% (n=33/94). The figures were 32.1% (n=16/50) and 38.6% (n=17/44) for Engerix B and GenHevac B vaccines, respectively. Seroconversion rate in patients younger than 10 years old was found to be higher (39.11%) than older patients (24%), but this was not statistically significant. This study indicates that one third of the leukemic children undergoing maintenence chemotherapy responded to HB vaccine with protective titers of anti-HBs. We recommend HB vaccination especially in developing countries.

HEMOPHAGOCYTIC SYNDROME: A Rare Life-Threatening Complication of Visceral Leishmaniasis in a Young Boy

The authors report a case of hemophagocytic syndrome (HPS) associated with acute visceral leishmaniasis (VL). A 4-year-old boy was admitted with high fever, hepatosplenomegaly, and pancytopenia. Elevated serum ferritin and triglyceride, low fibrinogen levels, and bone-marrow (BM) histiocytic hyperplasia with prominent hemophagocytosis were consistent with a HPS. An initial diagnosis of kala-azar was refuted because of negativity of BM aspiration and serology for this parasite, and the diagnosis of HPS was made. Three months after first admission, reevaluation of the BM aspiration revealed many amastigotes of Leishmania parasites. The serology of VL became positive, finally establishing the diagnosis of VL. Although specific therapy for VL was instituted, the patient died 4 weeks after the diagnosis.

DRAMATIC RESOLUTION OF PLEURAL EFFUSION IN CHILDREN WITH CHRONIC MYELOMONOCYTIC LEUKEMIA FOLLOWING SHORT-COURSE HIGH-DOSE METHYLPREDNISOLONE

High-dose methylprednisolone (HDMP) which can induce--differentiation and -apoptosis of myeloid leukemic cells has been shown to be very effective in the treatment of extramedullary infiltration (EMI) of children with acute myeloblastic leukemia (AML). In the present study 2 children with chronic myelomonocytic leukemia (CMML) who had pleural effusions were given a single daily dose of oral methylprednisolone (20 mg/kg or 30 mg/kg). In addition to dramatic improvement of respiratory symptoms, pleural effusions disappeared in four days in both patients possibly due to apoptotic cell death induced by HDMP treatment. Further studies are needed to determine whether high-dose corticosteroids are also effective on the resolution of pleural effusions associated with other malignant disease.

The Role of Prohepcidin in Anemia Due to Helicobacter pylori Infection

Background: Hepcidin, a key regulator of iron homeostasis, increases when inflammation and some infections occur. It plays a critical role in macrophage iron retention, which underlies inflammation/infection caused anemia. It is known that Helicobacter pylori (HP) may lead to iron deficiency (ID) due to occult blood loss or reduced iron absorption. This study investigates the role of prohepcidin, hepcidins precursor, in ID and ID anemia (IDA) with a concurrent HP infection. Methods: In this prospectively designed study, 15 patients with IDA and a concurrent HP infection (group 1), 11 patients with an ID and a concurrent HP infection (group 2), and 18 patients with HP infection (group 3) were observed. All groups received only HP eradication therapy. Twenty-five age- and sex-matched children without ID/IDA and HP infection were included in the study as the control group. In all groups and control group, measurements were taken for pre- and posttreatment hemoglobin, serum prohepcidin, serum ferritin, serum iron (SI), transferrin saturation, erythrocyte sedimentation rate, fibrinogen, and C-reactive protein levels. Results: The pretreatment prohepcidin levels were significantly higher only in group 1 compared to the control group (P < .05). In group 1, a significant increase in hemoglobin and SI levels and a significant reduction in prohepcidin levels were additionally observed following HP eradication treatment (P < .05). However, in groups 2 and 3, significant differences in hemoglobin, iron, and prohepcidin levels between pre- and posttreatment were not observed. Conclusion: Elevated serum prohepcidin might indicate the role of inflammation in the etiology of anemia concurrent with HP.

ACUTE RENAL FAILURE DURING ATRA TREATMENT

All-trans-retinoic acid (ATRA), which is used in acute promyelocytic leukemia, is usually well tolerated, but some side effects can be observed. Retinoic acid syndrome is the most severe side effect. Triazole derivatives such as fluconazole inhibit the NADPH-dependent cytochrome P-450-mediated catabolism of ATRA and are increased plasma levels of ATRA. Here, the authors report a case of APL who developed acute renal failure during ATRA and concurrent use of fluconazole.

Deferasirox therapy in children with Fanconi aplastic anemia.

Thirty-nine children with Fanconi aplastic anemia (FAA) have been followed up in our center between January 2008 and November 2010. Eight of these children (20%) with a transfusional iron overload had been undergoing deferasirox treatment during the study period. In the English literature, transfusional iron overload and the use of an iron chelator in children with FAA has not yet been evaluated. Here, we have presented the effectivity and tolerability of deferasirox in children with FAA and a transfusional iron overload. Before the deferasirox treatment, the mean serum ferritin level was 3377±2200 ng/mL. After a mean 13.6-month treatment duration, the mean ferritin level decreased to 2274±1300 ng/mL (P<0.05). In our series, 3 patients had renal and 3 had hepatic toxicity during the treatment. Two patients had peliosis hepatis and 2 had congenital renal abnormalities before the treatment. There may be differences in the side-effect profiles of deferasirox treatment in patients with FAA. In our series, despite the low number of cases, nephrotoxicity and hepatotoxicity were common side effects instead of gastrointestinal disturbances reported in other studies. Deferasirox is an oral, easily applicable, and effective iron chelator; baseline hepatotoxicity and nephrotoxicity may increase the development of toxic side effects in children with FAA. Patients with FAA receiving deferasirox treatment should be followed up closely for these side effects.

Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study.

Objective: Venous thromboembolism (VTE) in children who undergo hematopoietic stem cell transplantation (HSCT) has high morbidity. The aim of this study is to assess the incidence of VTE in allogeneic pediatric HSCT recipients and the contribution of pretransplant prothrombotic risk factors to thrombosis. Materials and Methods: We retrospectively evaluated 92 patients between April 2010 and November 2012 undergoing allogeneic HSCT who had completed 100 days post-HSCT. Before HSCT, coagulation profiles; acquired and inherited prothrombotic risk factors including FV G1691A (factor V Leiden), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein (a), plasma antithrombin III, protein C, and protein S levels were obtained from all patients. Results: In the screening of thrombophilia, 8 patients (9%) were heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozygous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A mutation. We observed VTE in 5 patients (5.4%); a prothrombotic risk factor was found in 3 out of these 5 patients, while 4 out of 5 patients had central venous catheters. It was determined there was no significant relationship between VTE and inherited prothrombotic risk factors. Conclusion: VTE after HSCT seems to be a low-frequency event that may be due to low-dose, low-molecular-weight heparin prophylaxis, and the role of inherited prothrombotic risk factors cannot be entirely excluded without a prospective study.