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.

Evaluation of the Clinical and Laboratory Characteristics of Previously Followed-up Thalassemia Intermedia Patients to Provide Them Better Care in the Future.

The increased awareness about the severity of complications in thalassemia intermedia patients led authorities to develop strategies for better management and follow-up of these patients. In this study, we aimed to define the clinical and laboratory characteristics in previously followed-up ß-thalassemia intermedia patients and wanted to gain an insight about the follow-up of this patient population in a developing country to provide them better care in the future. The mean age at diagnosis was 4 years, and the mean hemoglobin was 7.13 g/dL. The mean age at the beginning of regular transfusion was 4.8 years. An overall 74% of patients were on a regular transfusion program. The mean ferritin values at diagnosis and the last follow-up were 487 and 1225 ng/mL, respectively. The most common mutations detected in patients were IVS-I-110, IVS-I-6, IVS-II-1, and FCS 8/9 in order of frequency. Complications were seen in 48% of patients. The most common complications were osteopenia/osteoporosis (34%), growth retardation (24%), hypogonadism (18%), and cardiomyopathy (13%). In conclusion, the relatively higher complication rate in our patients who were previously treated highlights once again the need for an increased effort for optimal management and follow-up of this specific group of patients.

CANDLE syndrome: a recently described autoinflammatory syndrome.

CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) is a recently described autoinflammatory syndrome characterized by early onset, recurrent fever, skin lesions, and multisystemic inflammatory manifestations. Most of the patients have been shown to have mutation in PSMB8 gene. Herein, we report a 2-year-old patient with young onset recurrent fever, atypical facies, widespread skin lesions, generalized lymphadenopathy, hepatosplenomegaly, joint contractures, hypertrglyceridemia, lipodystrophy, and autoimmune hemolytic anemia. Clinical features together with the skin biopsy findings were consistent with the CANDLE syndrome. The pathogenesis and treatment of this syndrome have not been fully understood. Increased awareness of this recently described syndrome may lead to recognition of new cases and better understanding of its pathogenesis which in turn may help for development of an effective treatment.

The long-term results of childhood acute lymphoblastic leukemia at two centers from Turkey: 15 years of experience with the ALL-BFM 95 protocol.

Dramatic progress in the treatment of childhood acute lymphoblastic leukemia (ALL) has been achieved during the last two decades in Western countries, where the 5-year event-free survival (EFS) rate has risen from 30 to 85 %. However, similarly high cure rates have not always been achieved in all centers in developing countries due to limited sources. We evaluated the treatment results of the ALL-Berlin-Frankfurt-Münster (BFM) 95 protocol as used between 1995 and 2009 in the pediatric hematology departments of two university hospitals. A retrospective analysis of 343 children newly diagnosed with ALL (M/F 200/143, median age 6.8 years) was performed. The overall survival (OS) and EFS according to age, initial leukocyte count, immunophenotype, chemotherapy responses (on days 8, 15, and 33), and risk groups were analyzed by Kaplan-Meier survival analysis. Median follow-up time was 6.4 years. Complete remission was achieved in 97 % of children. Five-year EFS and OS were found to be 78.4 and 79.9 %, respectively. Children younger than 6 years old had significantly better EFS and OS (83.7 and 85.2 %) than children aged ≥6 years (71.4 and 72.8 %). Adolescents achieved 63 % EFS and 65 % OS. Patients who had initial leukocyte counts of <20 × 10(9)/L had better EFS and OS (82.2 and 84.6 %) than children with higher initial leukocyte counts (72.6 and 72.6 %). EFS for B-cell precursor and T-cell ALL was 81.5 and 66.7 %, respectively. Children with a good response to prednisolone on day 8 (87 %) achieved significantly better EFS and OS (81.2 and 81.9 % vs. 55.3 and 60.5 %). Children whose bone marrow on day 15 was in complete remission had higher EFS and OS (83.7 and 86.6.1 % vs. 56.4 and 61.5 %). Children in the standard-risk and medium-risk groups obtained statistically significantly higher EFS (95.5 and 82.7 %) and OS (97.7 and 82.3 %) compared to the high-risk group (EFS 56.3 %, OS 63.4 %). The relapse rate was 14.8 %. The median relapse time from diagnosis was 23.2 months. Death occurred in 69 of 343 patients (20.1 %). The major causes of death were infection and relapse. None of the patients died of drug-related toxicity. The ALL-BFM 95 protocol was applied successfully in these two centers. In developing countries in which minimal residual disease cannot be monitored, this protocol can still be used with high survival rates.

Assessment of neuropsychological late effects in survivors of childhood leukemia.

The neurologic dysfunctions caused by treatment may affect health and quality of life in survivors of childhood leukemia. The objective of this study was to identify the neuropsychological late effects of leukemia treatment to provide an assessment about the degree and incidence of these late effects. Neurological and ophtalmological examination, cranial magnetic resonance imaging (MRI), auditory and neurocognitive tests, and questionnaires of quality of life were performed to 44 acute leukemia survivors at least 5 years after diagnosis. Median time since completion of chemotherapy was 7.5 years (2-18) and median age at the time of the study was 16.4 years (8-31). At least one or more late effects detected by physical examination (PE), neurological tests, or neurocognitive tests encountered in 80% of the patients, and 64% of the patients specified at least one complaint in the quality of life questionnaire. MRI revealed pathological findings in 18% and electroencephalogram (EEG) abnormalities were present in 9% of the patients. Evaluation of total intelligence scores revealed that 30% of patients' IQ scores were <80 and 70% of the patients' scores demonstrated neurocognitive dysfunctions. The patients >6 years at the time of diagnosis were found to have more psychological problems and higher rates of smoking and alcohol consumption. The most frequent complaint was headache and the most common problem in school was denoted as difficulty in concentration. Our study demonstrated that most of the survivors of childhood leukemia are at risk of developing neuropsycological late effects.

Thrombocytopenia in neonates: causes and outcomes.

Thrombocytopenia is one of the most common hematological abnormalities found in neonates. The causes, treatment modalities, and outcomes of neonatal thrombocytopenia have to be evaluated for providing better care and follow-up. In this study, our aim was to assess the prevalence, causes, treatment modalities, and outcomes of thrombocytopenia in neonates. A retrospective analysis was conducted on the medical records of all neonates hospitalized at our hospital between January 2007 and December 2011 and those with thrombocytopenia were included in the study. Of the 3,515 neonates, 134 (3.8%) had thrombocytopenia. Ninety-seven of them (72%) were preterm. In the patients admitted to neonatal intensive care unit, the prevalence of thrombocytopenia was found as 12%, whereas it was found as 1.2% in neonatal service. The highest prevalence was detected in the year 2008 by 5.3%, and the lowest prevalence was detected in the year 2011 by 2.4%. Sepsis was the most common etiologic factor between years 2007 and 2009. Intrauterine growth restriction, metabolic disorders, drugs, and asphyxia were more common causes in the recent years. Severe thrombocytopenia was found in 26% of neonates and 11 % of thrombocytopenic neonates had major hemorrhage. Intracranial hemorrhage ratio was 5.9% and all of these patients were preterm. Thrombocytopenia improved in 92.5% of patients and persisted in 3% of patients. Death occurred in 4.5% of neonates. This study shows that the causes of neonatal thrombocytopenia may show variations with respect to time and the prevalence, complications, and risks of thrombocytopenia may be lowered by eliminating preventable factors.

Multicentric plasma cell type of castleman disease in a child: difficulty in diagnosis and treatment.

Multicentric plasma cell variant of Castleman disease (CD) has rarely been reported and the optimal therapeutic approach is unknown, especially in childhood. In this case report, we discuss the case of a 7-year-old boy with multicentric plasma cell variant of CD, who presented with cervical lymphadenopathies, autoimmune hemolytic anemia, bone marrow insufficiency, pulmonary, renal, hepatic, and gastrointestinal involvement, emphasizing the difficulty in diagnosis and treatment approach.

Endocrinological and cardiological late effects among survivors of childhood acute lymphoblastic leukemia.

OBJECTIVE: Survival rates for childhood acute lymphoblastic leukemia (ALL) have significantly improved and late effects of therapy have been important in the follow-up of survivors. The objective of this study is to identify the endocrinological and cardiological late effects of ALL patients treated in our pediatric hematology unit. MATERIALS AND METHODS: Patients treated for ALL with BFM protocols after at least 5 years of diagnosis and not relapsed were included in the study. Endocrinological late effects (growth failure, obesity, insulin resistance, dyslipidemia, thyroid gland disorders, osteopenia/osteoporosis, and pubertal disorders) and cardiological late effects were evaluated. The study group was evaluated with anthropometric measurements, body mass index, and laboratory testing of fasting glucose, insulin, serum lipids, thyroid functions, and bone mineral densities. Echocardiography and pulsed wave Doppler imaging were performed for analysis of cardiac functions. RESULTS: Of the 38 ALL survivors, at least 1 adverse event occurred in 23 (60%), with 8 of them (21%) having multiple problems. Six (16%) of the survivors were obese and 8 (21%) of them were overweight. Subjects who were overweight or obese at the time of diagnosis were more likely to be overweight or obese at last follow-up. Obesity was more frequently determined in patients who were younger than 6 years of age at the time of diagnosis. Insulin resistance was observed in 8 (21%) subjects. Insulin resistance was more frequently seen in subjects who had family history of type 2 diabetes mellitus. Hyperlipidemia was detected in 8 (21%) patients. Hypothyroidism or premature thelarche were detected in 2 children. Two survivors had osteopenia. Cardiovascular abnormalities occurred in one of the subjects with hypertension and cardiac diastolic dysfunction. CONCLUSION: We point out the necessity of follow-up of these patients for endocrinological and cardiological late effects, since at least one adverse event occurred in most of our cases. CONFLICT OF INTEREST: None declared.

A rare complication of intrathecal methotrexate in a child with acute lymphoblastic leukemia.

Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous and most commonly intrathecal routes of MTX have been implicated in acute, subacute, and chronic neurotoxicity syndromes. Subacute MTX neurotoxicity occurs within days to weeks after the intravenous or intrathecal therapy and characterized by a distinct presentation with remarkable clinical resemblance to stroke, including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Herein the authors describe the clinical and typical neuroimaging features of a female patient with ALL who presented with subacute MTX neurotoxicity that rapidly progressed to a severe clinical condition in a few hours but eventually resolved completely with dexamethasone and folinic acid. Subacute MTX neurotoxicity is a transient neurological dysfunction that should be considered in patients presenting with stroke-like and various neurological symptoms 10 to 14 days after intrathecal therapy and diffusion-weighted magnetic resonance imaging should be undertaken for the correct diagnosis and exclusion of possible ischemic infarct. Discontinuation of subsequent intrathecal MTX therapies should be considered in severe cases and treatment with dexamethasone and folinic acid may help to resolve the symptoms.

A case with unexplained bleeding from multiple sites: munchausen syndrome by proxy.

Munchausen syndrome by proxy (MBP) is an extreme form of child abuse where children were unnecessarily treated or investigated for medical conditions that were falsified by their caregivers. Here the authors report a 16-year-old female with the complaints of bleeding from multiple and unusual sites, including hemoptysis, hematuria, bloody tears, and bloody nipple discharge, all of which are only witnessed by her mother. Extensive investigation revealed no organic etiologies for bleeding. The diagnosis of MBP was put by a multidisciplinary team. The diagnosis of MBP must be kept in mind in conditions where there is no underlying organic pathology in a bleeding patient.

Severe iron overload and hyporegenerative anemia in a case with rhesus hemolytic disease: therapeutic approach to rare complications.

A 33 weeks' gestation, a baby with rhesus hemolytic disease (RHD), who had received intrauterine transfusions twice, developed cholestatic hepatic disease and late hyporegenerative anemia. Her serum ferritin and bilirubin levels increased to 8842 ng/ml and 17.9 mg/dl, respectively. Liver biopsy showed cholestasis and severe iron overload. Treatment with recombinant erythropoietin (rHuEPO) decreased the transfusion need, and intravenous deferoxamine resulted in a marked decreased in serum ferritin levels and normalization of liver function. In patients who have undergone intrauterine transfusions due to RHD, hyperferritinemia and late hyporegenerative anemia should be kept in mind. Chelation therapy in cases with symptomatic hyperferritinemia and rHuEPO treatment in cases with severe hyporegenerative anemia should be considered.

Rhabdomyolysis due to Escherichia coli sepsis in three pediatric patients with acute lymphoblastic leukemia.

Rhabdomyolysis with myoglobinuria is an uncommon complication of bacterial sepsis. The authors describe three pediatric acute lymphoblastic leukemia patients who developed rhabdomyolysis during a neutropenic sepsis episode due to Escherichia coli. All of the patients needed hemodynamic supportive treatment because of septic shock. Broad-spectrum antibiotics, alkalinization, and intravenous fluid therapy was given. One patient with renal insufficiency died, despite aggressive treatment. Muscle pain and dark urine color should alert physicians to the possibility of rhabdomyolysis in immunocompromised patients with sepsis. Early and appropriate treatment is critical in these patients to prevent renal failure and shock, and for a better outcome.

Clinical features, treatment responses, and outcome of children with idiopathic thrombocytopenic purpura.

The authors investigated demographics, clinical and laboratory features, treatment responses, and outcomes of 93 children (median age 5 years) admitted for idiopathic thrombocytopenic purpura (ITP). The therapy responses of high-dose methylprednisolone (HDMP) (n = 77) and intravenous immunoglobulin (IVIG) (n = 10) treatments were similar. None of the patients with hemorrhage died. Fifteen patients (16.1%) had progressed into chronic ITP. Seven infants had a probable relationship with vaccination; none of these infants progressed into chronic ITP. In conclusion, the overall prognosis in childhood ITP is good. The therapy responses of HDMP and IVIG treatments are similar. Also, ITP cases who havw vaccination history have a benign course.

Isolated myelosarcoma development in an adolescent chronic myeloid leukemia patient with t(9;22)(q34;q11.2), +8, +14, +21, and der(1)(p36).

Additional chromosomal abnormalities are found in 5-20% of patients during chronic phase of chronic myeloid leukemia and in 60-80% preceding or accompanying blast crisis. These abnormalities are important in disease progression and, because they may occur before hematological and clinical symptoms, can be taken as a prognostic indicator. An adolescent with chronic myeloid leukemia initially presented with extreme thrombocytosis, increased megakaryopoiesis with dysmorphic features, and focal myelofibrosis in bone marrow examinations and then developed isolated myelosarcoma 1 year after onset, with t(9;22)(q34;q11.2), +8, +14, +21, and der(1)(p36).

Evaluating pulmonary complications in childhood acute leukemias.

SUMMARY: We evaluated the frequency, etiologic factors, outcome, and the comorbid conditions affecting the morbidity and mortality of pulmonary complications in acute childhood leukemia. Sixty-six (40.4%) out of 163 patients developed 79 pulmonary complications. Infectious etiology was the leading cause (92.4%). The most identified infectious agents were Gram (-) bacteria, followed by fungi. Acute respiratory distress syndrome, leukostasis, lymphomatoid granulomatosis, pulmonary edema, and pneumothorax were among the noninfectious causes. The pulmonary complications in the induction and consolidation phase of leukemia therapy were more severe and the mortality rate was higher. Tachypnea, shock, oxygen and mechanical ventilation requirement, disseminated intravascular coagulation, involvement of other organs or systems, cytopenias, requirement of modification in antimicrobial drugs were found to be related with increased mortality risk. The mortality rate of pulmonary complications was 8.9%. Pulmonary infections in the maintenance phase of the therapy were frequently treated with oral antibiotics, and they were generally rapidly taken under control. In conclusion, pulmonary complications are frequent in children with acute leukemia, and early diagnosis and appropriate management are important to avoid mortality owing to pulmonary complications, especially in neutropenic patients receiving induction or consolidation phase of chemotherapy.

Assessment of febrile neutropenia episodes in children with acute leukemia treated with BFM protocols.

The authors overviewed 239 febrile neutropenia (FN) episodes in 82 pediatric leukemia cases treated with BFM treatment protocols. FN was observed mostly during consolidation therapy. Mucositis was the most identified focus; gram-negative microorganisms were the most identified pathogens. Five patients developed invasive fungal infections. Fever resolved after mean 5.3 days and mean antibiotic administration time was 12.7 days. Addition of G-CSF to antimicrobial therapy shortened the duration of neutropenia, but it did not affect duration of fever resolution and antibiotic administration. The duration of neutropenia, fever resolution, and antibiotic administration was significantly longer in children with acute myeloid leukemia. The authors conclude that children with acute leukemia have severe prolonged neutropenia and are in high risk. In these patients, prediction of the risk of bacteremia based on clinical and laboratory features is important for immediate empiric broad-spectrum antimicrobial therapy and for higher survival rate.

Chemotherapy-induced acral erythema in a pediatric patient with acute monoblastic leukemia.

Chemotherapy-induced acral erythema or palmoplantar erythrodysesthesia syndrome is a well-defined reaction to some of the chemotherapeutic agents such as methotrexate, cytarabine, doxorubicin, fluorouracil, and bleomycin. This reaction is characterized by symmetrical, well-demarcated, painful erythema of the palms and soles, which may progress to desquamation. The authors present a case of acral erythema in a young patient with acute monoblastic leukemia to emphasize this high-dose chemotherapy-induced side effect, which is rarely seen in children and is usually self-limited.

Veno-occlusive disease in a child with rhabdomyosarcoma after conventional chemotherapy: report of a case and review of the literature.

Although veno-occlusive disease of the liver is a well-known complication of high-dose chemotherapy and bone marrow transplantation, it has rarely been observed in children who receive conventional chemotherapy. Most cases in the literature consists of children with Wilms tumor. It has been very uncommon in rhabdomyosarcoma patients until recently, although they commonly receive similar anticancer agents. Here the authors report a 2-year-old boy with rhabdomyosarcoma who developed veno-occlusive disease while receiving VAC (vincristine, actinomycin D, cyclophosphamide) chemotherapy regimen according to the IRS-IV protocol. The patient gradually recovered during 2 weeks with supportive treatment only.

Hyperleukocytosis in childhood acute lymphoblastic leukemia: complications and treatment outcome.

Hyperleukocytosis, defined as a peripheral leukocyte count ≥ 100x109/L, is seen in 5-20% of newly diagnosed cases of childhood leukemia and is a poor prognostic factor. In this study, we aimed to examine the presenting clinical and laboratory features, complications, and treatment outcome of 47 children with acute lymphoblastic leukemia (ALL) and hyperleukocytosis who were diagnosed and treated in four medical centers of Izmir between January 1990 and January 2001. The median age was 5.0 years (range: 0.1-16.3 years). Median white blood cell count was 495x109/L (range: 107x109/L- 794x109/L). Forty-two of 47 patients (90%) had hepatosplenomegaly, 5 (11%) had respiratory distress, 3 (6%) had neurologic symptoms, 3 (6%) had diffuse cervical lymphadenopathy, and 3 (6%) had acute renal failure at admission. Ten of 47 patients (21%) had central nervous system involvement, and 17 (36%) had mediastinal mass. Ten patients (21%) had coagulopathy and 15 patients (32%) had metabolic complications (8 patients had hyperuricemia, 4 had hyperphosphatemia, 2 had hyperuricemia, hyperphosphatemia and hypercalcemia, and 1 had hypocalcemia) before the initiation of therapy. Forty of 47 patients (85%) with hyperleukocytosis were effectively managed with intravenous hydration, alkalinization, and allopurinol therapy. Early death during remission induction therapy occurred in 5 patients (11%) with respiratory distress and sepsis. Kaplan-Meier estimates of event free survival and overall survival were 37.0% and 40.5%, respectively.