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Background Intensified therapy with platinum-based regimens for pediatric brain tumors has dramatically increased the number of pediatric brain tumor survivors (PBTS) but frequently causes permanent sensorineural hearing loss (SNHL). Although neurocognitive decline in PBTS is known to be associated with radiation therapy (RT), SNHL represents a potential additional contributor whose long-term impact has yet to be fully determined. Methods The neurocognitive impact of significant SNHL (Chang scale ≥ 2b) in PBTS was assessed through a retrospective cohort study of audiograms and neurocognitive testing. Scores for neurocognitive domains and subtest task performance were analyzed to identify specific strengths and weakness for PBTS with SNHL. Results In a cohort of PBTS (n = 58) treated with platinum therapy, significant SNHL was identified in more than half (55%, n = 32/58), of which the majority required hearing aids (72%, 23/32). RT exposure was approximately evenly divided between those with and without SNHL. PBTS were 6.7 ± 0.6 and 11.3 ± 0.7 years old at diagnosis and neurocognitive testing, respectively. In multivariate analyses adjusted for RT dose, SNHL was independently associated with deficits in intelligence, executive function, and verbal reasoning skills. Subtests revealed PBTS with SNHL to have poor learning efficiency but intact memory and information acquisition. Conclusions SNHL in PBTS increases the risk for severe therapy-related intellectual and neurocognitive deficits. Additional prospective investigation in malignant brain tumors is necessary to validate these findings through integration of audiology and neurocognitive assessments and to identify appropriate strategies for neurocognitive screening and rehabilitation specific to PBTS with and without SNHL.

Obesity is associated with poorer event-free survival (EFS) in pediatric acute lymphoblastic leukemia (ALL). Persistent minimal residual disease (MRD) in the bone marrow as measured by multidimensional flow cytometry (MDF) is a key early prognostic indicator and is strongly associated with EFS. We therefore hypothesized that obesity during induction would be associated with positive end-of-induction MRD (≥0.01%). We analyzed MDF of end-induction bone marrow samples from a historical cohort of 198 children newly diagnosed with B-precursor ALL (BP-ALL) and treated with Children's Oncology Group induction regimens. We assessed the influence of body mass index on risk for positive end-induction MRD in the bone marrow. In our cohort of BP-ALL, 30 children (15.2%) were overweight and 41 (20.7%) were obese at diagnosis. Independent of established predictors of treatment response, obesity during induction was associated with significantly greater risk for persistent MRD (odds ratio, 2.57; 95% confidence interval, 1.19 to 5.54; P = .016). Obesity and overweight were associated with poorer EFS irrespective of end-induction MRD (P = .012). Obese children with newly diagnosed BP-ALL are at increased risk for positive end-induction MRD and poorer EFS.

The rarity of mixed-phenotype acute leukemia (MPAL) has resulted in diffuse literature consisting of small case series, thus precluding a consensus treatment approach. We conducted a meta-analysis and systematic review to investigate the association of treatment type (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], or “hybrid” regimens), disease response, and survival. We searched seven databases from inception through June 2017 without age or language restriction. Included studies reported sufficient treatment detail for de novo MPAL classified according to the well-established European Group for Immunological Characterization of Acute Leukemias (EGIL) or World Health Organization (WHO2008) criteria. Meta-analyses and multivariable analyses of a patient-level compiled case series were performed for the endpoints of complete remission (CR) and overall survival (OS). We identified 97 reports from 33 countries meeting criteria, resulting in 1,499 unique patients with data, of whom 1,351 had sufficient detail for quantitative analysis of the study endpoints. Using either definition of MPAL, meta-analyses revealed that AML induction was less likely to achieve a CR as compared to ALL regimens, (WHO2008 odds ratio [OR] = 0.33, 95% confidence interval [95% CI] 0.18–0.58; EGIL, OR = 0.18, 95% CI 0.08–0.40). Multivariable analysis of the patient-level data supported poorer efficacy for AML induction (versus ALL: OR = 0.45 95% CI 0.27–0.77). Meta-analyses similarly found better OS for those beginning with ALL versus AML therapy (WHO2008 OR = 0.45, 95% CI 0.26–0.77; EGIL, OR = 0.43, 95% CI 0.24–0.78), but multivariable analysis of patient-level data showed only those starting with hybrid therapy fared worse (hazard ratio [HR] = 2.11, 95% CI 1.30–3.43). MPAL definition did not impact trends within each endpoint and were similarly predictive of outcome. Using either definition of MPAL, ALL-therapy is associated with higher initial remission rates for MPAL and is at least equivalent to more intensive AML therapy for long-term survival. Prospective trials are needed to establish a uniform approach to this heterogeneous disease.

While early studies reported superior survival for cancer patients enrolled on clinical trials, recent findings are inconclusive. We investigated the association between enrollment on contemporary trials and event-free survival (EFS) in pediatric B-cell acute lymphoblastic leukemia (B-ALL). In a retrospective cohort of 274 children (1-21 years) treated for B-ALL from 2008 to 2015, 55.5% enrolled with no disparity in enrollment by age, sex, or ethnicity. Three-year EFS was similar for enrolled and not enrolled patients (90.1% [95% CI, 82.5-94.5] versus 86.5% [95% CI, 77.7-92.0]). Clinical trial enrollment did not affect pediatric B-ALL survival, albeit in a limited-size cohort treated at a single academic institution.

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.

Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin. In this study, it is determined whether adipocytes clear daunorubicin from the tumor microenvironment (TME). Intracellular daunorubicin concentrations were evaluated using fluorescence. Daunorubicin and its largely inactive metabolite, daunorubicinol, were analytically measured in media, cells, and tissues using liquid chromatography/mass spectrometry (LC/MS). Expression of daunorubicin-metabolizing enzymes, aldo-keto reductases (AKR1A1, AKR1B1, AKR1C1, AKR1C2, AKR1C3, and AKR7A2) and carbonyl reductases (CBR1, CBR3), in human adipose tissue, were queried using public databases and directly measured by quantitative PCR (qPCR) and immunoblot. Adipose tissue AKR activity was measured by colorimetric assay. Adipocytes absorbed and efficiently metabolized daunorubicin to daunorubicinol, reducing its antileukemia effect in the local microenvironment. Murine studies confirmed adipose tissue conversion of daunorubicin to daunorubicinol in vivo. Adipocytes expressed high levels of AKR and CBR isoenzymes that deactivate anthracyclines. Indeed, adipocyte protein levels of AKR1C1, AKR1C2, and AKR1C3 are higher than all other human noncancerous cell types. To our knowledge, this is the first demonstration that adipocytes metabolize and inactivate a therapeutic drug. Adipocyte-mediated daunorubicin metabolism reduces active drug concentration in the TME. These results could be clinically important for adipocyte-rich cancer microenvironments such as omentum, breast, and marrow. As AKR and CBR enzymes metabolize several drugs, and can be expressed at higher levels in obese individuals, this proof-of-principle finding has important implications across many diseases. Implications: Adipocyte absorption and metabolism of chemotherapies can reduce cytotoxicity in cancer microenvironments, potentially contributing to poorer survival outcomes. Mol Cancer Res; 15(12); 1704–13. ©2017 AACR.

Objectives Diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) requires immunophenotypic evidence of B-lineage and absence of specific myeloid or T-lineage markers. Rare cases of otherwise typical B-ALL express myeloperoxidase (MPO) detectable by flow cytometry with an absence of other myeloid markers, but the clinical significance of this finding is not well studied. Methods A retrospective cohort analysis of flow cytometry and clinical data was performed to investigate the clinical outcome of this specific group of patients. Results Twenty-nine cases of otherwise typical B-ALL that expressed MPO by flow cytometry (B-ALL-isoMPO) without expression of other myeloid markers were identified. The B-ALL-isoMPO group had a significantly increased incidence of relapse (univariate log rank P = .0083; multivariate hazard ratio, 2.50; 95% confidence interval, 1.07-5.85; P = .034) and significantly worse event-free survival by univariate analysis (log rank P = .0066) compared with a reference group of patients with B-ALL from the same time period (n = 264). Conclusions To our knowledge, this is the first report to document the clinical outcomes in a group of pediatric patients with B-ALL that expresses MPO in the absence of other myeloid markers. This group had an increased rate of relapse and a worse event-free survival than the patients with B-ALL who did not express MPO.

As discussed elsewhere in this textbook, increased treatment intensity over the past decades for childhood acute lymphoblastic leukemia (ALL) has improved outcomes and 90% of children with newly diagnosed with ALL are now expected to become long-term survivors [1–3]. Concurrently, the burden of intensified therapeutic regimens has become evident; treatment-related toxicity (TRT) not only leads to long-term morbidity and late effects in survivors of childhood ALL [4], but also compromises optimal delivery of otherwise curative chemotherapy [5–9]. Early efforts to reduce TRT focused on refinements in risk-stratification to better identify groups that may benefit from high morbidity treatment modalities. This approach led to significant mitigation in the use of cranial radiation and anthracyclines with reduction of late mortality [10]. However, the prevalence of TRT during therapy has nevertheless remained relatively constant. Despite an increased focus on medical supportive care, severe grade 3 or 4 toxicity is reported in ~40–75% of those treated on recent ALL consortia trials [11–13]. Non-disease related treatment related mortality (TRM) continues to be problematic on current regimens, affecting 1–3% of children treated for pediatric ALL irrespective of the specific regimen or consortia [6, 14–17]. While relapse of disease remains the number one cause of death in children with ALL, improvement in disease response has reduced the number of relapse-related deaths. As a result, the relatively constant rate for TRM over the years now constitutes an increasing proportion of mortality; approximately one in five deaths on therapy are now due to TRM rather than the disease itself [1]. The highest risk for TRM occurs within the initial Induction phase, with up to 50% of non-disease related deaths occurring within those first 28 days [6, 16]. The Induction phase of ALL chemotherapy is therefore not only critical for obtaining a remission for eventual cure [18], but also the period of greatest risk for a life-threatening event. In the following chapter, we provide an overview of the key toxicities that occur during ALL treatment with an emphasis on the current states of the science and future directions. The overall goal of this chapter is to provide insight into common supportive care issues impacting therapy and to aid the clinician in providing anticipatory supportive care and prompt recognition and intervention for serious toxicity.

Three central venous catheters types are commonly used in pediatric cancer: totally implantable catheters (ICs; eg, mediports, portacaths), tunneled externalized catheters (eg Broviac® or Hickman® catheters [Bard Medical]) and peripherally inserted central catheters. While previous studies have examined risks for catheter-related infections, this is the first large multicenter study to compare catheter-associated infectious morbidity through patient outcomes and hospital utilization.A historical cohort analysis was conducted using data from the Pediatric Health Information System reporting 1167 hospitalizations of neutropenic patients with childhood cancer and a central venous catheters. Multivariate analyses controlled for age, ethnicity, gender, malignancy category and transplant status. Outcomes included incidence of serious bacterial infection, mortality, duration of hospitalization, time and use of intensive care unit and antibiotic usage.Neutropenic cancer patients with totally ICs (n = 429) have a statistically significant approximately 50% decrease in length of hospitalization (P0.001), risk for requiring an intensive care unit stay (P = 0.002), documented serious bacterial infection (P = 0.001) and days on antibiotics (P0.001) when compared with patients with tunneled externalized catheters (n = 463). Similar differences were found comparing hospitalizations of patients with ICs to those with peripherally inserted central catheters (n = 275). No difference in mortality was observed among catheters groups.In neutropenic pediatric oncology patients with a central venous catheters, ICs are associated with the least hospital utilization including shortest duration of hospitalization, intensive care unit time and antibiotic therapy when compared with tunneled external catheters and peripherally inserted central catheters. The impact of differences in catheter-associated infectious morbidity on patient outcomes and hospital utilization should be included in clinical decision making.

Background Anthracycline agents are used for treatment of acute myeloid leukemia (AML) but may cause late-onset cardiomyopathy. Current frontline therapy for AML in North America, as reflected in the approach of the Children's Oncology Group (COG) and other pediatric consortia, is adapted from the anthracyline-intensive Medical Research Council (MRC) regimen. The purpose of this study was to describe early post-treatment cardiac function as a potential indicator of acute and long-term risk associated with this approach. Procedure A multi-center retrospective cohort analysis was conducted of AML survivors diagnosed from 2004 to 2009 and treated with MRC-based regimens. Change in left ventricular shortening fraction (LVSF) on echocardiogram was determined from baseline to latest post-treatment/pre-relapse value; associations with potential predictors were examined. Results This cohort of pediatric survivors (n = 52) was assessed at a median interval of 13 months from end of treatment. Mean cumulative anthracycline dose was 339 ± 14 mg/m2. Mean baseline and post-treatment LVSF were 39.3 ± 0.8% and 35.4 ± 0.9%, respectively; mean percent change for individuals was −8.4 ± 2.8% (P

The growing epidemic of obesity has resulted in a large increase in multiple related diseases. Recent evidence has strengthened the proposed synergistic relationship between obesity-related insulin resistance (IR) and/or diabetes mellitus (DM) and cancer. Within the past year, many studies have examined this relationship. Although the precise mechanisms and pathways are uncertain, it is becoming clear that hyperinsulinemia and possibly sustained hyperglycemia are important regulators of not only the development of cancer but also of treatment outcome. Further, clinical decision-making regarding the treatment of choice for DM will likely be impacted as we learn more about the non-metabolic effects of the available hyperglycemic agents. In our review, we endeavored to synthesize the recent literature and provide a concise view of the journey from macro-level clinical associations to specific mechanistic relationships being elucidated in cell lines and animal models.

Background The UK ALLR3 (R3) regimen has been adopted to treat pediatric relapsed acute lymphoblastic leukemia (ALL) by many centers in the United States and has become a preferred therapeutic backbone for testing novel agents in clinical trials. A detailed toxicity profile of this platform has not previously been reported. The toxicity and response rates for its use beyond first relapse are unknown. Procedures We performed a multi-institutional, retrospective study including children with relapsed ALL treated with the R3 reinduction chemotherapy backbone block 1 across five pediatric centers. Data were extracted from medical records and analyzed. Results Fifty-nine patients were included in the study, including 16 patients with ≥2nd relapse. Ninety-seven percent of patients experienced at least one Grade ≥3 nonhematologic adverse event (AE). Grade 3 or higher infection was reported in 90% of patients. Other nonhematologic Grade ≥3 AEs included electrolyte abnormalities, elevation in hepatic enzymes, and pain. Eighty-five percent of patients achieved a complete remission (CR). There were no significant differences in the incidence of AEs, CR rate, and rate of minimal residual disease negativity between patients with 1st or ≥2nd relapse. Conclusion Our study confirmed that R3 block 1 is a highly active reinduction regimen in childhood relapsed ALL. However, it was associated with a high incidence of severe toxicities, particularly infection. The toxicity profiled in our report should be used to inform optimal supportive care and future clinical trial design with the R3 backbone, particularly when new agents are combined with this regimen.

Obesity as defined by body mass index percentile (BMI%) is strongly associated with relapse and poorer survival in childhood ALL. Whether BMI% accurately reflects body fat percentage (BF%) in this population is unknown. We conducted a prospective study assessing body composition during frontline ALL therapy. Dual-energy X-ray absorptiometry measured BF% and lean muscle mass (LMM) at diagnosis, end of Induction, and end of Delayed Intensification. Sarcopenic obesity (gain in BF% with loss of LMM) was surprisingly common during ALL treatment, resulting in poor correlation between changes in BMI% (expressed as Z-score) and BF% overall (r = -0.05) and within patients (r = -0.09). BMI Z-score and BF% changed in opposite directions in >50% of interval assessments. While BMI% at diagnosis is a suitable predictor of obesity/BF% for epidemiological studies, change in BMI% (as expressed as Z-score) does not reflect body composition. Studies evaluating obesity in leukemia should consider using direct measures of body composition.

INTRODUCTION: Mixed phenotype acute leukemia (MPAL) is a category of acute leukemia established in the World Health Organization (WHO) 2001 classification, significantly modified in WHO2008, and again refined in the most recent WHO2016 update. The current WHO2016 iteration conceptualizes MPAL as a stem cell disorder whereby most cases will manifest heterogeneity of lineage-specific antigen expression by multi-parameter flow cytometry. The WHO2016 definition also urges caution for cases otherwise consistent with B-cell acute lymphoblastic leukemia (B-ALL) that express myeloperoxidase (MPO) as the sole representation of myeloid lineage. These cases met the WHO2008 definition but may not meet the newer WHO2016 criteria. There is limited data on the clinical impact of these recent changes in the WHO classification for MPAL. METHODS: Six institutions identified cases diagnosed as MPAL between 2008 and 2016 according to WHO criteria. The diagnostic flow cytometry was then reanalyzed by two independent hematopathologists blinded to clinical outcomes. The cases were evaluated as to whether they met criteria for WHO2008 MPAL and/or WHO2016 MPAL. Cases of WHO2008 MPAL were further subdivided into those that otherwise met criteria for B-ALL (including non-lineage specific expression of ±CD13, ±CD15, ±CD33) but qualified as MPAL due to MPO expression (MPO+MPAL) and all remaining cases of MPAL that demonstrated additional myeloid lineage specificity as described by the WHO criteria (MLS+MPAL). Data for a distinct cohort of pediatric B-ALL without significant MPO expression diagnosed during the same study period was submitted from one participating site to serve as a reference cohort (n=258). Endpoints of interest to evaluate clinical outcomes according to the WHO classification were event-free and overall survival (EFS, OS). All statistical tests were two-sided with significance set at p RESULTS: The cohort consisted of 112 cases submitted for central review; 94/112 met the strict criteria for WHO2008 MPAL. Of these, 21/94 cases also had sufficiently comprehensive testing performed at diagnosis to meet criteria for WHO2016 MPAL. Five-year EFS and OS for patients identified as WHO2016 MPAL (63±11% and 69±11%) was significantly worse than the remainder meeting only the WHO2008 criteria (69±7% and 87±5%, p=0.024 and p CONCLUSIONS: Reported survival rates for MPAL continue to vary with changes to the WHO classification. The subset fulfilling WHO2016 criteria demonstrated significantly worse EFS and OS than the WHO2008 cohort; WHO2016-defined MPAL may better represent the concept of MPAL as a stem cell disorder. Applying WHO2016 versus WHO2008 criteria to diagnostic flow cytometry in this retrospective cohort resulted in fewer patients classified as MPAL. As a retrospective study, the antigen combinations necessary to fulfill newer WHO2016 criteria for blast heterogeneity were not tested in many cases; however, it remains likely that the updated WHO2016 criteria will reduce apparent disease prevalence. While cases of WHO2008 MPAL otherwise meeting criteria for B-ALL apart from MPO expression were less likely to have favorable prognostic features at diagnosis, survival on multivariable analysis was similar to B-ALL; it remains unclear how best to categorize this group of MPO+ acute leukemia. Better understanding of the biology of MPAL is therefore essential to appropriately classify these rare leukemias and to develop optimal therapy. Disclosures O'Gorman: Becton Dickinson: Consultancy.

BACKGROUND: Mixed phenotype acute leukemia (MPAL) is a rare form of leukemia in children. Current evidence supports the use of acute lymphoblastic leukemia (ALL)-directed regimens as initial therapy for MPAL; Children's Oncology Group (COG) ALL regimens are commonly used for pediatric ALL in the United States. Data for the predictive value of minimal residual disease (MRD) to risk-stratify therapy for pediatric MPAL is sparse overall and currently unknown in the context of COG ALL regimens. The primary objective for this study was to therefore examine the predictive value of MRD for event-free and overall survival (EFS, OS) in a centrally-reviewed, strictly-defined pediatric MPAL cohort treated according to COG ALL regimens. METHODS: A retrospective cohort of pediatric MPAL treated from 2008-2016 was assembled from six institutions in the United States. All sites submitted primary diagnostic flow cytometry for central review. Two independent hematopathologists blinded to clinical outcomes confirmed the diagnosis of MPAL according to the WHO2008 and/or WHO2016 classification and assigned a MPAL phenotype. MRD was assessed by multi-parameter flow cytometry ("negative" defined as RESULTS: Of the 112 cases diagnosed by institutions as MPAL, 94 (84%) fulfilled strict WHO criteria. The majority of MPAL patients were B/Myeloid (89%), with a single blast population (87%), and without hyperleukocytosis (WBC≥50K/uL) or central nervous system involvement at presentation (Table 1). Within the cohort, 85/94 were treated with a COG ALL regimen with EOI MRD available (1/85 suffered an induction death prior to MRD assessment). ALL induction therapy resulted in a MRD-negative CR in 72% (61/85); three MRD-negative patients nonetheless converted to non-ALL therapy. Of those EOI MRD+ (≥0.01%), 12 of 14 who continued with COG ALL therapy achieved an EOC MRD-negative CR (i.e. 70/85 [82%] were MRD-negative by EOC). Induction failure (IF) occurred in 7% (6/85) and was defined as disease progression prior to EOI (n=2) or by EOI MRD ≥5% (n=4). The two patients with early disease progression were successfully "salvaged" with AML therapy (0.50 for both); five-year EFS and OS for ALL chemotherapy without HSCT (n=73) were 78±6% and 90±4%, respectively. The presence of multiple blast populations of distinct lineages at diagnosis was similarly rare and was potentially associated with worse OS on multivariable analysis (p=0.024). No other candidate predictors were associated with EFS or OS. No difference in the predictive value of MRD was present when analyses were limited to patients with "neutral" cytogenetics. CONCLUSION: In a retrospective analysis of pediatric MPAL, the majority of patients treated with ALL chemotherapy achieved a MRD-negative CR by EOC (~week 12 of therapy); overall survival in this group was excellent. Further prospective validation of MRD is essential to refine risk-stratified therapy for pediatric MPAL. Optimal salvage for those who fail to achieve remission with ALL chemotherapy is unknown and requires further study. Disclosures O'Gorman: Becton Dickinson: Consultancy.

Introduction Off-target effects of induction therapy to treat Acute Lymphoblastic Leukemia (ALL) can lead to hepatotoxicity, cardiotoxicity, and neuropathy, particularly in patients with previous co-morbidities. Incorporation of pegylated L-asparaginase (L-ASP) into pediatric and adult ALL induction regimens has increased remission rate but results in severe hepatotoxicity. Levocarnitine (L-carnitine), a small amino-acid derivative, has been reported in small case series in children and adults with ALL to reduce asparaginase-induced hepatotoxicity. L-carnitine functions as a transport molecule and facilitates long-chain free fatty acid beta-oxidation; exogenous supplementation with L-carnitine may therefore protect hepatocytes through facilitation of fatty acid transport and maintenance of antioxidant balance in mitochondria. However, the effects of L-carnitine on ALL cell survival and possible contributions of L-carnitine to chemotherapy resistance in ALL are not known. Given the ability of L-carnitine to enhance energy production, we sought to investigate whether L-carnitine could compromise the efficacy of common induction chemotherapy agents against ALL cells. Methods Human ALL cells, BV173 and RS4;11 were treated with L-carnitine and either daunorubicin (DNR) or vincristine (VCR) for 72 hours (n=4-6). RS4;11 cells were additionally treated with L-ASP (n=4), and current testing to assess dexamethasone in RS4;11 is in progress. Experiments were performed in 96-well culture plates with a seeding density of 90,000-120,000 cells/well (~5 x105 cells/mL). Growth media (RPMI 1640, 1% sodium pyruvate, 1% glutamine, 10% fetal bovine serum) was supplemented to physiologic (50 μM) and supraphysiologic (100-200 μM) levels of L-carnitine (normal reference range: 25-70 μM). Chemotherapy doses were chosen to represent ~EC90 concentrations (BV173: 2 nM VCR and 25 nM DNR; RS4;11: 2 nM VCR, 20 nM DNR, and 0.1 IU/mL L-ASP). After 72 hours, cell viability was measured by trypan blue exclusion and confirmed with spectrophotometric analysis with the Alamar Blue cell viability assay. Data were analyzed using one-way analysis of variance (ANOVA) with significance defined as p Results Addition of L-carnitine did not significantly affect cytotoxicity of VCR or DNR in BV173 (n=6) or cytotoxicity of VCR, DNR, or L-ASP in RS4;11 (n=4) as measured by trypan blue exclusion at 72 hours (Figure 1A). L-carnitine also did not affect cell viability assessed using Alamar Blue colorimetric assay, presented as the difference in reduction of resazurin (resorufin) compared to untreated RS4;11 or BV173 cells (Figure 1B). Conclusion Our data show L-carnitine has no significant effect on the cytotoxicity of VCR, L-ASP, or DNR in two human ALL cell lines. For providers incorporating L-carnitine into induction therapy to reduce asparaginase-induced hepatotoxicity, this data supports its use without compromising the efficacy of induction therapy. Further investigation is necessary to determine whether L-carnitine alters efficacy of glucocorticoid drugs, particularly dexamethasone, and other chemotherapies used in the treatment of ALL and across other ALL subtypes. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Obesity is associated with increased treatment-related toxicity during therapy for acute lymphoblastic leukemia (ALL). During induction, hepatotoxicity due to L-asparaginase results in significant morbidity and chemotherapy delays/modifications. While hepatotoxicity is more common in older adolescent and young adult (AYA) patients, it cannot be predicted with high accuracy. Obesity defined by the surrogate marker of body mass index (BMI) has been shown to be a risk factor for hepatotoxicity; however, BMI does not accurately reflect body adiposity during ALL therapy due to concurrent muscle loss and adiposity gain. Because excess adiposity is generally believed to be responsible for most of the comorbidities of obesity, we hypothesized that body fat measured by direct assessment would be a better predictor of asparaginase-induced hepatotoxicity, and that non-obese patients with increased adiposity might be identified as an at-risk population which would not otherwise be recognized. METHODS: We conducted an interim analysis of a prospective trial for an obesity intervention in pre-adolescent and AYA patients ≥10 years old newly diagnosed with B-ALL (NCT02708108). Whole-body dual-energy x-ray absorptiometry (DXA) performed at diagnosis and end of induction (EOI) directly quantified adiposity as total body fat percentage (TBF%) and fat mass (FM). Overweight or obesity (OW/OB) was defined using CDC-norms as a BMI percentile (BMI%) ≥85%. All patients were treated with Children's Oncology Group ALL regimens using a four-drug induction inclusive of glucocorticoids, daunorubicin, vincristine, and pegylated L-asparaginase. Obese and/or patients ≥15 years were considered at-risk for hepatotoxicity and thus eligible to receive exogenous supplementation with levocarnitine for hepatoprotection per provider discretion. The primary endpoint for the analysis was CTCAE Grade 3+ hepatotoxicity. Stepwise multivariable logistic regression models were constructed for the primary endpoint inclusive of TBF% and FM at diagnosis, change in FM during induction, and demographic candidate predictors. All tests were two-sided and significance was set at p RESULTS: We analyzed a cohort of 25 subjects enrolled on trial with DXA results at diagnosis. The cohort was divided equally by age ≥15 years (48%) and sex (44% female). The majority were of Hispanic ethnicity (64%) consistent with institutional demographics. Over half the cohort was OW/OB at diagnosis with mean TBF% of 39.5±1.3% and FM 31.7±2.5kg. In this AYA population, Grade 3+ hepatotoxicity occurred in 10/25 (40%) overall; all episodes included transaminitis (10/10) ± concurrent hyperbilirubinemia (2/10). Two of these patients met criteria for CTCAE Grade 4 hepatotoxicity (2/25, 8%); both were older, obese, with TBF% >40% at diagnosis. After accounting for age, radiographic measures of adiposity at diagnosis were not significant predictors of hepatotoxicity on multivariable analyses (FM at diagnosis p=0.299; TBF% at diagnosis p=0.599). Similarly, gain or loss of FM was not significantly associated with hepatotoxicity after adjusting for age or starting BMI category (p=0.818). Successful loss of fat due to the intervention occurred in 7/13 (54%) of OW/OB patients (mean loss -3.9±8.9kg) but was similarly not associated with decreased risk of hepatotoxicity (p=0.734). Only age ≥15 years was significantly associated with risk for Grade 3 hepatotoxicity across all models. Levocarnitine supplementation was prescribed by the primary providers to five of six eligible at-risk patients; no reported adverse events occurred. No severe, CTCAE Grade 4 hepatotoxicity occurred in the four patients adherent to levocarnitine supplementation. CONCLUSION: Contrary to our hypothesis, neither directly measured adiposity at diagnosis nor changes in adiposity during ALL induction predicted hepatotoxicity for this AYA cohort. Older AYA patients were at significant risk for hepatotoxicity irrespective of level of adiposity. However, the potential impact of extreme obesity on hepatotoxicity requires further investigation. Validation of these results is necessary in a larger cohort; should they be confirmed, future trials targeting hepatotoxicity reduction from ALL induction should focus on age-related differences in drug metabolism and effects. Disclosures No relevant conflicts of interest to declare.

Background Hepatotoxicity and pancreatitis are common treatment-related toxicities (TRTs) during contemporary treatment regimens for acute lymphoblastic leukemia (ALL). Limited detailed data from Children's Oncology Group (COG) regimens has been previously reported to enable identification of patient and treatment risk factors for these toxicities and their impact on outcomes. Procedure We analyzed a retrospective pediatric ALL cohort treated at a single institution according to COG regimens from 2008 to 2015. The primary endpoint was cumulative incidence of study-defined "severe" hepatotoxicity (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 4 transaminitis or Grade ≥ 3 hyperbilirubinemia) and clinically significant pancreatitis (any grade). Pancreatitis was additionally classified using the Ponte di Legno (PdL) toxicity criteria. Secondary endpoints were chemotherapy interruptions, early disease response (end of induction [EOI] minimal residual disease [MRD]), and event-free survival (EFS). Results We identified 262 patients, of whom 71 (27%) and 28 (11%) developed hepatotoxicity and pancreatitis, respectively. Three cases of pancreatitis did not fulfill PdL criteria despite otherwise consistent presentations. Both TRTs occurred throughout therapy, but approximately 25% of hepatotoxicity (18/71) and pancreatitis (8/28) occurred during induction alone. Both obesity and age (≥10 years) were identified as predictors of hepatotoxicity (subdistribution hazard ratio [SHR] obesity = 1.75, 95% confidence interval [95% CI] 1.04-2.96; SHR age ≥10 = 1.9, 95% CI 1.19-3.10) and pancreatitis (SHR obesity = 2.18, 95% CI 1.01-4.67; SHR age ≥ 10 = 2.76, 95% CI 1.19-6.39, P = 0.018). Dose interruptions were common but neither toxicity influenced EOI MRD nor EFS. Conclusions Obese and/or older children are particularly at risk for hepatotoxicity and pancreatitis, and may benefit from toxicity surveillance and chemoprotective strategies to prevent or mitigate associated morbidity.

There remains uncertainty regarding the optimal treatment for mixed phenotype acute leukemia (MPAL), an uncommon leukemia that represents ~3% of de novo acuteleukemia. Because of the dearth of clinical trials, varying approaches are employed: acute lymphoblastic leukemia (ALL) regimens as well as more intensive acute myeloid leukemia (AML) and hybrid therapies. The evolution in the prevailing diagnostic criteria from the EGIL classification to the more narrowly defined WHO2008 and WHO2016 criteria has made the existing literature difficult to interpret. Increasing insight into the molecular heterogeneity of MPAL adds further complexity. Recently published studies (retrospective clinical case series), however, are beginning to suggest that ALL therapy may be the most appropriate form of initial therapy for MPAL. To further assess the efficacy of ALL therapy for pediatric MPAL, we reviewed the Children's Oncology Group (COG) experience. Possible MPAL cases were identified through the ALL biology studies (both AALL03B1 and AALL08B1 were open to MPAL) and from AAML0531, the phase 3 trial for de novo AML (patients enrolled on this trial subsequently found to have MPAL were taken off study). All identified cases were reviewed centrally. In cases where the original flow cytometry testing was inadequate to establish the diagnosis, flow cytometry was repeated with an expanded antibody panel using banked diagnostic specimens. Only cases meeting WHO2016 criteria were retained. Patients were treated per physician discretion and not on a therapeutic clinical trial. Supplemental data on treatment and outcomes were collected. From the study databases, 97 potential MPAL cases were identified; of these, 54 cases (56%) were confirmed to be MPAL via central review. Patients were diagnosed between 2003 and 2016. The majority of patients were This series represents a large cohort of centrally-reviewed pediatric MPAL cases diagnosed according to the most recent WHO2016 criteria and treated with COG-style chemotherapy. Our results add to the growing body of literature suggesting that ALL regimens may be effective for pediatric MPAL. It also suggests, however, that induction failure and relapse are still relatively common with ALL therapy and that alternative forms of treatment are necessary for some. The limited size of the sample and its heterogeneity preclude any conclusions regarding the relative efficacy of AML therapy and role for HSCT. Given the greater morbidity and mortality associated with these forms of therapy, consideration should be given to reserving their use for patients with a suboptimal response to ALL therapy. Continued variability in accurately diagnosing and treating MPAL as seen here also underscores the necessity of well-delineated clinical trials with integrated central review to advance MPAL therapy. Our results therefore further support the basis for the first-ever prospective evaluation of high risk ALL therapy for pediatric MPAL in a trial now being planned within the COG. In this trial, minimal residual disease testing with multiparameter flow cytometry will be employed to identify patients responding well to ALL therapy versus those who may benefit from more intensive AML therapy and transplantation. Disclosures Mullighan: Loxo Oncology: Research Funding; Amgen: Consultancy. Hunger: Erytech Pharmaceuticals: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Honoraria; Amgen: Consultancy, Equity Ownership. Berman: AGADA Therapeutics: Research Funding. Zweidler-McKay: ImmunoGen: Employment.

Diminished bone density and skeletal fractures are common morbidities during and following therapy for acute lymphoblastic leukemia (ALL). While cumulative doses of osteotoxic chemotherapy for ALL have been reported to adversely impact bone density, the timing of onset of this effect as well as other changes to bone structure are not well characterized. We therefore conducted a prospective cohort study in pre-adolescent and adolescent patients (10-21 years) newly diagnosed with ALL (n=38) to explore leukemia-related changes to bone at diagnosis and the subsequent impact of the first phase of chemotherapy (“Induction”). Using quantitative computerized tomography (QCT), we found that pre-chemotherapy bone properties were similar to age- and sex-matched controls. Subsequently over the one month Induction period, however, cancellous volumetric bone mineral density (vBMD) decreased markedly (-26.8%, p

Background Intensifying treatment for pediatric acute myeloid leukemia (AML) has improved survival, with infections now being a leading cause of morbidity. Because quinolone prophylaxis is effective in adults with AML and in transplant populations, ciprofloxacin prophylaxis (CPx) was introduced as the standard for pediatric AML. We report here the impact of CPx in this population. Methods Prevalence of fever and neutropenia, frequency and pathogen spectrum of infections, antibiotic use, supportive care and mortality before and after implementation of CPx were retrospectively compared in children with AML. Results The cohort included 35 patients with de novo and 10 with relapsed AML, who together underwent 153 chemotherapy courses. Fever and neutropenia resulting in the use of empiric antibiotics occurred in 90% of chemotherapy courses (137/153); this was associated with proven bacteremia in 26%. The use of CPx did not change the incidence of febrile or infectious episodes, number of days of fever or antibiotic treatment or mortality. CPx was associated with a significant decrease in infections caused by Gram-negative rods (13.4% vs 4.7%) but a concomitant significant increase in bacteremia caused by viridans streptococci (12% vs 28%), resulting in no significant overall difference in the incidence of bacteremia between the 2 groups (35.9% vs 31.5%). Conclusions CPx neither alter the incidence of overall bacteremia nor change the pattern of fever or use of supportive care. Our experience supports further investigation into the use of extended-spectrum quinolone prophylaxis during therapy for pediatric AML.

Obesity is associated with poorer outcome from many cancers, including childhood acute lymphoblastic leukemia (ALL). We have previously shown that adipocytes protect ALL cells from the anthracycline, daunorubicin (DNR). We therefore investigated whether adipocytes sequester and/or metabolize DNR in the ALL microenvironment. Using fluorescence and LC/MS measures, we demonstrated that adipocytes absorb DNR, reducing the intracellular DNR concentration in co-cultured BV173 ALL cells (after 48 hours, median fluorescent intensity of ALL cultured with adipocytes was 1.7±1.0 vs. 5.0±1.7 of those cultured alone, p Citation Format: Xia Sheng, Jean-Hugues Parmentier, Jonathan Tucci, Hua Pei, Omar Cortez-Toledo, Christina Dieli-Conwright, Matthew Oberley, Michael Neely, Etan Orgel, Stan Louie, Steven D. Mittelman. Adipocytes sequester and metabolize daunorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2960. doi:10.1158/1538-7445.AM2017-2960

Purpose Previous studies regarding the influence of weight on event-free survival (EFS) and treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL) considered only weight at diagnosis. Inasmuch as weight varies substantially over treatment, we hypothesized its impact on EFS is instead determined by cumulative time spent at an extreme weight during therapy and on TRT by weight at the time of toxicity. Patients and Methods In a cohort of 2,008 children treated for high-risk ALL in Children's Oncology Group study CCG-1961, we determined the effect on EFS of cumulative time receiving therapy at an extreme weight (either obese or underweight) between end of induction and start of maintenance therapy. We also evaluated the association between weight category and incidence and patterns of TRT during 13,946 treatment courses. Results Being obese or underweight at diagnosis and for ≥ 50% of the time between end of induction and start of maintenance therapy resulted in inferior EFS (hazard ratios, 1.43 and 2.30, respectively; global P < .001). Normalization of weight during that period resulted in mitigation of this risk comparable to never being obese or underweight. Obese or underweight status at start of each treatment course was significantly associated with specific patterns of TRT. Conclusion Influence of weight extremes on EFS and TRT is not set at diagnosis as previously reported but is moderated by subsequent weight status during intensive postinduction treatment phases. These observations suggest that weight is a potentially addressable risk factor to improve EFS and morbidity in pediatric ALL.

Background: Mixed phenotype acute leukemia (MPAL) is a high risk leukemia with features of acute myeloid (AML) and acute lymphoblastic leukemia (ALL), either due to co-expression of antigens of multiple lineages, or the presence of multiple immunophenotypically distinct populations. WHO 2008 classifies MPAL as T/myeloid (T/M), B/myeloid (B/M), MLL rearranged (MLL) MPAL, BCR-ABL1 (Ph+) MPAL, and MPAL not otherwise specified (NOS). Patients are managed with divergent chemotherapeutic approaches with survival estimates of 50-70%. Apart from Ph+ and MLL rearrangement, the genetic basis of MPAL is poorly defined. Our goal was to define the molecular basis of MPAL, and to compare with potentially related forms of leukemia (AML, T-ALL and early T-cell precursor (ETP) ALL) as a rational foundation for future trials. Furthermore, we examined whether multi-lineal cases harbor genetically distinct subclones, or arise from the acquisition of founding alterations in a multi-lineage hematopoietic progenitor. Methods: 155 cases of pediatric leukemia initially diagnosed as MPAL were studied by central pathology review and/or central flow cytometry (134 cases), confirming the diagnosis according to WHO criteria in 115 cases (fig. 1). Median age was 7 years (0-18) with 52 T/M, 37 B/M, 15 MLL, 8 NOS, and 2 Ph+ (fig. 2). Samples were studied by whole genome and/or exome, RNA sequencing, and SNP array analysis. 44 multi-lineal samples were flow sorted into 2-4 lymphoid, myeloid, and ambiguous subpopulations (15 T/M, 19 B/M, 7 MLL, 1 Ph+, 2 NOS) and subjected to exome sequencing and SNP array. Mutational data were compared to data from 196 AML, 39 ETP-ALL, and 245 T-ALL cases. Results: We identified 35 recurrently mutated genes, the most common of which were WT1 (21%), FLT3 (18%), NRAS (16%), JAK3 (11%), RUNX1 (11%), KMT2D (9%), PTPN11 (9%), ASXL1 (7%), and CREBBP (7%). T/M and B/M subtypes are characterized by distinct patterns of genomic alteration. 48% of T/M cases harbored in-frame chimeric fusion, several of which are described in T-ALL, including ETV6-NCOA2 and ZEB2-BCL11B, NUP214-ABL1 and PICALM-MLLT10, and novel fusions involving hematopoietic regulators (e.g. ETV6-MAML and MNX1-IKZF1). 42% of B/M cases had in-frame fusions of ZNF384 with CREBBP, EP300, and TCF3, while we also identified isolated fusions involving ERG and NF1. Mutations of Ras signaling genes were present in 50% of B/M cases, in contrast to 10% of T/M cases. Epigenetic modifying genes, including CREBBP, SETD2, KMT2D, EZH2 and SUZ12 were mutated in 45% of the combined T/M and B/M cohorts. Cases with MLL gene rearrangements had few sequence alterations. In comparison to other subtypes of leukemia, the mutational spectrum of T/M MPAL, with alterations in transcription factors (60% cases), epigenetic genes (50%) and JAK-STAT signaling (35%) was more similar to ETP-ALL (64%, 72%, 44%) and T-ALL (49%, 60%, 21%) than to AML (19%, 21%, 11%). Similarly, B/M cases have increased alterations in these pathways (42%, 42%, 25%) compared to AML. Sequencing of MPAL subpopulations revealed that 27% of cases had the same SNVs/indels in each subpopulation, and 47% of cases had at least two-thirds of mutations present in each subpopulation. All multi-lineal cases with alterations of regulators WT1 and RUNX1 showed similar allele frequencies of these mutations in all populations. Alternatively, cases with mutations in signaling (FLT3, NRAS, KRAS, PTPN11) or epigenetic regulatory genes (CREBBP, KMT2D, SETD2) only showed consistent presence of alterations across each subpopulation in 60% of the cases. Conclusions: Our analysis has shown that T/M and B/M MPAL are distinct subtypes of leukemia. B/M MPAL is characterized by frequent RAS pathway mutations and ZNF384 fusions with multiple different fusion partners, suggesting that this gene plays a critical role in hematopoietic development for progenitor cells with B lymphoid and myeloid potential. The findings of mutational similarity to ETP ALL, and sharing of genomic lesions between subclones in the majority of cases strongly suggests that MPAL represents part of a spectrum of immature leukemias that arise in a hematopoietic progenitors that may propagate multiple immunophenotypic populations. These results will guide the design of therapeutic strategies for each subtype of MPAL and ETP ALL, and xenografts representative of each subtype are being used to examine sensitivity to therapeutic agents. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Loh: Abbvie: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Zwaan:Pfizer: Research Funding; Pfizer: Consultancy. Reinhardt:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Other: Travel Accomodation. Inaba:Arog: Research Funding. Mullighan:Loxo Oncology: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau.

BACKGROUND : Mixed phenotype acute leukemia (MPAL) as defined according to the World Health Organization 2016 guidelines (WHO2016) comprises approximately 2-3% of acute leukemia. In other acute leukemias, minimal residual disease (MRD) has emerged as the predominant predictor of relapse. MRD at end of Induction (EOI) is therefore a key risk-stratifying feature for lymphoid and myeloid disease regimens. To our knowledge, no studies to date have reported on the predictive value of MRD for treatment of MPAL. Although the absence of randomized trials for MPAL precludes a clear determination of optimal regimen, acute lymphoblastic leukemia (ALL) directed-therapy is increasingly considered frontline treatment internationally. The primary objective for this study was to evaluate the association of EOI MRD with event free survival (EFS) from ALL regimens used for treatment of MPAL. METHODS : Flow cytometry data for all acute leukemias diagnosed 2008-2015 and treated with Children's Oncology Group regimens for ALL were examined by two flow cytometrists blinded to clinical outcomes (MO, SL). Data was analyzed using CellQuestPro and FACSDiva software (BD Biosciences, San Jose, CA). A comprehensive panel of 21 B-, T-, and myeloid markers were evaluated in all cases. A diagnosis of MPAL was strictly established according to the WHO2016 definition. EOI MRD was performed routinely by flow cytometry using a "difference from normal" approach. Cases with insufficient flow cytometry to either (1) establish the diagnosis of MPAL or (2) evaluate the presence and quantity of MRD were excluded. Due to the rarity of the T/myeloid phenotype in the dataset (n=1), the analysis was restricted to B/Myeloid. The primary endpoint was EFS; secondary outcomes explored predictors of EOI MRD positivity and the prevalence of recurrent cytogenetic abnormalities. MRD was categorized as a binomial (negative Results: Of 59 cases identified as MPAL, 53 met inclusion criteria for analysis (1 Induction death, 1 insufficient MRD for analysis, 2 received AML therapy, 1 T/myeloid, 1 MPAL lymphoma). At a mean follow-up time of 3.5±1.7 years, EFS for the overall cohort was 88.0±4.6%. However, EFS was significantly greater for those MRD- versus those MRD+ (94.4±3.9% vs 67.5±12.1%, p=0.0005; Figure 1). Multivariable analysis confirmed MRD as a significant predictor of EFS even after accounting for treatment regimen (hazard ratio 5.0, 95%CI 1.7-15.3, p=0.0036). No other candidate predictors remained significant in the final multivariable models. Although different levels of MRD positivity were significantly associated with poorer EFS, visual examination of the dataset showed the 0.01% threshold to be most representative. Recurrent cytogenetic abnormalities were found in 15/53 children (Trisomy 4+10 n=11/53, TELAML n=1/53, iAMP21 n=2/53, BCRABL n=1/53). No MLL rearrangements were identified. The single patient with BCRABL received continuous imatinib during therapy (no event). No differences at diagnosis were present in those EOI MRD+ versus MRD-, although a WBC count ≥50K/uL was borderline significant (p=0.051). Conclusion : Using a "difference from normal" approach, EOI MRD at a threshold of 0.01% significantly predicts risk for strikingly poorer EFS in children with B/Myeloid MPAL. Children who achieve an EOI MRD-negative remission demonstrate excellent survival with ALL chemotherapy alone. Future investigation is necessary to prospectively validate these findings, examine MRD in T/myeloid and cytogenetic subgroups, and to explore the success of myeloid salvage therapy ±SCT to "rescue" those with a poor response to ALL therapy. Figure 1 Event free survival by end of Induction MRD status (negative Disclosures O'Gorman: Becton, Dickinson and Company: Consultancy, Research Funding.

Introduction Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with an excellent survival rate due to advancements in therapy. However, significant chemotherapy treatment-related toxicities (TRTs) are associated with the intensity of such treatments, which can affect quality of life, preclude the ability to provide optimal therapy, and impact survival. Further, outcomes are worse among certain minority populations, including Hispanic patients. At this single institution with a predominately Hispanic population, we sought to review several TRTs and determine whether Hispanic ethnicity may be a risk factor for increased severe, short-term TRTs and to explore the effects of TRTs on event-free survival (EFS). Methods This study is a retrospective chart-review of patients diagnosed with ALL at Children's Hospital Los Angeles from January 2008 to December 2010. Infants, patients with Down's syndrome and those who transferred to another institution during therapy were excluded from this study. Demographic and TRT information were collected from the electronic medical record, from the start of treatment until 30 days after the end of primary therapy, relapse, transplant, or death. TRTs were graded per the Common Terminology Criteria for Adverse Events version 4.0; only toxicities severe enough to negatively effect patients' quality of life, chemotherapy continuation, and survival were included. The specific TRTs were fractures, osteonecrosis, and peripheral neuropathy of ≥ grade 2, fungal and culture-positive bacterial infections, thrombosis, pancreatitis, and hyperbilirubinemia ≥ grade 3, and hepatic transaminitis ≥ grade 4. The X2 test was used to compare the proportions of Hispanic and non-Hispanic patients with and without the selected TRTs. Univariable and multivariable Cox regression models were used to examine the association of patient demographics with EFS and time to TRT. All analyses were performed using a 2-sided test and completed using the statistical software Stata. Results Of the 172 patients diagnosed with ALL between 2008 and 2010, 138 patients are included in this study, 124 with B-cell ALL and 14 with T-cell ALL. Among the 138 patients, 57.2% were male, 24.6% were obese, 76.1% were Hispanic, and 58% were classified as high-risk by the NCI Rome criteria. The median age at diagnosis was 7.9 years (range 1.1 to 20). All patients were treated according to ongoing Children's Oncology Group therapeutic studies. During the course of therapy, 23 patients relapsed, 3 developed secondary malignancy, and 2 patients died from infection. There were 156 TRTs observed in 85 patients, with 61.6% of patients experiencing one or more of the selected TRTs. The most common TRTs were infectious and gastrointestinal/hepatobiliary events. While Hispanic patients had 2.2 times higher frequency of pancreatitis than non-Hispanic patients and 1.8 times more hyperbilirubinemia, there were no statistically significant differences in the incidence of any TRTs by ethnicity. NCI high risk and older age were the only significant predictors of any TRT (p Discussion In this relatively small cohort of patients, we did not identify ethnicity as a risk factor for increased TRTs during therapy for ALL, although certain TRTs such as pancreatitis and hyperbilirubinemia may be more common among Hispanic patients. As expected, Hispanic ethnicity, NCI risk, and age at diagnosis were risk factors for increased relapse and death. These results may suggest that additional factors, such as genetics, disease biology, or medication compliance, may play a more significant role in worse outcomes for Hispanic patients, rather than difference in tolerance of the treatment itself. Analyses of a larger cohort of patients are ongoing to confirm these results and to comprehensively analyze the determinants of pancreatitis and hepatic toxicity, and their interaction with obesity in Hispanic patients with ALL. Disclosures Bhojwani: Amgen: Other: Blinatumumab global pediatric advisory board 2015.

Background: Therapy for children with acute myeloid leukemia (AML) is intensive and treatment-related mortality (TRM) occurs in about 5 to 10% of patients. Previous data illustrated that obese children and adolescents with AML treated according to CCG 2961 were more likely to experience TRM, with HR 2.66 (95% CI 1.38-5.11; P = 0.003), when compared to middleweight patients. Since this trial, the backbone of AML chemotherapy and supportive care have changed and thus, it is unknown whether the impact of obesity persists in contemporary trials. The objective was to determine whether obesity was associated with increased TRM, reduced survival and prolonged compared to middleweight patients with AML. Methods: AAML0531 enrolled patients between August 14, 2006 and June 15, 2010. For this analysis, we included patients 0 to 18 years of age with de novo AML. Chemotherapy consisted of 5 cycles of chemotherapy and patients were randomized to receive or not receive gemtuzumab once during Induction I and Intensification II. Best allogeneic donor hematopoietic stem cell transplantation (HSCT) was recommended for those with > 15% bone marrow blasts after Induction I in those without favorable risk cytogenetics and poor risk cytogenetics irrespective of response following Induction I. Matched family donor HSCT was recommended for those with good response after Induction I with standard risk cytogenetics and an available donor. Obesity was defined using definitions from the Centers for Disease Control and Prevention (CDC). Underweight was defined as a body mass index percentile less than 5th percentile, and obese 95th percentile and greater. Categories were determined using z-scores for the weight-for-height data for those 0 to 2 years of age. All outcomes were censored at the time of HSCT. The primary outcome was TRM, defined as death as first event occurring on therapy or within 30 days of going off therapy. Cumulative incidence of TRM was estimated treating relapse and failure as competing events. Kaplan Meier analysis was conducted for overall survival (OS), event free survival (EFS), and disease free survival (DFS). Cumulative incidence of relapse rate (RR) was estimating treating deaths as competing events. Results: There were 1004 patients included. When comparing middleweight and obese patients, there was no significant difference in gender (P=0.814), white vs non-white race (P=0.116), cytogenetic risk group (all P>0.05) or MRD positivity after Induction 1 (P=0.750). The median age was higher for obese patients (12.0 vs 9.4 years; P=0.007 years) compared with middle weight patients. The proportion of patients who were Hispanic or Latino patients was higher among obese compared with middle weight patients (28% vs 17%; P=.001). Survival outcomes are shown in Table 1. When evaluating median time to neutrophil recovery, obese patients, when compared to middleweight patients, had shorter duration of neutropenia for cycles 1-3 (P Conclusions: TRM rates continue to be higher for obese patients treated with contemporary AML protocols. Toxicity is not mediated through prolonged neutropenia. Future work should compare the rate of toxicity among obese versus non-obese patients and evaluate the impact of underweight status. Disclosures No relevant conflicts of interest to declare.

Cancer therapy routinely requires Pneumocystis jiroveci prophylaxis. In those intolerant of trimethoprim/sulfamethoxazole, aerosolized pentamidine is convenient and effective. Intravenous pentamidine is often substituted in young children but its efficacy remains controversial. In this retrospective study of a large pediatric oncology cohort, we confirm intravenous pentamidine to be effective and well-tolerated as second-line prophylaxis across all ages.

Anthracycline agents are used for treatment of acute myeloid leukemia (AML) but may cause late-onset cardiomyopathy. Current frontline therapy for AML in North America, as reflected in the approach of the Children's Oncology Group (COG) and other pediatric consortia, is adapted from the anthracyline-intensive Medical Research Council (MRC) regimen. The purpose of this study was to describe early post-treatment cardiac function as a potential indicator of acute and long-term risk associated with this approach.A multi-center retrospective cohort analysis was conducted of AML survivors diagnosed from 2004 to 2009 and treated with MRC-based regimens. Change in left ventricular shortening fraction (LVSF) on echocardiogram was determined from baseline to latest post-treatment/pre-relapse value; associations with potential predictors were examined.This cohort of pediatric survivors (n = 52) was assessed at a median interval of 13 months from end of treatment. Mean cumulative anthracycline dose was 339 ± 14 mg/m(2) . Mean baseline and post-treatment LVSF were 39.3 ± 0.8% and 35.4 ± 0.9%, respectively; mean percent change for individuals was -8.4 ± 2.8% (P0.001). Cardiac-directed medications were initiated in four patients (7.7%). Decline in LVSF was significantly associated with cumulative anthracycline dose, increasing BMI and Hispanic ethnicity.Early, significant decline in LVSF was observed following treatment with these MRC-based regimens. Elevated BMI and Hispanic ethnicity were identified as new independent risk factors. Children and adolescents so treated are at substantial risk for late-onset cardiomyopathy, require monitoring with annual echocardiogram per current COG survivorship guidelines, and are good candidates for appropriate cardioprotection strategies.

Patient surveys consistently show physician communication remains less than ideal. While previous studies have demonstrated a lack of trainee confidence in delivering bad news, our study explores communication skills at all levels of practice and highlights potential barriers to improvement.Pediatric residents, fellows, and attendings involved in direct patient care at a major academic center participated in a voluntary questionnaire, consisting of self-assessed scales of comfort level, knowledge level, amount of training, and attitudes towards communication education. We also elicited barriers to learning and teaching as well as significant experiences.Eligible responses (n = 253) were evenly divided between trainees and faculty. Almost half of attendings and two thirds of fellows did not feel sufficiently knowledgeable to deliver bad news. Many attendings felt disproportionately more comfortable than they felt knowledgeable. All trainees felt insufficiently knowledgeable for independent practice of this skill. Educational barriers centered on time constraints, a deemphasis, a lack of positive modeling, and minimal awareness of existing resources. Poor experiences revolved around inappropriate language and settings as well as insufficient empathy or preparedness. Positive anecdotes highlighted the importance of education and the impact of role models.Independent of level of training, this study reveals a lack of self-assessed preparedness from many responsible for delivering bad news to patients and families. A significant barrier to improvement is the disproportionate level of self-assessed comfort versus knowledge level. Educational models should include both didactics to learn the skills and practice-based learning to refine the techniques.

Introduction Obesity is associated with increased morbidity and mortality in children diagnosed with high-risk acute lymphoblastic leukemia (HR-ALL). The mechanism of this adverse influence is thought to be due to adipose tissue and adipokines affecting immune function and/or decreasing chemotherapy efficacy. Adiposity, and not body weight, is therefore the central feature for exploring the influence of obesity on outcome in HR-ALL. To date, multiple international consortia have investigated this association using the surrogate measure of Body Mass Index (BMI). BMI estimates body composition based on height and weight and is therefore not able to distinguish between fat mass, bone density, and lean muscle. While BMI is generally a good indicator of overall adiposity, changes in weight that may occur over the course of therapy reflect not only a change in fat mass, but also changes in other components of body composition. We therefore hypothesized that BMI may not be a sensitive measure for assessing change in adiposity during therapy. Methods Body composition was assessed serially by BMI and the gold-standard Dual-energy X-ray Absorptiometry (DXA) as an ancillary aim in children with newly diagnosed HR-ALL enrolled on a prospective clinical trial investigating bone health. Children were treated as per Children’s Oncology Group HR-ALL regimens (CCG1961, AALL0232, AALL1131). Body composition was compared at three time-points (TP): within 24 hours of diagnosis (TP1), 28 days later (TP2, end of induction), and at the end of delayed intensification (TP3, mean interval of 8.2 months in the cohort). Age and tanner stage at diagnosis, gender, and ethnicity were collected. DXA was used to analyze body composition as defined by total mass of “body minus head” and separated into respective percentages of lean muscle, fat mass, and bone mineral content. BMI was converted to a percentage per Center for Disease Control and Prevention age- and gender- population norms. BMI percentage was compared to body fat percentage (BF%) overall and individually at each TP. Changes in body composition across TPs were evaluated by DXA. IRB approval was obtained and informed consent documented for all subjects. Results Of 51 subjects enrolled in the trial, a sub-cohort of 34 (66.6%) had sufficient DXA data for analysis. Of these, 85% (29/34) had DXA and BMI data at all 3 TPs, while 5/34 were too ill at diagnosis to complete the imaging. There were no significant differences in age, gender, and tanner stage between those included in the DXA sub-cohort and excluded; the cohort with DXA data consisted of a significantly higher prevalence of self-identified Hispanic subjects (31/34, 91% vs 11/17 65%). BF% by DXA was significantly correlated with BMI when observations from all TPs were combined (n=96, Spearman rho 0.6, p=0.002) and at each TP (TP1 rho=0.6, p=0.002; TP2 rho =0.7, p

Background: The epidemic of childhood obesity poses substantial treatment challenges for the care of children with acute lymphoblastic leukemia (ALL). Obesity at time of diagnosis of ALL is associated with worse survival as well as treatment-related morbidity. Inability to achieve a deep initial remission following Induction as evidenced by persistent MRD in the bone marrow is associated with poor survival and has thus become the predominant modern prognostic indicator. We therefore hypothesized that obesity at time of diagnosis of ALL is associated with MRD positivity at the end-of-Induction disease evaluation. Methods: In a cohort of children 1 - 20 years old treated for B-precursor ALL (BP-ALL) at our institution from 2008 to 2013 on Children's Oncology Group (COG) treatment regimens, we examined MRD at end-of-Induction as determined by multidimensional flow cytometry. A threshold of 0.01% was used to determine MRD positive versus negative as per COG regimens. Overweight and obese categories were defined as 85-95th and ≥95th percentile for body mass index (BMI) according to the CDC population norms. Logistic regression analyses were performed controlling for age, gender, ethnicity/race, presence/absence of Down Syndrome (due to the high prevalence of obesity), National Cancer Institute (NCI) risk category, cytogenetic classification (standard, favorable, unfavorable, unknown), and CNS status at diagnosis. BMI was evaluated as both a continuous variable and also as per normal, overweight, obese categories. Results: We identified 198 patients with BP-ALL and evaluable MRD, 119 with NCI SR-ALL and 79 with NCI HR-ALL. Of these, 55 (27.8%) had positive MRD at end-of-Induction [27 SR-ALL (22.7%), 28 HR-ALL (35.4%). In the obese group, 45.2% (19/42) were MRD+, compared to only 22.8% (29/127) of normal weight and 24.1% (7/29) of overweight patients. After controlling for above covariates, obese patients had a statistically significantly increased risk for MRD positivity at end-of-Induction [Odds Ratio (OR) 2.64, 95 percent Confidence Interval (95%CI) 1.13-6.19, p=0.025]. Similarly, each percentile increase in BMI significantly corresponded to an increased risk for MRD positivity (OR 1.08, 95%CI 1.00-1.17, p=0.046). Conclusion: Obese children at diagnosis of BP-ALL are at significantly increased risk for persistent MRD in the bone marrow at end-of-Induction. With the established strong adverse association of persistent MRD with poorer survival, this implies that obesity adversely influences survival as early as this initial phase of treatment. Our results support the need for further research into mechanisms underlying this phenomenon and potential up-front strategies to improve efficiency of remission induction in this population. Citation Format: Etan Orgel, Jonathan Tucci, Wassem Alhushki, David R. Freyer, Hisham Abdel-Azim, Steven D. Mittelman. Childhood obesity is associated with persistent minimal residual disease (MRD) following induction therapy for pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2185. doi:10.1158/1538-7445.AM2014-2185

Abstract 3574 Intensification of therapy for acute lymphoblastic leukemia (ALL) has improved long-term survival but is associated with considerable treatment-related toxicity (TRT). While obesity has been shown to affect event-free survival (EFS) and overall survival (OS) in ALL, little information exists as to the effect of extremes of weight (underweight or obese) on morbidity due to TRT. To this end, we conducted a secondary analysis of 1,902 children treated on the Children's Oncology Group study CCG-1961 to determine whether weight extremes influence development of TRT and EFS/OS in children with higher risk ALL. CCG-1961 was a randomized study for patients 1–21 years old with National Cancer Institute High-Risk ALL (HR-ALL) that evaluated marrow response at day 7 of Induction and compared regimens of differing intensity and/or duration (for Rapid Early Responders, RER) or anthracycline used in Delayed Intensification (for Slow Early Responders, SER). Weight category was determined using the United States Centers for Disease Control and Prevention Z-scores for body mass index (BMI) by age (age ≥ 2 yrs) and weight by length (age 95th percentile). At diagnosis, 107 patients (5.6%) were underweight and 264 were obese (13.9%). Multivariate linear and logistic regression analyses controlled for age, gender, race/ethnicity, payer type (as a surrogate for socioeconomic status), initial white blood cell count, presence of central nervous system disease, RER/SER status, and phase of treatment independent of regimen. All of the preceding predictors were independently significantly associated with development of grade 3/4 non-hematological toxicity in multivariate analysis (p Our results demonstrate statistically significant increases in toxicity for both extremes of weight. Weight category at start of each phase was predictive of developing grade 3/4 non-hematological toxicity during that phase (p Our data indicate that for children with HR-ALL, extremes of weight are associated with significantly increased risk for TRT that is more infectious/hematopoietic in underweight patients and more hepatic/pancreatic in obese patients. With a median follow-up of 7.1 years, EFS was lower at both weight extremes versus healthy/overweight children, but in this analysis did not reach statistical significance. These findings provide insights into the nutritional status of children and adolescents with ALL that could lead to interventions designed to mitigate the impact of weight extremes upon their tolerance of therapy, quality of life and survival. Disclosures: No relevant conflicts of interest to declare.