Haldun Öniz

Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching

Haematopoietic stem cell transplantation (HSCT) remains the best therapeutic option for many acquired and inherited paediatric haematological disorders. Unfortunately, the probability of finding an HLA matched donor is limited. An alternative technique is PGD combined with HLA matching, which offers the possibility of selecting unaffected embryos that are HLA compatible with the sick child, with the aim of possible use of stem cells from the resulting baby in future. Since the first successful report for Fanconi anaemia a decade ago, the therapeutic success of this technique was reported in a few cases and for a limited number of disorders. Here, we report full recovery of 44 sick children who received HSCT from healthy infants conceived after pre-implantation HLA matching for the following 10 indications; beta-thalassaemia, Wiskott-Aldrich syndrome, Fanconi anaemia, sickle cell anaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, Glanzmanns thrombasthaenia, Diamond-Blackfan anaemia, X-linked adrenoleukodystrophy and mucopolysaccharidosis type I. No serious complications were observed among recipients and donors. Graft failure occurred in four children with beta-thalassaemia where a second HSCT was planned. Preimplantation HLA matching is a reliable technique and provides a realistic option for couples seeking treatment for an affected child when no HLA-matched donor is available.

A SINGLE INSTITUTIONAL EXPERIENCE: Is Epoetin Alpha Effective in Anemic Children with Cancer?

The authors aimed to investigate the efficacy of epoetin-alpha on hemoglobin levels and red cell transfusion requirement in children with both hematologic malignancy (HM, n = 27) and solid tumors (ST, n = 14). Epoetin-alpha was given (150 U/kg or 250 U/kg, thrice weekly) for 12 weeks. Epoetin alpha significantly increased the hemoglobin levels at the 2nd and 3rd months of therapy (p <. 05). At the 3rd month, the patients required less red cell transfusion. At the dose of 150 U/kg, only three patients with HM, but none of the ST patients, required red cell. However, none required red cell transfusion after 2nd month on epoetin alpha 250 U/kg. Epoetin-alpha administration increases hemoglobin levels and decreases red cell transfusion requirement in children with malignancy.

Evaluation of telomerase mRNA (hTERT) in childhood acute leukemia

Human telomerase reverse transcriptase (hTERT) is the catalytic component of telomerase enzyme and has been shown to be associated with telomerase activity (TA). Although many studies in adult leukemia have established the importance of TA, very few have been reported in the children. In this study hTERT levels in childhood leukemia was evaluated and compared with the prognostic factors described before. The LightCycler instrument was used (online real-time PCR) for the quantification of hTERT in peripheral blood and bone marrow in 23 cases with acute lymphoblastic leukemia (ALL) and in 8 cases with acute myeloblastic leukemia (AML). Ten cases with normal peripheral blood (PB) and bone marrow (BM) were selected as control group. Cytogenetic analyses were available in 21 patients with leukemia. In all cases with acute leukemia and in control group, peripheral blood (PB) hTERT levels correlated significantly with bone marrow (BM) hTERT levels. Before treatment, patients with ALL had significantly higher hTERT levels than that of AML patients and control cases. Among patients with ALL, higher hTERT levels were observed in patients with pre-B leukemia, followed by B cell and T cell leukemia patients. Initially increased hTERT levels decreased to the nearly normal levels during remission in cases with ALL. No correlation was observed between the initial hTERT levels and the known prognostic factors except cytogenetic findings. Higher hTERT levels were detected in patients having karyotypic abnormalities which indicate poor prognosis. hTERT levels are significantly high in childhood ALL with the highest level of pre-B cell leukemia before treatment. Those high levels of hTERT decrease to almost normal levels in remission. hTERT levels might be useful in monitoring of leukemia in children.

ANALYSIS OF PEDIATRIC THROMBOTIC PATIENTS IN TURKEY

This study analyzes the data of thrombotic children who were followed up in different pediatric referral centers of Turkey, to obtain more general data on the diagnosis, risk factors, management, and outcome of thrombosis in Turkish children. A simple two-page questionnaire was distributed among contact people from each center to standardize data collection. Thirteen pediatric referral centers responded to the invitation and the total number of cases was 271. All children were diagnosed with thromboembolic disease between January 1995 and October 2001. Median age at time of first thrombotic event was 7.0 years. Of the children 4% of the cases were neonates, 12% were infants less than 1 year old, and 17% were adolescents. Thromboembolic event was mostly located in the cerebral vascular system (32%), deep venous system of the limbs, femoral and iliac veins (24%), portal veins (10%), and intracardiac region (9%). Acquired risk factors were present in 86% of the children. Infection was the most common underlying risk factor. Inherited risk factors were present in 30% of the children. FVL was the most common inherited risk factor. Acquired and inherited risk factors were present simultaneously in 19% of the patients. Eleven children had a history of familial thrombosis. Due to the local treatment preferences, the treatment of the children varied greatly. Outcome of the 142 patients (52%) was reported: 88 (62%) patients had complete resolution, 47 (33%) had complications, 12 (9%) had recurrent thrombosis, and 34 (24%) died. Three children (2.1%) died as a direct consequence of their thromboembolic disease. The significant morbidity and mortality found in this study supports the need for multicentric prospective clinical trials to obtain more generalizable data on management and outcome of thrombosis in Turkish children.

HLA‐matched family hematopoetic stem cell transplantation in children with beta thalassemia major: The experience of the Turkish Pediatric Bone Marrow Transplantation Group

Yesilipek MA, Ertem M, Cetin M, Öniz H, Kansoy S, Tanyeli A, Anak S, Kurekci E, Hazar V. HLA‐matched family hematopoetic stem cell transplantation in children with beta thalassemia major: The experience of the Turkish Pediatric Bone Marrow Transplantation Group.

NEUROPSYCHOLOGIC SEQUELAE IN THE LONG-TERM SURVIVORS OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

The neurotoxicity of either systemic chemotherapy or central nervous system prophylaxis was studied in 19 children treated for acute lymphoblastic leukemia (ALL). They had completed ALL therapy at least a year before and survived more than 5 years after diagnosis. The duration between age at diagnosis and age at investigation was 8.6 +/- 2.7 years (5-15 years). Neuropsychologic tests, cranial magnetic resonance imaging (MRI), and evoked potentials (EP) were studied. Seventeen healthy siblings were taken as a control group. Emotional evaluation was done using the childhood depression inventory and Beck depression inventory. Cognitive functions were evaluated using Wechslers Intelligence Scale for Children-Revised (WISC-R) or the Wechslers Adult Intelligence Scale-Revised (WAIS-R) tests, which were adapted to Turkish children. Performance and total IQ scores (94.0 +/- 16.8 and 92.2 +/- 16.5) were significantly low as compared to the control group (112.1 +/- 18.9 and 105.4 +/- 14.2) (p = .007 and p = .02). Abnormal MRI findings were found in 33.3% (6/18). Three out of 18 patients (16.6%) had abnormal auditory while 5 out of 17 patients (29.5%) displayed abnormal visual EPs. Abnormal findings in MRI, cognitive examination, and electrophysiologic testing were not associated with age at diagnosis, radiotherapy doses, intermediate/high-dose systemic methotrexate administration or central nervous system involvement. But more patients must be studied to demonstrate discrete outcomes of neurotoxicity in long-term survivors of childhood leukemia.

Experience of the Izmir Pediatric Oncology Group on Neuroblastoma: IPOG-NBL-92 Protocol

This multicentric study aimed to bring neuroblastoma patients together under IPOG-NBL-92 protocol and evaluate the results within the period between 1992 and 2001 in Izmir. Sixty-seven neuroblastoma patients from 4 pediatric oncology centers in Izmir were included in the study. IPOG-NBL-92 protocol modified from German Pediatric Oncology (GPO)-NB-90 protocol was applied: Patients in stage 1 received only surgery, while surgery plus 4 chemotherapy courses (cisplatin, vincristine, ifosfamide) were given in stage 2 and surgery plus 6 chemotherapy courses (cisplatin, vincristine, ifosfamide, epirubicin, cyclophosphamide) were given in stages 3 and 4 patients. In patients who were kept in complete remission (CR), a maintenance therapy of one year was applied. Radiotherapy was given to the primary site following induction chemotherapy plus surgery in stages 3 and 4 patients with partial remission (PR). The stages of the patients were as follows: 5% in stage 1, 39% in stage 3, 49% in stage 4, and 7% in stage 4S. Primary tumor site was abdomen in 88% of cases. CR rates were as 100% in stage 1, 76% in stage 3, 35% in stage 4, and 75% in stage 4S. Relapse was observed in 32% of patients in a median of 19 months. The median follow-up time for survivors was 33 (17-102) months. Five-year OS rate was 31% and the EFS rate was 30% in all patients. Five-year overall and event-free survival rates were 63 and 30% in stage 3, but 6 and 5%, respectively, in stage 4 patients. Univariate analysis established that the age, stage, primary tumor site, and high LDH and NSE levels conferred a significant difference. The IPOG-NBL-92 protocol has proved to be satisfactory with tolerable toxicity and reasonable CR and survival rates. However, more effective treatments suitable to Turkeys social and economic conditions are urgently needed for children over 1 year of age with advanced neuroblastoma.

POLYCYTHEMIA VERA IN A 12-YEAR-OLD GIRL: A Case Report

A case of a 12-year-old girl presenting with headache and splenomegaly and fulfilling the diagnostic criteria of polycythemia vera is reported. Her peripheral blood values were as follows: hemoglobin 18 g/dL, red blood cells 7,000,000/mm 3 , white blood cells 22,000/mm 3 , and platelets 1,248,000/mm 3 . Phlebotomy was performed initially but was ineffective. Afterward 100 mg/kg per day aspirin and 30/mg/kg per day hydroxyurea were given. The patient has been asypmtomatic for 1 year and her recent hemoglobin level is 15.5 g/dL, platelet count 922,000/mm 3 , and white blood cell 12,800/mm 3 . Polycythemia vera is an extremely uncommon disease in childhood and for this reason its treatment is not well established.

Variant clinical courses in children with immune thrombocytopenic purpura: Sixteen year experience of a single medical center

OBJECTIVE Immune thrombocytopenic purpura (ITP) is the most common cause of acquired thrombocytopenia in children. The objective of this study was to evaluate the presenting features, variation in the clinical courses, initial response rate to therapy, and long-term outcome in patients with ITP. METHODS Three hundred and fifty out of 491 newly diagnosed patients with ITP between the initial diagnosis ages of 6 months to 16 years were included in this retrospective, descriptive study. Patients with acute vs chronic ITP, acute vs recurrent ITP and chronic vs recurrent ITP were compared in terms of age at diagnosis, gender, initial platelet count, response rate to initial therapy, long-term outcome, and total duration of follow-up. RESULTS The clinical courses of the patients were determined as acute, chronic and recurrent in 63.8%, 29.1%, and 7.1%, respectively. Platelet count >20x109/L and initial diagnosis age >10 years were found to increase the probability of chronic outcome by at least two-fold. CONCLUSION It is concluded that ITP in childhood is a common disease with low morbidity and mortality. In addition to the acute and chronic form, a rare recurrent form, which accounts for about 4-7% of all ITP patients, should be considered.

Outcome of autologous hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory Hodgkin's lymphoma.

This study evaluates the outcome of 66 pediatric patients with rrHL who underwent autoHSCT. Twenty‐nine patients experienced early relapse, and 19 patients experienced late relapse. Of 18 newly diagnosed with HL, 13 were primary refractory disease and five had late responsive disease. At the time of transplantation, only 68% of the patients were chemosensitive. The majority of patients received BCNU + etoposide + ara‐C + melphalan for conditioning (45/66), and peripheral blood (56/66) was used as a source of stem cells. After a median follow‐up period of 39 months, 46 patients were alive. At five yr, the probabilities of OS, EFS, the relapse rate, and the non‐relapse mortality rate were 63.1%, 54.3%, 36.4%, and 9.1%, respectively. The probability of EFS in chemosensitive and chemoresistant patients at five yr was 72.3% and 19%, respectively (p < 0.001). Multivariate analysis showed that chemoresistant disease at the time of transplantation was the only factor predicting limited both OS (hazard ratio = 4.073) and EFS (hazard ratio = 4.599). AutoHSCT plays an important role for the treatment of rrHL in children and adolescents, and survival rates are better for patients with chemosensitive disease at the time of transplantation.