ALBERT

Description: Background. Pediatric patients with newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk for developing bacterial infections, particularly during the induction treatment phase. Infections are the primary cause of treatment-related mortality during the induction phase, and also lead to prolonged hospitalization, as well as delays and dose modifications in planned chemotherapy. On DFCI ALL Consortium Protocol 05-001 (2005-2011), 26.6% of 794 enrolled patients (pts) experienced at least one infectious complication during induction. In the subsequent study, DFCI Protocol11-001, we studied whether the use of prophylactic fluoroquinolones during induction would decrease the incidence of bacterial infections. Patients and methods.Between 2012-2015, 229 pts with ALL (aged 1-21 years) were enrolled on Protocol 11-001 at 9 participating sites. Induction therapy, regardless of risk group, included vincristine, methylprednisolone, doxorubicin, low-dose methotrexate and pegylated L-asparaginase. Afebrile pts were started on fluoroquinolone prophylaxis at the time of initiation of therapy and continued until count recovery at the end of induction. Pts were switched to broad-spectrum antibiotics (eg, cefepime) for fever or documented infection. Pts with fever at presentation were started on broad spectrum antibiotics rather than fluoroquinolone, and either remained on broad-spectrum antibiotics or were switched to fluoroquinolone prophylaxis until count recovery per treating clinician. Antifungal prophylaxis was not required. All episodes of microbiologically documented bacterial infection, microbiologically and/or radiographically documented fungal infection, and Clostridium difficile (C. diff) enterocolitis were prospectively collected. Using a 1-sample binomial test, rates of infections on Protocol 11-001 were compared to those from the predecessor study, DFCI Protocol 05-001, which included nearly identical induction chemotherapy but did not include guidelines regarding antibiotic prophylaxis or duration during induction. Results. Of the 229 pts, 89% had B-ALL and 11% T-ALL. Median age was 5.1 yrs (range 1.0-20.9). Eighty-six afebrile pts (37.5%) were administered upfront antibiotic prophylaxis and 141 (61.6%) had fever at diagnosis and received broad-spectrum antibiotics; two afebrile patients did not receive antibiotic prophylaxis for unknown reasons. Of the 86 pts who began prophylaxis, 37 (43%) subsequently developed fever. Toxicity data was available for 222 pts. Thirty-eight episodes of infection occurred in 29 patients. Age, presenting white blood cell count and immunophenotype were not associated with the development of infection. The proportion of pts experiencing an infection on Protocol 11-001 (13.1%) was significantly lower than on Protocol 05-001 (26.6%, p

Description: Current treatment regimens for childhood ALL have resulted in long-term event-free survival (EFS) of approximately 80%. On DFCI ALL Consortium Protocol 05-001, patients (pts) with newly diagnosed ALL aged 1-18 years (yrs) who achieved complete remission (CR) were eligible to participate in a randomized comparison of native E.coli asparaginase (ASP) given intramuscularly (IM) and PEG ASP, the polyethylene glycol conjugate of E.coli ASP, given intravenously (IV). The objective was to compare the serum ASP activity (SAA), toxicity, and EFS of the two ASP preparations. An intensified consolidation regimen for VHR pts, including B-ALL pts with high end-induction minimal residual disease (MRD), was also evaluated. Methods All pts received 1 dose of PEG ASP (2500 IU/m2) during the 4-week (wk) multiagent induction phase. After CR was achieved, final risk group was assigned based on age, presenting WBC, CNS status, cytogenetics and end-induction MRD (assessed by PCR). All T-ALL pts were considered HR. Pts were considered VHR if they met one of the following criteria: i) B-ALL with high end-induction MRD; or ii) adverse cytogenetics (MLL gene rearrangement or hypodiploidy). BCR-ABL positive pts began daily imatinib at Day 18 and were allocated to allogeneic transplant in 1st CR. Beginning at wk 7, pts began the consolidation phase including 30 wks of ASP, either IM E.coli ASP 25000 IU/m2 weekly or IV PEG 2500 IU/m2 every 2 wks. In addition, SR pts received every 3-wk cycles with vincristine, dexamethasone, 6MP and low-dose methotrexate (mtx) during consolidation; HR pts received doxorubicin (cumulative dose 300 mg/m2) with dexrazoxane instead of mtx during this phase. VHR pts received 2 additional cycles beginning at week 7 (cyclophosphamide/low-dose araC/6-MP and then high-dose araC/etoposide/dexamethasone), followed by the HR consolidation phase. Continuation phase was identical for all pts. Total duration of therapy was 25 months. Serum samples were obtained every 6 wks just prior to an ASP dose to measure SAA. EFS rates were calculated from date of registration, except for EFS by randomized arm, risk group, and end-induction MRD, which were calculated from time of randomization. Results Between 2005-2010, 551 evaluable pts enrolled, of whom 526 (95%) achieved CR. 463 pts participated in the ASP randomization. Median nadir SAA was significantly higher with IV PEG than with IM E.coli ASP,(Table 1) with more IV PEG-randomized pts achieving nadir SAA ≥ 0.1 IU/mL (p

Description: Background: Risk-adapted treatment strategies have contributed to excellent outcomes in pediatric acute lymphoblastic leukemia (ALL); however, treatment-associated acute and long-term toxicities persist. Therapy-associated toxicities of note in pediatric ALL are related to a treatment backbone that relies heavily on corticosteroids (prednisone and dexamethasone) and asparaginase (ASP). The most frequently observed toxicities include, but are not limited to, serious infection, pancreatitis, thrombosis and bony morbidities including osteonecrosis (ON) and fracture. Previous studies suggest that children of racial and ethnic minorities are at higher risk for treatment-associated toxicities. We assessed the incidence of treatment-related toxicities in Hispanic and non-Hispanic patients undergoing treatment for pediatric ALL. Patients and Methods: Retrospective cohort study investigating the incidence of treatment-related toxicities including infection, allergy to ASP, pancreatitis, thrombosis and bony morbidities in Hispanic and non-Hispanic children and adolescents with newly diagnosed ALL undergoing therapy on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. The ethnicity of each patient was designated at the time of study enrollment by research coordinators. Descriptive statistics were calculated, mean +/- SD for continuous variables and frequency and percentages for categorical variables. Toxicity rates were based on number of patients. Comparison between groups was done by Chi-square test or FisherÕs exact test and p -value 〈 0.05 was considered significant. Results: Between 2005 and 2011, 794 children and adolescents (ages 1 - 18 years) were enrolled on Protocol 05-001, 730 of whom were evaluable for this investigation: 150 Hispanic (18%), 580 non-Hispanic (73%). Sixty-four patients did not have ethnicity documented. There was no significant difference in disease-risk group, age or gender between the two groups. Weight was significantly higher in Hispanic patients (31.9 ± 24.4 kg in Hispanic and 26.9 ± 18.7 kg in non-Hispanic, p = 0.021). There was no significant difference in the incidence of ASP-related toxicities (allergy, pancreatitis, thrombosis) between Hispanic and non-Hispanic patients. There was no significant difference in the overall incidence of infection between the two groups (42% in Hispanic and 50% in non-Hispanic, p = 0.081). Non-Hispanic patients had significantly higher rates of opportunistic infection (Pneumocystis pneumonia) than Hispanic patients (0.7% in Hispanic and 4% in non-Hispanic, p = 0.041). A similar difference in the incidence of bacteremia between the two groups approached, but did not reach statistical significance (p = 0.052). The overall incidence of fracture in all patients was 14.5% and was significantly higher in non-Hispanic patients (6% in Hispanic and 16.7% in non-Hispanic, p 〈 0.001). The overall incidence of ON was 8.9% and was significantly higher in non-Hispanic patients (3.3% in Hispanic and 10.3% in non-Hispanic, p = 0.007). (Table 1) Conclusion: The incidence of opportunistic infections and bony morbidities was significantly higher in non-Hispanic patients undergoing treatment for pediatric ALL on the DFCI ALL Consortium Protocol 05-001. The risk for, and impact of therapy-related toxicities varies by a patientÕs treatment tolerance, perhaps as a function of age and gender or as a result of disease biology or genetic polymorphisms affecting drug metabolism. Additionally, non-biologic factors such as medication adherence and nutritional status may also contribute to toxicity incidence in patients undergoing treatment for pediatric ALL. Prospective studies to further investigate our findings are warranted. Table. All Patients, (N = 730) Non-Hispanic, (N = 580) Hispanic, (N = 150) p -value Overall Infection 353/730 (48.4%) 290/580 (50%) 63/150 (42%) 0.081 Bacteremia 289/730 (39.6%) 240/580 (41.4%) 49/150 (9.3%) 0.052 Opportunistic Infection 24/730 (3.3%) 23/580 (4%) 1/150 (0.7%) 0.041 Fracture 106/730 (14.5%) 97/580 (16.7%) 9/150 (6%)

Description: Background. Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a diverse spectrum of chromosomal rearrangements resulting in novel chimeric fusions associated with poor prognosis when treated with conventional chemotherapy. These fusions are observed more frequently in NCI High-Risk (HR) B-ALL compared with NCI Standard Risk (SR) patients. They often activate ABL and JAK-STAT signaling pathways and have demonstrated sensitivity to the relevant tyrosine kinase inhibitors (TKIs) in in vitro assays and ex vivomodels. The objective of this study was to determine the frequency of NCI HR B-ALL patients enrolled on DFCI ALL Consortium Protocol 05-001 with a kinase-activating fusion that would be amenable to TKI therapy and to describe their associated clinical characteristics and outcomes. Methods. Between 2005-2011, 219 NCI HR, Philadelphia chromosome (Ph)-negative, B-ALL patients were enrolled on DFCI ALL Consortium Protocol 05-001, 105 of whom had sufficient material to undergo kinase fusion testing by validated multiplex reverse transcription polymerase chain reaction (RT-PCR) assays. A total of 35 kinase fusions of ABL-class (ABL1, ABL2, PDGFRB, CSF1R), JAK2 and CRLF2 rearrangements were examined. IGH@-CRLF2 and EPOR rearrangements were not assessed. Fusion products were predicted by NCBI BLAST algorithms, confirmed by singleplex PCR and Sanger sequencing and aligned using CLC Main Workbench Version 7.6.1. IKZF1 deletion (del) status had previously been assessed by multiplex ligation-dependent probe amplification (MLPA). Fisher's exact test and the Wilcoxon rank sum test were used to compare patient characteristics to those with and without any identified fusion for categorical and continuous variables respectively. Event-free survival (EFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared using a log rank test. Univariate and multivariable Cox proportional hazards models of EFS were constructed. Results. Among 105 NCI HR, Ph-negative, B-ALL patients, 16 (15%) were found to harbor an ABL-class fusion (ETV6-ABL1: n=1; FOXP1-ABL1: n=1; SFPQ-ABL1: n=1; ZC3HAV1-ABL2: n=1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n=8; PAX5-JAK2: n=4). Sixty-nine percent of patients with an identified fusion (Fusion +) had a concomitant IKZF1 del (n=11). Features associated with fusion-positivity were age of 10 years or older (p=0.003), male sex (p=0.03), Hispanic ethnicity (p=0.01) and IKZF1 del (p=0.0005) (Table 1). Fifty percent of Fusion+ patients experienced an event (induction death (n=1); induction failure (n=1); or relapse (n=6)) compared to 24% of patients without a fusion. The 5-year EFS and OS were 48% (95% CI 22-70%) and 68% (95% CI 39-85%) for Fusion+ patients compared to 78% (95% CI 67-85%) and 88% (95% CI 79-93%) for those without fusions (Figure 1). In univariate analysis, fusion-positivity (HR: 2.66, p=0.02) and IKZF1 del (HR: 3.21; p=0.0018) were each significantly associated with inferior EFS, while age and presenting leukocyte count were not. In multivariable analysis, IKZF1 del, but not fusion-positivity, retained statistical significance (HR: 2.64, p=0.02). Conclusion. Fifteen percent of NCI HR, Ph-negative, B-ALL patients enrolled on DFCI ALL Consortium 05-001 were found to have a kinase-activating fusion. Fusion+ patients frequently harbored concomitant IKZF1 deletion and had an inferior outcome. Future studies should focus on developing clinical strategies to rapidly identify these patients at diagnosis and to test whether the addition of the relevant TKIs to their treatment will improve their outcome. Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Loh:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.

Description: Background: E.coli L-asparaginase (L-ASP) is an important component of treatment for childhood acute lymphoblastic leukemia (ALL), but the optimal preparation and dosing remain to be determined. Pegaspargase (SS-PEG) is a pegylated L-ASP formulation commonly used in frontline therapy. Calaspargase pegol (SC-PEG) is a novel formulation that uses the same ASP enzyme and PEG moiety as SS-PEG but a different linker molecule that is more hydrolytically stable, leading to a longer half-life. On Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols, patients (pts) typically receive a single dose SS-PEG during induction, and then 15 doses every 2-weeks (wks) during post-induction in order to maintain therapeutic serum asparaginase activity (SAA), defined as ≥ 0.1 IU/mL, for 30 consecutive wks. We hypothesized that SC-PEG could be administered less frequently than SS-PEG during post-induction therapy with a similar SAA and toxicity profile. Methods: Between 2012-2015, pts aged 1-21 years with newly diagnosed ALL or lymphoblastic lymphoma (LL) were eligible to enroll on DFCI ALL Consortium Protocol 11-001. Pts were randomized at study entry to receive either SS-PEG (N=120) or SC-PEG (N=119), each given intravenously (IV) at a dose of 2500 IU/m2. Both groups received a single dose during multi-agent remission induction. Post-induction, pts assigned to SS-PEG received 15 doses every 2-wks and those assigned to SC-PEG received 10 doses every 3-wks along with other risk-stratified chemotherapy. Serum samples were obtained 4, 11, 18 and 25 days after the induction dose to determine SAA and prior to each post-induction dose (2 wks after each SS-PEG and 3 wks after each SC-PEG dose) to determine nadir SAA (NSAA) by a validated biochemical assay. Pts were switched to Erwinia asparaginase for Grade 2 or higher allergy or for silent inactivation (defined as 2 consecutive non-detectable NSAA). Asparaginase was permanently discontinued for pancreatitis and held for thrombosis (but re-started once the clot improved). End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCRPCR assay, with low MRD defined as 〈 0.001. Results: 239 eligible pts were enrolled (230 ALL and 9 LL). There were no significant differences in presenting characteristics between randomized arms. SAA during induction and NSAA during post-induction are displayed in Figure 1. SAA was similar for the two preparations at 4, 11 and 18 days after the induction dose, with SAA ≥ 0.1 IU/mL in ≥ 95% of pts at these time points on both arms. 25 days after the induction dose, SAA was higher with SC-PEG (median 0.298 IU/mL vs 0.056 for SS-PEG), with significantly more pts on SC-PEG arm with SAA ≥ 0.1 IU/mL (88% vs 15%, p

Description: Background: Despite outstanding cure rates of pediatric acute lymphoblastic leukemia (ALL), Blacks and Hispanics have inferior survival than Whites. We recently reported that among 794 children from DFCI ALL Consortium Protocol 05-001 trial, Hispanic patients had significantly lower rates of fracture and osteonecrosis, but higher risk of relapse and death compared with non-Hispanic Whites (PMID: 29090520). Studies from other groups have reported inferior ALL outcomes in children with Native American ancestry, however the association between genetic ancestry and skeletal toxicities has not been explored. We examined whether genetic inheritance could provide an explanation for the reduced incidence of skeletal toxicities in Hispanic patients in DFCI 05-001. Methods: A total of 576 DNA samples extracted from bone marrow samples or blood samples obtained during remission, including 2% blind duplicates, were genotyped using the Illumina OmniExpress Beadchip array. After data QC and cleaning, 449 ALL patients were retained in the final analysis. Estimates of global genetic ancestry were derived from STRUCTURE program, which was used to re-classify individuals with discordant clinical race/ethnicity as reported by study site, and to assign individuals with unknown race/ethnicity information to an ethnic group when possible. Regression model for the subdistribution hazard of the cumulative incidence function was used to relate clinical race/ethnicity, genetically reclassified race/ethnicity, and genetic ancestry respectively with risk of fracture and osteonecrosis, with death and recurrence as competing risk factors while controlling for age, gender and baseline clinical factors. Cox proportional regression models were used to test race/ethnicity and ancestry with overall survival (OS) and event-free survival (EFS). Results: Among the 449 patients analyzed, average age was 6.7 years; 26% of patients were ≥10 years and 44% were female. The demographic and clinical characteristics of patients with genotype data were similar to those of the overall cohort, although the proportion of Hispanics was slightly lower in the genotyped sub-cohort (17% vs. 21%), whereas the rates of fracture and osteonecrosis were higher (fracture: 25% vs. 18%; osteonecrosis: 10% vs. 8%). Based on clinical race/ethnicity, 66% of patients were non-Hispanic White, 17% were Hispanic, 5% were non-Hispanic Black, 3% were Asian, and 10% were reported as Other. Genetic ancestry analyses revealed that non-Hispanic White patients had a median of 96% European ancestry, non-Hispanic Black patients had a median of 76% African ancestry, and Asian patients had a median of 58% Asian ancestry. The genetic make-up of Hispanic patients in the 05-001 cohort was more admixed, with 23% Native American and 17% African ancestry, higher than the national average (18% and 6%, respectively). After genetic reassignment, racial/ethnic groups were as follows: 68% non-Hispanic White, 17% Hispanic, 9% non-Hispanic Black, 6% Asian, and 1% unassigned. In analysis of genetically reassigned race/ethnicity with skeletal toxicities, Hispanic and Black patients had significantly lower risk of fracture compared with white patients (Hispanic: subdistribution hazard ratio [SHR]=0.42, 95% confidence interval [CI]=0.22, 0.81; Black: HR=0.28, 95%CI=0.10, 0.75). These groups also had significantly less osteonecrosis (Hispanic: SHR=0.24, 95%CI=0.08, 0.78; Black: SHR=0.12, 95%CI=0.02, 0.93). Similar results were observed when using clinical race/ethnicity. Further analyses revealed that African genetic ancestry, but not Native American ancestry was associated with lower risk of fracture and osteonecrosis in a dose-dependent manner (Table 1). In analysis of death and recurrence, those with higher proportion of Native American ancestry had significantly higher risk of death/recurrence after adjustment (OS: hazard ratio [HR]=4.00, 95%CI=1.45, 11.02; EFS: HR=2.07, 95%CI=1.13, 3.79). Analysis of single variants and polygenic risk scores with skeletal toxicities and survival outcomes is ongoing. Conclusion: Hispanic children and adolescents from the DFCI 05-001 cohort, had highly heterogenous genetic ancestral make-up. Among Hispanic patients, the observed lower risk of skeletal toxicities might be driven by African ancestry, whereas poorer survival observed might be driven by Native American ancestry. Disclosures Silverman: Servier: Consultancy, Research Funding; Takeda: Consultancy.

Description: Background Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are shown to have increased therapy-related morbidity and mortality. Hence, therapy modifications and/or dose-reductions are common treatment strategies for this patient (pt) population. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for children with and without DS and ALL. Aim: To define the toxicity profile and outcome of children with DS and de novo ALL treated on DFCI ALL Consortium therapy protocols 00-001 and 05-001 using therapy identical to non-DS patients. Methods: Demographic, clinical and outcome data of DS and non-DS patients enrolled on the DFCI ALL protocols 00-001 (2000-2004) and 05-001 (2005-2011) were analyzed. Risk categorization and protocol therapy have previously been described (J Clin Oncol 2013; 31:1202-10; Lancet Oncol 2015;16:1677-90). On both protocols, DS ALL pts were treated identically to non-DS pts without any dose reduction or modification, except for the option for DS ALL pts to receive 3 doses of leucovorin after IT methotrexate. Fisher's exact test was used to compare toxicities in the DS and non-DS pts and Gray test was used to compare the cumulative incidence of fracture and osteonecrosis. Overall survival (OS) was defined as time from registration to death. Event-free survival (EFS) was defined as time from registration to first event (defined as induction failure, relapse, second malignant neoplasm (SMN) or death due to any cause). Induction failure and induction death were included as events at time zero. Disease-free survival (DFS) was defined as time from complete remission (CR) to relapse, SMN or death. Pts without an event were censored at the last known follow-up. The Kaplan-Meier method was used for survival estimation and Greenwood's formula for calculation of 95% confidence interval (CI) of survival estimates. Outcome of DS patients was also examined using Ponte di Legno (PdL) risk group [Low risk (LR) was defined as age at diagnosis ≤ 6 yr. and white cell count 〈 10X109/L and, remainder as high risk (HR)].(Blood 2014;123:70-7). Two-sided p values

Description: Background: Deletions in the Ikaros gene (IKZF1) have been associated with a poor outcome in pediatric B-ALL, but the interaction of IKZF1 deletions with other established prognostic factors, such as minimal residual disease (MRD), is still under investigation. Here we report the IKZF1 deletion status of 405 patients (pts) with acute lymphoblastic leukemia (ALL) and its association with other presenting features, end-induction MRD, and outcome. Methods: Between 2005-2011, 794 eligible pts (aged 1-18 yrs) with newly diagnosed pediatric ALL (B-ALL: 697; T-ALL: 97) were enrolled on DFCI ALL Consortium Protocol 05-001. End-induction MRD was assessed prospectively on all pts by allele-specific oligonucleotide-PCR assay. DNA was extracted from archived diagnostic blood or bone marrow samples from 399 B-ALL and 6 T-ALL pts with sufficient available material. Using a commercially available kit (SALSA MLPA P202 IKZF1, MRC-Holland), IKZF1 deletion status was assessed by multiplex ligation-dependent probe amplification (MLPA). Event free survival (EFS) and relapse free survival (RFS) were estimated using the method of Kaplan and Meier. Results: IKZF1 deletion was detected in 69 (17%) of the 405 evaluated pts. IKZF1 deletion was more common in pts over 10 years old (p

Description: Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal hematologic syndrome characterized by hyperinflammation due to uncontrolled proliferation of activated lymphocytes, resulting in prolonged fever, pancytopenia, jaundice, and hepatosplenomegaly. While infection with Epstein Barr virus (EBV) is the most common recognized cause of infection-triggered HLH, there have been cases associated with other viral infections including dengue. Dengue is an acute febrile illness that is caused by any of four related but serologically distinct, mosquito-borne dengue viruses (DENV-1–4) that are endemic throughout the tropics and subtropics including Puerto Rico, a territory of the United States. Dengue can lead to a wide range of clinical outcomes, ranging from no symptoms or mild fever to potentially fatal severe dengue. In Puerto Rico, dengue most commonly affects adolescents 10–19 years old. Dengue-associated HLH (dengue-HLH) has been described in 26 case reports since 1966, but has not been previously recognized in Puerto Rico. During the start of a dengue epidemic in December 2012, the Centers for Disease Control and Prevention Dengue Branch were notified of several dengue-HLH cases at four hospitals in Puerto Rico. An investigation was conducted to: 1) determine the incidence of HLH in children since 2008; and 2) determine the infecting agent(s) associated with HLH cases. Medical records were queried to identify patients with findings compatible with HLH. To date, 681 records have been reviewed and 38 patients identified that met accepted criteria for HLH. The majority (25 patients) of the HLH cases had diagnostic evidence of DENV infection by anti-dengue IgM Enzyme Linked Immunosorbent Assay (36%) and/or DENV Polymerase Chain Reaction (68%): DENV types -1 and -4 were detected. Other causes of HLH identified were EBV and Cytomegalovirus co-infections (2), Herpes Simplex Virus (2), EBV (1), and systemic onset juvenile arthritis (2). There was one fatal dengue-HLH case (case-fatality rate [CFR]: 4.0%). Dengue-HLH cases ranged in age from 0.1–16 years, 48% were infants, and all resided in northern Puerto Rico. Among children aged 0–16 years, the average annual incidence of dengue-HLH cases in Puerto Rico from 2008 through 2011 was 0.1 cases per 100, 000 versus 2.2 cases per 100,000 in the last 12 months from June 1, 2012 to May 31, 2013, which demonstrates the dramatic increase in recent cases. The number of HLH cases may have been higher since in 14 additional cases with suspected HLH who only fullfilled 4 of the required 5/8 diagnostic criteria, laboratory investigations were incomplete. This is an unusual cluster of dengue-HLH cases in time and space afflicting mostly infants and cannot be explained by heredity. Currently there is no explanation for this outbreak of dengue-HLH. Some cases of dengue-HLH may have been overlooked in the past if severe dengue cases were not investigated for the presence of HLH criteria. We are presently conducting a case-control study to identify risk factors for developing dengue-HLH and determine why in contrast to previous experience infants were predominantly affected. Physicians in dengue endemic areas should be made aware that infection with dengue virus may lead to the hyperinflammatory syndrome HLH. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 874 E. coli L-asparaginase (E. coli ASP) is an important component of treatment for childhood ALL, but is associated with multiple toxicities, including allergy, pancreatitis, and thrombosis. It is typically given intramuscularly (IM). Because most pediatric ALL patients have indwelling venous catheters, intravenous (IV) administration of asparaginase would be a more convenient and less painful option than IM injection. PEG-asparaginase (PEG), the polyethylene glycol conjugate of E. coli ASP, has a longer circulating half-life and so may be given less frequently. We have previously demonstrated that a single dose of PEG 2500 IU/m2 given IV is tolerable in children with ALL, with potentially therapeutic serum enzyme activity (≥ 0.1 IU/mL) maintained for at least 18 days in most patients.[Blood 2010;115:1351-3] On DFCI ALL Consortium Protocol 05-01, all patients (pts) with newly diagnosed ALL aged 1–18 years (yrs) who achieved complete remission were eligible to participate in a randomized comparison of IM E. coli ASP and IV PEG during the 30-week (wk) multi-agent post-induction Consolidation phase. Beginning at week 7 of therapy, pts received either IM E. Coli ASP 25000 IU/m2 weekly × 30 wks or IV PEG 2500 IU/m2 every 2 wks × 30 wks. Serum samples were obtained every 6 wks just prior to an ASP dose and were assayed for ASP enzyme activity by a validated biochemical assay. Between 2005–2010, 463 pts were enrolled in the randomized comparison. Median age was 5 yrs (range 1.2–17.9 yrs). There was no significant difference in presenting characteristics between the two arms, except that more pts on the E. coli ASP arm presented with a mediastinal mass (9% vs 3%, p=0.04). Median follow-up was 2.8 years. Median nadir serum ASP activity (NSAA) at each assayed timepoint during the Consolidation phase was significantly higher with IV PEG than with IM E. coli ASP (Table 1). An NSAA of ≥ 0.1 IU/mL was achieved in ≥ 95% of IV PEG pts compared with 〈 50% of IM E. coli ASP pts (p