Risk factors and clinical impact of thrombosis during induction chemotherapy for pediatric acute lymphoblastic leukemia: A report from CYP-C.

Thromboembolism (TE) is associated with reduced survival in pediatric acute lymphoblastic leukemia (ALL). It has been hypothesized that TE might signal leukemic aggressiveness. The objective was to determine risk factors for TE during ALL induction (TEind ) therapy and whether TEind is associated with treatment refractoriness. This retrospective cohort study using the population-based Cancer in Young People Canada (CYP-C) registry included children <15 years of age diagnosed with ALL (2000-2019) and treated at one of 12 Canadian pediatric centers outside of Ontario. Univariate and multivariable logistic regression models were used to determine risk factors for TEind and whether TEind predicted induction failure and ALL treatment intensification. The impact of TEind on overall and event-free survival was estimated using Cox proportional hazard regression models. The study included 2589 children, of which 45 (1.7%) developed a TEind . Age (<1 year and ≥10 years vs. 1-<10 years), T-cell phenotype, high-risk ALL, and central nervous system involvement were all associated with TEind in univariate analysis. Age and T-cell phenotype remained independent predictors of TEind in multivariable analysis. Induction failure occurred in 53 patients (2.1%). TEind was not associated with induction failure (OR: not estimable) or treatment intensification (adjusted OR [95% CI]: 0.66 [0.26-1.69]). TEind was independently associated with overall survival (adjusted HR [95% CI]: 2.54 [1.20-5.03]) but not event-free survival (adjusted HR [95% CI] 1.86 [0.98-3.51]). In this population-based study of children treated with contemporary chemotherapy protocols, TEind was associated with age and T-cell phenotype and mortality but did not predict induction failure.

Impairment of health-related quality of life for children with acute lymphoblastic leukemia over the first year of therapy: A report from the DFCI ALL Consortium.

BACKGROUND: Children treated for acute lymphoblastic leukemia (ALL) receive prolonged treatment, resulting in toxicities that affect health-related quality of life (HR-QoL). Longitudinal assessment of HR-QoL allows improved understanding of experiences with ALL. PROCEDURE: Parent-proxy and child self-report HR-QoL over the first year of chemotherapy were evaluated in the context of DFCI Protocol 05-001, a phase 3 therapeutic trial for childhood ALL. HR-QoL was assessed with the Pediatric Quality-of-Life inventory (PedsQL) domains for Pain and Hurt, Procedural Anxiety, Treatment Anxiety, Emotional Functioning, General Fatigue, and Sleep/Rest Fatigue. RESULTS: Total of 281 subjects participated, with 141 contributing at least one child report and 280 at least one parent report. Children with ALL experienced impairment in HR-QoL by both patient and parent report compared to the published PedsQL reference population at each time point on each subscale. Agreement between parent and child assessment of HR-QoL impairment was high, particularly among those for whom HR-QoL was not impaired. During the consolidation phase, which included intensive asparaginase administration, multivariable models demonstrated more impairment in Treatment Anxiety and Procedural Anxiety for children treated with intramuscular asparaginase than intravenous asparaginase, but randomized groups were otherwise similar in HR-QoL. Impairments in fatigue, both General and Sleep/Rest, were evident throughout and worse during intensive asparaginase therapy. CONCLUSIONS: This report examines HR-QoL for children with ALL during treatment longitudinally by parent and patient report across multiple domains. Children with ALL demonstrated substantial impairment in HR-QoL, particularly related to fatigue during intensive consolidation therapy including asparaginase.

Predictors of thrombosis in children receiving therapy for acute lymphoblastic leukemia: Results from Dana-Farber Cancer Institute ALL Consortium trial 05-001.

BACKGROUND/OBJECTIVES: Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial. METHODS: Clinical and laboratory data including TE events were prospectively collected. PCR-based allelic discrimination assay identified single-nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL-immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence of TE. Cox regression modeling explored the impact of TE on survival. RESULTS: Of 794 patients [median age 4.97 (range, 1.04-17.96) years; males 441], 100 developed TE; 25-month cumulative incidence 13.0% (95% CI, 10.7%-15.5%). Univariate analyses identified older age (≥10 years), presenting leucocyte count, T-ALL, high-risk ALL, and non-O blood group as risk factors. Age and non-O blood group were independent predictors of TE on multivariable regression; the blood group impact being most evident in patients 1-5 years of age (P = 0.011). TE did not impact survival. Induction TE was independently associated with induction failure (OR 6.45; 95% CI, 1.64-25.47; P = 0.008). CONCLUSION: We recommend further evaluation of these risk factors and consideration of thromboprophylaxis for patients ≥10 years (especially those ≥15 years) when receiving asparaginase.

Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: A report from CYP-C.

There are conflicting data about whether the development of cancer-associated thrombo-embolism (TE) negatively impacts survival in children. The objective was to determine whether TE during treatment was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). We performed a population-based retrospective cohort study using the Cancer in Young People-Canada registry. Children <15 years of age were diagnosed with de novo ALL (2000-2016). The primary exposure variable was radiologically-confirmed thrombo-embolism requiring medical intervention. Multivariable Cox regression models were used to determine the impact of thrombo-embolism on survival, where TE was time-dependent. We included 2006 children (median age: 4 years, 88.5% precursor B-cell ALL). Thrombo-embolism occurred in 113 patients (5.6%), at a median time of 107 days (interquartile range: 35-184 days) after ALL diagnosis. Among standard/low-risk patients, 41/1165 (3.5%) developed TE while among high/very high-risk patients, 72/841 (8.6%) developed TE. Patients with TE had a significantly worse OS (adjusted HR [aHR] of death: 2.61, 95% CI: 1.62-4.22, p < 0.001) and EFS (aHR of an event [death, relapse, second malignancy]: 2.03, 95% CI: 1.35-3.05, p = 0.001), compared with patients without TE. No statistically significant difference was seen in standard/low risk ALL for OS and EFS, but TE was associated with a significantly lower OS and EFS in children with high/very high-risk ALL (aHR of death: 2.90, 95% CI: 1.79-4.72, p < 0.001; aHR of an event: 2.02, 95% CI: 1.30-3.12, p = 0.002). Thus, TE led to a statistically significant reduction in OS and EFS in children with high risk/very high-risk leukemia.

Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001.

BACKGROUND/OBJECTIVES: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy. DESIGN/METHODS: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes. RESULTS: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10-4 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS. CONCLUSIONS: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.

Relationships of Bone Mineral Density to Whole Body Mass, Fat Mass and Fat-free Mass in Long-term Survivors of Acute Lymphoblastic Leukemia in Childhood.

Body size influences bone mineral density (BMD) in health. Relationships of BMD with body mass index, fat mass (FM), fat-free mass, and appendicular lean mass were explored in acute lymphoblastic leukemia (ALL) survivors (n=75; 41 males; 45 standard risk ALL) >10 years from diagnosis. Dual energy radiograph absorptiometry performed body composition analysis. Relationships were assessed by regression analyses and Pearson correlation coefficients (r). Twenty subjects (26.3%) were osteopenic; lumbar spine (LS) BMD Z score <-1.00. Age at diagnosis, sex, ALL risk-category, type of post-induction steroid or cranial radiation did not correlate with LS or whole body (WB) BMD. Body mass index correlated significantly with LS BMD (r=0.333, P=0.004) and WB BMD (r=0.271, P=0.033). FM index (FM/height²) Z score showed no significant correlation with LS or WB BMD. Fat-free mass index Z score correlated strongly with LS BMD (r=0.386, P=0.013) and WB BMD (r=0.605, P<0.001) in males but not in females. The appendicular lean mass index, a surrogate for skeletal muscle mass, correlated significantly with LS BMD (r=0.367, P=0.018) and WB BMD (r=0.604, P<0.001) in males but not in females. Future studies to evaluate interventions to enhance BMD focused on improving body composition particularly skeletal muscle mass are warranted.

Feasibility and safety of delivering full-dose anticoagulation therapy in children treated according to Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium therapy protocols.

BACKGROUND: The literature is void of an evidence-based anticoagulation therapy (ACT) management strategy in the context of thrombocytopenia. We examined the impact of thrombocytopenia on low-molecular-weight heparin (LMWH) dosing and incidence of bleeding in children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) who developed thromboembolism (TE) during therapy according to DFCI ALL protocols. PROCEDURE: Patient records from our tertiary care center were reviewed for demographics, details of diagnoses and therapy of ALL/LL and TE diagnoses, platelet counts during ACT, LMWH dosing, and bleeding episodes. RESULTS: Thirty-nine TEs were diagnosed in 33 patients [mean age 9 years (range, 2.5-18); 16 males and 31 with ALL] during the study period. A majority (85%) of patients were diagnosed with TE in the consolidation phase with mean time to TE 5.75 months from ALL/LL diagnosis. All patients received LMWH, and the median duration of ACT was 5.9 months (range, 1-11 months). Platelets were measured weekly. On 29 occasions, platelet nadir was <50 × 109 /L, and twice it was < 20 × 109 /L. One (3%) patient had major bleeding episode while on ACT. Platelet count at the time of bleeding was 222 × 109 /L. Ninety-two procedures [83 lumbar punctures (LPs), 9 central venous line (CVL) insertion/revision] were completed without bleeding complications. Asparaginase was held temporarily with TE diagnosis in 48% of patients; most (88%) patients completed all scheduled doses as per protocol. CONCLUSIONS: Ability to administer full-dose LMWH, expected bleeding rate, and completion of asparaginase doses while on ACT suggest full-dose ACT is feasible and safe in children with ALL/LL who develop TE during DFCI ALL consortium therapy protocols.

Body composition in long-term survivors of acute lymphoblastic leukemia diagnosed in childhood and adolescence: A focus on sarcopenic obesity.

BACKGROUND: The late effects of treatment for acute lymphoblastic leukemia (ALL) include disordered body composition, especially obesity. Less attention has been focused on the loss of skeletal muscle mass (SMM) and the combined morbidity of sarcopenic obesity. METHODS: A cross-sectional study of body composition was undertaken via dual-energy x-ray absorptiometry in 75 long-term survivors of ALL (more than 10 years after the diagnosis). Measures were obtained of the fat mass (FM), fat-free mass (equivalent to the lean body mass [LBM]), and whole-body bone mineral content. Health-related quality of life (HRQL) was measured with the Health Utilities Index. RESULTS: The sum of the FM, LBM, and whole-body bone mineral content matched the total body weight measured directly (r = 0.998). The appendicular lean mass (ALM) was derived from the LBM in all 4 limbs and accounted for approximately 75% of the SMM. According to the fat mass index (FMI; ie, FM/height2 ), 12% of females and 18% of males were frankly obese by World Health Organization criteria. The median FMI z score was + 0.40, whereas the median z score for the appendicular lean mass index (ALMI; ie, ALM/height2 ) was -0.40. Sarcopenic obesity, defined as a positive FMI z score with a negative ALMI z score, was present in 32 subjects (43%). There were statistically significant and clinically important differences in overall HRQL between subjects with and without sarcopenic obesity. CONCLUSIONS: Sarcopenic obesity is prevalent in long-term survivors of ALL, and this places them in double jeopardy from excess body fat and inadequate SMM (eg, a combination of metabolic and frailty syndromes). It is associated with an adverse impact on overall HRQL. Cancer 2018;124:1225-31. © 2017 American Cancer Society.

Impact of baseline clinical and laboratory features on the risk of thrombosis in children with acute lymphoblastic leukemia: A prospective evaluation.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) have increased risk of thromboembolism (TE). However, the predictors of ALL-associated TE are as yet uncertain. OBJECTIVE: This exploratory, prospective cohort study evaluated the effects of clinical (age, gender, ALL risk group) and laboratory variables (hematological parameters, ABO blood group, inherited and acquired prothrombotic defects [PDs]) at diagnosis on the development of symptomatic TE (sTE) in children (aged 1 to ≤18) treated on the Dana-Farber Cancer Institute ALL 05-001 study. PROCEDURES: Samples collected prior to the start of ALL therapy were evaluated for genetic and acquired PDs (proteins C and S, antithrombin, procoagulant factors VIII (FVIII:C), IX, XI and von Willebrand factor antigen levels, gene polymorphisms of factor V G1691A, prothrombin gene G20210A and methylene tetrahydrofolate reductase C677T, anticardiolipin antibodies, fasting lipoprotein(a), and homocysteine). RESULTS: Of 131 enrolled patients (mean age [range] 6.4 [1-17] years) 70 were male patients and 20 patients (15%) developed sTE. Acquired or inherited PD had no impact on the risk of sTE. Multivariable analyses identified older age (odds ratio [OR] 1.13; 95% confidence interval [CI]: 1.01, 1.26) and non-O blood group (OR 3.64, 95% CI: 1.06, 12.51) as independent predictors for development of sTE. Patients with circulating blasts had higher odds of developing sTE (OR 6.66; 95% CI: 0.82, 53.85). CONCLUSION: Older age, non-O blood group, and presence of circulating blasts, but not PDs, predicted the risk of sTE during ALL therapy. We recommend evaluation of these novel risk factors in the development of ALL-associated TE. If confirmed, these easily accessible variables at diagnosis can help develop a risk-prediction model for ALL-associated TE.

An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001.

PURPOSE: This study compared the relative incidence of treatment-related toxicities and the event-free and overall survival between Hispanic and non-Hispanic children undergoing therapy for acute lymphoblastic leukemia (ALL) on Dana-Farber Cancer Institute ALL Consortium protocol 05-001. PATIENTS AND METHODS: Secondary analysis of prospectively collected data from a phase III multicenter study in children and adolescents of 1-18 years with previously untreated ALL. RESULTS: Between 2005 and 2011, 794 eligible patients enrolled on DFCI 05-001, 730 of whom were included in this analysis (19% [N = 150] Hispanic, 73% [N = 580] non-Hispanic). Hispanic patients were more likely to be ≥10 years of age (32% vs. 24%, P = 0.045) at diagnosis. Toxicity analyses revealed that Hispanic patients had significantly lower cumulative incidence of bone fracture (P < 0.001) and osteonecrosis (ON; P = 0.047). In multivariable risk regression, the risk of ON was significantly lower in Hispanic patients ≥10 years (HR 0.23; P = 0.006). Hispanic patients had significantly lower 5-year event-free survival (EFS) (79.4%; 95% CI: 71.6-85.2) and overall survival (OS) (89.2%; 95% CI: 82.7-93.4) than non-Hispanic patients (EFS: 87.5%; 95% CI: 84.5-90.0, P = 0.004; OS: 92.7%; 95% CI: 90.2-94.6, P = 0.006). Exploratory analyses revealed differences between Hispanic and non-Hispanic patients in the frequency of common variants in genes related to toxicity or ALL outcome. CONCLUSION: Hispanic children treated for ALL on DFCI 05-001 had fewer bone-related toxicities and inferior survival than non-Hispanic patients. While disease biology is one explanatory variable for outcome disparities, these findings suggest that biologic and non-biologic mechanisms affecting drug delivery and exposure in this population may be important contributing factors as well.

Outcome of children and adolescents with Down syndrome treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols 00-001 and 05-001.

BACKGROUND: Children and adolescents with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are reported to have increased relapse rates and therapy-related mortality (TRM). Treatment regimens for DS-ALL patients often include therapy modifications. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for patients with and without DS. PROCEDURES: We compared clinical and outcome data of DS (n = 38) and non-DS (n = 1,248) patients enrolled on two consecutive DFCI ALL trials 00-001 (2000-2004) and 05-001 (2005-2011) with similar risk adapted therapy regardless of DS status. RESULTS: There was no difference in demographic or presenting clinical features between two groups except absence of T-cell phenotype and lower frequency of hyperdiploidy in DS-ALL group. All DS-ALL patients achieved complete remission; four relapsed and one subsequently died. There was no TRM in DS-ALL patients. DS-ALL patients had significantly higher rates of mucositis (52% vs. 12%, p < 0.001), non-CNS thrombosis (18% vs. 8%; p = 0.036), and seizure (16% vs. 5%, p = 0.010). Compared to non-DS-ALL patients, DS-ALL patients had a higher incidence of infections during all therapy phases. The 5-year event-free and overall survival rates of DS-ALL patients were similar to non-DS-ALL patients (91% [95% confidence interval (CI), 81-100] vs. 84% [95% CI, 82-86]; 97% [95% CI, 92-100] vs. 91% [95% CI, 90-93]). CONCLUSION: The low rates of relapse and TRM indicate that uniform risk-stratified therapy for DS-ALL and non-DS-ALL patients on DFCI ALL Consortium protocols was safe and effective, although the increased rate of toxicity in the DS-ALL patients highlights the importance of supportive care during therapy.

Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study.

BACKGROUND: Thromboembolism (TE) is a serious complication in children with acute lymphoblastic leukemia (ALL). The incidence of symptomatic thromboembolism is as high as 14% and case fatality rate of ~15%. Further, development of thromboembolism interferes with the scheduled chemotherapy with potential impact on cure rates. The exact pathogenesis of ALL-associated thromboembolism is unknown. Concomitant administration of asparaginase and steroids, two important anti-leukemic agents, is shown to increase the risk of ALL-associated TE. Dana-Farber Cancer Institute (DFCI) ALL studies reported ~10% incidence of thrombosis with significantly increased risk in older children (≥10 yrs.) and those with high-risk ALL. The majority (90%) of thromboembolic events occurred in the Consolidation phase of therapy with concomitant asparaginase and steroids when high-risk patients (including all older patients) receive higher dose steroids. Certain inherited and acquired prothrombotic defects are known to contribute to the development of TE. German investigators documented ~50% incidence of TE during therapy with concomitant asparaginase and steroids, in children with at least one prothrombotic defect. However, current evidence regarding the role of prothrombotic defects in the development of ALL-associated TE is contradictory. Although thromboprophylaxis can prevent thromboembolism, ALL and it's therapy can increase the risk of bleeding. For judicious use of thromboprophylaxis, identifying a population at high risk for TE is important. The risk factors, including prothrombotic defects, predisposing to thrombosis in children with ALL have not been defined. METHODS: This prospective, observational cohort study aims to evaluate the prevalence of inherited prothrombotic defects in children with ALL treated on DFCI 05-01 protocol and the causal relationship of prothrombotic defects in combination with patient and disease-related factors to the development of TE. We hypothesize that the combination of prothrombotic defects and the intensive therapy with concomitant high dose steroids and asparaginase increases the risk of TE in older patients and patients with high-risk ALL. DISCUSSION: The results of the proposed study will help design studies of prophylactic anticoagulant therapy. Thromboprophylaxis given to a targeted population will likely reduce the incidence of TE in children with ALL and ultimately improve their quality of life and prospects for cure.

Minimal Residual Disease and Childhood Leukemia: Standard of Care Recommendations From the Pediatric Oncology Group of Ontario MRD Working Group.

Minimal residual disease (MRD) is an independent predictor of relapse risk in children with leukemia and is widely used for risk-adapted treatment. This article summarizes current evidence supporting the use of MRD, including clinical significance, current international clinical practice, impact statement, and recommended indications. The proposed MRD recommendations have been endorsed by the MRD Working Group of the Pediatric Oncology Group of Ontario and provide the foundation for a strategy that aims at equitable access to MRD evaluation for children with leukemia.

Fanconi Syndrome Secondary to Deferasirox in Diamond-Blackfan Anemia: Case Series and Recommendations for Early Diagnosis.

Deferasirox is an oral iron chelator used to treat patients with transfusion-related iron overload. We report, from two institutions, two children with Diamond-Blackfan anemia who developed Fanconi syndrome secondary to deferasirox administration, along with a review of the literature. The current recommendation for the laboratory monitoring of patients receiving deferasirox does not include serum electrolytes or urine analysis. Thus, despite routine clinic visits and bloodwork, these two patients presented with life-threatening electrolyte abnormalities requiring hospitalization. Hence, we propose the inclusion of serum electrolytes and urine analysis as part of routine monitoring to facilitate the early diagnosis of Fanconi syndrome in the context of high doses of deferasirox therapy.

Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial.

BACKGROUND: l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. METHODS: DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m(2) every 2 weeks) or intramuscular native E colil-asparaginase (30 doses of 25 000 IU/m(2) weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. FINDINGS: Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E colil-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E colil-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E colil-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E colil-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). INTERPRETATION: Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. FUNDING: National Cancer Institute and Enzon Pharmaceuticals.

The development of thromboembolism may increase the risk of osteonecrosis in children with acute lymphoblastic leukemia.

Previous studies indicate pathophysiological and epidemiological parallels between osteonecrosis (ON) and thromboembolism (TE), two common treatment-related morbidities in acute lymphoblastic leukemia (ALL). To elucidate risk factors for ON and explore the relationship between ON and TE, we undertook a retrospective study of children (n = 208) with ALL. Twenty-one (10.1%) children developed ON and 42 (20.2%) TE on therapy. Thromboembolism was a significant predictor of ON on univariate (OR 8.85) and multivariate analysis, along with older age and PEGylated asparaginase. This observation supports a role for hypercoagulability in the pathogenesis of ON. Larger prospective studies are needed to further test these findings.

Pyomyositis Causing Temporary Quadriparesis During Induction Therapy for Acute Lymphoblastic Leukemia: Case Report and Review of the Literature.

Pyomyositis (PM) is a purulent infection of skeletal muscle. It is often associated with immunosuppression in temperate climates. Herein, we report a case of PM causing temporary quadriparesis in a 14-year-old girl undergoing induction therapy for acute lymphoblastic leukemia and we review the reported pediatric cases associated with induction therapy for hematologic malignancies. Early symptoms of PM can be mistaken for the side effects of chemotherapeutic agents. Greater awareness of the clinical picture of PM will aid in early diagnosis and treatment. With appropriate medical therapy and timely abscess drainage, morbidity and mortality is greatly reduced.

Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia.

BACKGROUND: Doxorubicin is associated with progressive cardiac dysfunction, possibly through the formation of doxorubicin-iron complexes leading to free-radical injury. The authors determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin-associated cardiotoxicity in survivors of childhood high-risk acute lymphoblastic leukemia. METHODS: Peripheral blood was tested for 2 common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), which are biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography. RESULTS: A total of 184 patients had DNA results for at least 1 variant, and 167 had DNA results for both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations (P = .039), but not NT-proBNP. At a median of 2.2 years (range, 1.0 years-3.6 years) after diagnosis, the mean Z-scores for LV fractional shortening (-0.71 [standard error (SE), 0.25]; P = .008), mass (-0.84 [SE, 0.17]; P < .001), and end-systolic (-4.36 [SE, 0.26], P < .001) and end-diastolic (-0.68 [SE, 0.25]; P = .01) posterior wall thickness were found to be abnormal in children with either allele (n = 32). Noncarriers (n = 63) also were found to have below-normal LV mass (-0.45 [SE, 0.15]; P = .006) and end-systolic posterior wall thickness (-4.06 [SE, 0.17]; P < .001). Later follow-up demonstrated similar results. CONCLUSIONS: Doxorubicin-associated myocardial injury was associated with C282Y HFE carriers. Although LV mass and wall thickness were found to be abnormally low overall, they were even lower in HFE carriers, who also had reduced LV function. Screening newly diagnosed cancer patients for HFE mutations may identify those at risk for doxorubicin-induced cardiotoxicity.