Background: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic... Show moreBackground: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contem-porary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking. Method and patients: Questionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Informa-tion on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis. Results: Newly diagnosed patients with ALL (n Z 5880), aged 1-24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence in-terval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9-16% and 23-29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively. Conclusion: The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase. Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy. Show less
Brigitha, L.J.; Fiocco, M.; Pieters, R.; Albertsen, B.K.; Escherich, G.; Lopez-Lopez, E.; ... ; Ponte di Legno Toxicity Working Group 2022
Background: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic... Show moreBackground: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contem-porary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking. Method and patients: Questionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Informa-tion on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis. Results: Newly diagnosed patients with ALL (n Z 5880), aged 1-24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence in-terval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9-16% and 23-29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively. Conclusion: The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase. Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy. Show less
Michels, N.; Boer, J.M.; Enshaei, A.; Sutton, R.; Heyman, M.; Ebert, S.; ... ; Boer, M.L. den 2021
Background Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations ... Show moreBackground Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations (eg, IKZF1 deletion). We aimed to investigate the potential underlying effect of Down syndrome versus the effects of adverse cancer genetics on clinical outcome.Method Patients (aged 1-23 years) with Down syndrome and acute lymphocytic leukaemia and matched non-Down syndrome patients with acute lymphocytic leukaemia (matched controls) from eight trials (DCOG ALL10 and ALL11, ANZCHOG ALL8, AIEOP-BFM ALL2009, UKALL2003, NOPHO ALL2008, CoALL 07-03, and CoALL 08-09) done between 2002 and 2018 across various countries (the Netherlands, the UK, Australia, Denmark, Finland, Iceland, Norway, Sweden, and Germany) were included. Participants were matched (1:3) for clinical risk factors and genetics, including IKZF1 deletion. The primary endpoint was the comparison of MRD levels (absolute MRD levels were categorised into two groups, low [<0.0001] and high [>= 0.0001]) between patients with Down syndrome and acute lymphocytic leukaemia and matched controls, and the secondary outcomes were comparison of long-term outcomes (event-free survival, overall survival, relapse, and treatment-related mortality [TRM]) between patients with Down syndrome and acute lymphocytic leukaemia and matched controls. Two matched cohorts were formed: for MRD analyses and for long-term outcome analyses. For both cohorts, matching was based on induction regimen; for the long-term outcome cohort, matching also included MRD-guided treatment group. We used mixed-effect models, Cox models, and competing risk for statistical analyses.Findings Of 251 children and adolescents with Down syndrome and acute lymphocytic leukaemia, 136 were eligible for analyses and matched to 407 (of 8426) non-Down syndrome patients with acute lymphocytic leukaemia (matched controls). 113 patients with Down syndrome and acute lymphocytic leukaemia were excluded from matching in accordance with predefined rules, no match was available for two patients with Down syndrome and acute lymphocytic leukaemia. The proportion of patients with high MRD at the end of induction treatment was similar for patients with Down syndrome and acute lymphocytic leukaemia (52 [38%] of 136) and matched controls (157 [39%] of 403; OR 0.97 [95% CI 0.64-1.46]; p=0.88). Patients with Down syndrome and acute lymphocytic leukaemia had a higher relapse risk than did matched controls in the IKZF1 deleted group (relapse at 5 years 37.1% [17.1-57.2] vs 13.2% [6.1-23.1]; cause-specific hazard ratio [HR cs] 4.3 [1.6-11.0]; p=0.0028), but not in the IKZF1 wild-type group (relapse at 5 years 5.8% [2.1-12.2] vs 8.1% [5.1-12.0]; HR cs 1.0 [0.5-2.1]; p=0.99). In addition to increased induction deaths (15 [6%] of 251 vs 69 [0.8%] of 8426), Down syndrome and acute lymphocytic leukaemia was associated with a higher risk of post-induction TRM compared with matched controls (TRM at 5 years 12.2% [7.0-18.9] vs 2.7% [1.3-4.9]; HR cs 5.0 [2.3-10.8]; p<0.0001).Interpretation Induction treatment is equivalently effective for patients with Down syndrome and acute lymphocytic leukaemia and for matched patients without Down syndrome. Down syndrome itself provides an additional risk in individuals with IKZF1 deletions, suggesting an interplay between the germline environment and this poor risk somatic aberration. Different treatment strategies are warranted considering both inherent risk of relapse and high risk of TRM. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Boer, M.L. den; Cario, G.; Moorman, A.V.; Boer, J.M.; Groot-Kruseman, H.A. de; Fiocco, M.; ... ; Ponte Legno Childhood ALL Working 2021
Background: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic... Show moreBackground: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era.Methods: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model.Findings: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59.1% (95% CI 50.5-69.1), 5-year overall survival was 76.1% (68.6-84.5), and the 5-year cumulative incidence of relapse was 31.0% (95% CI 22.4-40.1). MRD at the end of induction therapy was high (>= 10(-2) cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10(-2) cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of >= 10(-2) vs those with a MRD of <10(-2) 3.33 [95% CI 1.46-7.56], p=0.0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17.8% [95% CI 7.7-31.3]) was lower than in the 43 patients who did not undergo HSCT (45.1% [28.4-60.5], p=0.013), but event-free survival and overall survival did not differ between these two groups.Interpretation: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Show less
