Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. ...Treatment intensity depends on the initial CNS status. In trial AIEOP-BFM ALL 2009, patients with cytomorphological detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal methotrexate on systemic toxicity in induction therapy is unknown. Between June 01, 2010 and February 28, 2017, 6136 patients at the age of 1 to 17 years with ALL were enrolled onto the trial AIEOP-BFM ALL 2009. The effect of three versus five doses of intrathecal methotrexate during induction therapy on the incidence of severe infectious complications was analyzed. Among 4706 patients treated with three intrathecal methotrexate doses, 77 (1.6%) had a lifethreatening infection during induction as compared to 59 of 1350 (4.4%) patients treated with five doses (p.
Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic ...complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 range, 1.28-4.16) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.
Acquired TP53 alterations are present in > 90% of cases of paediatric low-hypodiploid acute lymphoblastic leukaemia (ALL), and ≈ 50% of patients with this subtype harbor germline pathogenic / likely ...pathogenic (P/LP) TP53 alterations. Despite dose intensified, conventional chemotherapy, survival in low-hypodiploid ALL remains dismal compared to other paediatric ALL. Individuals with underlying Li-Fraumeni Syndrome (LFS) are known to have increased sensitivity to genotoxic effect of chemotherapy and radiotherapy. Recent evidence shows a 25.1% 5-year cumulative incidence of SMNs post ALL therapy in an LFS population as compared to 0.7% in patients with either a wild type or VUS TP53. The parallel high risks of both relapse and SMN present unpalatable choices facing clinicians.
Electronic medication management (eMM) systems are designed to improve safety, but there is little evidence of their effectiveness in paediatrics. This study assesses the short-term (first 70 days of ...eMM use) and long-term (one-year) effectiveness of an eMM system to reduce prescribing errors, and their potential and actual harm. We use a stepped-wedge cluster randomised controlled trial (SWCRCT) at a paediatric referral hospital, with eight clusters randomised for eMM implementation. We assess long-term effects from an additional random sample of medication orders one-year post-eMM. In the SWCRCT, errors that are potential adverse drug events (ADEs) are assessed for actual harm. The study comprises 35,260 medication orders for 4821 patients. Results show no significant change in overall prescribing error rates in the first 70 days of eMM use (incident rate ratio IRR 1.05 95%CI 0.92-1.21, but a 62% increase (IRR 1.62 95%CI 1.28-2.04) in potential ADEs suggesting immediate risks to safety. One-year post-eMM, errors decline by 36% (IRR 0.64 95%CI 0.56-0.72) and high-risk medication errors decrease by 33% (IRR 0.67 95%CI 0.51-0.88) compared to pre-eMM. In all periods, dose error rates are more than double that of other error types. Few errors are associated with actual harm, but 71% 95%CI 50-86% of patients with harm experienced a dose error. In the short-term, eMM implementation shows no improvement in error rates, and an increase in some errors. A year after eMM error rates significantly decline suggesting long-term benefits. eMM optimisation should focus on reducing dose errors due to their high frequency and capacity to cause harm.
The incidence of hypersensitivity reactions (HSRs) to PEG‐asparaginase (PEG‐ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP‐BFM ALL 2009 study. Patients with B‐cell ...precursor‐acute lymphoblastic leukemia (BCP‐ALL) were stratified as standard‐risk/medium‐risk (MR)/high‐risk (HR) and those with T‐ALL as non‐High/HR. PEG‐ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG‐ASNase doses in induction; thereafter non‐HR versus HR patients received 1 versus 6 PEG‐ASNase doses, respectively. After the single regular dose of PEG‐ASNase at the beginning of delayed intensification, BCP‐ALL‐MR patients were randomized to receive 9 additional PEG‐ASNase doses every 2 weeks (experimental arm EA) versus none (standard arm SA); HR patients were randomized to receive, in consolidation, 4 weekly PEG‐ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T‐non‐ HR/BCP‐Standard‐Risk, BCP‐MR‐SA, BCP‐MR‐EA, HR‐SA and HR‐EA patients had 1‐year‐CI‐HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG‐ASNase did not significantly impact on HSR incidence in BCP‐MR patients (1‐y‐CI‐HSR 3.8% 0.8 versus 3.2% 0.6 in MR‐EA versus MR‐SA; P = 0.55), while impacted significantly in HR patients (1‐y‐CI‐HSR 6.4% 1.3 versus 17.9% 1.8 in HR‐EA and HR‐SA, respectively; P < 0.001). The CI‐HSR was comparable among non‐HR groups and was not increased by a substantial intensification of PEG‐ASNase in the BCP‐MR‐EA group whilst it was markedly higher in HR‐SA than in HR‐EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG‐ASNase reduces the risk of developing an HSR.
Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment ...regimens has not been well studied.
We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included.
No SNPs reached genome-wide significance (
< 5 × 10
) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (
< 1 × 10
), two loci had concordant effects in both cohorts:
(rs1804772) (MAF: 1%;
= 3.95 × 10
) that influences arachidonic acid metabolism and thus platelet aggregation, and
(rs570684) (MAF: 1%;
= 4.34 × 10
) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease.
This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
In children with acute lymphoblastic leukemia (ALL), risk groups for invasive fungal disease (IFD) with need for antifungal prophylaxis are not well characterized, and with the advent of new ...antifungal compounds, current data on outcome are scarce. Prospectively captured serious adverse event reports of children enrolled in the international, multi-center clinical trial AIEOP-BFM ALL2009 were screened for proven/probable IFD, defined according to the updated EORTC/MSG consensus definitions. In a total of 6136 children (median age 5.2 years), 224 proven/probable IFDs (65 yeast and 159 mold) were reported. By logistic regression, the risk for proven/probable IFDs was significantly increased in children ≥12 years and those with a blast count ≥10% in the bone marrow on day 15 (P < 0.0001 each). Proven/probable IFDs had a 6-week and 12-week mortality of 10.7% and 11.2%, respectively. In the multivariate analysis, the hazard ratio for event-free and overall survival was significantly increased for proven/probable IFD, age ≥12 years, and insufficient response to therapy (P < 0.001, each). Our data define older children with ALL and those with insufficient treatment-response at high risk for IFD. As we show that IFD is an independent risk factor for event-free and overall survival, these patients may benefit from targeted antifungal prophylaxis.
Pneumocystis jirovecii can cause life-threatening pneumonia (PjP), and patients with haematological malignancies are at high risk of this infection. Prophylactic measures have significantly decreased ...morbidity and mortality, but there is a paucity of contemporary data on the incidence and clinical course of PjP in well-defined and homogenous patient populations, such as children suffering from acute lymphoblastic leukaemia (ALL). In the multi-international trial AIEOP-BFM ALL2009, PjP was diagnosed in six children (incidence 1/1000) and was associated with insufficient prophylaxis in five of them. Although none of the patients died of PjP, the long-term impact of the infection is unclear.
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