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•Giroctocogene fitelparvovec is the first gene therapy for hemophilia A that uses a recombinant AAV serotype 6–based vector.•Giroctocogene fitelparvovec was generally well tolerated with appropriate clinical management and showed efficacy at the highest dose.

Increasing availability of genomic testing poses new challenges to clinicians, particularly where variant interpretation from commercial sources may be equivocal. The authors report a patient with recurrent rhabdomyosarcoma and subsequent bilateral breast cancer who was found to harbor a previously undescribed germline TP53sequence alteration annotated by the commercial laboratory as a variant of uncertain significance. By investigating publicly available databases of aggregated normal germline and malignant somatic genomic sequences, the authors conclude that this missense variant, c.476C>T (p.A159V), is a novel, pathogenic Li-Fraumeni syndrome mutation and demonstrate the utility of these resources in clinical pediatric hematology and oncology practice.

Objective.To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey.Methods.International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course.Results.A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide.Conclusion.The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

Acquired von Willebrand factor (vWF) disease is associated with a decrease in the amount of circulating high molecular weight (HMW) vWF multimers. vWF has not been previously investigated in children on extracorporeal membrane oxygenation (ECMO) support. We hypothesized that HMW vWF multimers and vWF activity decrease over the course of ECMO support in these patients. This prospective, single center, observational, cohort pilot study was carried out between December 2010 and April 2011 and included patients 0 to 18 years old requiring ECMO support at our institution. Blood samples were tested for various aspects of vWF. Mean and standard deviation were estimated for vWF activity and multimers, whereas a generalized linear model was developed to estimate multimer changes over time.The study included six pediatric patients. The mean age of the patients was 54.9 ± 55.3 (mean ± standard deviation) months. The mean HMW vWF multimer percentage was 23.4 ± 7.3 in the pre-ECMO samples and significantly decreased over time (p<0.003). There was no significant change in low molecular weight vWF multimer percentage. An immediate decrease in vWF HMW multimers as a percentage of all multimers once ECMO is initiated was noted and persisted across the study period.

Visweshwar: Biogen Idec: Membership on an entity's Board of Directors or advisory committees. Leavitt: Pfizer: Research Funding; Rigel: Consultancy; HEMA Biologics: Consultancy; BPL: Consultancy; Behring: Consultancy; Syntimmune: Research Funding; Sangamo Therapeutics: Research Funding; BioMarin: Consultancy, Research Funding; Catalys: Consultancy; CSL DOVA: Consultancy; Merck: Consultancy. Konkle: Genentech USA Inc.: Honoraria; Sigilon Therapeutics: Honoraria; BioMarin Pharmaceutical Inc.: Other: Data and safety monitoring; CSL Behring: Other: Data and safety monitoring. Giermasz: ATHN: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy; UniQure: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; Sangamo Therapeutics,: Research Funding; BioMarin: Consultancy, Research Funding. Stine: Applied Stem Cell Therapeutic: Consultancy; BioMarin: Consultancy. Rupon: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Di Russo: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Tseng: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. de los Angeles Resa: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ganne: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Agathon: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Plonski: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Rouy: Sangamo Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Cockroft: Sangamo Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fang: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Arkin: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Achieving hemostasis in patients with hemophilia A or B is complicated by the presence of inhibitors and is made even more difficult when these individuals require surgery. Over a 4-year period, 6 patients with inhibitors to factor VIII and 1 patient with inhibitors to factor IX underwent surgery or invasive procedures at our institution. A total of 26 procedures were performed, primarily using the bypassing agent FEIBA for bleeding control. Excellent hemostasis was obtained in all cases, adding to accumulating data indicating that FEIBA is safe and effective in hemophilia patients with inhibitors who require surgery.

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P= ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P= .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.

Determination of the absolute neutrophil count (ANC) is a critical test prior to initiation of chemotherapy and is a standard component of cancer therapy protocols. Automated determination of this parameter potentially shortens the turnaround time necessary between specimen phlebotomy and chemotherapy infusion in an outpatient setting. However, there are certain factors that can lead to spuriously elevated or lowered ANCs, possibly leading to inappropriate dosage. We therefore compared ANC results in a series of samples in which both automated and manual results were available. Sets of 111 specimens, tested over a 1-month period, had matched automated and manual ANC results available for initial retrospective analysis. An additional set of 35 specimens with ANCs of &lt; 1.5 × 10⁹/L were subsequently analyzed in a similar fashion. Automated ANC results were obtained with a Cell-Dyn 3500^® (Abbott Diagnostics, Santa Clara, CA, USA) automated hematology analyzer, and manual ANC results were obtained using 100 cell differentials performed by 1 of 13 medical technologists. Results were tabulated and analyzed using standard linear regression and scatter plot analyses. Of the initial 111 specimens, automated ANC values ranged from 0.16–14.2 × 10⁹/L (median = 2.6 × 10⁹/L), as compared with 0.24–13.9 × 10⁹/L (median 3.0 × 10⁹/L) for manual ANC values (R² = 0.99; SE = 0.49). Differences between the ANC values ranged from −55 to + 33% (SD = 14%) of the manual value. Of the second set of 35 specimens, regression analysis yielded an R² value of 0.92, with a SE of 0.11. Both data sets yielded acceptable degrees of variation on scatter plot analyses. Automated ANC values appear adequate for determining suitability for chemotherapy and lessen the turnaround time between specimen phlebotomy and result verification. Med Pediatr Oncol 2002;38:183–186. © 2002 Wiley-Liss, Inc.

Pediatric patients with Langerhans cell histiocytosis (LCH) may become refractory to conventional therapy or present with repeated recurrences over several years. Current therapeutic options such as prednisone, vinblastine, etoposide, and cyclosporine are associated with significant acute toxicities and late effects. Recent reports suggested that 2-chlorodeoxyadenosine (2-CDA) may be an effective agent in adults with LCH. The purpose of this study was to determine the safety and efficacy of 2-CDA in children with LCH. This report presents the data collected from the first three patients that have completed this trial. Patients were enrolled in a prospective study after informed consent was obtained. Patients had a confirmed diagnosis of LCH that had recurred several times or not responded to standard therapy. Patients were given a starting dose of 5 mg/M2 of daily continuous infusion for three days duration. Two patients had their dose increased to 6.5 mg/M2/day. A total of 4–6 courses were given, and courses were repeated every 3–4 weeks. Thirteen of fifteen courses were given as outpatients at home. Each patient completed therapy with myelosuppression the primary toxicity. Pt. 1 initially received a higher dose of 2-CDA and developed sepsis. The dose was reduced to current study levels and no other incidence of infection, fever, and neutropenia, or blood product transfusion was required. All three patients are free of active disease 10–18 months after completing 2-CDA. Three patients with LCH refractory to standard therapy had CR to 2-CDA, given at 5–6.5 mg/M2/day for 3 days, without significant toxicity. Med. Pediatr. Oncol. 29:288–292, 1997. © 1997 Wiley-Liss, Inc.

Current therapy for patients with trilateral retinoblastoma, consisting primarily of surgical intervention and radiotherapy, has resulted in no long-term survivors. The use of adjuvant chemotherapy has not improved this outcome. After observing a tumor response to cyclophosphamide in a patient with suprasellar retinoblastoma, we treated a subsequent patient with trilateral retinoblastoma with both vincristine and cyclophosphamide. Objective tumor regression resulted. Although the tumor ultimately progressed in both patients, these findings suggest that vincristine and cyclophosphamide are active in patients with intracranial (trilateral) retinoblastoma.

Abstract: Background. Skeletal complications are responsible for significant morbidity in Gaucher patients. Plain radiographs have been unreliable in assessing bone marrow infiltration and activity. A way to assess bone marrow improvement is needed during enzyme therapy. Objective. The purpose of this paper is to assess the usefulness of MR in following improvement of abnormal bone marrow in Gaucher patients on enzyme therapy. Materials and methods. Three patients aged 2, 7, and 24 years underwent serial MR scans of the lower extremities before and during treatment with Alglucerase (two patients) and Imiglucerase (one patient). T1-weighted, T2-weighted, STIR and FSE T2-weighted images were utilized. Two patients were imaged after 16 months of therapy, and one patient was imaged after 6 months of therapy. Results. All patients had improvement in marrow signal consistent with partial reconversion to fatty marrow during treatment. The findings were more marked after prolonged therapy. T1-weighted images demonstrated findings most clearly. Conclusion. MR consistently showed improvement in marrow signal in Gaucher patients on enzyme therapy. As smaller doses of enzyme therapy are the trend, MR can be utilized to determine if therapy is effecting a change in the bone marrow.

Introduction:Hemophilia A is a rare bleeding disorder caused by pathogenic variants in the F8gene, resulting in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)-mediated gene transfer enables the delivery of a modified functional F8gene to hepatocytes that subsequently synthesize FVIII at levels that may prevent bleeding events in the absence of exogenous FVIII. Updated results and follow-up from the Alta study, an ongoing gene therapy study in patients with severe hemophilia A, are presented.

Introduction: Hemophilia A is a rare blood disorder caused by an F8variant resulting in insufficient Factor VIII (FVIII) activity. Updated results and follow-up of an ongoing gene therapy study in patients with severe hemophilia A are presented.

Giermasz: uniQure: Consultancy, Other: Research; Sangamo: Other: Research; Bioverativ/Sanofi: Consultancy, Speakers Bureau; BioMarin: Consultancy, Other: Research; Genentech/Roche: Consultancy, Other: Research, Speakers Bureau. Arkin:Pfizer: Employment, Equity Ownership. Di Russo:Pfizer: Employment, Equity Ownership. Snyder:Sangamo Therapeutics: Employment. Woolfson:Sangamo Therapeutics: Employment, Equity Ownership. Rouy:Sangamo Therapeutics: Employment, Equity Ownership.

Patients with Ehlers-Danlos syndrome (EDS), especially types IV, VI, and VIII, are at increased risk of bleeding, and most do not have specific hemostatic deficiencies that would be amenable to replacement therapy. We have investigated the ability of DDAVP (desmopressin acetate) to control bleeding in EDS.

A 17-month-old boy in whom immune-mediated throm-bocytopenia (ITP) was the presenting manifestation of infection with human immunodeficiency virus (HIV) is being successfully managed with intermittent high-dose intravenous gamma globulin (IVIG) allowing maintenance of hemostatic platelet counts while avoiding the immunosuppression associated with other therapeutic modalities used to treat ITP. He continues to demonstrate marked responsiveness to IVIG, and has been maintained on weekly or bimonthly infusions for 12 months. The serendipitous documentation of HIV infection prior to IVIG therapy for immune-mediated thrombocytopenia in this child documents the importance of HIV testing prior to IVIG therapy to prevent erroneous assignment of IVIG as the vehicle responsible for transmission of HIV infection. This case history also documents the importance of HIV testing in the diagnostic evaluation of immune-mediated thrombocytopenias.

No abstract

Children with acute, severe cardiopulmonary compromise may require support with ECMO. Adequate anticoagulation without inducing life-threatening hemorrhage plays a critical role in the management of these patients. Recent data from adult studies suggest that patients undergoing cardiac bypass for coronary artery bypass grafting (CABG) often have reduced Factor XIII levels (FXIII). This relative FXIII deficiency may be predictive of hemorrhage or severe blood loss. Such studies have never been conducted in the pediatric population. Our primary objective will be to determine if a relative deficiency in FXIII occurs in children undergoing ECMO and to determine any time dependency of these changes. Our secondary objective will be to determine if blood loss and/or transfusion requirements during ECMO correlates with FXIII levels.Single center ongoing study utilizing a prospective design involving pediatric patients (ages 0-18) undergoing ECMO. Samples for FXIII, D-Dimers, Fibrinogen and Thrombin Time are being drawn at designated time points as follows: prior to or during ECMO cannulation, 2 hours, 24 hours, 3-5 days and 14-21 days after initiation of ECMO and 1-3 days after discontinuation of ECMO. Mixed effects analysis of covariance (ANCOVA) will be used for data analysis.To date, fifteen patients have been enrolled and analyses have been conducted for n=7 patients with a total of 36 time points of data. Figure 1a and 1b show the mean and standard deviation (SD) of FXIII and Fibrinogen, respectively. Figure 1c shows the mean ratio of FXIII to Fibrinogen. Error bars represent 1 SD around the mean (central point).This is the first pediatric study evaluating FXIII activity in children undergoing ECMO. Firm conclusions cannot be drawn with the interim analyses conducted to date. If variations in FXIII are found, our results will provide important information towards determining if children undergoing ECMO could potentially benefit from FXIII replacement, in turn minimizing bleeding complications and/or transfusion requirements often encountered with this treatment modality.No relevant conflicts of interest to declare.

Children with acute, severe cardiopulmonary compromise may require support with ECMO. Adequate anticoagulation without inducing life-threatening hemorrhage plays a critical role in the management of these patients. Recent data from adult studies suggest that patients undergoing cardiac bypass for coronary artery bypass grafting (CABG) often have reduced Factor XIII levels (FXIII). This relative FXIII deficiency may be predictive of hemorrhage or severe blood loss. Such studies have never been conducted in the pediatric population. Our primary objective will be to determine if a relative deficiency in FXIII occurs in children undergoing ECMO and to determine any time dependency of these changes. Our secondary objective will be to determine if blood loss and/or transfusion requirements during ECMO correlates with FXIII levels.

Pediatric Immune Thrombocytopenia (ITP) has an incidence of 4–6/100,000 with 1/3 of cases becoming chronic. Treatment choice is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies (Neunert CE, et al. Pediatr Blood Cancer 2008; 51(4):513). Previous studies in ITP have not examined predictors of response to rituximab or whether response to prior treatments predicts response.To evaluate univariate and multivariable predictors of platelet count response to rituximab.After local IRB approval, 550 patients with chronic ITP enrolled in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 16 weeks of rituximab and within 14 days of steroids. Steroids were prescribed as 1–4 mg/kg prednisone or adult equivalent over 4–14 days with or without taper. The NACIR captured treatment responses both retrospectively prior to enrollment and then prospectively, and both periods were included in this analysis. The multivariable logistic regression modeling process utilized SAS 9.1 using binary variables which were either significant in the univariate analysis or clinically important. A backwards elimination procedure was used to select the final model.Seventy-six (13.8%) patients were treated with rituximab. Demographics of the patients treated with rituximab include: 42% male; 81% Caucasian, 17% Black, and 2% Asian. The mean age at diagnosis of ITP was 8.4 ± SD 5.1 years. The median platelet count at diagnosis of acute ITP was 10,000/uL (IQR 5,000-20,000/uL). 19 (25%) patients had secondary ITP or Evans syndrome. Treatment with rituximab had an overall response rate of 63.2% (48/76). Univariate predictors of response to rituximab are shown in Table I. The strongest univariate predictor of response to rituximab was response to steroids. Gender, ethnicity, and race were not predictive of response to rituximab. Furthermore, other variables which did not predict rituximab response include: history of a bleeding score ≥3 (Buchanan and Adix, J Pediatr 2002; 141: 683), symptoms ≥1 month prior to ITP diagnosis, older age (age >5 years), platelets ≥20,000/uL at acute ITP diagnosis, and a positive ANA. In multivariable analysis, response to steroids remained a strong predictor of response to rituximab with an OR 6.2 (95% CI 1.8–21.3, p=0.004). Secondary ITP also remained a strong a predictor of a positive response to rituximab with an OR 5.9 (95% CI 1.2–33.3, p=0.03).In the NACIR, response to steroids and secondary ITP were strong predictors of response to rituximab, a finding not previously reported in children or adults. Although this finding requires further validation, this result may provide evidence that rituximab should be most considered in patients previously responsive to steroids.Off Label Use: Rituximab for chronic ITP. Lambert:Cangene: Membership on an entity's Board of Directors or advisory committees. Klaassen:Novartis: Research Funding; Cangene: Research Funding. Neufeld:Novartis, Inc: Research Funding.

Chronic pediatric immune thrombocytopenia (ITP) has an incidence of 1–2/100,000. Due to its low incidence, large studies in pediatric chronic ITP are difficult. This registry includes patients from 16 sites in the US and Canada and represents one of the largest longitudinal datasets of children/adolescents with chronic ITP.To describe the North American Chronic ITP Registry (NACIR) study population and evaluate univariate predictors of platelet count response to therapies, including IVIG, anti-D globulin (anti-D), steroids (5–14 day course), and splenectomy.After local IRB approval, 550 patients with chronic ITP enrolled in the NACIR between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 7 days of IVIG, 10 days of anti-D, 14 days of steroids, and 30 days of splenectomy. 365 subjects had at least one 6 month follow-up report after enrollment; median duration of follow-up was 2.1 yrs. Demographics of participants include: 46% male; 84% Caucasian, 7% Black, and 7% Asian; and 20% Hispanic. Mean age at diagnosis of acute ITP was 8.7 ± SD 5.2 years. At the time of enrollment in NACIR, subjects had received a median of 2 prior treatments (range 0–7).The median platelet count at diagnosis of acute ITP was 11,000/uL (IQR 6,000–31,000/uL) and at chronic ITP was 35,000/uL (IQR 18,000–66,000/uL). 69 (12.5%) patients had secondary ITP or Evans syndrome. Of those tested, 25.6% (98/359) of patients had a positive ANA (titer > 1:40), and 75/337 (22.3%) had a positive direct anti-globulin test (DAT). 27.5% of patients had an antecedent viral illness. Of the 550 subjects, 2 (0.4%) experienced life-threatening bleeding. Patients were treated as follows: 259 (47.1%) with steroids, 253 (46%) with IVIG, 189 (34.4%) with anti-D, and 64 (11.6%) with splenectomy. Overall responses to therapy included: 69.1% response to steroids, 74.3% response to IVIG, 66.7% response to anti-D, and 85.9% response to splenectomy. Univariate predictors of response to treatments are shown in Table I. Higher platelet count at chronic ITP diagnosis and DAT positive predicted a platelet response to a short course of steroids in univariate analysis. This was confirmed in multivariable analysis of potential confounders, using logistic regression with a backwards elimination procedure. Response to one type of therapy was often strongly associated with a response to a second therapy. Gender, ethnicity, race, older age, and platelets ≥20,000/uL at acute ITP diagnosis were not associated with response to any single therapy.The demographics and laboratory findings of the large, well characterized NACIR population are consistent with other reports of young people with chronic ITP. The novel finding that DAT positivity predicts steroid response, even with multivariable adjustment for confounders, provides evidence that the NACIR is a robust and useful tool for trying to predict response to ITP treatment strategies.Klaassen: Novartis: Research Funding; Cangene: Research Funding. Lambert: Cangene: Membership on an entity's Board of Directors or advisory committees.

Abstract 3681

Abstract 2509

Patients receiving chemotherapy for malignancies are at increased risk for fever-neutropenia (F-N), which may lead to sepsis. A strategy to identify and differentiate “high-risk” patients at presentation would be of critical significance so that these patients may receive timely aggressive intervention. Conversely, early identification of “low-risk” patients allows for development of appropriate risk-stratified management. We hypothesize that certain acute phase reactants at the time of F-N presentation could be used to predict clinical outcome.Children (age 1-21 years) receiving chemotherapy for various malignancies were enrolled in this prospective study. Blood samples from F-N episodes were collected at presentation and thereafter on three consecutive days. These samples were tested for high-sensitivity C-reactive protein (hs-CRP), Soluble IL-2 receptor (s-IL2R), interleukins (IL)-1,3,6,8,10 and Tumor Necrosis Factor-alpha (TNF-a). Samples were analyzed by Luminex technology (Miliplex Cytokine Kit). Clinical outcome data were collected and correlated with the respective bio-markers at presentation. “High-risk” patients were defined as those with any one of the following criteria: prolonged hospitalization (>7 days), admission to pediatric intensive care unit, or a positive bacterial blood culture. “Low- risk” patients had none of the above criteria. Data were analyzed using SAS 9.2 software. Cluster analysis was performed on all variables using the Pearson correlation coefficient. Multivariate logistic regression analysis was performed to develop a risk based predictive model, which was validated using a Receiver Operating Characteristic (ROC) curve.An interim analysis was performed on the acute phase reactant dataset that included 29 children (males 56%, females 44%) representing 51 F-N event. Univariate analysis showed that 56% of events met “high-risk” criteria while 44% of events were “low-risk”. At presentation, significant differences were observed for median values for hs-CRP, s-IL2R, IL-6, and IL-8 between the “high-risk” and the “low-risk” groups (Table 1).Cluster analysis showed a strong correlation between IL-6, IL-8, IL-10 and TNF-a. Within this cluster, IL-6 was selected as critical biomarker, since it explained most of the variability within the cluster. IL-6 was subsequently analyzed with other significant variables (hs-CRP and s-IL2R) in multivariate logistic regression. Logistic regression analysis showed that at F-N presentation, hs-CRP (p=0.02) and s-IL2R (p=0.06) were the most significant bio-markers that correlated with “high-risk” clinical course (Figure-1). Calculated “half-sample” Odds Ratio (OR) for hs-CRP was 6.87 (CI 1.35-34.96, p=0.02) and for s-IL2R was 4.94 (CI 0.94-26.01, p=0.06). After controlling for other variables in study, the analysis found that at F-N presentation, an increase in hs-CRP levels from 42 mg/L to 196 mg/L was associated with 7-fold increased likelihood of subsequent “high-risk” clinical course. Similarly, a rise in s-IL-2R from 262 pg/ml to 692 pg/ml increased the likelihood of “high-risk” by almost 5-fold. However, a rise in IL-6 from 39 pg/ml to 878 pg/ml at presentation was not statistically significant and did not predict an increased risk for complicated F-N course (OR 1.16, CI 0.72-1.88, p=0.54). This risk stratified predictive model was validated using Receiver Operating Characteristic (ROC) curve analysis (Area-Under-Curve AUC=0.84) Figure-2.High-sensitivity CRP and sIL-2R at presentation may represent biomarkers of “high-risk” for clinical sepsis and complicated course among children with fever neutropenia. These biomarkers should be further tested as screening tools for risk-stratification and as response variables to assess the effectiveness of interventions in children with fever neutropenia.Mian: Arkansas Children's Hospital Research Institute (ACHRI), Little Rock, Arkansas. : Research Funding.

Abstract 1406

Introduction: Thromboelastography (TEG) is a point-of-care whole blood coagulation test used commonly with cardiac and liver operations, surgeries for which intraoperative and postoperative bleeding and coagulopathies occur and transfusion is likely. Angiotensinconverting enzyme inhibitors (ACEI) have been found to decrease plasminogen activator inhibitor I (PAI-1), increase tissue plasminogen activator (tPA), decrease tissue factor (TF) production by monocytes, and decrease platelet aggregation. Methods: With IRB approval, kaolin-activated heparinase TEG data were collected on 634 infants and children under 18 yr presenting for elective cardiac surgery between January 2004 and December 2007 for retrospective review utilizing the Haemoscope Thromboelastograph® Coagulation Analyzer (Haemoscope Corp., Niles, IL). Six TEG parameters are analyzed: R (reaction time to reach clot initiation), K (time to reach 20 mm amplitude after R), alpha (clot kinetics), MA (maximum amplitude), LY30 (amount of lysis 30 min after MA), and CI (coagulation index). Infants and children are analyzed based on preoperative therapy with an ACEI. Results: In those receiving ACEI, the time to initial fibrin formation is faster (R, p=0.0007), although subsequent clot formation is slower (K, p=0.0201; alpha, p=0.0092) than without ACEI drugs. Moreover, there is markedly less fibrinolysis (LY30, p=0.0019) in those receiving an ACEI. Clot strength and overall clot dynamics (MA and CI, p=NS) were similar in both groups (Table 1). Subjects with baseline oxygen saturation of 88% differ in that they do not have a significant change in K or alpha but do have a higher CI. Table 1. Ranges for Kaolin-activated Heparinase Thromboelastography Parameters Group R (min) K (min) alpha (degrees) MA LY30% CI Control 7.27±2.20 1.83±0.68 65.0±8.4 64.2±6.4 2.28±2.87 −0.68±2.81 ACEI 6.54±1.88 1.99±0.81 62.7±10.2 63.3±5.8 1.12±2.05 −0.39±2.87 p value 0.0007 0.0201 0.0092 NS 0.0019 NS Discussion: A number of investigators have found antithrombotic effects of ACEI drugs in adults but children have not been studied. The TEG provides an ex vivo means of assessing whole blood clotting dynamics. This preliminary analysis of infants and children reveals a delay in the time required to initiate clot via the intrinsic coagulation cascade as activated by kaolin (R) and slowed clot formation (K and alpha). Final clot strength shows no difference and LY30 shows less fibrinolysis. A shift in plasma hemostasis towards fibrinolysis would potentially delay R, prolong K, decrease alpha, and increase LY30. Paradoxically, we see a decrease in R and LY30. Reduced platelet aggregation is consistent with slowed kinetics of clot formation (K and alpha) but would be expected to cause a reduction in MA that is not seen. Further analysis of this data will separate the subjects into age groups as TEG parameters vary with age in infants and children. Also, since there is evidence that enalapril may not have the antiplatelet effects of captopril and may increase tPA in women but not men, further analysis of gender and type of ACEI given will be completed.

Introduction: Thromboelastography (TEG) is a point-of-care whole blood coagulation test used commonly with cardiac and liver operations, surgeries for which intraoperative and postoperative bleeding and coagulopathies occur and transfusion is likely. Angiotensinconverting enzyme inhibitors (ACEI) have been found to decrease plasminogen activator inhibitor I (PAI-1), increase tissue plasminogen activator (tPA), decrease tissue factor (TF) production by monocytes, and decrease platelet aggregation.

Objective: To determine individual/institutional practices at hemophilia treatment centers (HTCs) regarding management of severe hemophilia patients during minor surgery (e.g., central venous line insertion, cataract surgery, lymph node biopsy), both in the absence and presence of low and high titer inhibitors to Factor VIII (FVIII). Background: The management of hemophilia patients undergoing surgery has changed over the past 20 years as product choice and availability has evolved. Individual preference and experience may affect treatment decisions in the absence of data from clinical trials. Methods: The survey was distributed to both adult and pediatric hematologists at HTCs listed on the CDC website. 93 surveys were successfully emailed. Survey questions evaluated management of minor surgery, both in the absence and presence of a low and high titer inhibitor to FVIII. Results: Surveys from 32 HTCs were received. Twenty-two respondents were affiliated with a University Hospital. For patients without inhibitor, the majority of respondents prefer a pre-operative bolus dose of FVIII 50 U/kg (73%, 22/30; range 25–50 U/kg); only 3 respondents reported a continuous infusion (range 4–8 u/kg/hr). For the post-operative dose, most (n=22) prefer a bolus dose (25–50 U/kg); only 6 reported using a continuous dose (range 2–8 U/kg/hr). Total number of days treated pre-operatively was reported as less than a day in 88% (23/26) respondents; days of post operative treatment ranged from 1–14 with a median of 4 days (n=22). Desired FVIII level ranged from 50–100% for 1–10 days. Fifty percent (15/30) reported adjuvant use of Amicar. For patients with high inhibitor levels no one reported a pre or post operative FVIII bolus or continuous infusion rate. Fifty percent (9/18) reported adjuvant Amicar use. The reported rFVIIa dose in patients with high titer inhibitors, ranged from 90–200 mcg/kg (most commonly 90 mcg/kg), usual frequency of every 2 hours, for a range of 1–10 days. The reported FEIBA dose in patients with high titer inhibitors, ranged from 50–100 U/kg (most commonly 75–100 U/kg with a frequency of every 12 hours, for 1–10 days. Conclusion: Substantial practice variations exist in managing minor surgeries in hemophilia patients, both with and without low and high titer inhibitors, as is evident with this survey.

Objective: To determine individual/institutional practices at hemophilia treatment centers (HTCs) regarding management of severe hemophilia patients during major surgery (e.g., knee replacement, appendectomy), both in the absence and presence of low and high titer inhibitors to Factor VIII (FVIII). Background: There are considerable variations in the management of hemophilia patients undergoing surgery. The use of alternative products like Amicar, recombinant Factor VIIa (rFVIIa) and FEIBA is also growing. Methods: The survey was distributed to both adult and pediatric hematologists at HTCs listed on the CDC website. Ninety-three surveys were successfully emailed. Survey questions evaluated management of hemophilia patients during major surgical procedures, both in the absence and presence of a low and high titer inhibitor. Results: Surveys from 32 HTCs were received. Twenty-two respondents were affiliated with a University Hospital. For patients without inhibitor, the majority of respondents prefer a pre-operative bolus dose of 50 U/kg (84%, 22/28, range 40–70 U/kg); 15 respondents prefer a continuous dose (range 2–8 U/kg/hr). For the post-operative dose, 11 reported a bolus dose, usually 25–50 u/kg; 17 reported using a continuous dose (range 2–8 U/kg/hr). Total number of days treated pre-operatively was reported as less than a day by 90% (18/20) respondents; days of post operative treatment ranged from 7–42 with a median of 13 days (n=22). Desired FVIII level ranged from 50–100% for 3– 15 days. Median number of days inpatient was 6 (n=21). Eight percent (2/25) reported adjuvant use of Amicar. Thirty-nine percent (11/28) reported use of thrombotic prophylaxis after surgery. For patients with high titer inhibitor levels, only 1 respondent reported a pre or post operative FVIII bolus or continuous dose. The reported rFVIIa dose in patients with high titer inhibitor, ranged from 90–270 mcg/kg (most reporting 90 mcg/kg), with most reporting a frequency of every 2 hours for a range of 1–14 days. The reported FEIBA dose in patients with high titer inhibitors ranged from 50–100 U/kg (most 75 U/kg) with most reporting a frequency of every 12 hours for 6–14 days. Sixty four percent (7/11) reported use of thrombotic prophylaxis after surgery. Conclusion: Substantial practice variations exist in managing major surgeries in hemophilia patients, both with and without low and high titer inhibitors. This data will assist in developing future clinical trials and practice guidelines for management of hemophilia patients undergoing surgical procedures.

INTRODUCTION: Children with DS and AML have a superior response to chemotherapy and improved survival compared to non-DS AML patients. However, DS patients have been shown to have excessive treatment-related mortality. We report the outcomes of DS-AML patients treated on POG protocol 9421 with particular attention to cardiotoxicity. RESULTS: Fifty-seven DS-AML patients were enrolled. Median age was 20 months (range 1–40 months) including 8 (14%) infants < 12 months, 30 (52.6%) children ≥12months and ≤ 24 months, 16 (28.1%) children >24months and ≤ 36 months, and 3 (5.3%) children > 36 months. 45 patients (78.9%) had FAB-M7 morphology. There was one induction failure and 2 early deaths with the remainder of the patients (54/57 = 94.7%) achieving first remission (CR1). Early deaths included one patient who presented with meningococcemia at the time of diagnosis of AML and was in critical condition prior to induction. The second patient had unrepaired tetralogy of Fallot (TOF) and died during induction of presumed sepsis precipitating a fatal TOF cyanotic event. CR1 rate was 8 of 8 (100%) for age ≤ 12 months, 29 of 30 (97%) for age > 12 mos and ≤ 24mos, 15 of 16 (93.8%) for age >24 mos and ≤ 36 mos, and 2 of 3 (66%) for age > 36months. Of the 54 patients achieving CR1, 3 relapsed. Two died of disease and one patient underwent allogeneic bone marrow transplant and died of complications. There have been no other relapses with follow-up ranging from 2–10 years. One patient with partially repaired AV canal was removed from study after induction 1 due to congestive heart failure (CHF) and pulmonary hemorrhage and remains alive in CR1 9 years later. There were 6 additional deaths unrelated to leukemia. Two patients died following consolidation 2, one with RSV pneumonia and the other with CHF. Four patients died following completion of treatment: two of unknown causes, one due to CHF, and one due to “respiratory illness." Review of the data reveals a concerning incidence of cardiotoxicity. Nineteen (33%) patients had documented structural cardiac disease. The majority had either repaired cardiac disease or isolated ASD or VSD which was thought to be clinically insignificant. All patients had documentation of adequate cardiac function by echocardiography prior to the start of treatment. Cumulative anthracycline exposure on this protocol was high, including 135mg/m2 of daunorubicin and 80mg/m2 of mitoxantrone. Twelve of 57 patients (21%) had documented CHF requiring chronic diuretics and/or inotropes with diminished fractional shortening on echocardiogram; four patients died. Eight of these 12 patients had prior cardiac disease although 4 had either functionally insignificant ASD or repaired VSD. Dilated cardiomyopathy developed during or soon after completion of treatment in all patients. CONCLUSION: In summary, this treatment regimen for DS-AML was highly effective in both remission induction and long-term leukemia-free survival. However, there was a high incidence of dilated cardiomyopathy, which lends support to current strategies for dose reduction of anthracyclines in this patient population. Additional follow-up data on these children is currently being collected to further delineate the burden of long-term cardiac dysfunction among survivors.

The role of allogeneic bone marrow transplantation (BMT) in the treatment of pediatric patients (PT) with de novo AML continues to be discussed: Who should receive BMT? Should BMT be done during the first complete remission (CR)? In the POG 9421 trial 654 PTs with AML were genetically randomized between allogeneic BMT or a chemotherapy regimen; this protocol has been previously published. If a matched sibling was identified during induction, and CR was achieved, the PT received BMT after the second course of induction chemotherapy. The BMT preparative regimen consisted of Total Body Irradiation (TBI; 1200 cGy given as 150 cGy bid for 4 days) and high dose etoposide (60 mg/Kg IV over 4 hrs on day -3). Methotrexate and cyclosporine comprised the GVHD prophylaxis. The use of TBI in prepubertal children is a concern of many clinicians. We are analyzing growth and development data from the PTs who completed the induction and BMT regimen of POG9421 and present here the body mass index (BMI) findings from those PTs whose height and weight data were supplied to the COG Data Center. Of the 654 PTs registered on POG 9421, 32 were ineligible due to wrong diagnosis or major protocol violation. 501 non-Down Syndrome PTs were eligible for BMT if a matched sibling donor was located. 89 (17.8%) of the patients had a donor, proceeded to BMT, and were eligible for evaluation. Of those, 53 (60%) had data supplied for height (ht) and weight (wt) after BMT. Time from BMT ranged from 6 months to 5 yrs and PTs age at diagnosis ranged from 1–20 years. The height data were divided into 2 age groups, <= 10 yrs at diagnosis and > 10 yrs at diagnosis. The younger group consisted of 19 males and 12 females. Of these, 2 males and 2 females had heights that were below the 3rd percentile at last follow-up. The BMI data were then sorted into 2 age groups: <= 14 yrs and > 14 yrs at the time most recent ht and wt data were supplied. The mean age of the younger group was 7.6 yrs and and that of the older group was 17 yrs. The average BMI of the younger group was 18.19, and that of the older group was 22.85. The average time off therapy when the BMI was calculated was 2.3 yrs for both groups. In the young group, 3 males and 1 female were obese; in the older group, 2 males were overweight and 1 male and 1 female were obese. The median BMIs in the young group were 17 at the 84th percentile for females and 17.8 at the 65th percentile for males; those values in the older group were 19.6 for females and 21.3 for males. Percentile is not given for older patients. In conclusion, the BMT preparative regimen did not cause a severe acute change in BMI in this population. Overweight or obesity was not a common problem in this group, and after 4 yrs follow-up, short stature was not evident. Further data regarding stature will need to be evaluated to determine other long term growth effects of TBI and allogeneic BMT in the younger population with AML.

INTRODUCTION: Children with DS and AML have a superior response to chemotherapy and improved survival compared to non-DS AML patients. However, DS patients have been shown to have excessive treatment-related mortality. We report the outcomes of DS-AML patients treated on POG protocol 9421 with particular attention to cardiotoxicity.

Objective: To determine individual/institutional practices at hemophilia treatment centers (HTCs) regarding management of severe hemophilia patients during minor surgery (e.g., central venous line insertion, cataract surgery, lymph node biopsy), both in the absence and presence of low and high titer inhibitors to Factor VIII (FVIII).

Objective: To determine individual/institutional practices at hemophilia treatment centers (HTCs) regarding management of severe hemophilia patients during major surgery (e.g., knee replacement, appendectomy), both in the absence and presence of low and high titer inhibitors to Factor VIII (FVIII).

The role of allogeneic bone marrow transplantation (BMT) in the treatment of pediatric patients (PT) with de novo AML continues to be discussed: Who should receive BMT? Should BMT be done during the first complete remission (CR)? In the POG 9421 trial 654 PTs with AML were genetically randomized between allogeneic BMT or a chemotherapy regimen; this protocol has been previously published. If a matched sibling was identified during induction, and CR was achieved, the PT received BMT after the second course of induction chemotherapy. The BMT preparative regimen consisted of Total Body Irradiation (TBI; 1200 cGy given as 150 cGy bid for 4 days) and high dose etoposide (60 mg/Kg IV over 4 hrs on day -3). Methotrexate and cyclosporine comprised the GVHD prophylaxis. The use of TBI in prepubertal children is a concern of many clinicians. We are analyzing growth and development data from the PTs who completed the induction and BMT regimen of POG9421 and present here the body mass index (BMI) findings from those PTs whose height and weight data were supplied to the COG Data Center. Of the 654 PTs registered on POG 9421, 32 were ineligible due to wrong diagnosis or major protocol violation. 501 non-Down Syndrome PTs were eligible for BMT if a matched sibling donor was located. 89 (17.8%) of the patients had a donor, proceeded to BMT, and were eligible for evaluation. Of those, 53 (60%) had data supplied for height (ht) and weight (wt) after BMT. Time from BMT ranged from 6 months to 5 yrs and PTs age at diagnosis ranged from 1–20 years. The height data were divided into 2 age groups, <= 10 yrs at diagnosis and > 10 yrs at diagnosis. The younger group consisted of 19 males and 12 females. Of these, 2 males and 2 females had heights that were below the 3rdpercentile at last follow-up. The BMI data were then sorted into 2 age groups: <= 14 yrs and > 14 yrs at the time most recent ht and wt data were supplied. The mean age of the younger group was 7.6 yrs and and that of the older group was 17 yrs. The average BMI of the younger group was 18.19, and that of the older group was 22.85. The average time off therapy when the BMI was calculated was 2.3 yrs for both groups. In the young group, 3 males and 1 female were obese; in the older group, 2 males were overweight and 1 male and 1 female were obese. The median BMIs in the young group were 17 at the 84thpercentile for females and 17.8 at the 65thpercentile for males; those values in the older group were 19.6 for females and 21.3 for males. Percentile is not given for older patients. In conclusion, the BMT preparative regimen did not cause a severe acute change in BMI in this population. Overweight or obesity was not a common problem in this group, and after 4 yrs follow-up, short stature was not evident. Further data regarding stature will need to be evaluated to determine other long term growth effects of TBI and allogeneic BMT in the younger population with AML.

The role of allogeneic bone marrow transplant (BMT) in pediatric patients (pts) with de novo AML in first complete remission remains controversial. One of the objectives of POG 9421, a phase 3 trial for children with newly diagnosed AML, was to compare the disease free survival between pts genetically randomized between allogeneic BMT and consolidation chemotherapy. All pts enrolled on POG 9421 were randomized to standard dose (SD) ara-C or high dose (HD) ara-C during course 1 of induction prior to knowing if there was an HLA matched (5/6 or 6/6) sibling that might be a potential marrow donor. The intent of the study was for pts who achieved a CR and had an HLA matched sibling and did not have Down syndrome (DS) to receive a BMT following the second course of induction. The protocol preparative regimen included TBI (1200 cGy at 150 cGy bid for 4 days) and high dose etoposide (60 mg/kg iv over 4 hours on day -3). GVHD prophylaxis utilized methotrexate and cyclosporine. Six hundred and fifty-four patients were registered on POG 9421, and 32 were ineligible due to wrong diagnosis or major protocol violation and 57 had DS. Five hundred and one of 560 evaluable pts achieved a CR and were eligible for transplant if a matched sibling donor was identified. 83/501 or 16.5% of the patients had a donor and proceeded to transplant and were eligible for evaluation. Of the 83 pts, 39 received SD ara-c for induction and 44 received HD ara-c for induction. The median times from registration to CR were 39.0 days and 33.0 days, and the median times from CR to transplant were 39.0 days and 46.5 days for SD and HD ara-c, respectively. Twenty-nine of 83 pts had post BMT events including 10 deaths from toxicity, 18 relapses, and 1 second malignancy. Of the 29 events, 6 deaths and 6 relapses occurred in the SD arm and 4 deaths, 12 relapses, and 1 secondary malignancy in the HD arm. The 3yr DFS of patients who received SD ara-c induction was 71.8 +/− 7.6%, and was not significantly different from that of HD ara-c induction (3-year DFS 63.3 +/− 8.2%, p=0.49). Seven deaths occurred within 100 days of transplant. The rates of patients off protocol therapy due to event in cytogenetic subgroups are as follows: 7/25 for patients with normal cytogenetics; 3/10 for patients with 11q23 abnormalities; 6/13 for patients with t(8;21), and 7/18 for patients with miscellaneous abnormalities; there were no events during the protocol therapy among the 6 patients with inv16. The 3-year DFS and 3-year overall survival for the 83 transplanted patients were 67.3 +/− 5.6% and 69.7 +/− 5.4%, respectively. The DFS for the transplanted patients was superior to consolidation chemotherapy (N=418, 3-year DFS=37.5+/− 2.7%, p<0.001). Five pts had GVHD, 2 with grade 3, 2 with grade 2, and 1 with grade 1. Conclusion: Patients were able to receive their transplants within the goal of 8 weeks of induction II. The outcome of BMT was superior to consolidation chemotherapy as has been reported by other groups. The ara-c schedule had no significant impact on the outcome. The reported low incidence of GVHD in this study prevents us from evaluating its impact on outcome.

Most studies of childhood ITP focus on platelet count as the sole outcome measure. Although side effects of drug treatment for ITP are mentioned in some studies, serial quantitative measures of drug toxicity over time have not been measured. We hypothesized that it was possible to develop a valid instrument to quantitate drug side effects in children with ITP for use in future clinical trials and to assist with patient management. Accordingly, we designed a “Childhood ITP Symptom Checklist” for completion by parents of children with ITP daily for 7 days following initiation of therapy. Parents were asked to rate on a 0 to 4 scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe) the severity of 11 possible side effects (headache, hyperphagia, vomiting, moodiness, fever, insomnia, chills, fatigue, leg/arm pain, abdominal pain, nausea). Seventy-four children (50 male) with ITP (46 newly-diagnosed and 28 established) were enrolled from six centers across North America. Age ranged from 6 mo to 17 yr (median 4 yr). Median platelet count on day 0 (when drug therapy was initiated) was 9,000 per mm3(range 1 to 75,000 per mm3). Fourteen patients received corticosteroids, 28 intravenous immunoglobulin (IVIG), 20 anti-D immunoglobulin, 2 multiple drugs, and 10 no drug therapy. Parent acceptance of and compliance with the instrument was good. All 11 side effects were noted in patients in each group, but the percentage of patients with side effects and the severity and time course varied greatly. Severe or very severe (S/VS) complications were seen with each drug therapy. IVIG-treated patients had maximal side effects on day 1 including headache (in 54% of patients, S/VS 25%), vomiting (36%, 14% S/VS), fever (50%, 14% S/VS), chills (33%, 7% S/VS), and nausea (41%, 11% S/VS). Side effects diminished on day 2 and were minimal thereafter. Toxicity with anti-D was similar, but the profile differed, being maximal on day 0, continuing throughout the week, but not usually S/VS. Thirty-three percent of children receiving anti-D had headache, 38% fever (worse on day 1), 25% chills, and 22% nausea. The side effects were different with corticosteroids. Hyperphagia occurred throughout the entire 7 days in at least 50% of patients and was sometimes S/VS. Moodiness occurred daily and was S/VS one-third of the time. Moodiness and insomnia as well as fatigue were also commonly reported in other patient groups (including no drug therapy). Mild arm/leg pain and abdominal pain were seen with all treatments but was more persistent with corticosteroids. Mild to moderate headache, fever, and insomnia was noted in 10–30% of patients irrespective of therapy received. We conclude that the nature, timing, and severity of side effects reported by parents of children with ITP can be scored using an instrument such as the one employed here. Further research should determine the specific effect of drug dose and treatment schedule, relationships among different side effects, and the impact of these toxicities on the child's and family's quality of life.

Most studies of childhood ITP focus on platelet count as the sole outcome measure. Although side effects of drug treatment for ITP are mentioned in some studies, serial quantitative measures of drug toxicity over time have not been measured. We hypothesized that it was possible to develop a valid instrument to quantitate drug side effects in children with ITP for use in future clinical trials and to assist with patient management. Accordingly, we designed a “Childhood ITP Symptom Checklist” for completion by parents of children with ITP daily for 7 days following initiation of therapy. Parents were asked to rate on a 0 to 4 scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe) the severity of 11 possible side effects (headache, hyperphagia, vomiting, moodiness, fever, insomnia, chills, fatigue, leg/arm pain, abdominal pain, nausea). Seventy-four children (50 male) with ITP (46 newly-diagnosed and 28 established) were enrolled from six centers across North America. Age ranged from 6 mo to 17 yr (median 4 yr). Median platelet count on day 0 (when drug therapy was initiated) was 9,000 per mm3 (range 1 to 75,000 per mm3). Fourteen patients received corticosteroids, 28 intravenous immunoglobulin (IVIG), 20 anti-D immunoglobulin, 2 multiple drugs, and 10 no drug therapy. Parent acceptance of and compliance with the instrument was good. All 11 side effects were noted in patients in each group, but the percentage of patients with side effects and the severity and time course varied greatly. Severe or very severe (S/VS) complications were seen with each drug therapy. IVIG-treated patients had maximal side effects on day 1 including headache (in 54% of patients, S/VS 25%), vomiting (36%, 14% S/VS), fever (50%, 14% S/VS), chills (33%, 7% S/VS), and nausea (41%, 11% S/VS). Side effects diminished on day 2 and were minimal thereafter. Toxicity with anti-D was similar, but the profile differed, being maximal on day 0, continuing throughout the week, but not usually S/VS. Thirty-three percent of children receiving anti-D had headache, 38% fever (worse on day 1), 25% chills, and 22% nausea. The side effects were different with corticosteroids. Hyperphagia occurred throughout the entire 7 days in at least 50% of patients and was sometimes S/VS. Moodiness occurred daily and was S/VS one-third of the time. Moodiness and insomnia as well as fatigue were also commonly reported in other patient groups (including no drug therapy). Mild arm/leg pain and abdominal pain were seen with all treatments but was more persistent with corticosteroids. Mild to moderate headache, fever, and insomnia was noted in 10–30% of patients irrespective of therapy received. We conclude that the nature, timing, and severity of side effects reported by parents of children with ITP can be scored using an instrument such as the one employed here. Further research should determine the specific effect of drug dose and treatment schedule, relationships among different side effects, and the impact of these toxicities on the child’s and family’s quality of life.

The role of allogeneic bone marrow transplant (BMT) in pediatric patients (pts) with de novo AML in first complete remission remains controversial. One of the objectives of POG 9421, a phase 3 trial for children with newly diagnosed AML, was to compare the disease free survival between pts genetically randomized between allogeneic BMT and consolidation chemotherapy. All pts enrolled on POG 9421 were randomized to standard dose (SD) ara-C or high dose (HD) ara-C during course 1 of induction prior to knowing if there was an HLA matched (5/6 or 6/6) sibling that might be a potential marrow donor. The intent of the study was for pts who achieved a CR and had an HLA matched sibling and did not have Down syndrome (DS) to receive a BMT following the second course of induction. The protocol preparative regimen included TBI (1200 cGy at 150 cGy bid for 4 days) and high dose etoposide (60 mg/kg iv over 4 hours on day -3). GVHD prophylaxis utilized methotrexate and cyclosporine. Six hundred and fifty-four patients were registered on POG 9421, and 32 were ineligible due to wrong diagnosis or major protocol violation and 57 had DS. Five hundred and one of 560 evaluable pts achieved a CR and were eligible for transplant if a matched sibling donor was identified. 83/501 or 16.5% of the patients had a donor and proceeded to transplant and were eligible for evaluation. Of the 83 pts, 39 received SD ara-c for induction and 44 received HD ara-c for induction. The median times from registration to CR were 39.0 days and 33.0 days, and the median times from CR to transplant were 39.0 days and 46.5 days for SD and HD ara-c, respectively. Twenty-nine of 83 pts had post BMT events including 10 deaths from toxicity, 18 relapses, and 1 second malignancy. Of the 29 events, 6 deaths and 6 relapses occurred in the SD arm and 4 deaths, 12 relapses, and 1 secondary malignancy in the HD arm. The 3yr DFS of patients who received SD ara-c induction was 71.8 +/− 7.6%, and was not significantly different from that of HD ara-c induction (3-year DFS 63.3 +/− 8.2%, p=0.49). Seven deaths occurred within 100 days of transplant. The rates of patients off protocol therapy due to event in cytogenetic subgroups are as follows: 7/25 for patients with normal cytogenetics; 3/10 for patients with 11q23 abnormalities; 6/13 for patients with t(8;21), and 7/18 for patients with miscellaneous abnormalities; there were no events during the protocol therapy among the 6 patients with inv16. The 3-year DFS and 3-year overall survival for the 83 transplanted patients were 67.3 +/− 5.6% and 69.7 +/− 5.4%, respectively. The DFS for the transplanted patients was superior to consolidation chemotherapy (N=418, 3-year DFS=37.5+/− 2.7%, p<0.001). Five pts had GVHD, 2 with grade 3, 2 with grade 2, and 1 with grade 1. Conclusion: Patients were able to receive their transplants within the goal of 8 weeks of induction II. The outcome of BMT was superior to consolidation chemotherapy as has been reported by other groups. The ara-c schedule had no significant impact on the outcome. The reported low incidence of GVHD in this study prevents us from evaluating its impact on outcome.

Thrombosis is a known risk in pediatric patients with leukemia. This risk is increased when L-asparaginase is administered. However, children with cancer may have thrombotic complications similar to adults even in the absence of L-asparaginase. The risk may be related to the presence of central lines, surgery, immobilization, or inherited thrombophilia. Cancer in adult patients is also associated with an increased risk of thrombosis that may be related to the disease itself. Low molecular weight heparin such as enoxaparin has become widely used in adult patients with thrombosis. However, there is little data regarding the use of enoxaparin in children undergoing myelosuppressive therapy for malignancies. The purpose of this study was to review the utilization of low molecular weight heparin, enoxaparin (Lovenox), in children with cancer at our institution who had thrombosis while undergoing myelosuppressive chemotherapy. In particular we were interested in the efficacy of enoxaparin in these patients, and if these children were able to continue their chemotherapy without adjustment or interruption secondary to bleeding complications. We conducted a retrospective review from 1999 through April 1, 2004 which yielded seven patients with malignancies and a vascular thrombotic event. The age range was 4–17 years. Diagnosis include: B-precursor ALL (n=3), T-ALL, Hodgkin’s disease, Anaplastic large cell lymphoma, and rhabdomyosarcoma (n=1 each). Six patients developed a deep vein thrombus or clot of the vena cava. One of these 6 patients also had a pulmonary embolus. One patient presented with manifestations of a unilateral cerebral vascular accident without evidence of a DVT. U/S and CT/MRI were performed on patients when appropriate. All patients were screened for Protein C & S deficiency, ATIII deficiency, Factor V Leiden mutation, prothrombin 20210a mutation, and lupus anticoagulant. Treatment was enoxaparin, 1–1.5 mg/kg/dose twice daily to maintain a heparin anti-Xa level of 0.5-1.5 IU/mL. Once the clot had resolved, the enoxaparin was maintained daily for a total of 3–6 months of therapy. All patients had resolution of their thrombosis within 1–2 months of initiation of enoxaparin, and none required delays or dose-reduction of their chemotherapy regimens while on anti-coagulation. There were 10 documented occurences of thrombocytopenia (platelet count < 50,000) in 2 patients without bleeding complications. There was a minimum of 50 days of documented thrombocytopenia while on enoxaparin. We conclude that enoxaparin is effective and safe treatment for thrombotic complications in children undergoing cancer chemotherapy.

Thrombosis is a known risk in pediatric patients with leukemia. This risk is increased when L-asparaginase is administered. However, children with cancer may have thrombotic complications similar to adults even in the absence of L-asparaginase. The risk may be related to the presence of central lines, surgery, immobilization, or inherited thrombophilia. Cancer in adult patients is also associated with an increased risk of thrombosis that may be related to the disease itself. Low molecular weight heparin such as enoxaparin has become widely used in adult patients with thrombosis. However, there is little data regarding the use of enoxaparin in children undergoing myelosuppressive therapy for malignancies. The purpose of this study was to review the utilization of low molecular weight heparin, enoxaparin (Lovenox), in children with cancer at our institution who had thrombosis while undergoing myelosuppressive chemotherapy. In particular we were interested in the efficacy of enoxaparin in these patients, and if these children were able to continue their chemotherapy without adjustment or interruption secondary to bleeding complications. We conducted a retrospective review from 1999 through April 1, 2004 which yielded seven patients with malignancies and a vascular thrombotic event. The age range was 4–17 years. Diagnosis include: B-precursor ALL (n=3), T-ALL, Hodgkin's disease, Anaplastic large cell lymphoma, and rhabdomyosarcoma (n=1 each). Six patients developed a deep vein thrombus or clot of the vena cava. One of these 6 patients also had a pulmonary embolus. One patient presented with manifestations of a unilateral cerebral vascular accident without evidence of a DVT. U/S and CT/MRI were performed on patients when appropriate. All patients were screened for Protein C & S deficiency, ATIII deficiency, Factor V Leiden mutation, prothrombin 20210a mutation, and lupus anticoagulant. Treatment was enoxaparin, 1–1.5 mg/kg/dose twice daily to maintain a heparin anti-Xa level of 0.5-1.5 IU/mL. Once the clot had resolved, the enoxaparin was maintained daily for a total of 3–6 months of therapy. All patients had resolution of their thrombosis within 1–2 months of initiation of enoxaparin, and none required delays or dose-reduction of their chemotherapy regimens while on anti-coagulation. There were 10 documented occurences of thrombocytopenia (platelet count < 50,000) in 2 patients without bleeding complications. There was a minimum of 50 days of documented thrombocytopenia while on enoxaparin. We conclude that enoxaparin is effective and safe treatment for thrombotic complications in children undergoing cancer chemotherapy.