Pancreas-related persisting sequelae in ALL survivors with a history of asparaginase-associated pancreatitis: A part of the ALL-STAR study.

OBJECTIVES: Asparaginase-associated pancreatitis (AAP) occurs in up to 18% of patients treated for acute lymphoblastic leukemia (ALL); however, long-term sequelae are largely unexplored. We aimed to explore pancreatic sequelae among ALL survivors with and without AAP. METHODS: We investigated pancreatic sequelae in a national cohort of ALL survivors, aged 1-45 years at ALL diagnosis treated according to the NOPHO-ALL2008 protocol and included sex- and age-matched community controls. RESULTS: We included 368 survivors (median follow-up 6.9 years), including 47 survivors with AAP and 369 controls. The p-lipase and p-pancreas-type amylase levels were lower in AAP survivors compared with both non-AAP survivors (Medians: 23 U/L [IQR 14-32] and 18 U/L [IQR 10-25] versus 29 [IQR 24-35] and 22 [17-28], p < .001 and p = .002) and community controls (28 U/L [IQR 22-33] and 21 U/L [IQR 17-26], both p < .006). Fecal-elastase was more frequently reduced in AAP survivors compared with non-AAP survivors (7/31 vs. 4/144, p = .001). Persisting pancreatic sequelae were found in 15/47 of AAP survivors and 20/323 of non-AAP survivors (p < .001), including diabetes mellitus in 2/39 of AAP survivors and 2/273 of non-AAP survivors. CONCLUSIONS: ALL survivors with AAP are at increased risk of persisting pancreatic dysfunction and require special attention during follow-up.

Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia.

BACKGROUND: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population. METHODS: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM). RESULTS: 68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m2 were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction. CONCLUSION: The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1-18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m2 for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.

Quality of life in children and adolescents after treatment for acute lymphoblastic leukemia according to the NOPHO ALL2008 protocol.

BACKGROUND: The improved outcome of childhood acute lymphoblastic leukemia (ALL) over the last decades has increased the importance of assessing late effects and health-related quality of life (HRQoL), particularly when evaluating and comparing outcomes in clinical trials. This study aimed to assess HRQoL in children treated for ALL according to the NOPHO ALL2008 protocol. PROCEDURE: Children, aged 1 to less than 18 years at diagnosis, alive in first remission, and their parents, were asked to complete PedsQL 4.0 Generic Core Scales (self- and proxy-report) at ≥6 months after end of therapy. Data on socioeconomic factors and parent-reported toxicity were collected through a study-specific questionnaire, and the NOPHO ALL2008 database was used to identify eligible families and add additional disease- and treatment-related data. HRQoL data were collected during 2013-2019 in Sweden, Finland, and Denmark. RESULTS: A total of 299 children were included. The older children (8 years and older) reported similar HRQoL scores compared to Finnish reference data, except lower scores for School Functioning in high-risk patients. Scores from the parent-proxy and self-reports from 5-7-year olds were notably lower than reference. Parent-reported toxicity was associated with lower total and physical HRQoL scores in adjusted models for younger as well as older children in the self-report and parent-proxy versions, and also with lower psychosocial score in the parent-proxy. CONCLUSIONS: Self-reported HRQoL was similar to reference population. The most important determinant for HRQoL after end of ALL treatment was parent-reported toxicity during treatment. Thus, minimizing complications is an obvious focus for future treatment protocols.

Sequelae and post-thrombotic syndrome after venous thromboembolism in acute lymphoblastic leukemia survivors treated on the NOPHO ALL2008 protocol.

The treatment of acute lymphoblastic leukemia (ALL) is frequently complicated by toxicity, including venous thromboembolism (VTE) affecting roughly 8% of patients. VTE can lead to post-thrombotic syndrome (PTS), a group of signs and symptoms developed as a complication to deep venous thrombosis (DVT), imposing risk of permanent disability and reduced quality of life (QoL). PTS prevalence ranges from 0% to 70%, reflecting very heterogenous cohorts and assessment tools. We aimed to estimate sequelae, including PTS and QoL in children and adults (<45 years old) who had a DVT during ALL treatment. PTS and QoL scores were obtained through use of Villalta and Modified Villalta Scale, PedsQL, and Short Form-36 questionnaires. The cohort comprised 20 children (<18 years) and seven adults (median age: 12.9 years, range: 2-44 years) at the time of DVT diagnosis. In total, 25 ALL survivors underwent PTS examination. The examination took place when survivors were 7-48 years (median age: 20.3 years, median follow-up time 6.8 years). QoL was assessed correlating cases with three matching ALL survivors without VTE. Two adults (15.4%) showed mild or moderate PTS. Eight children (66.7%) were diagnosed with mild PTS, while three cases had collaterals as sole symptoms. Pain or symptoms affecting daily life were reported by 16%. No difference in QoL was found (p = .9). This study underscores the need for comprehensive population-based investigations with validation of PTS instruments in ALL survivors.

Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia.

Truncation of asparaginase treatment due to asparaginase-related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1 to 17 years, diagnosed with ALL between July 2008 and February 2016, treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (including extended asparaginase exposure [1000 IU/m2 intramuscularly weeks 5-33]). Patients were included with delayed entry at their last administered asparaginase treatment, or detection of SI, and followed until relapse, death, secondary malignancy, or end of follow-up (median, 5.71 years; interquartile range, 4.02-7.64). In a multiple Cox model comparing patients with (n = 358) and without (n = 1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (HR; aHR) was 1.33 (95% confidence interval [CI], 0.86-2.06; P = .20). In a substudy including only patients with information on enzyme activity (n = 1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI, 6.9-15.4) vs 6.7% (95% CI, 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI, 1.05-2.74, P=.03). The unadjusted bone marrow relapse-specific HR was 1.83 (95% CI, 1.07-3.14, P=.03) and 1.86 (95% CI, 0.90- 3.87, P=.095) for any central nervous system relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible. This trial was registered at www.clinicaltrials.gov as #NCT03987542.

Long-term effects of asparaginase-associated pancreatitis.

Pancreatitis is a common and severe toxicity that occurs during asparaginase treatment for acute lymphoblastic leukemia, and has received increasing attention during the last decades. However, no consensus regarding follow-up exists. In this commentary, we highlight potential long-term health-related effects following asparaginase-associated pancreatitis, thereby providing clinicians with a framework when following these patients during and after cessation of therapy.

Parental experiences of the informed consent process in randomized clinical trials-A Nordic study.

BACKGROUND: Randomized clinical trials (RCTs) are an essential part of improving acute lymphoblastic leukemia (ALL) treatment. This population-based questionnaire study investigated parents' experiences of the informed consent process in the RCTs within the Nordic NOPHO (Nordic Society of Paediatric Haematology and Oncology) ALL2008 trial. PROCEDURE: Parents in Sweden, Denmark, and Finland whose child was alive and in first remission after end of therapy and who were asked to participate in any RCT in the ALL2008 protocol, were asked to complete 15 questions/items regarding their experience of the RCT consent process. RESULTS: A total of 483 parents of 279 children met the inclusion criteria and answered the study questionnaire. Most (91%) agreed/strongly agreed to having received sufficient information to make a well-informed decision, felt confidence in the study design (86%), and thought that the process was satisfactory (86%). Those who did not consent reported a generally more negative experience of the process. More than a third of all parents and over half of parents who had refused participation felt that it was burdensome to decide. Most parents (66%) in general, and one-third of those with children 8 years or older, reported that their child was not involved in the process. CONCLUSIONS: Parents were in general satisfied with the informed consent process, although many parents, particularly those who refused participation, reported it as burdensome to make the decision concerning RCT. Fewer than expected of the school-aged children were involved in the decision process, which calls for attention on how children are included in the consent procedure in clinical trials.

Correlation between asparaginase enzyme activity levels and coagulation parameters during childhood acute lymphoblastic leukemia treatment.

Thromboembolism is a serious toxicity in the treatment of acute lymphoblastic leukemia (ALL), but little is known about the correlation between asparaginase enzyme activity (ASA) levels and coagulation parameters. We included 65 non-high risk ALL patients, aged 1-17 years. Coagulation parameters and corresponding ASA levels were measured during asparaginase treatment. We found ASA to be negatively correlated with antithrombin and fibrinogen up to ASA levels of 250 IU/L, after which these parameters reached a plateau and did not decrease further with further increase of ASA. Patients with silent inactivation of asparaginase had normal coagulation parameters.

PEG-asparaginase treatment regimens for acute lymphoblastic leukaemia in children: a network meta-analysis.

BACKGROUND: Asparaginase has played a crucial role in the improvement of survival in children with acute lymphoblastic leukaemia (ALL), which is the commonest cancer among children. Survival rates have steadily increased over decades since the introduction of asparaginase to ALL therapy, and overall survival rates reach 90% with the best contemporary protocols. Currently, polyethylene glycolated native Escherichia coli-derived L-asparaginase (PEG-asparaginase) is the preferred first-line asparaginase preparation. Besides its clinical benefits, PEG-asparaginase is well known for severe toxicities. Agreement on the optimal dose, treatment duration, and frequency of administration has never been reached among clinicians. OBJECTIVES: Primary objective To assess the effect of the number of PEG-asparaginase doses on survival and relapse in children and adolescents with ALL. Secondary objectives To assess the association between the number of doses of PEG-asparaginase and asparaginase-associated toxicities (e.g. hypersensitivity, thromboembolism, pancreatitis and osteonecrosis). To undertake a network meta-analysis at dose-level in order to generate rankings of the number of doses of PEG-asparaginase used in the treatment for ALL, according to their benefits (survival and relapse) and harms (toxicity). SEARCH METHODS: We searched CENTRAL, PubMed, Embase, Web of Science databases and three trials registers in November 2021, together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing different PEG-asparaginase treatment regimens in children and adolescents (< 18 years of age) with first-line ALL treated with multiagent chemotherapy including PEG-asparaginase. DATA COLLECTION AND ANALYSIS: Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using a standardised tool (RoB 2.0) and assessed the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included overall survival, event-free survival and leukaemic relapse. Secondary outcomes included asparaginase-associated toxicities (hypersensitivity, thromboembolism, pancreatitis, sinusoidal obstruction syndrome and osteonecrosis as well as overall asparaginase-associated toxicity). We conducted the review and performed the analyses in accordance with the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We included three RCTs in the review, and identified an additional four ongoing studies. We judged outcomes of two RCTs to be at low risk of bias in all the Cochrane risk of bias (RoB 2) domains. We rated the remaining study as having some concerns regarding bias. Due to concerns about imprecision, we rated all outcomes as having low- to moderate-certainty evidence.  One study compared intermittent PEG-asparaginase treatment (eight doses of PEG-asparaginase, 1000 IU/m2, intramuscular (IM) administration) versus continuous PEG-asparaginase treatment (15 doses of PEG-asparaginase, 1000 IU/m2, IM) in 625 participants with non-high risk ALL aged 1.0 to 17.9 years. We found that treatment with eight doses probably results in little to no difference in event-free survival compared to treatment with 15 doses (RR 1.01, 95% CI 0.97 to 1.06; moderate-certainty evidence). Compared to treatment with 15 doses, treatment with eight doses may result in either no difference or a slight reduction in hypersensitivity (RR 0.64, 95% CI 0.21 to 1.93; low-certainty evidence), thromboembolism (RR 0.55, 95% CI 0.22 to 1.36; low-certainty evidence) or osteonecrosis (RR 0.68, 95% CI 0.35 to 1.32; low-certainty evidence). Furthermore, we found that treatment with eight doses probably reduces pancreatitis (RR 0.31, 95% CI 0.12 to 0.75; moderate-certainty evidence) and asparaginase-associated toxicity (RR 0.53, 95% CI 0.35 to 0.78; moderate-certainty evidence) compared to treatment with 15 doses. One study compared low-risk standard treatment with additional PEG-asparaginase (six doses, 2500 IU/m2, IM) versus low-risk standard treatment (two doses, 2500 IU/m2, IM) in 1857 participants aged one to nine years old with standard low-risk ALL. We found that, compared to treatment with two doses, treatment with six doses probably results in little to no difference in overall survival (RR 0.99, 95% CI 0.98 to 1.00; moderate-certainty evidence) and event-free survival (RR 1.01, 95% CI 0.99 to 1.04; moderate-certainty evidence), and may result in either no difference or a slight increase in osteonecrosis (RR 1.65, 95% CI 0.91 to 3.00; low-certainty evidence). Furthermore, we found that treatment with six doses probably increases hypersensitivity (RR 12.05, 95% CI 5.27 to 27.58; moderate-certainty evidence), pancreatitis (RR 4.84, 95% CI 2.15 to 10.85; moderate-certainty evidence) and asparaginase-associated toxicity (RR 4.49, 95% CI 3.05 to 6.59; moderate-certainty evidence) compared to treatment with two doses. One trial compared calaspargase (11 doses, 2500 IU/m2, intravenous (IV)) versus PEG-asparaginase (16 doses, 2500 IU/m2, IV) in 239 participants aged one to 21 years with standard- and high-risk ALL and lymphoblastic lymphoma. We found that treatment with 11 doses of calaspargase probably results in little to no difference in event-free survival compared to treatment with 16 doses of PEG-asparaginase (RR 1.06, 95% CI 0.97 to 1.16; moderate-certainty evidence). However, treatment with 11 doses of calaspargase probably reduces leukaemic relapse compared to treatment with 16 doses of PEG-asparaginase (RR 0.32, 95% CI 0.12 to 0.83; moderate-certainty evidence). Furthermore, we found that treatment with 11 doses of calaspargase results in either no difference or a slight reduction in hypersensitivity (RR 1.17, 95% CI 0.64 to 2.13; low-certainty evidence), pancreatitis (RR 0.85, 95% CI 0.47 to 1.52; low-certainty evidence), thromboembolism (RR 0.83, 95% CI 0.48 to 1.42; low-certainty evidence), osteonecrosis (RR 0.63, 95% CI 0.15 to 2.56; low-certainty evidence) and asparaginase-associated toxicity (RR 1.00, 95% CI 0.71 to 1.40; low-certainty evidence) compared to treatment with 16 doses of PEG-asparaginase. AUTHORS' CONCLUSIONS: We were not able to conduct a network meta-analysis, and could not draw clear conclusions because it was not possible to rank the interventions. Overall, we found that different numbers of doses of PEG-asparaginase probably result in little to no difference in event-free survival across all studies. In two studies, we found that a higher number of PEG-asparaginase doses probably increases pancreatitis and asparaginase-associated toxicities.

Quality of life in mothers and fathers of children treated for acute lymphoblastic leukaemia in Sweden, Finland and Denmark.

Acute lymphoblastic leukaemia (ALL) has a high survival rate, but treatment is lengthy with risk of severe side-effects, which may also impact parents' health-related quality of life (HRQOL). We present data on 526 parents of 310 children treated for ALL according to the NOPHO ALL2008-protocol, in Sweden, Finland and Denmark. Parents were asked to complete the 36-Item Short Form Survey (SF-36) at least 6 months after end of treatment and data were compared with Norwegian reference data. Parental background factors were collected via a study-specific questionnaire. Participating parents scored significantly lower than the reference population on both physical and mental summary indexes, but only surpassed a minimal clinically important difference for the mental summary index (Mental Component Summary [MCS]). Mothers scored lower than fathers in the MCS and stopped working and took care of the affected child more often than the fathers. Higher mental HRQOL was associated with male gender and living in Finland or Denmark (compared to Sweden). Correlations within spouses in physical and mental scores were weak to moderate. In conclusion, ALL negatively affects parental HRQOL, especially the mental domains, even after treatment. Findings suggest that mothers are more affected than fathers and may require extra support.

Asparaginase encapsulated in erythrocytes as second-line treatment in hypersensitive patients with acute lymphoblastic leukaemia.

Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase-related hypersensitivity causes treatment discontinuation, which is associated with decreased event-free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR-GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1-45 years; median: 6.1 years) with non-high-risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG-asparaginase). Eryaspase (150 u/kg) was scheduled to complete the intended course of asparaginase (1-7 doses) in two Nordic/Baltic treatment protocols. Forty-nine (96.1%) patients had asparaginase enzyme activity (AEA) ≥100 iu/l 14 ± 2 days after the first eryaspase infusion [median AEA 511 iu/l; interquartile range (IQR), 291-780], whereas six of nine (66.7%) patients had AEA ≥100 iu/l 14 ± 2 days after the fourth infusion (median AEA 932 iu/l; IQR, 496-163). The mean terminal half-life of eryaspase following the first infusion was 15.3 ± 15.5 days. Few asparaginase-related adverse events were reported; five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half-life of eryaspase confirmed that a 2-week schedule is appropriate.

A survey on thromboprophylaxis and coagulation assessment in children and young adults with acute lymphoblastic leukaemia (ALL) in the Nordic and Baltic countries: Different practices of assessment and management.

Patients undergoing treatment for acute lymphoblastic leukaemia (ALL) are at risk of coagulopathy, especially thromboembolism. We conducted a survey on practices in the assessment and management of coagulopathy during the new ALLTogether protocol in 29 (17 paediatric, 12 adult) Nordic and Baltic cancer centres. While 92% of adult centres used thromboprophylaxis with low-molecular-weight heparin, no paediatric centre did. Almost all providers performed baseline coagulation studies, but only 59% continued the assessment. Fibrinogen replacement was conducted in 59%, and antithrombin replacement in 28% of the centres. The survey highlights the need for guidelines in the management of coagulopathy during ALL therapy.

Obesity as a predictor of treatment-related toxicity in children with acute lymphoblastic leukaemia.

Obesity is associated with poor outcomes in childhood acute lymphoblastic leukaemia (ALL). We explored whether severe treatment-related toxicity and treatment delays could explain this observation. This study included 1 443 children aged 2·0-17·9 years with ALL treated with the Nordic Society of Pediatric Haematology and Oncology (NOPHO) ALL2008 non-high-risk protocol. Prospective treatment-related toxicities registered every three-month interval were used. Patients were classified according to sex- and age-adjusted international childhood cut-off values, corresponding to adult body mass index: underweight, <17 kg/m2 ; healthy weight, 17 to <25 kg/m2 ; overweight, 25 to <30 kg/m2 ; and obese, ≥30 kg/m2 . Obese children had a higher incidence rate ratio (IRR) for severe toxic events {IRR: 1·55 [95% confidence interval (CI) 1·07-2·50]}, liver and kidney failures, bleeding, abdominal complication, suspected unexpected severe adverse reactions and hyperlipidaemia compared with healthy-weight children. Obese children aged ≥10 years had increased IRRs for asparaginase-related toxicities compared with healthy-weight older children: thromboses [IRR 2·87 (95% CI 1·00-8·21)] and anaphylactic reactions [IRR 7·95 (95% CI 2·15-29·37)] as well as higher risk for truncation of asparaginase [IRR 3·54 (95% CI 1·67-7·50)]. The high prevalence of toxicity and a higher risk of truncation of asparaginase may play a role in the poor prognosis of obese children aged ≥10 years with ALL.

Changes in body mass index during treatment of childhood acute lymphoblastic leukemia with the Nordic ALL2008 protocol.

OBJECTIVES: Children with acute lymphoblastic leukemia (ALL) have a tendency to gain weight during treatment. As overweight and obesity associate with health problems, prophylactic interventions are warranted. Therefore, it is important to identify the children most prone to gain weight. METHODS: Patients aged 2.0-17.9 years at ALL diagnosis were identified from the NOPHO ALL2008 registry. Registry data was complemented with height and weight at the end of therapy from questionnaires. Body mass index (BMI) was classified according to international age- and sex-adjusted International Obesity Task Force BMI cut-offs. BMI values were transformed into standard deviation scores (SDS) to calculate the difference in BMISDS during treatment. RESULTS: Data on BMI change were available for 765 children. Overweight and obesity doubled during treatment: 9.7% were overweight and 2.1% obese at diagnosis and 21.8% and 5.4% at the end of therapy, respectively. The mean BMISDS change was +0.64. Younger (2.0-5.9 years) and healthy weight children were most prone to become overweight (mean change in BMI SDS +0.85 and + 0.65, respectively). CONCLUSIONS: Younger children (2.0-5.9 years) with healthy weight at diagnosis were most prone to becoming overweight and therefore are an important group to target while considering interventions.

Socioeconomic position and maintenance therapy in children with acute lymphoblastic leukemia: A national cohort study.

BACKGROUND: Socioeconomic differences in survival among children with acute lymphoblastic leukemia (ALL) have been reported in high-income countries and there is an unmet need for strategies to identify vulnerable patient subgroups. Reported differences in survival for children from families with different socioeconomic positions seem to arise when starting maintenance therapy. This could reflect reduced physician's compliance or family adherence to maintenance therapy. METHODS: This nationwide cohort study with extensive monitoring of systemic methotrexate (MTX)/6-mercaptopurine (6MP) dosing and metabolite levels, retrospectively investigated 173 Danish children treated according to The Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol from 2008 to 2016. RESULTS: Significantly lower prescribed doses of MTX and 6MP were seen in the children in families with short parental education (short vs. medium vs. higher education: mMTX: 13.8, 16.2, and 18.6 mg/m2 /week; p < .01; m6MP: 47.4, 64.9, and 66.1 mg/m2 /day; p = .03) or parents unemployed/not in workforce (unemployed/not in workforce vs. mixed vs. at work: mMTX: 15.0, 19.9, and 17.2 mg/m2 /week; p < .01; m6MP: 54.8, 72.0, and 65.1 mg/m2 /day; p < .01). When assessing family adherence by analyzing MTX and 6MP metabolite levels, including per prescribed dose of MTX and 6MP, we found no significant differences by levels of parental education, affiliation to work market, or income (p > .05 for all comparisons). CONCLUSIONS: These results indicate that inferior physician compliance to protocol recommendations on drug dosage rather than families' adherence to therapy may contribute to the association between socioeconomic position and cure rates in childhood ALL, although precise mechanisms remain to be explored.

Bloodstream Infections in Children With Cancer: Pathogen Distribution and Antimicrobial Susceptibility Patterns Over a 10-Year Period.

Bloodstream infections (BSIs) adversely affect clinical outcome in children with cancer. Over 1 decade, this retrospective cohort study describes pathogen distribution in BSIs and antimicrobial susceptibility against empirical antibiotics frequently prescribed in children with cancer. The antibiotic efficacy was evaluated through the determination of minimal inhibitory concentrations for piperacillin-tazobactam and meropenem and by disk diffusion for remaining antibiotics. From 2004 to 2013, 398 BSIs occurred in 196 children with cancer (median age: 5.4 y), resulting in 457 bacteria. Overall, 266 (58.2%) were Gram-positive, and 191 (41.8%) were Gram-negative with a significant Gram-positive increase over time (P=0.032). Coagulase-negative staphylococci (74, 16.2%), viridans group streptococci (67, 14.7%), Escherichia coli (52, 11.4%), and Staphylococcus aureus (39, 8.5%) were the most common pathogens. Susceptibility to piperacillin-tazobactam (95.9%, P=0.419) and meropenem (98.9%, P=0.752) was stable over time, and resistance was observed among viridans group streptococci against piperacillin-tazobactam (18%) and meropenem (7%) and among Enterobacterales against piperacillin-tazobactam (3%). Vancomycin showed 98% Gram-positive activity, gentamicin 82% Gram-negative activity and ampicillin, cefotaxime, and cefuroxime were active in 50%, 72%, and 69% of pathogens, respectively, and BSI-related mortality was 0%. In conclusion, over 1 decade, we report an increase in Gram-positive BSIs, and stable, low-resistance rates against currently recommended empirical antibiotics, piperacillin-tazobactam and meropenem.

Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia.

Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP 1.0 to 17.9 yo) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.

Detection mode of childhood acute lymphoblastic leukaemia relapse and its effect on survival: a Nordic population-based cohort study.

Relapse constitutes the greatest threat to event-free survival after completion of treatment for childhood acute lymphoblastic leukaemia (ALL). However, evidence on optimal follow-up schedules is limited. The aims of the present population-based cohort study were to assess the value of current follow-up schedules after completion of Nordic Society of Paediatric Haematology and Oncology ALL protocol treatment and to estimate the impact of relapse detection mode on overall survival (OS). Among 3262 patients diagnosed between 1992 and 2014 and who completed treatment, 338 developed a relapse. Relapse detection was equally distributed between extra visits (50·8%) and scheduled follow-up visits (49·2%). All cases detected at an extra visit and 64·3% of cases detected at a scheduled visit presented with symptoms or objective findings. Neither the mode of detection {adjusted hazard ratio 0·95, [95% confidence interval (CI) 0·61-1·48] for scheduled visits} nor the duration of symptoms was an independent risk factor for OS after relapse. The estimated number of scheduled blood samples needed to diagnose one subclinical relapse during the first 5 years after treatment cessation was 1269 (95% CI 902-1637). In conclusion, based on OS data, scheduled visits after cessation of therapy seem to yield no extra benefit. These results should frame future follow-up strategies.

Flow cytometric analysis of cerebrospinal fluid improves detection of leukaemic blasts in infants with acute lymphoblastic leukaemia.

Infants with acute lymphoblastic leukaemia (ALL) have a high frequency of central nervous system (CNS) involvement. Flow cytometric analysis of cerebrospinal fluid (CSF) was recently demonstrated to be a sensitive method for detecting CNS involvement in childhood ALL. In the present study, CSF from 14 infants was collected at routine lumbar punctures and analysed by multicolour flow cytometry. At initial diagnosis, leukaemic blasts were detected in CSF by flow cytometry in 11 patients (78·6%) compared to seven patients (50%) by cytospin. Larger studies are needed to determine if CSF flow cytometry has prognostic value in infant ALL.

Increments in DNA-thioguanine level during thiopurine-enhanced maintenance therapy of acute lymphoblastic leukemia.

Maintenance therapy containing methotrexate and 6-mercapto - purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6- fold higher cytosolic levels of thioguanine nucleotides than does 6- mercapto purine, we added low-dose 6-thioguanine to methotrexate/6- mercapto purine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the "Thiopurine Enhanced ALL Maintenance therapy" (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher [95% confidence interval: 160-341; P<0.0001]), and with historical patients receiving standard methotrexate/6-mercapto - purine maintenance therapy (on average 272 fmol/mg DNA higher [95% confidence interval: 147-398; P<0.0001]). TEAM did not increase myelotoxicity or hepatotoxicity. In conclusion, TEAM is an innovative and feasible approach to improve maintenance therapy and results in higher DNA-TG levels without inducing additional toxicity. It may therefore be an effective strategy to reduce the risk of ALL relapse through increased DNA-TG. This will be tested in a randomized ALLTogether-1 substudy.