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Objectives of this study were to determine the extend of soluble Fas (sFas) and soluble FasL (sFasL) at the time of diagnosis and to evaluate its prognostic relevance under chemotherapy in childhood lymphoproliferative malignancies. The authors measured the circulating sFas and sFasL by ELISA in 25 children with newly diagnosed either ALL or NHL, as well as their expression of Fas and FasL at the time of diagnosis and remission. They did not observe any statistically significant difference between the patient group and age-matched healthy controls for sFas levels, whereas sFasL concentration in study population at the time of diagnosis was significantly higher than that in control subjects (1.05 +/- 1.46 vs. 0.36 +/- 0.18 ng/mL, p = .024). At remission the authors observed a significant decrease in the sFasL levels of all patients whose sFasL concentrations were above the minimal detectable level at the time of diagnosis (p = .008). sFasL and Fas/FasL immunohistochemical staining did not have an effect on survival. sFasL may be a marker in monitoring complete remission in children with LPM.

WOS: 000220951700008, PubMed ID: 15034541, Cytomegalovirus (CMV) disease remains an important cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). We evaluated high-dose acyclovir (HDACV) and pre-emptive ganciclovir to prevent CMV disease in 76 children who underwent peripheral blood stem cell transplantation (PBSCT) and were at risk for CMV reactivation and disease ( both recipient and donor seropositive) from May 1998 to April 2003. All received HDACV from day - 9 to 6 months post transplant in conjunction with weekly CMV pp65 antigenemia monitoring. The incidence of antigenemia in this cohort was 19.7%, at a median of 22 days post-PBSCT. The frequencies were 26.4 and 4.4% in allogeneic and autologous groups, respectively ( P = 0.03). Patients with nonmalignant disease had higher CMV antigenemia than those with malignant disease (30.8 vs 8.1%, P = 0.02). Age at PBSCT, sex, graft-versus-host disease (GVHD) prophylaxis regimen and presence of acute GVHD did not affect the risk of CMV antigenemia. No ne of the patients who had positive pp65 antigenemia developed CMV disease during the study period. We conclude that pp65 anti-genemia-guided HDACV and pre-emptive ganciclovir may prevent CMV disease in children undergoing PBSCT.

European Society for Blood and Marrow Transplantation

BACKGROUND AND OBJECTIVES: The aim of the study was to assess the incidence and clinical relevance of active Human Herpes Virus 6 (HHV6) infections in pediatric patients after allogeneic stem cell transplantation. DESIGN AND SETTINGS: Retrospective analysis of samples prospectively collected at Akdeniz University Medical Faculty Hospital, Antalya, Turkey, between May 2006 and July 2007 from 15 pediatric patients with allogeneic hematopoietic stem cell transplantation (HSCT). SUBJECTS AND METHODS: A commercial quantitative real-time polymerase chain reaction kit was used to analyze plasma samples collected from 15 pediatric allogeneic HSCT recipients. RESULTS: HHV6 DNA was found positive in 8 (53%) patients. HHV6 DNA levels above 1000 copies/mL were found only in 2 patients and they were also consecutively positive for HHV6 DNA. Age at transplantation, use of ATG, and receiving grafts other than HLA identical siblings increased the risk, with a statistically significant difference, of having HHV6 reactivation with levels exceeding 1000 copies/mL (P values, respectively, P=.03, .001, .025). Active HHV6 infections with HHV6 viremia levels higher than 1000 copies/mL were associated with subsequent delayed platelet engraftment (P=.001), acute graft versus host disease (P=.001), skin rash, and fever of unknown origin. CONCLUSION: More than half of pediatric allogeneic HSCT patients develop active HHV6 infection, and especially in patients with high viremic loads, the infection can result in serious clinical situations. A clinically significant cutoff value for viremia seems to be necessary to predict serious clinical complications.

Fifteen patients with beta-thalassemia received an allogeneic peripheral blood stem cell transplant. Median age was 3.5 years (1-15 years). Six were class I, four class II and five class III according to the Pesaro criteria. All of the donors were HLA-phenotypically identical (13 siblings and two parents). Nine patients were given BU + CY and six BU + CY plus ATG as conditioning. All patients received MTX (+1, +3, +6) and CsA (9-12 months) post transplant for GVHD prophylaxis. The median neutrophil and platelet engraftment times were day 12 and day 16, respectively. cGVHD was observed in three patients. Two patients died. Thirteen patients are well, and transfusion-independent 2-30 months after PSCT. No recurrences of thalassemia have been seen. Overall and event-free survival were 86.6%. In conclusion, we suggest that PSCT can be considered a safe and effective treatment for children with beta- thalassemia.

IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT. We describe a case of a patient with FA that developed acute idiopathic hyperammonemia after the preparative regimen for HSCT.

We report two pediatric cases who developed veno-occlusive disease-like hepatotoxicity while receiving chemotherapy for Wilms' tumor and clear cell sarcoma of kidney. The chemotherapeutics, including vincristine, actinomycin D, and epirubicin in case 1 and vincristine and actinomycin D in case 2, were given before the hepatotoxicity developed. Other possible causes of hepatotoxicity were excluded. Recovery was observed with supportive therapy after 2 and 1 weeks, respectively. After recovery, the children tolerated continued chemotherapy without any decrease in the doses of drugs. We conclude that vincristine and actinomycin D were the cause of this rare from of hepatotoxicity and that chemotherapy for the underlying malignant disease could be given safely after clinical recovery.

Hypercalcemia in a 4-year-old boy with non-Hodgkin lymphoma treated with pamidronate is presented. The child had relapsed disease with bone metastasis. Hypercalcemia is rare in children, and bisphosphonates are relatively new agents for the treatment of hypercalcemia. Information concerning their use in the treatment of hypercalcemia in childhood is limited. We found that pamidronate is effective and has no significant side effects in a child.

Introduction TPOG-NBL 2003 national protocol was designed to improve treatment results of the high risk patients by adjunction of stem cell rescue with intensive multimodal therapy. Material and Methods High risk stratification was made according to COG criteria. Just before the third cycle of chemotherapy, patients without progression were allocated into two treatment groups non-randomly by physicians’ and/or parent’s choices guided to the center’s facility, toxicity and social-economical facility to attain the megatherapy. After an induction of 6 chemotherapy cycles, the protocol was divided into two arms which were designed to continue the intensive conventional chemotherapy (CCT), or initiate myeloablative therapy with autologous stem-cell rescue (ASCR). All patients were also given 13-cis-retinoic acid as maintenance therapy. Results Fifty-six percent (272 patients) of all neuroblastoma patients was evaluated as high risk. Response rate to induction chemotherapy was 81% (CR/VGPR: 32%, PR: 49%) in patients at the end of induction chemotherapy. Overall EFS and OS at 3-years were 36% and 45%, respectively. Intention-to-treat analysis documented post-induction (after the six cycles of induction chemotherapy) EFS of 46% in CCT arm (137 patients) and 37% in ASCR group (55 patients) (p= 0.037); whereas, OS was 59% and 43%, respectively (p=0.052). Thirty-one patients (11%) died of treatment-related complications. Conclusion Survival rates of high-risk neuroblastoma have improved over the last decade in Turkey. The main problems when managing these patients were an effective local control, early progression and death. Megatherapy has not augmented the therapeutic end point in our country’s circumstances. However; the better the supportive care and the higher the patients’ compliance is attained, the higher the survival rates might be obtained in Turkish neuroblastoma patients. Disclosures: No relevant conflicts of interest to declare.

We aimed to assess early-onset chronic progressive cardiotoxicity in the left and right ventricles with increasing cumulative anthracycline doses. We evaluated 72 patients within the first year after doxorubicin and/or daunorubicin treatment (median 1.3 months; range 0.3–11.5) and 31 healthy controls. Pretreatment and posttreatment QT interval analyzes were performed in 27 newly diagnosed patients. The echocardiographic data of all examinations of 72 patients were classified into three groups according to instant cumulative anthracycline doses: treatment group (TG)-I (≤120 mg/m2; n = 26), TG-II (120–240 mg/m2; n = 39), and TG-III (≥240 mg/m2; n = 40). Diastolic and systolic parameters were analyzed by conventional echocardiography and tissue Doppler imaging (TDI) and compared with those of healthy controls. The mean age for patients and controls was 8.2 ± 4.5 and 9.6 ± 4.2 years, respectively (p > 0.05). QTc dispersion significantly increased after anthracycline treatment (p = 0.02). TDI showed decreased E′ velocity (p

WOS: 000388566200044 PubMed ID: 27858879 We explored the clinical course of acute high-grade gastrointestinal graft-versus-host disease in children in a single center. This was a retrospective analysis of 28 pediatric patients who presented with a clinical diagnosis of stage III and IV acute graft-versus-host disease (aGVHD) of the gastrointestinal system (GIS). Generally, skin involvement was the initial manifestation of aGVHD that began in the first 3 weeks of hematopoietic stem cell transplantation (HSCT); on the other hand, GIS involvement predominated after the second week of HSCT. Reported adult data show a survival rate of only 25%; however, our study showed more favorable outcomes in children with a survival rate of 55%. We monitored levels of albumin and immunoglobulin G and observed low levels overall during treatment of unresponsive patients, although only albumin levels were shown to be significantly different. We observed a significant increase in mortality with the use of antithymocyte globulin in GIS aGVHD, although antithymocyte globulin used for graft-versus-host disease prophylaxis had no demonstrable effect on GIS aGVHD mortality. Whether the significantly lower GIS aGVHD mortality among the children recruited in our study than among their historical adult counterparts is a primary result of the specific attributes of the pediatric GIS, or whether it originated from HSCT kinetics remains to be determined by future studies.

From January 1991 to June 2009, 245 children with beta thalassemia major who underwent their first allogeneic HSCT in Turkey and who were followed for a minimum of one yr post-transplantation were enrolled this study. The median age of the patients was 6.6 yr old (range, 1-22 yr). The distribution of Pesaro risk class I, II, and III categories was 41, 130, and 63 children, respectively. The median serum ferritin level was 2203 ng/mL. Eighty-eight patients received bone marrow (BM) stem cells; 137, peripheral blood (PB) stem cells; and 20, cord blood (CB) stem cells. The donors were HLA-matched siblings or parents. Median engraftment times were shorter in PBSCT patients compared with the BMT group (p0.001). Grade II-IV acute GvHD was observed in 33 children (13.5%), while cGvHD was observed in 28 patients (12.5%), eight of whom had the extensive form. Thalassemic reconstitution was observed in 43 (17%) of the transplant patients. Post-transplant aplasia occurred in three patients, and the TRM rate was 7.75%. Seventeen patients were lost after 100 days. The thalassemia-free survival and OS rates were 68% (95% CI, 61.8-74.2) and 85.0% (95% CI, 80.2-89.8), respectively. We believe that this study is important because it is the first multicenter national data for children with beta thalassemia major receiving HSCT.

Although successful hematopoietic stem cell transplantation (HSCT) can offer a cure in thalassemia major, there are only a few and noncomprehensive studies of its effect on the quality of life (QoL), as it is expected to increase the QoL by ending transfusion-related issues. Our objective was to compare the health-related quality of life (HRQoL) of transplanted and nontransplanted thalassemia major patients in a developing country. We have studied the QoL effect of HSCT in consecutively invited 50 nontransplanted and 49 transplanted patients who had received transplants from HLA matched related donors at least two years ago. PedsQL questionnaire was used for the patients under 18 years of age and World Health Organization's WHOQoL-BREF questionnaire for above 18 years of age. Higher QoL was determined in HSCT performed group surveyed in 5-18 years' age group. Detailed analysis marked the profound difference in 8-12 year subgroup, particularly in physical activity questionnaires. QoL scores in HSCT performed adult group are higher than the transfusion-dependent group, especially in physical activity domain. Transplanted adult patients rated their overall health significantly better than patients on conventional therapy. The patients who still have chronic graft versus host disease rated worse compared to those without it. In conclusion, thalassemia major patients who have undergone HSCT at least two years before assessment are not inferior to the transfusion-dependent group with regard to the QoL and have a better QoL than transfusion-dependent patients in some areas. The QoL score is better for school children and adolescents; therefore, we suggest HSCT before primary school. GVHD reduces the QoL significantly and it is obvious that GVHD prevention should be one of the primary goals of post-HSCT follow-up.

Renal cell carcinoma is very rare in childhood. It is a different entity from its adult counterpart. We report a case of renal cell carcinoma presented with hypocalcemia in a 16-year-old girl that is, to the best of our knowledge, the first such published incident. The patient was treated by radical nephrectomy with regional lymphadenectomy. Hypocalcemia amended after surgery. Neither chemotherapy nor radiotherapy was given. She has remained disease free for 34 months.

Posttransplant lymphoproliferative disorder (PTLD) is the most common malignancy in children after solid organ transplantation. We present a patient, who developed Epstein-Barr virus (EBV)-related PTLD in the liver after renal transplantation. A 10-year-old EBV-seronegative boy with cystinosis underwent a living related preemptive renal transplantation. He received antiviral prophylaxis with valacyclovir. At 5.5 months posttransplantation he displayed a primary EBV infection with an high fever, hepatosplenomegaly, monocytosis, and positive EBV DNA levels. Two months there after, a hypoechoic nodular 20-mm lesion in the left lobe of liver was detected on abdominal ultrasonography, performed because of anorexia and weight loss. EBV-DNA copy number was 7820 copies per milliliter. Liver biopsy showed a diffuse large B-cell lymphoma that was compatible with PTLD. We stopped all immunosupressive agents other than prednisolone. Chemotherapy consisting of two courses of cyclophosphamide, vincristine, prednisolone, and adriamycin was followed by rituximab. Within 2 months, the lesion resolved and within 18 months, he was free of disease.

Children with β-thalassemia major (β-TM) have multiple risk factors for developing cognitive impairment. The aim of the present study was to evaluate cognitive function in patients with β-TM.Twenty children with β-TM were enrolled into the study and were compared with a control group consisting of 21 healthy children. All participants were evaluated with neuropsychological tests and event-related potentials (ERP).All of the participants had normal IQ scores, but the patient group had significantly lower full-scale, performance, and verbal IQs compared with the control group (P0.05). The number of children with visuomotor dysfunction was higher in the patient group compared with the control group (P0.05). In the P300 test, the patient group had significantly prolonged N1, P2 and N2 latencies at the FZ, and a prolonged N1 latency at the Cz compared with the control group (P0.05). The patient group also had lower N1 and P3N4 amplitudes at the Fz, and lower N1, N1P2 and P3N4 amplitudes at the Cz when compared with the control group (P0.05). Mismatch negativity latency and duration were longer in the patient group (P0.05).Neuropsychological tests are safe, and reliable for the diagnosis of cognitive impairment in β-TM patients, and the use of ERP may facilitate early diagnosis. The number of β-TM patients in the present study was limited, however, and larger numbers of patients are required in further studies.

Higher mortality and morbidity are well established in children with malignancies in whom intensive care admissions are required. A retrospective cohort study was conducted to assess the risk factors for children with cancer in the pediatric intensive care unit (PICU) for short-term outcome (survival vs. nonsurvival when leaving the PICU). The records of 36 children with a median age of 5 years (range: 0.5 to 21) between August 2004 and August 2007 were reviewed. Mortality rate was 55%, higher than the yearly overall PICU mortality rate of 12% (P0.0001). The mean Pediatric Risk of Mortality Score (PRISM) III score among survivors was lower than that among nonsurvivors (9.4+/-5.7 vs. 16.4+/-5.3, P=0.001). Comparison of observed and predicted mortality derived from the PRISM III score showed that distribution of outcome was not different and the prediction model performed well (goodness of fit test: chi=3.64, df=6, P=0.725). The mortality rates were 66.6% and 33.3% in patients with high (10 points) and low (or =10 points) PRISM III score, respectively (P=0.05). Mortality rate was significantly related to presence and number of organ system dysfunction (P=0.031 and P=0.013, respectively), sepsis (P=0.05), mechanical ventilation (P=0.005), and positive inotropic support (P=0.003). By using multiple logistic regressions, the independent risk factor was PRISM III score at the time of admission to PICU (P=0.05). The PRISM III score performed well as a predictor of outcome. For decision to admit such patients to the PICU or to forgo life-sustaining therapies, other factors such as need for mechanical ventilation and positive inotropic support, presence and numbers of organ system dysfunction should be taken into consideration as well.

The aim of this study was to assess glomerular and tubular renal function after HSCT in children in a prospective trial.Renal function was assessed prospectively before HSCT (on day -10), on days +30, +100, and at least 6 months after transplantation in 34 patients (21 females/13 males) with a mean age of 8.2 years. The following parameters were investigated: glomerular filtration rate (GFR) by creatinine clearance (CrCl), cystatin C (CysC)-based formula and plasma clearance of radiolabeled diethylenetriaminepentaacetic acid ((99m)Tc-DTPA), urinary excretion of beta(2)-microglobulin (beta(2)M), beta-N-acetylglucosaminidase (beta-NAG), fractional excretion of sodium (FE(Na)) and fractional tubular phosphate reabsorption (TP/CrCl).Nine patients (26.4%) suffered from acute renal insufficiency within the first 100 days after transplantation. All patients who developed acute renal insufficiency were treated successfully without renal replacement therapy. Age, sex, primary diagnosis, sepsis, veno-occlusive disease, acute graft versus host disease, and use of vancomycin were not significant risk factors for the development of acute renal insufficiency. The medians (99m)Tc-DTPA-based GFR of patients after HSCT showed a statistically significant decrease when compared with pre-transplant values. beta-NAG excretion was significantly elevated in the first 30 days after HSCT.Acute and chronic renal impairment can be developed in patients who undergo HSCT even though the pre-transplant renal function is in normal limits and the conditioning regimen does not include TBI. Both glomerular and tubular renal function evaluation should be part of a long-term follow-up in children following HSCT.

Fusarium species are saprophytic molds which cause disseminated or localized infections in humans. Disseminated Fusarium infection can cause significant morbidity and mortality in immunocompromised patients. We present a case of disseminated fusariosis caused by Fusarium verticillioides in a patient with acute lymphoblastic leukemia and successfully treated using both liposomal amphotericin B and voriconazole.

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein-Barr virus (EBV)-related clinical diseases, from a benign mononucleosis-like illness to a fulminant non-Hodgkin's lymphoma. Because a large proportion of children are seronegative at the time of transplantation, recipients are at high risk of contracting primary EBV infection and subsequently developing PTLD. Surveillance techniques with antibody titers and/or polymerase chain reaction (PCR) may have a role in some high-risk settings. A 12-year-old boy whose serologic response to EBV was negative during follow-up after liver transplantation (LTx) developed Burkitt's lymphoma, a rare and the most severe variant of EBV-related PTLD, 32 months after LTx. He expired possibly due to side effects of treatment. We recommend that viral monitoring must be done using PCR during follow-up of pediatric LTx to prevent dramatic outcomes.

Cytomegalovirus (CMV) disease is a frequent cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. In order to investigate the relationships between antigenemia, high-dose acyclovir (HDACV) prophylaxis, preemptive ganciclovir (GCV) therapy, and outcomes, we analyzed the records of 105 patients, including both pediatric and adult populations, who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) and who were at risk for CMV reactivation and disease (both recipient and donor seropositive). All received HDACV until neutrophil engraftment, but prophylaxis was continued till post-transplant day 180 only in pediatric patients in conjunction with weekly CMV pp65 antigenemia monitoring. Antigenemia-guided preemptive strategy with GCV was used for all patients. CMV antigenemia developed in 45 patients (42.9%) and CMV disease in 13 (12.4%). The frequencies for antigenemia were 31.3 and 63.2% in pediatric and adult groups (P = 0.002). All CMV diseases were in the adult group (P0.001). Age at transplantation, underlying disease, long-term HDACV prophylaxis and acute graft versus host disease (aGVHD) were all found to be a significant risk factors for antigenemia. All of these factors other than aGVHD and conditioning regimen were also the significant risk factors for CMV disease. However, when we analyzed the pediatric and adult patients separately, dropping "long-term HDACV prophylaxis," none of these parameters were significant risk factors for CMV disease. In conclusion, we hypothesize that long-term HDACV prophylaxis in the GCV era results in a low incidence of CMV reactivation and disease in patients undergoing PBSCT.

The existence of acute lymphoblastic leukemia (ALL) and osteosarcoma is described. An 8-year-old girl had osteosarcoma diagnosed on radiologic and pathologic examination during ALL maintenance treatment. Cytogenetic analyses in primary cell culture of osteosarcoma tissue from the patient showed complex chromosomal abnormalities including t(1;19), usually seen in B precursor cell ALL, and del 13, found in a great majority of primary osteosarcomas. To show the possibility of the existence of the genetic susceptibility caused by gene rearrangements, we used molecular technique. But we could not determine any association between gene and genetic susceptibility.

Successful hematopoietic SCT from non-identical twins to two sisters with β-thalassemia major by using preimplantation genetic diagnosis and HLA typing

Background: Graft-versus-host disease (GVHD) is a serious complication with a significant negative impact on survival following allogeneic hematopoietic stem cell transplantation (HSCT) in both adults and children. Immunosuppressants like steroids remain the mainstay of treatment which carries risks of increased infection frequency, a negative impact on the graft-versus-leukemia effect, and an increased probability of secondary malignancies. Extracorporeal photopheresis (ECP) treatment, seems to ameliorate GVHD by immunomodulation, rather than immunosuppression. However it is difficult to perform in pediatric population. This is a retrospective review of 17 pediatric patients who underwent photopheresis with the Therakos Cellex system for graft-versus-host disease (GVHD). Procedure: Extracorporeal photopheresis regimen was same for all acute and chronic GVHD patients: initially every week (2 sessions/week) for two months, then every two weeks for two months; and finally, every month for at least one year. Demographic data, degree of GVHD before photopheresis, adverse reactions during photopheresis procedure, modification in immunosuppressive treatment, and response to photopheresis were recorded. Results: Acute GVHD occurred in seven patients, overlap and chronic GVHD occurred in five patients in each group. The improvement observed in eleven of twelve patients who have acute GVHD (90%) and in seven of ten chronic GVHD patients (70%). Thirteen patients had skin involvement before ECP and eleven of them responded to treatment (84%). Gastrointestinal involvement occurred in ten patients and seven of them improved during ECP treatment (70%). All of the four patient´s liver involvements failed to respond. No serious adverse reactions occurred. Conclusions: In conclusion, our study demonstrates that ECP with the Therakos Cellex system is a safe treatment option for GVHD in children. Disclosures No relevant conflicts of interest to declare.

Congenital amegakaryocytic thrombocytopenia (CAMT) is an unusual cause of thrombocytopenia without radial or other congenital anomalies in the newborn. Generalized bone marrow dysfunction developing later in life has been reported. We present a 13-month-old girl who was diagnosed as having congenital amegakaryocytic thrombocytopenia and was successfully treated with allogeneic peripheral stem cell transplantation (PSCT) from her fully matched sibling donor. The neutrophil engraftment was on post transplant day 12 and platelet engraftment was on day 14. Her last hemogram revealed platelets of 168 × 109/l 20 months post transplant. Bone Marrow Transplantation (2000) 26, 571–572.

Although Hodgkins disease (HD) is one of the common malignancies in childhood there is limited information from developing countries in the English literature. The aim of this study is to give epidemiologic features and treatment results of 210 previously untreated children with HD from a developing country. Between 1 June 1984 and 31 December 1992 all children seen who were younger than 18 years old with newly diagnosed untreated biopsy-proven Hodgkins disease were included in this study. A clinical staging system was used to determine the dissemination of the disease. While patients with stage I-II disease received canape treatment protocol (3 cycles COPP [cyclophosphamide vincristine procarbazine prednisolone] or ABVD [doxorubicin bleomycine vinblastine dacarbazine] plus low-dose involved-field radiotherapy) patients with stage III-IV disease were treated by sandwich protocol (6 cycles COPP plus low-dose involved-field radiotherapy). A total of 210 patients with a median age 8 years were eligible for this study. Male to female ration was 3:1 and 37 (17.6%) were less than 5 years of age. The major histologic subtype was mixed cellularity (69.6%). Overall survival rates were 91.5% and 87.7% and event-free survival rates were 71.5 and 70.5% at 5 and 10 years respectively. No secondary malignancy has been observed so far. The prevalence of Hodgkins disease in young children is higher and the distribution of histologic subtypes is also different from many Western countries. Canape and sandwich treatment protocols could be used safely in clinically staged childhood HD with tolerable toxicity. (authors)

Abstract 4521 The only curative option for ß talasemia remains allogeneic hematopoietic stem cell transplantation (HSCT) to correct the genetic defect and provide a normal hemoglobin level in the recipient. Engraftment of donor derived cells is necessary for a success of transplantation. However, it has been shown that complete donor hematopoesis is not essential for sustained engraftment in thalassemia. Donor and recipient cells may coexist and produce a functional graft commonly referred to as donor/recipient mixed chimerism (MC) even with a low amount of engrafted donor cells. We documented our experience in a cohort of 19 beta thalassemia patients receiving DLI (donor lymphocyte infusions) following 21 transplantations with unstable mixed chimerism (MC). Seven patients received DLI with the indication of having more than 25% residual host cells (RHC) (MClevel3(residual host cells>25%)) early after transplantation and assigned as early-DLI group. Four patients although had MClevel3 in the early period, received deferred DLI and assigned as late-DLI group. The difference between these two groups, in respect to preserving functional graft, was not found statistically significant. However the chimerism kinetics of these early and late-DLI groups were also different and a slower decline in percentage of donor cells were observed in patients preserving grafts. Ten patients received DLI in the later period and although a significant increase in percentage of donor cells was not detected, increase in hemoglobin levels was provided. The infusions were safe with acceptable risk for GVHD. We believe that patients with more than 25% of RHC within two months early intervention with DLI seems feasible. Deferring DLI to a later period especially if the decrease in percentage of donor cells is so prompt, seems less effective. In the later period, we propose to consider the hemoglobin level as the main determinative factor for DLI application rather than the percentage of donor cells in line with expectance of better long-term tolerance. A better understanding of the mechanisms underlying the occurrence of persistent MC and strategies for induction and maintenance of tolerance will provide better interventions and outcomes for these patients. Disclosures: No relevant conflicts of interest to declare.

Veno-occlusive disease (VOD) of the liver is a major complication of allogeneic or autologous stem cell transplantation (HSCT), particularly after busulfan-based conditioning regimens. Clinically, VOD is characterized by fluid retention, weight gain, hyperbilirubinemia and painful hepatomegaly. Efficacy and safety of defibrotide for the treatment of VOD, especially in pediatric patients, has not been adequately confirmed or the results are still preliminary. This retrospective report describes experience with defibrotide in children with hepatic veno-occlusive disease (HVOD) following HSCT in a single institution. Materials and Method: Children who had undergone HSCT between April 2005–June 2006 and who received defibrotide for the treatment of HVOD during their admission were identified. Demographic data and clinical information of these patients were abstracted from their health records. Results: Eight children (median age: 4.5 years; range: 1–14 years) who underwent HSCT during the study period received defibrotide for the treatment of HVOD; 5 were boys and 3 were girls. Three patients underwent HSCT for hematologic malignancies, 2 for neuroblastoma, 1 for hemoglobinopathy, 1 for severe combined immunodeficiency (SCID) and 1 for fanconi aplastic anemia. Conditioning regimens included busulfan (16 mg/kg) in four, melphelan (140 mg/m2) in two and total body irradiation in 1 patient as being risk factors for HVOD. Two patients with neuroblastoma had undergone autologous HSCT, three patients had been transplanted from matched sibling donor and the other three were either unrelated donor or unrelated cord blood transplantation. HVOD was diagnosed on transplant day +4 to +19 (median: +12 ). The median initial defibrotide dose was 31.5 mg/kg/day (25–46 mg/kg/day). The median duration of defibrotide therapy was 27 days (1–46 days). Defibrotide was discontinued due to clinical improvement (5), gastrointestinal hemorrhage (2), death (1). Two patients in whom defibrotide was discontinued because of gastrointestinal hemorrhage died. The primary cause of death in these two children was: progressive HVOD and multiorgan failue following sepsis. As a result of this experience and under the light of literature, we believed that defibrotide is an effective treatment for children with HVOD and should be instituted in each children without delay in the event of at least one of the criteria for HVOD is established. But it is necessary to carry out further studies in larger group of patients with longer follow-up to validate the efficacy and safety of defibrotide.

Although improvements in conventional treatment have enhanced the prognosis of thalassaemia, stem cell transplantation remains the only cure. Studies have shown that peripheral blood stem cell transplantation (PBSCT) results in rapid hematological and immunological recovery but increased risk for graft versus host disease (GVHD). We report the PBSCT experience of Akdeniz University School of Medicine Pediatric Hematology&Oncology department concerning 54 patients with beta-thalessemia. Median age was 6 years (1–18 years), 26 were girls, 28 were boys. Thirteen were Class I, twenty-two were Class II, nineteen were Class III according to Pesaro criteria. 12 patients were given BU+CY and 39 BU+CY plus ATG as conditioning regimen. Three Class III patients were conditioned with Pesaro protocol 26. BU dosage was 16 mg/kg for Class I and Class II patients followed by CY 200 mg/kg totally. Class III patients received 14 mg/kg BU and 160 mg/kg CY. All patients received MTX (+1, +3, +6) and CsA for GVHD prophylaxis. All of the donors were HLA identical (51 sibling, 3 parents). Median age of the donors was 7 years (range: 2–40 years). G-CSF was given for 5 days with the dosage of 5 μgr/kg/day to child and 10 μgr/kg/day to adult donors for peripheral blood stem cell mobilization. Stem cell apheresis was performed on fifth day, but continued to day 7 if adequate cell count was not achieved. In older children and parents if appropriate, antecubital veins were used for harvesting but for younger donors, femoral dual lumen catheters were emplaced. Fresenius AS. TEC204 or Haemonetics MCS+ cell separators were used for apheresis. The median apheresis count was 1 (range 1–3). Median transfused MNC and CD34 cell counts were 10.1×108/kg (range:5.3–27.7×108/kg) and 4,65×106/kg (range:1.1–29.4×106 /kg) respectively. Median neutrophil and platelet engraftment times were day 14 and day 15, respectively. Grade II–IV acute GVHD were observed in five patients, chronic GVHD were in four of two were extensive. One patient died on posttransplant day 32 because of acute GVHD. Death because of chronic GVHD was not observed. At a median follow-up of 26 months (1–92 months), overall survival for the whole group is 92.6 % and evet-free survival is %80.4. Autologous reconstitution developed in six patients and graft failure in two.

High dose chemo-radiotherapy followed by either allogeneic or autologous hematopoietic stem cell transplantation (HSCT) is the treatment of choice for an increasing number of congenital or acquired diseases of childhood. One of the major drawbacks of this procedure is the prolonged period of profound neutropenia and complications associated with neutropenia. Although administration of granulocyte colony-stimulating factor (G-CSF) to adult patients undergoing high-dose chemotherapy and HSCT is believed to accelerate neutrophil recovery, the actual clinical benefits of G-CSF in children remain a controversial point requiring controlled studies and also the optimal timing for G-CSF infusion has not been established yet. It is well-known that children frequently recover faster than adults after HSCT and suffer less from life-threatening infections. In addition, studies demonstrating that these cytokines may also modify T-cell and dendritic cell function brought about a question whether the effect is strong enough to alter the risk of graft-versus-host disease (GVHD). In this retrospective three armed study we reviewed our experience at Akdeniz University School of Medicine Pediatric Hematology/Oncology Department to determine whether G-CSF administration on posttransplant period affects neutrophil and platelet engrafment time and alters the risk of acute or chronic GVHD in a relatively homogeneous nonmalignant group, thalassemia major patients. Fortyseven patients transplanted with peripheral blood stem cells were studied. G-CSF, if administered, were started on posttransplant day 1 or day 5. 25 patients in day 1 and 11 patients in day 5 group with other 11 non-administered patients were revealed retrospectively in respect to main outcomes that were hematopoietic recovery (neutrophil and platelet recovery defined by a neutrophil count of ≥0.5x109/L for 3 consecutive days and nontransfused platelet count of ≥20x109/L for 7 consecutive days) and GVHD. They were all given methotrexate combined with cyclosporine as GVHD prophylaxis with ATG in 35 patients. In G-CSF non-administered group neutrophil recovery was delayed compared with G-CSF administered group (16.5±2.8 vs 13.8±3.6 p=0.009) although transplanted MNC count was higher (16.8±3.5 vs 9.4±4.1 p0.05). The mean days to neutrophil recovery (14.0 ±3.7 vs 3.7±3.5 p>0.05) and the mean days to platelet recovery (22.7±15.5 vs 19.8±12.6 p>0.05) were not significantly different between day 1 and day 5 group. There were 5 grade II-IV acute and 5 chronic GVHD, both in G-CSF administered group but there were not any statistical differences in respect to GVHD between G-CSF or non-administered group and also within the G-CSF administered group according to administration time. In conclusion, administration of G-CSF after allogeneic PBSCT in children with thalassemia cause faster neutrophil recovery but administration on day 1 seems as if there is no additive effect compared to day 5 and do not alter the risk of acute or chronic GVHD. More studies in larger scales are needed to determine whether greater delay or non-use is feasible or not.

Allogeneic hematopoietic stem cell transplantation (SCT) from healthy donors is the only treatment modality for the correction of hematological abnormalities in Fanconi aplastic anemia (FAA) patients. We have performed SCT by using two different non total body irradiation conditioning regimens. While anti-thymocyte globulin (ATG, 10–30mg/kg/day, 3 days), cyclophosphamide (5mg/kg/day, 4 days) and thoraco-abdominal radiation (total 5Gy) were used for six patients (regimen A), fludarabine (120–150mg/m2 totally), cyclophosphamide (10mg/kg/day, 4 days), ATG (30mg/kg/day, 3 days) were given to four patients (regimen B). Six of the patients received regimen A and 4 regimen B. Donors were HLA-matched sibling in 5, HLA-matched parent in 2, partly HLA-matched parent in 2 and HLA-matched unrelated donor in one. All patients and donors were screened by diepoxybutane (DEB) test. Seven of the patients were DEB positive. All donors were DEB negative. Median age of the patients was 10 years. All patients received antimicrobial, antifungal prophylaxis and intravenous immunoglobulin (IVIG, 500 mg/kg weekly) from day −7 to day +180. Cyclosporin A (CsA) was used for graft-versus-host disease (GVHD) prophylaxis in eight patients and CsA plus mycophenolate mofetil in one matched unrelated patient. Neutrophil and platelet engraftment occurred in all patients on day 10 (median) and day 21 (median), respectively. Grade II-IV acute GVHD occurred in two patients who received regimen A. Conditioning-related toxicity was milder in regimen B than that in regimen A. Three patients succumbed from complications of grade IV acute GVHD, post-transplant acute myeloid leukemia and fungal pulmonary infection in regimen A group. All of the regimen B group were alive with normal hematological parameters. Totally, seven patients are alive with sustained engraftment and transfusion independent with median follow-up 19 months (range 2–50). We conclude that fludarabine based conditioning regimen is well tolerated and ideally suited to reduce regimen-related toxicities while achieving sustained engraftment in FAA patients SCT using sibling, related and unrelated donor.