Pediatric acute myeloid leukemia - novel approaches.

PURPOSE OF REVIEW: Despite higher remission and survival rates than observed in adults, children with acute myeloid leukemia (AML) still suffer unacceptably high rates of treatment failure and late toxicities. Ongoing work aims to improve these long-term outcomes through improvements in the utilization of current therapies, the incorporation of novel chemotherapy agents, and improved use of current or novel cellular and immunotherapeutic approaches. In this review, we highlight recent advances and contextualize them within this evolving landscape. RECENT FINDINGS: Novel agents such as the B-cell lymphoma 2 inhibitor venetoclax and the menin inhibitors have shown promising results with implications for large portions of the pediatric AML population. Older agents are being used in novel combinations (e.g. gemtuzumab ozogamicin) or are expanding into pediatrics after longer use in adults (e.g. Fms-like tyrosine kinase 3 inhibitors). Finally, immunotherapeutic approaches offer new options for patients with high-risk or relapsed disease. SUMMARY: Recent findings have altered the landscape of pediatric AML therapy with exciting immediate and long-term implications. Ongoing studies may soon define this as standard as well. After many years in which few new therapies have become available for children with AML, recent and upcoming advances may soon dramatically alter the therapeutic landscape.

Genomic analysis of venous thrombosis in children with acute lymphoblastic leukemia from diverse ancestries.

Venous thrombosis is a common adverse effect of modern therapy for acute lymphoblastic leukemia (ALL). Prior studies to identify risks of thrombosis in pediatric ALL have been limited by genetic screens of pre-identified genetic variants or genome- wide association studies (GWAS) in ancestrally uniform populations. To address this, we performed a retrospective cohort evaluation of thrombosis risk in 1,005 children treated for newly diagnosed ALL. Genetic risk factors were comprehensively evaluated from genome-wide single nucleotide polymorphism (SNP) arrays and were evaluated using Cox regression adjusting for identified clinical risk factors and genetic ancestry. The cumulative incidence of thrombosis was 7.8%. In multivariate analysis, older age, T-lineage ALL, and non-O blood group were associated with increased thrombosis while non-low-risk treatment and higher presenting white blood cell count trended toward increased thrombosis. No SNP reached genome-wide significance. The SNP most strongly associated with thrombosis was rs2874964 near RFXAP (G risk allele; P=4x10-7; hazard ratio [HR] =2.8). In patients of non-European ancestry, rs55689276 near the α globin cluster (P=1.28x10-6; HR=27) was most strongly associated with thrombosis. Among GWAS catalogue SNP reported to be associated with thrombosis, rs2519093 (T risk allele, P=4.8x10-4; HR=2.1), an intronic variant in ABO, was most strongly associated with risk in this cohort. Classic thrombophilia risks were not associated with thrombosis. Our study confirms known clinical risk features associated with thrombosis risk in children with ALL. In this ancestrally diverse cohort, genetic risks linked to thrombosis risk aggregated in erythrocyte-related SNP, suggesting the critical role of this tissue in thrombosis risk.

Clinical and genomic characterization of an ATRA-insensitive acute promyelocytic leukemia variant with a FNDC3B::RARB fusion.

The promyelocytic leukemia-retinoic acid receptor-α (PML::RARA) fusion is the hallmark of acute promyelocytic leukemia (APL) and is observed in over 95% of APL cases. RARA and homologous receptors RARB and RARG are occasionally fused to other gene partners, which differentially affect sensitivity to targeted therapies. Most APLs without RARA fusions have rearrangements involving RARG or RARB, both of which frequently show resistance to all-trans-retinoic acid (ATRA) and/or multiagent chemotherapy for acute myeloid leukemia (AML). We present a 13-year-old male diagnosed with variant APL with a novel FNDC3B::RARB in-frame fusion that showed no response to ATRA but responded well to conventional AML therapy. While FNDC3B has been identified as a rare RARA translocation partner in ATRA-sensitive variant APL, it has never been reported as a fusion partner with RARB and it is only the second known fusion partner with RARB in variant APL. We also show that this novel fusion confers an RNA expression signature that is similar to APL, despite clinical resistance to ATRA monotherapy.

Characterisation of children and adolescents with acute lymphoblastic leukaemia who presented without peripheral blood blasts at diagnosis.

Of 1003 children with acute lymphoblastic leukaemia (ALL), 147 (14.7%) presented without peripheral blood blasts (PBB). While absence of PBB was not independently associated with survival outcomes when compared to those with PBB, patients without PBB had distinct genetic and clinical characteristics. Notably, we identified a novel genotype-phenotype relationship, in that the patients without PBB had a significantly higher incidence of hyperdiploid B-ALL, accounting for almost half of all patients without PBB (46.9% vs. 22.7%, p < 0.001). Further, absence of PBB was associated with decreased rates of leukaemia involvement of the central nervous system (p < 0.001).

Top advances of the year: Pediatric oncology.

Accelerated discovery and collaborative research continue to highlight the remarkable progress that has been made in the diagnosis and treatment of pediatric cancers. This manuscript highlights important discoveries on how precision oncology is being incorporated into the diagnosis and treatment of childhood cancer at the national level to identify promising new therapies using a tumor-agnostic approach. In addition, we have highlighted three articles that incorporate genomics and cell-free DNA to better classify, monitor and incorporate risk-based therapies for children with medulloblastoma. Finally, we highlighted the important role of monclonal antiobody therapy in the treatment of recurrent B-cell leukemia and newly diagnosed high-risk neuroblastoma.

Comprehensive analysis of dose intensity of acute lymphoblastic leukemia chemotherapy.

Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St. Jude Total 15 (T15, n=365) and pegaspargase in Total 16 (T16, n=524), we tallied the dose intensities for all drugs on the low-risk or standard-risk arms, analyzing 504,039 dosing records. The median dose intensity for each drug ranged from 61-100%. Dose intensities for several drugs were more than 10% higher on T15 than on T16: cyclophosphamide (P<0.0001 for the standard- risk arm), cytarabine (P<0.0001 for the standard-risk arm), and mercaptopurine (P<0.0001 for the low-risk arm and P<0.0001 for the standardrisk arm). We attributed the lower dosages on T16 to the higher asparaginase dosages on T16 than on T15 (P<0.0001 for both the low-risk and standard-risk arms), with higher dose-intensity for mercaptopurine in those with anti-asparaginase antibodies than in those without (P=5.62x10-3 for T15 standard risk and P=1.43x10-4 for T16 standard risk). Neutrophil count did not differ between protocols for low-risk patients (P=0.18) and was actually lower for standard-risk patients on T16 than on T15 (P<0.0001) despite lower dosages of most drugs on T16. Patients with low asparaginase dose intensity had higher methotrexate dose intensity with no impact on prognosis. The only dose intensity measure predicting a higher risk of relapse on both studies was higher mercaptopurine dose intensity, but this did not reach statistical significance (P=0.03 T15; P=0.07 T16). In these intensive multiagent trials, higher dosages of asparaginase compromised the dosing of other drugs for acute lymphoblastic leukemia, particularly mercaptopurine, but lower chemotherapy dose intensity was not associated with relapse.

Dasatinib does not exacerbate dexamethasone-induced osteonecrosis in murine models of acute lymphoblastic leukemia therapy.

INTRODUCTION: There are clinical reports that the incorporation of dasatinib may increase the frequency of osteonecrosis in acute lymphoblastic leukemia (ALL) treatment regimens. No rigorous testing of this hypothesis is available to guide clinicians. METHODS: We tested whether oral dasatinib increased the frequency of dexamethasone-induced osteonecrosis in a murine model and tested its effects on dexamethasone's antileukemic efficacy in a murine BCR-ABL+ model of ALL. RESULTS: Dasatinib did not change the frequency of osteonecrosis (p = .99) nor of arteriopathy (p = .36) in dexamethasone-treated mice when given at dosages that achieved clinically relevant steady-state dasatinib plasma concentrations of 53.1 ng/ml (95% CI: 43.5-57.3 ng/ml). These dasatinib exposures were not associated with increased dexamethasone plasma exposure in nonleukemia-bearing mice. These same dosages were not associated with any decrement in antileukemic efficacy of dexamethasone in a responsive BCR-ABL+ model of ALL. CONCLUSIONS: Based on the results of our preclinical murine studies, we conclude that dasatinib is unlikely to increase the osteonecrotic effects of dexamethasone in ALL regimens.

Fenofibrate reduces osteonecrosis without affecting antileukemic efficacy in dexamethasone-treated mice.

Recent clinical trials in children with acute lymphoblastic leukemia (ALL) indicate that severe hypertriglyceridemia (> 1000 mg/dL) during therapy is associated with increased frequency of symptomatic osteonecrosis. Interventions to lower triglycerides have been considered, but there have been no pre-clinical studies investigating impact of lowering triglycerides on osteonecrosis risk, nor whether such interventions interfere with the antileukemic efficacy of ALL treatment. We utilized our clinically relevant mouse model of dexamethasone-induced osteonecrosis to determine if fenofibrate decreased osteonecrosis. To test whether fenofibrate affected the antileukemic efficacy of dexamethasone, we utilized a BCR-ABL+ model of ALL. Serum triglycerides were reduced with fenofibrate throughout treatment, with the most pronounced 4.5-fold decrease at week 3 (p<1x10-6). Both frequency (33% versus 74%, p=0.006) and severity (median necrosis score of 0 versus 75; p=6x10-5) of osteonecrosis were reduced with fenofibrate. Fenofibrate had no impact on BCR-ABL+ ALL survival (p=0.65) nor on the antileukemic properties of dexamethasone (p=0.49). These data suggest that lowering triglycerides with fenofibrate reduces dexamethasone-induced osteonecrosis while maintaining antileukemic efficacy, and thus may be considered for clinical trials.

Effects of zoledronic acid on osteonecrosis and acute lymphoblastic leukemia treatment efficacy in preclinical models.

BACKGROUND: Osteonecrosis is a devastating side effect of acute lymphoblastic leukemia (ALL) therapy. Associations between bone density loss and osteonecrosis have sparked interest in using bisphosphonates to reduce this complication. PROCEDURE: We assessed the impact of zoledronic acid (ZA) on the development of osteonecrosis in murine models when used either throughout therapy (continuous administration) or late in therapy after vascular lesions have developed but before osteonecrosis has occurred. Effects on bone density were measured using microcomputed tomography (µCT)-assessed tibial cortical thickness, while osteonecrosis was assessed histologically in the distal femur. Effects on antileukemic efficacy of chemotherapy were evaluated in both immunocompetent/syngeneic and patient-derived xenograft (PDX) models. RESULTS: Continuous administration of ZA with chemotherapy prevented chemotherapy-associated bone loss (p < .001) and reduced osteonecrosis (p = .048). Late initiation of ZA diminished bone loss (p < .001) but had no impact on the development of osteonecrosis (p = .93). In the immunocompetent murine ALL model, mice treated with ZA and chemotherapy succumbed to leukemia sooner than mice treated with chemotherapy alone (p = .046). Analysis using PDX showed a nonsignificant decrease in survival with ZA (p = .17). CONCLUSION: Our data indicate ZA may prevent osteonecrosis if begun with chemotherapy but showed no benefit when administered later in therapy. However, ZA may also reduce the antileukemic efficacy of chemotherapy.

Ultrasound has limited diagnostic utility in children with acute lymphoblastic leukemia developing pancreatitis.

PURPOSE: Acute pancreatitis (AP) due to chemotherapy-induced pancreatic injury is a common side effect of treatment for acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The American College of Radiology recommends ultrasound (US) for initial imaging of AP in all populations to assess for ductal obstruction. However, US may be insensitive to diagnose and assess chemotherapy-associated AP. METHODS AND MATERIALS: The institutional review board approved this retrospective study. Patients with ALL and AP were identified from protocol databases, using Common Terminology Criteria for Adverse Events (CTCAE) version 3. Chemotherapy dosing, amylase/lipase levels, clinical symptoms, and US/computed tomography (CT) reports within 10 days of diagnosis were recorded. All CT images were reviewed for revised Atlanta classification and CT severity index (CTSI). RESULTS: Sixty-nine patients, aged 2-21 years, experienced 88 episodes of AP, undergoing 98 US and 44 CT. Seventy-two events (82%) occurred within 30 days of asparaginase administration. Sixty-nine episodes (78%) were initially diagnosed by the presence of abdominal pain and pancreatic enzyme elevation. Overall sensitivities for AP detection were 47% using US and 98% for CT. US sensitivity was greatest in CTCAE grade 4 (86%) and necrotizing pancreatitis (67%). CONCLUSIONS: Most cases of AP in children with ALL can be diagnosed with clinical history and labs. US has limited sensitivity in detecting pancreatitis in this population. Imaging to diagnose AP in this patient population could be limited to clinically equivocal cases.

Epidural blood patch for post-dural puncture headaches in adult and paediatric patients with malignancies: a review.

Many anaesthetists are hesitant to perform epidural blood patch in patients with cancer because of the potential risk of seeding the CNS with malignant cells. Recent evidence suggests that anaesthetists may view malignancy as a relative contraindication to epidural blood patch rather than an absolute contraindication. This review article summarises the clinical dilemma, reviews the existing literature, and proposes a treatment algorithm that includes the utilisation of for the management of post-dural puncture headache in the oncology population.

Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study.

BACKGROUND: Outcomes for children with relapsed or refractory acute myeloid leukaemia remain poor. The BCL-2 inhibitor, venetoclax, has shown promising activity in combination with hypomethylating agents and low-dose cytarabine in older adults for whom chemotherapy is not suitable with newly diagnosed acute myeloid leukaemia. We aimed to determine the safety and explore the activity of venetoclax in combination with standard and high-dose chemotherapy in paediatric patients with relapsed or refractory acute myeloid leukaemia. METHODS: We did a phase 1, dose-escalation study at three research hospitals in the USA. Eligible patients were aged 2-22 years with relapsed or refractory acute myeloid leukaemia or acute leukaemia of ambiguous lineage with adequate organ function and performance status. During dose escalation, participants received venetoclax orally once per day in continuous 28-day cycles at either 240 mg/m2 or 360 mg/m2, in combination with cytarabine received intravenously every 12 h at either 100 mg/m2 for 20 doses or 1000 mg/m2 for eight doses, with or without intravenous idarubicin (12 mg/m2) as a single dose, using a rolling-6 accrual strategy. The primary endpoint was the recommended phase 2 dose of venetoclax plus chemotherapy and the secondary endpoint was the proportion of patients treated at the recommended phase 2 dose who achieved complete remission or complete remission with incomplete haematological recovery. Analyses were done on patients who received combination therapy. The study is registered with ClinicalTrials.gov (NCT03194932) and is now enrolling to address secondary and exploratory objectives. FINDINGS: Between July 1, 2017, and July 2, 2019, 38 patients were enrolled (aged 3-22 years; median 10 [IQR 7-13]), 36 of whom received combination therapy with dose escalation, with a median follow-up of 7·1 months (IQR 5·1-11·2). The recommended phase 2 dose of venetoclax was found to be 360 mg/m2 (maximum 600 mg) combined with cytarabine (1000 mg/m2 per dose for eight doses), with or without idarubicin (12 mg/m2 as a single dose). Overall responses were observed in 24 (69%) of the 35 patients who were evaluable after cycle 1. Among the 20 patients treated at the recommended phase 2 dose, 14 (70%, 95% CI 46-88) showed complete response with or without complete haematological recovery, and two (10%) showed partial response. The most common grade 3-4 adverse events were febrile neutropenia (22 [66%]), bloodstream infections (six [16%]), and invasive fungal infections (six [16%]). Treatment-related death occurred in one patient due to colitis and sepsis. INTERPRETATION: The safety and activity of venetoclax plus chemotherapy in paediatric patients with heavily relapsed and refractory acute myeloid leukaemia suggests that this combination should be tested in newly diagnosed paediatric patients with high-risk acute myeloid leukaemia. FUNDING: US National Institutes of Health, American Lebanese Syrian Associated Charities, AbbVie, and Gateway for Cancer Research.

Diabetes mellitus among adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Greater than one-half of children who are treated for acute lymphoblastic leukemia (ALL) develop ≥1 treatment-related medical conditions in their lifetime, many of which are known risk factors for diabetes mellitus. In the current study, the authors evaluated the prevalence and risk factors of diabetes mellitus among clinically assessed adult survivors of childhood ALL METHODS: The authors performed a retrospective evaluation of data from survivors of ALL and community controls who were enrolled in the St. Jude Lifetime Cohort Study between October 1, 2007, and June 30, 2016. Participants were adults with ≥10 years of survival of childhood ALL and community controls who completed clinical and laboratory evaluations. Data for the current analysis were abstracted from medical records. Exposures evaluated herein included chemotherapy and radiation exposures and medical history, including drug-induced diabetes mellitus. RESULTS: Of 1360 eligible adults who were ≥10-year survivors of childhood ALL, a total of 1044 completed the evaluations; these individuals had a mean age of 33.97±9.14 years and 50.86% were male. The 368 controls, 45.65% of whom were male, had a mean age of 35.33±10.21 years. Type 2 diabetes mellitus (T2DM) was found in approximately 7.47% of survivors and 3.80% of controls (odds ratio [OR], 2.07; 95% CI, 1.11-3.87). In adjusted models, among survivors, older age (OR, 1.05 for each additional year; 95% CI, 1.02-1.08), body mass index ≥30 kg/m2 (OR, 7.40; 95% CI, 2.61-20.97), and drug-induced diabetes mellitus occurring during ALL therapy (OR, 4.67; 95% CI, 2.53-8.61) were found to be associated with T2DM. CONCLUSIONS: Adult survivors of childhood ALL are at an increased risk of T2DM. Adult survivors of childhood ALL who are of older age, with an overweight or obese body mass index, and/or who developed drug-induced diabetes mellitus during treatment should be closely monitored for T2DM during long-term follow-up.

Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia.

BACKGROUND: Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML). METHODS: To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m2 ) before and in combination with fludarabine and cytarabine. RESULTS: All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status. CONCLUSIONS: Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.

Team approach: Management of osteonecrosis in children with acute lymphoblastic leukemia.

With current treatments for acute lymphoblastic leukemia (ALL), the overall prognosis for survival is favorable. Increasing emphasis is placed on recognizing and managing the long-term consequences of ALL and its treatment, particularly involving osteonecrosis. Early osteonecrosis diagnosis and management may improve outcomes and is best accomplished through coordinated teams that may include hematologic oncologists, radiologists, orthopedic surgeons, physical therapists, and the patient and their family. Magnetic resonance imaging is the "gold standard" for diagnosis of early-stage and/or multifocal osteonecrosis. Treatments for osteonecrosis in ALL patients are risk stratified and may include observation, corticosteroid or chemotherapy adjustment, and pharmaceutical or surgical approaches.

Higher plasma asparaginase activity after intramuscular than intravenous Erwinia asparaginase.

It is unclear if dosing intervals for Erwinase can be extended with intramuscular (i.m.) versus intravenous (i.v.) dosing. Children with acute lymphoblastic leukemia received Erwinase at 30 000-42 000 IU/m2 i.v. or i.m. I.m. Erwinase (n = 22) achieved activity above 0.1 IU/mL for longer than i.v. Erwinase (n = 33) (3.4 vs 2.9 days, P = 0.0007). With 30 000 IU/m2 Monday, Wednesday, Friday, more patients achieved adequate concentrations over the weekend with i.m. vs i.v. dosing (P = 5 × 10-36 ). A schedule with i.v. doses on Monday and Wednesday and i.m. doses on Friday of 30 000 IU/m2 maintained activity > 0.1 IU/mL over the weekend in 80% of patients.

Whole-joint magnetic resonance imaging to assess osteonecrosis in pediatric patients with acute lymphoblastic lymphoma.

BACKGROUND: Osteonecrosis is a debilitating complication in children and adolescents with acute lymphoblastic leukemia or acute lymphoblastic lymphoma (LLy). An objective screening test to identify patients at risk for symptomatic, extensive joint involvement will help manage osteonecrosis. METHODS: We performed a prospective, longitudinal pilot study with whole-joint magnetic resonance imaging (MRI) of shoulders, elbows, hips, knees, ankles, and hindfeet to evaluate the incidence and timing of osteonecrosis involving multiple joints in 15 patients with LLy aged 9-21 years at diagnosis. RESULTS: Osteonecrosis affecting ≥30% of the epiphysis occurred in eight of 15 patients, with a high prevalence in hips (12 of 26 examined [46%]) and knees (10 of 26 [38%]) post reinduction I and in shoulders (seven of 20 [35%]) post reinduction II. Most osteonecrotic hips and knees with ≥30% epiphyseal involvement became symptomatic and/or underwent surgery (100% and 82%, respectively). All eight patients with ≥30% epiphyseal involvement had multijoint involvement. Seven of these patients had hip or knee osteonecrosis by the end of remission induction, and only these patients developed osteonecrosis that became symptomatic and/or underwent surgery in their hips, knees, shoulders, ankles, and/or feet; all of these joints were associated with epiphyseal abnormalities on post reinduction I imaging. CONCLUSIONS: MRI screening in adolescent patients with LLy revealed osteonecrosis in multiple joints. Initial screening with hip and knee MRI at the end of induction may identify susceptible patients who could benefit from referrals to subspecialties, more extensive follow-up imaging of other joints, and early medical and surgical interventions.

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia.

BACKGROUND: Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l-asparaginase was front-line therapy versus the pegylated formulation (PEG-asparaginase) in Total XVI (TXVI). PROCEDURE: Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low-risk (LR) or standard/high-risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride-PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded. RESULTS: The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG-asparaginase (4.5-fold increase; P <1 × 10-15 ). SHR patients treated with PEG-asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l-asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride-PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4). CONCLUSION: Triglycerides were affected more by PEG-asparaginase than native l-asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.

Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.

BACKGROUND: Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated. PROCEDURE: Patients with ALL on St. Jude Total Therapy XV (n = 365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institute's Common Terminology for Adverse Events (version 3.0). In a preclinical model, Balb/cJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy. RESULTS: We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (≥grade 2) than those who did not (OR: 1.88; 95% CI, 1.03-3.41, P = 0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P = 0.00086) and arteriopathy (P = 0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P = 0.00045) and arteriopathy (P = 0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS. CONCLUSIONS: These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis.

No evidence that G6PD deficiency affects the efficacy or safety of daunorubicin in acute lymphoblastic leukemia induction therapy.

BACKGROUND/OBJECTIVES: Anthracyclines are used in induction therapy of pediatric acute lymphoblastic leukemia (ALL) and are known to generate oxidative stress; whether this translates into enhanced antileukemic activity or hemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency is unknown. DESIGN/METHODS: Among 726 pediatric patients with newly diagnosed ALL treated at St. Jude Children's Research Hospital, 22 had deficient G6PD activity. We compared the prevalence of positive minimal residual disease (MRD) ≥1% at Day 15/Day 19 of induction or ≥0.01% at Day 42/Day 46 (end of induction) and the number of red blood cell (RBC) transfusions after daunorubicin in induction between patients with or without G6PD deficiency, adjusting for ALL risk group, treatment protocol, age, and gender. RESULTS: There was no difference in Day 15/19 (P = 1) or end of induction MRD (P = 0.76) nor in the number of RBC transfusions (P = 0.73); the lack of association with MRD was confirmed in a dataset of 1192 newly diagnosed male patients enrolled in a Children's Oncology Group trial (P = 0.78). CONCLUSION: We found no evidence that G6PD deficiency affects daunorubicin activity during induction treatment for ALL.