Acute lymphoblastic leukemia (ALL) with KMT2A rearrangement is associated with poor prognosis. The t(4;11)(q21;q23) resulting in KMT2A-AFF1 fusion represents one of the most common translocations involving the KMT2A locus, comprising 2% of pediatric ALL and 5% of adult ALL cases. Pediatric patients, especially infants with t(4;11)(q21;q23), have been reported to have fewer additional cytogenetic abnormalities (ACA) compared with other primary established cytogenetic subgroups. Some studies have thus proposed that the KMT2A-AFF1 fusion may function as a major contributor in driving and maintaining the malignancy. However, the contribution of ACA to leukemogenesis, treatment, and disease evolution in ALL with KMT2A-AFF1 has yet to be determined. In this study, we evaluated the results of chromosome analysis and fluorescence in-situ hybridization (FISH) on 48 ALL cases with t(4;11)(q21;q23), as well as genomic microarray (GMA) data from 4 of these cases. Karyotype data were analyzed in the context of the frequencies of ACA in different age groups, the types of ACA, and potential clinical outcome correlation. The 48 t(4;11)-positive cases include 13 infants (<1 year old), 14 children (1-18 years old), and 21 adults (>18 years old). ACA with t(4;11)(q21;q23) was identified at diagnosis by karyotyping analysis in a total of 27/48 (56%) cases , including 5/13 (36%) infants, 8/14 (58%) children, and 14/21 (67%) adults. In addition, three t(4;11)-positive with ACA cases (two infants and one adult) occurred at relapse. Among the 30 cases with ACA, 8 cases (27%) had sole numerical abnormalities, 13 (43%) cases had sole structural abnormalities, and the remaining 9 (30%) cases carried both numerical and structural abnormalities. Gain of X chromosome was the most common numerical abnormality (n=6), followed by trisomy 8 (n=3) and trisomy 6 (n=2), while isochromosome 7q [i(7q)] represents the most frequent structural abnormality (n=4). Other recurrent structural abnormalities associated with lymphoid malignancy included del(6)(q15q21), del(13)(q12q14), del(17)(p11.2), isochromosome 17q, and isochromosome 21q, each observed in one case. The IGH rearrangement was identified by FISH as a secondary abnormality in 3 cases; of which, one case was found to carry a translocation between chromosomes 14 and 22 [t(14;22)(q32;q11)] by karyotyping. In addition, hyperdiploidy and tetraploidy were found in 4 cases. Concurrent GMA performed on the 4 cases with ACA revealed submicroscopic focal deletions, including a deletion of 9p21.3 involving the CDKN2A gene (n=2), a deletion of 5q31.3 involving the NR3C1 gene (n=1), and a deletion of 17p13.3p11.2 involving the TP53 gene (n=1). Assessed by available data, we also identified 8 cases with relapsed leukemia including 6 infants and 2 adults; among which, 5 cases showed cytogenetic clonal evolution with additional abnormalities at relapse. Collectively, our data provide additional insights into the occurrence, category and clinical significance of ACA in ALL with t(4;11)(q21;q23). In this ALL cohort with t(4;11)(q21;q23), a relatively lower ACA frequency was found at diagnosis in infants (36%) in contrast to the higher frequency of ACA in diagnostic specimens from children (58%) and adults (67%), which may suggest the mutational hits accumulated over time, implying a potential role of ACA in the initiation and progress of leukemia. The presence of ACA at relapse may indicate the occurrence of leukemic clonal evolution by acquiring more genetic alterations. Lines of evidences suggested that some ACA may affect the response to treatment in patients with t(4;11)(q21;q23). Further characterization of additional cytogenetic lesions with comprehensive cytogenetic and genomic analyses and a larger cohort of patients will help to elucidate the pathogenic roles of t(4;11)(q21;q23) potentially resulting in a tailored treatment.

Background/Objectives Slow-flow vascular malformations are abnormal vessels that can lead to activation and consumption of coagulation factors and thrombosis, known as localized intravascular coagulopathy (LIC). Most clinical and research evidence of vascular malformation hemostasis relies on conventional coagulation studies, which may not provide a complete picture. Thromboelastograpy (TEG) is a tool that can provide real-time assessment of a patient's coagulation dynamics, and may allow for a more individualized treatment approach. We hypothesized that patients with slow-flow vascular malformations will have changes in TEG parameters peri-procedure that will help predict blood product or medication administration. Design/Methods Institutional Review Board approved prospective study of patients with slow-flow vascular malformations undergoing a sedated, minor procedure. TEG and conventional coagulation studies were obtained preprocedure, 15 min, and when possible, at 30 min after the start of the procedure. Results Twenty-five patients were enrolled. Median age was 15 years (range 3-47 years). Procedures included laser and/or sclerotherapy. There were no changes in TEG parameters from baseline to 15 min or 30 min. The following decreased from baseline to 15 min: fibrinogen 313 to 287 mg/dL (P = .001), D-dimer 1.3 to 1.1 mg/L (P = .02), hemoglobin 12.8 to 11.8 g/dL (P = .001), and platelet count 272 000 to 256 000 (P = .006). No patient had a bleeding/thrombotic complication during or within 1 week postprocedure. Conclusion We saw no change in TEG parameters or bleeding or clotting complications despite significant numerical changes in conventional coagulation profiles, suggesting that conventional studies may not be as useful in determining risks of bleeding or thrombotic complications peri-procedure for minor procedures.

Introduction. ETO2-GLIS2 (aka CBFA2T3-GLIS2) is the most common (30%) alteration in pediatric de novo acute megakaryoblastic leukemia (AMKL). These patients have poor response to induction therapy, a high incidence of relapse (~90%), and dismal 5-year survival rates (<20%). Previous studies suggest that ETO2-GLIS2 induces leukemia through abnormal enhancer formation as a single oncogenic “hit”. Because ETO2-GLIS2 expression induces formation of leukemia-specific neo-superenhancer (SE) elements, we hypothesize that mediator (MED) proteins are involved in linking neo-SE elements to distal gene expression, and thus could be a therapeutic target. Here, we analyzed expression of MED-family genes in ETO2-GLIS2 positive AMKL patients in combination with enhancer-histone marks, and evaluated impact of MED-kinase inhibition with selective CDK8 inhibitors (CDKi) against cell viability.

BackgroundVascular malformations (VM) are congenital lesions that can be debilitating and cause significant aesthetic and functional limitations. The chemotherapeutic agent bleomycin has been utilized as a sclerosant, directly injected percutaneously into the VM. Unfortunately, little is known about the benefits and short-term side effects of bleomycin with intralesional injections. ProcedureAn IRB approved, retrospective chart review was performed on patients with VM who had been treated with intralesional bleomycin. Data included type of VM, number of treatments, total bleomycin dose per m(2), and adverse effects. A questionnaire was administered to available patients to assess subjective outcomes and side effects. ResultsForty-six patients were treated with 141 procedures of bleomycin sclerotherapy for VM. Patient ages ranged from 1 to 20years (median age 10 years). The median cumulative bleomycin dose was 16.3units/m(2)/person (range of 1.7-97.0units/m(2)/person). Sixty-three percent of patients were reached for a questionnaire to assess short-term side effects. Ninety percent of patients surveyed were satisfied to very satisfied with the results from the procedure. About 24% of patients experienced transient nausea, vomiting and/or local hyperpigmentation. ConclusionBleomycin sclerotherapy can be an effective treatment of VM with repeat exposure with minor risk of short-term side effects, however, long-term risks are of great concern. Further studies are required to assess systemic absorption and long-term risks.

Background Patients receiving myelosuppressive chemotherapy remain at increased risk for developing febrile neutropenia (FN). For this heterogeneous population, a biomarker based risk stratification of FN patients may be a useful clinical tool. We hypothesized that serum biomarkers during initial presentation of an FN event could be predictive of subsequent clinical outcome. Procedure Eighty-nine FN events from 36 non-consecutive subjects were analyzed. High-risk FN criteria included prolonged hospitalization (=7 days), admission to pediatric intensive care unit (PICU) or a microbiology confirmed bacteremia. Patients with low risk FN had none of the above. Biomarkers measured during the first 2 days of FN hospitalization were analyzed and correlated with respective clinical outcome. Results Of the 89 FN events, 44 (49%) fulfilled pre-defined high-risk criteria and 45 (51%) were low-risk. Procalcitonin level (>0.11?ng/ml) was found to be associated with the high-risk FN outcome with sensitivity of 97%. With an increase in log scale by 1, the odds of being high-risk FN increased twofold. Hs-CRP >100?mg/L had sensitivity of 88% in predicting high-risk FN. The odds of a high-risk FN event increased by approximately 1.8-fold with an increase in the log scale of hs-CRP by 1 (10-fold). In univariate analysis, IL-6, IL-8, and IL-10 were statistically significant and associated with high-risk FN. However, no statistically significant difference was found for IL-1a, sIL-2Ra, IL-3, or TNF-a. Conclusions Biomarkers with appropriate critical threshold values may be a useful clinical tool for appropriate risk stratification of children with FN. Pediatr Blood Cancer 2012;59:238245. (c) 2012 Wiley Periodicals, Inc.

Central line associated blood stream infections (CLABSI) among hematology-oncology patients significantly increase morbidity and mortality and remain a universal challenge. Strategies to decrease risk of CLABSI include adherence to standardized practices for central venous line (CVL) care with sustained long-term compliance on the part of caregivers. In our efforts to reduce CLABSI, a multidisciplinary task force was created to systematically introduce standardized CVL insertion and maintenance care bundles in the hematology-oncology inpatient unit. Data was collected in standardized format according to CDC criteria and compared to historical institutional CLABSI rates. During the first year after implementation of these interventions, our CLABSI rate decreased by 68% and rate reduction has been sustained during following two years. The overall impact (2009-2011) includes 40 CLABSIs prevented, 3 lives saved and institutional health care cost savings in excess of 1 million dollars.

Myeloid sarcomas are rare extramedullary tumors composed of immature myeloid cells. Most cases are seen in childhood acute myelogenous leukemia (AML). They can develop at many sites, but cardiac involvement is a rare finding. We report the case of a 24-year-old woman who, after being in remission from AML for 10 years, developed an isolated cardiac myeloid sarcoma.

Myeloid sarcomas are rare extramedullary tumors composed of immature myeloid cells. Most cases are seen in childhood acute myelogenous leukemia (AML). They can develop at many sites, but cardiac involvement is a rare finding. We report the case of a 24-year-old woman who, after being in remission from AML for 10 years, developed an isolated cardiac myeloid sarcoma.

KIT receptor tyrosine kinase mutations are implicated as a prognostic factor in adults with core binding factor (CBF) acute myeloid leukemia (AML). However, their prevalence and prognostic significance in pediatric CBF AML is not well established. We performed KIT mutational analysis (exon 8 and exon 17) on diagnostic specimens from 203 pediatric patients with CBF AML enrolled on 4 pediatric AML protocols. KIT mutations were detected in 38 (19%) of 203 (95% CI, 14%-25%) patient samples of which 20 (52.5%) of 38 (95% CI, 36%-69%) involved exon 8, 17 (45%) of 38 (95% CI, 29%-62%) involved exon 17, and 1 (2.5%; 95% CI, 0%-14%) involved both locations. Patients with KIT mutations had a 5-year event-free survival of 55% (+/- 17%) compared with 59% (+/- 9%) for patients with wild-type KIT (P = .86). Rates of complete remission, overall survival, disease-free survival, or relapse were not significantly different for patients with or without KIT mutations. Location of the KIT mutation and analysis by cytogenetic subtype [t(8;21) vs inv(16)] also lacked prognostic significance. Our study shows that KIT mutations lack prognostic significance in a large series of pediatric patients with CBF AML. This finding, which differs from adult series and a previously published pediatric study, may reflect variations in therapeutic approaches and/or biologic heterogeneity within CBF AML. Two of 4 studies included in this analysis are registered at http://clinicaltrials.gov as NCT00002798 (CCG-2961) and NCT00070174 (COG AAML03P1).

A 16-month-old boy had been diagnosed with B-cell acute lymphoblastic leukemia (ALL). Past medical and birth histories were unremarkable. Over the past 48 hours, he received and tolerated a slow transfusion of packed red blood cells for an Hgb concentration of 4.9 g/dL (49 g/L). Currently, he is receiving maintenance intravenous hydration. Physical examination shows no evidence of distress. His temperature is 97.5°F (36.4°C), respirations are 24 breaths/min, heart rate is 126 beats/min, blood pressure is 95/64 mm Hg, and oxygen saturation is 98% on room air. His chest is clear to auscultation, with normal heart sounds. Abdominal examination shows mild hepatosplenomegaly. He has scattered petechiae. Current laboratory results are: WBC count of 14.8×103/mcL (14.8×109/L), Hgb of 10.4 g/dL (104 g/L), Hct of 28.9% (0.29), and platelet count of 48×103/mcL (48×109/L). The values for serum electrolytes, BUN, creatinine, liver enzymes, and uric acid as well as results of coagulation studies are within normal limits. Chest radiography reveals normal findings. Prior to surgery for central line placement, he receives 1 unit of irradiated, leukocyte-reduced platelets.A central line is placed without difficulty. Within 2 hours of the platelet transfusion, he experiences acute cardiorespiratory deterioration (heart rate 165 beats/min, blood pressure 65/42 mm Hg, respiratory rate 48 breaths/min, oxygen saturation 78% on room air, and temperature 99°F [37.2°C]). Examination reveals symmetrically decreased breath sounds and diffuse crackles bilaterally, with normal heart sounds and capillary refill. Repeat radiography shows extensive “diffuse bilateral infiltrates consistent with pulmonary edema.” He is intubated and transferred to the intensive care unit. Additional evaluations reveal the diagnosis.A 13-month-old boy presents with a history of fever for 2 days and nonbloody diarrhea for 2 weeks. Other family members also report diarrhea over the past 2 weeks. He has been healthy, except for a 4-month history of easy bruising and a recent history of oral thrush. He is not taking any medications.On physical examination, his temperature is 102.9°F (39.4°C) and other vital signs are normal. He appears ill but not toxic. He has multiple petechiae and ecchymoses all over his body, white plaques on the oral mucosa, and bilateral anterior cervical lymphadenopathy. The remaining findings of his physical examination are normal. Initial laboratory tests show a WBC count of 2.3×103/mcL (2.3×109/L), with 62% bands, 22% neutrophils, 18% lymphocytes, and 5% monocytes; Hgb of 8.8 g/dL (88 g/L); and platelet count of 11×103/mcL (11×109/L). Stool studies yield negative results.He is started on empiric cefepime and fluconazole but soon becomes more irritable and develops nuchal rigidity as well as bilateral sixth cranial nerve palsy. A CT scan of his head shows mild ventriculomegaly. A lumbar puncture is performed, and analysis of the CSF shows glucose of 37 mg/dL, protein of 300 mg/dL, 420 red blood cells/mm3 and 1,319 WBCs/mm3. Blood and CSF cultures subsequently grow Listeria monocytogenes. Antibiotics are changed to ampicillin and gentamicin. An intraventricular catheter (IVC) is placed to relieve the increased intracranial pressure. Additional studies reveal why this patient contracted this unusual infection.A 17-year-old Hispanic boy presents to the ED with a 5-day history of fever and severe abdominal pain. The pain is intermittent and localized to the epigastrium and right flank. He denies vomiting, diarrhea, and bloody stools but complains of loss of appetite, weight loss, constipation, mild headache, and a dry cough over the past 2 weeks. The past medical history is unremarkable. There is no history of recent international travel or exposure to animals.Physical examination reveals an obese, alert adolescent whose temperature is 101.2°F (38.5°C), heart rate is 114 beats/min, respiratory rate is 24 breaths/min, blood pressure is 118/68 mm Hg, and oxygen saturation is 97% on room air. He has right upper quadrant abdominal tenderness, but his liver and spleen are not enlarged. Results of the rest of the examination are unremarkable.Laboratory studies show a WBC count of 24.1×103/mcL (24.1× 109/L) with 68% neutrophils, 13% bands, 13% monocytes, and 6% lymphocytes; Hgb of 14.3 g/dL (143 g/L); and platelet count of 334×103/mcL (334×109/L). The ESR is 62 mm/hr and C-reactive protein is 390.1 mg/L (39.0 mg/dL). Measurements of electrolytes, amylase, and lipase as well as renal function tests, liver function tests, and urinalysis are normal. ALT is mildly elevated at 44 U/L (normal, 10 to 40 U/L). Serologic tests for HIV and hepatitis A, B, and C are negative. Blood and stool cultures are negative for bacteria. Fecal ova and parasite examinations are negative. A purified protein derivative skin test is positive. Chest radiography shows increased interstitial markings with patchy opacities in the right middle lobe and both lower lobes.Imaging of the abdomen leads to an additional test that reveals the diagnosis.Immediately after the onset of respiratory symptoms, the serum electrolytes, BUN, and creatinine values were normal. His intake and output over the previous 24 hours were matched, and he had appropriately colored urine output. ECG was read as normal, and echocardiography showed normal anatomy with normal cardiac function and no evidence of left atrial hypertension. There was no obvious evidence of circulatory overload, underlying infection, bacterial contamination of the donor unit, or acute hemolytic or anaphylactic transfusion reactions. Transfusion-related acute lung injury (TRALI) was diagnosed.The patient was placed on mechanical ventilation for 2 days and started on prednisone for his induction chemotherapy protocol for ALL. He subsequently was extubated, received supportive management, and was discharged from the hospital on day 7.TRALI is a diagnosis of exclusion in a patient who presents with symptoms of acute respiratory distress, such as hypoxemia, tachycardia, or tachypnea, with bilateral diffuse infiltrates on frontal chest radiograph and no evidence of left atrial hypertension, noncardiogenic pulmonary edema, or pre-existing acute lung injury (ALI). The presentation occurs classically within 6 hours of receiving any blood product. In TRALI, a temporal relationship to an alternate risk factor for ALI, such as transfusion-associated circulatory overload (TACO), does not exist. TRALI is the leading cause of death in transfusion medicine, having an estimated mortality rate of 10%.TRALI and acute respiratory distress syndrome (ARDS) have many common clinical features, but there are notable clinical differences. In TRALI, most patients show clinical, physiologic, and radiographic resolution of symptoms within 2 to 3 days of the onset of the condition. Moreover, their underlying pulmonary injury is reversible, and there are no long-term residual pulmonary function deficits.All blood components have been implicated in TRALI, including red blood cells, platelets, plasma, cryoprecipitate, granulocytes, stem cells, immune globulin concentrates, and autologous red cells. The estimated incidence is 1 in 5,000 to 1 in 25,000 transfusions. There is consensus that many cases are not reported and mild cases may be unrecognized. Because there is no specific diagnostic test, the 2004 consensus panel on TRALI developed clinical guidelines (TableT1) to enhance awareness and improve reporting to local transfusion services. (1)The pathogenesis of TRALI is understood incompletely, but there are two major schools of thought. The first hypothesis involves the infusion of a blood product that contains an antibody against the human leukocyte antigen (HLA) or human neutrophil antigen (HNA) for which the recipient has the cognate antigen. This situation leads to leukoagglutination, congestion of the pulmonary vasculature, neutrophil degranulation, and subsequently, endothelial injury and capillary leak. The second hypothesized mechanism is a “two-hit” model in which the first hit is the underlying clinical condition that leads to the elaboration of cytokines, which causes pulmonary endothelial activation resulting in pulmonary sequestration of neutrophils. The second hit is the infusion of the blood product that contains a biologically active lipid (lysophosphatidylcholine) that causes neutrophils to degranulate, resulting in endothelial damage and subsequent capillary leak.The laboratory evaluation of TRALI and donor management is expensive and involves donor testing for antibodies against classes I and II HLA and HNA from a residual volume of the transfused blood component or a fresh blood specimen obtained from the blood donor. HLA typing on the recipient also is performed. A donor is regarded as “implicated” in TRALI if he or she is found to have HLA class I or II antibodies or HNA antibodies that have specificity for the recipient's WBCs. Once a donor has been implicated, the consensus panel recommends that the he or she be deferred permanently from donation, which is not applied universally because of a smaller donor pool. This recommendation is based on instances in which donors who had specific antibodies have been implicated in TRALI reactions involving multiple recipients.For patients experiencing acute pulmonary insufficiency following blood product transfusion, the differential diagnosis includes TACO, which may present as respiratory distress, hypertension, and tachycardia when there is a mismatch of intake and output. Patients who have TACO show rapid resolution and improvement with aggressive diuresis. Anaphylactic transfusion reactions develop very rapidly and commonly present with erythema, urticaria, bronchospasm, and laryngeal edema rather than the noncardiogenic pulmonary edema seen in TRALI. Bacterial contamination of the blood product, leading to sepsis, presents as a sudden high fever, with or without rigors or chills, and cardiovascular collapse. Among these patients, respiratory symptoms usually are not prominent. Acute hemolytic transfusion reactions may present with signs of intravascular hemolysis that typically would not be confused with TRALI. ARDS, due to causes such as toxins or infections, also may present as respiratory distress and needs to be considered in the appropriate clinical setting.Early recognition and prompt respiratory and hemodynamic supportive measures are the hallmarks of management. Almost all patients require supplemental oxygen. In severe hypoxemia, intubation and mechanical ventilation with relatively high positive end-expiratory pressure are necessary. Inotopes may be needed to support the hemodynamic status. Although patients may not experience volume overload, diuresis commonly is undertaken. The role of steroids is somewhat controversial, but many clinicians choose to administer a short course. Intravenous immunoglobulin administration does not alter the clinical course or outcome and is not indicated routinely. With appropriate timely management, most patients who have TRALI recover completely within 96 hours. Delay in management may lead to unnecessarily prolonged hospitalization as well as additional morbidity and mortality. Because anti-HLA antibodies may be implicated in TRALI and because multiparous women often have multiple HLA antibodies, some have recommended that such individuals be screened for HLA antibodies or excluded as donors of fresh frozen plasma and other blood products containing plasma.TRALI is a diagnosis of exclusion and should be considered in all patients who develop acute cardiorespiratory symptoms within 6 hours of blood product transfusion. Clinical criteria, developed by a TRALI consensus panel, serve as a useful diagnostic tool. Timely recognition and prompt supportive management are critical to decreasing mortality. Appropriate reporting and donor management also are critical and may serve to enhance understanding of the pathogenesis of TRALI. (Amir Mian, MD, David Becton, MD, Douglas P. Blackall, MD, University of Arkansas for Medical Sciences, Little Rock, Ark.)The occurrence of listeriosis at an atypical age in the setting of pancytopenia warranted additional investigation. T- and B-lymphocyte enumeration showed CD4 lymphopenia with 4% CD4 cells (normal, 31% to 54%) and an absolute CD4 count of 0.18×109/L (normal, 1 to 4.6×109/L). Results of human immunodeficiency virus (HIV) enzyme immunoassay and HIV DNA polymerase chain reaction (PCR) were negative. Immunoglobulin values and specific antibody titers were within normal limits. A bone marrow aspiration and biopsy revealed hypocellularity with an increased number of histiocytes demonstrating hemophagocytosis, but there were no blast cells, dysplasia, or fibrosis.Hemophagocytic lymphohistiocytosis was considered, but several key diagnostic features such as splenomegaly, hypofibrinogenemia, and hypertriglyceridemia were absent. Investigation into possible viral causes detected Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) by PCR. The patient was treated supportively with packed red blood cell and platelet transfusions, as well as with granulocyte-colony stimulating factor injections. The IVC was removed after 3 days. He completed a 21-day course of ampicillin and gentamicin. Although he improved clinically, his cell counts failed to improve. Therefore, a repeat bone marrow aspiration and biopsy were performed, which showed aplastic anemia. The patient did not have an HLA-matched bone marrow donor, so he underwent immunosuppressive therapy with cyclosporine and antithymocyte globulin (ATG). He responded well, and a follow-up bone marrow aspiration 1 year later yielded normal results.Listeria monocytogenes is a facultatively anaerobic gram-positive bacillus that most commonly causes illnesses in infants younger than 2 months of age, pregnant women, the elderly, and persons who have impaired cell-mediated immunity. Bacteremia and meningitis are the two most common invasive infections caused by Listeria. In contrast to other forms of bacterial meningitis, Listeria infection may involve the brain parenchyma and has been associated with encephalitis and brain abscesses. Listeria also causes a self-limited febrile gastroenteritis. Foods such as soft cheeses, deli meats, raw vegetables, unpasteurized milk, and poultry are common sources of Listeria.Gastrointestinal Listeria infections do not require treatment, but ampicillin is the antibiotic of choice for invasive listeriosis. Gentamicin may be added for synergistic effect. Trimethoprim-sulfamethoxazole is an alternative for penicillin-allergic patients. CNS infections should be treated for at least 21 days; bacteremia without meningitis may be treated with a shorter course.Aplastic anemia (AA) is defined as pancytopenia that has an underlying hypocellular bone marrow. Its annual incidence is estimated to be 2 to 4 cases per 1 million, with a peak in adolescents, young adults, and the elderly. AA has inherited, acquired, and idiopathic forms. Examples of inherited AA forms are Fanconi anemia and Shwachman-Diamond syndrome. Acquired AA may be due to irradiation, drugs (nonsteroidal anti-inflammatory drugs, cancer chemotherapeutic agents, chloramphenicol, psychotropic agents), chemical toxins (benzene), viruses (EBV, HHV-6, cytomegalovirus, herpes simplex virus, parvovirus, HIV, hepatitis virus), immune dysfunction (hypogammaglobulinemia, graft versus host disease, defects in cell-mediated immunity), and pregnancy. Myelodysplastic syndromes, malignancy, and other infections (babesiosis, ehrlichiosis, and tuberculosis) must be differentiated from AA as causes of pancytopenia and hypocellular bone marrow.The most common presentations of AA are symptoms related to low peripheral blood cell counts. Thrombocytopenia may present with easy bruising, petechiae, gingival bleeding, and epistaxis. Anemia may cause fatigue, lightheadedness, and dyspnea on exertion. Neutropenia presents with several bacterial or fungal infections.AA occasionally may be associated with a hemophagocytic syndrome, usually of viral origin, which was the case in this patient. Hemophagocytosis results when erythrocytes, leukocytes, platelets, and their precursors undergo phagocytosis by macrophages in the bone marrow, a process that is believed to be mediated by overproduction of cytokines. (1) Hemophagocytic syndromes cause pancytopenia, which develops during the convalescent phase of many viral infections, most commonly with the herpesviruses, but also with parvovirus and HIV. Hemophagocytosis also can be caused by bacterial, parasitic, and fungal infections.Clues in the history, physical examination, and laboratory data may point toward AA, but the diagnosis cannot be made without examination of the bone marrow and the finding of hypocellularity. After being diagnosed, AA should be considered a medical emergency, due to the potential complications of pancytopenia. Definitive treatment is with allogeneic hematopoietic stem cell transplantation, ideally from an HLA-matched sibling donor. Immunosuppressive therapy with cyclosporine or ATG is the treatment of choice if transplantation is not an option. Management also consists of correcting any significant cytopenias. Opportunistic infections should be treated aggressively, and prophylaxis should be provided until leukopenia resolves.The prognosis of AA is correlated directly with the severity of blood cell count depression at presentation, especially the degree of neutropenia. Untreated severe AA almost invariably is fatal, whereas more moderate AA has a very good long-term survival if treated. Some mild forms of AA are self-limited and do not require treatment.In the pediatric population, listeriosis after 2 months of age is unusual and should raise suspicion for an underlying deficiency in cell-mediated immunity. AA occasionally can be a cause of such an immunodeficiency due to profound leukopenia. In the setting of pancytopenia, bone marrow aspiration is necessary to distinguish among AA, hemophagocytic syndrome, malignancy, myelodysplastic syndromes, and viral suppression. If AA of any cause is found, definitive treatment with allogeneic stem cell transplantation should be undertaken as soon as possible. Immunosuppressive therapy is needed if a matching family or unrelated donor is not available. (Scott H. James, MD, University of Alabama at Birmingham, Birmingham, Ala; David M. Berman, DO, All Children's Hospital, St. Petersburg, Fla.)Contrast-enhanced CT scan of the abdomen (FigureF1) revealed a 5.7×7.2-cm peripherally enhancing, low-density lesion in the posterior right hepatic lobe, which was most suggestive of hepatic abscess. The differential diagnosis includes pyogenic and amebic liver abscesses (ALA). Distinguishing between them is critical because the treatment and prognosis differ. The microbiology of pyogenic abscesses is highly variable because infection can occur by hematogenous seeding or by contiguous spread from an intra-abdominal source. Leading causative organisms include Staphylococcus aureus, Salmonella, Klebsiella pneumoniae, Escherichia coli, and anaerobes. Among the other unusual pathogens are Bartonella henselae, Nocardia asteroides, Yersinia pseudotuberculosis, and Y enterocolitica. Nonpyogenic liver abscesses are rare in developed countries. Organisms causing nonpyogenic liver abscesses include amoeba, mycobacteria, Echinococcus, and fungi.The patient was admitted to the pediatric infectious disease service and was started on intravenous metronidazole, clindamycin, and ceftriaxone to treat both amebic and pyogenic infection. Percutaneous drainage of the abscess under fluoroscopy and ultrasonographic guidance was carried out for diagnostic purposes. Culture of abscess fluid was negative for bacteria and fungi. Serologic testing for Entamoeba histolytica antibodies was strongly positive (immunoglobulin G, 7.32; normal, <0.9). On the third day of hospitalization, the boy became afebrile and improved clinically. A repeat abdominal CT scan on day 6 of hospitalization showed significant decrease in the size of the abscess cavity. He received a 7-day course of intravenous metronidazole and was discharged to complete a 20-day course of iodoquinol at home. Although this patient had not traveled, he may have acquired this amebic infection from a family member who visited him from Mexico several months prior to presentation.Amebiasis, caused by the intestinal protozoal parasite Entamoeba histolytica, remains a global health problem, infecting about 50 million people and resulting in 40,000 to 100,000 deaths per year. The prevalence may be as high as 50% in tropical and subtropical countries where overcrowding and poor sanitation are common. In the United States, E histolytica infection is seen most commonly in immigrants from developing countries, long-term travelers to endemic areas (most frequently Mexico or Southeast Asia), institutionalized individuals, and men who have sex with men. In 1993, the previously known species E histolytica was reclassified into two genetically and biochemically distinct but morphologically identical species: the pathogenic E histolytica and the nonpathogenic commensal E dispar.E histolytica is transmitted via the fecal-oral route. The ingested amebic cysts are resistant to gastric acid and undergo excystation in the small intestine, releasing mobile trophozoites that infect the colon. The trophozoites adhere to the colonic epithelium, where pathogenic strains produce ulcerative lesions, resulting in colitis. Asymptomatic cyst excreters can transmit infection for years if left untreated. Extraintestinal disease results when trophozoites breach the colonic mucosal barrier and enter the portal circulation. The organ affected most commonly is the liver, although cases of lung, brain, and skin involvement have been reported. The abscess usually is solitary, and the right lobe of the liver is affected most commonly (80%), a finding attributed to the right lobe receiving most of the blood draining from the cecum and ascending colon.Most patients who have ALA present acutely (<10 days in duration) with fever, right upper quadrant abdominal pain, and weight loss. In general, amebic colitis precedes the development of ALA, but only 30% of patients report concurrent active dysentery. Hepatomegaly and weight loss often are encountered in patients who have a chronic illness (2 to 12 weeks in duration). Jaundice is unusual but may occur in patients who have severe disease and multiple abscesses. Cough may be present, and pulmonary examination may reveal dullness and rales in the right lung base. Approximately 4% to 9% of patients who have ALA may present with referred shoulder pain, which is related to involvement of the diaphragmatic surface of the liver. In neonates, ALA has a rapidly progressing course, mimicking neonatal sepsis.Laboratory abnormalities noted in patients afflicted with ALA include leukocytosis without eosinophilia, anemia, an elevated alkaline phosphatase, and minimal elevations in serum bilirubin and transaminase. Currently, serum antibody detection using indirect hemagglutination assay is the most useful diagnostic test for ALA and is positive in 95% to 99% of cases. It is unusual to find trophozoites in liver abscess aspirate. Stool microscopy usually is negative for E histolytica trophozoites or cysts. Molecular methods (using PCR) are the most sensitive for identifying and differentiating Entamoeba sp in stool. Chest radiography may reveal an elevated right hemidiaphragm and right-sided pleural effusion. Both ultrasonography and CT scan are sensitive in the detection of ALA, but ultrasonography is the preferred method due to its low cost, availability, and lack of adverse effects.Medical therapy with a 7- to 10-day course of intravenous or oral metronidazole alone can cure invasive disease in more than 95% of cases. Metronidazole is effective for elimination of both intestinal and extraintestinal infection. Percutaneous drainage is considered for large abscesses (>5 cm) to prevent spontaneous rupture, left-lobe abscesses that may rupture into the pericardial space, and failure to respond to medical therapy within 5 to 7 days. The need for open surgical drainage is rare. Following a course of metronidazole, patients should receive treatment with iodoquinol, paromomycin, or diloxanide furoate to treat the luminal carrier state. Serial radiographic studies indicate that ALA usually resolves within 6 months of treatment. Antimotility agents and corticosteroids can worsen symptoms of amebiasis and, therefore, are not recommended.Control measures for amebiasis include maintaining hand hygiene and good sanitation. Research is ongoing toward development of a vaccine against amebae. Oral and DNA-based vaccines have been tested successfully in animal models for immunogenicity and efficacy. Additional research is needed to determine the efficacy of the vaccine in humans.In developed nations where amebiasis is rare, failure to consider the infection may delay diagnosis. Hepatic amebiasis may be encountered in immigrants from resource-limited countries even if they have no history of recent travel. ALA may be the first manifestation of amebiasis without any preceding diarrheal illness. The diagnosis should be considered if aspirated material does not show bacteria and serologic testing for E histolytica is positive. Treatment with metronidazole alone may be curative in 95% of those who have ALA. (James A. Owusu, Charles Turner, MD, Laurence B. Givner, MD, Avinash K. Shetty, MD, Wake Forest University Health Sciences and Brenner Children's Hospital, Winston-Salem, NC)

Abstract Abstract 1406 Poster Board I-428 Introduction: 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. Methods: 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. Results: 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. Conclusion: 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. Disclosures: Mian: Arkansas Children's Hospital Research Institute (ACHRI), Little Rock, Arkansas. : Research Funding.

PURPOSE:There is considerable variation in the use of HLA-matched related bone marrow transplantation (BMT) for the treatment of pediatric patients with newly diagnosed acute myeloid leukemia (AML). Some oncologists have argued that BMT should be offered to most patients in first complete remission (CR). Others have maintained that transplantation in first remission should be reserved for patients with high-risk disease. We performed this study to determine how disease risk influences the efficacy of BMT.METHODS:We combined data from four cooperative group clinical trials: Pediatric Oncology Group 8821, Children's Cancer Group (CCG) 2891, CCG 2961, and Medical Research Council 10. Using cytogenetics and the percentage of marrow blasts after the first course of chemotherapy, patients were stratified into favorable, intermediate, and poor-risk disease groups. Patients who could not be risk classified were analyzed separately. Outcomes for patients assigned to BMT and for patients assigned to chemotherapy alone were compared.RESULTS:The data set included 1,373 pediatric patients with AML in first CR. In the intermediate-risk group, the estimated disease-free survival at 8 years for patients who did not undergo transplantation was 39% +/- 5% (2 SE), whereas it was 58% +/- 7% for BMT patients. The estimated overall survival for patients who did not undergo transplantation was 51% +/- 5%, whereas it was 62% +/- 7% for BMT patients. Both differences were significant (P < .01). There were no significant differences for survival in the other two risk groups or in the non-risk-stratified patients.CONCLUSION:Our study indicates that HLA-matched related BMT is an effective treatment for pediatric patients with intermediate-risk AML in first CR.

PURPOSE:To determine the outcomes, with particular attention to toxicity, of children with Down syndrome (DS) and acute myeloid leukemia (AML) treated on Pediatric Oncology Group (POG) protocol 9421.PATIENTS AND METHODS:Children with DS and newly diagnosed AML (n = 57) were prospectively enrolled onto the standard-therapy arm of POG 9421 and were administered five cycles of chemotherapy, which included daunorubicin 135 mg/m(2) and mitoxantrone 80 mg/m(2). Outcomes and toxicity were evaluated prospectively and were compared with the non-DS-AML cohort (n = 565). A retrospective chart review was performed to identify adverse cardiac events.RESULTS:In the DS-AML group, 54 patients (94.7%) entered remission. One experienced induction failure and two died. Of the 54 who entered remission, three relapsed and six died as a result of other causes. The remission induction rate was similar in the non-DS-French-American-British (FAB) M7 (91.7%) and non-DS-non-M7 (89.3%) groups. The 5-year overall survival was significantly better in the DS-AML group (78.6%) than in the non-DS-M7 (36.3%) or the non-DS-non-M7 (51.8%) groups (P < .001). No age-related difference in 5-year, event-free survival was seen between patients younger than 2 years (75.8%) and those aged 2 to 4 years (78.3%). Symptomatic cardiomyopathy developed in 10 patients (17.5%) with DS-AML during or soon after completion of treatment; three died as a result of congestive heart failure.CONCLUSION:The POG 9421 treatment regimen was highly effective in both remission induction and disease-free survival for patients with DS-AML. However, there was a high incidence of cardiomyopathy, which supports current strategies for dose reduction of anthracyclines in this patient population.

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 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.