A1 Refereed original research article in a scientific journal
Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites
Authors: Toksvang LN, De Pietri S, Nielsen SN, Nersting J, Albertsen BK, Wehner PS, Rosthoj S, Lahteenmaki PM, Nilsson D, Nystad TA, Grell K, Frandsen TL, Schmiegelow K
Publisher: WILEY
Publication year: 2017
Journal: Pediatric Blood and Cancer
Journal name in source: PEDIATRIC BLOOD & CANCER
Journal acronym: PEDIATR BLOOD CANCER
Article number: ARTN e26519
Volume: 64
Issue: 9
Number of pages: 8
ISSN: 1545-5009
eISSN: 1545-5017
DOI: https://doi.org/10.1002/pbc.26519
Abstract
BackgroundHepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.ProcedureIn children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.ResultsAmong 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain 2.5%, unexplained thrombocytopenia <75 x 10(9) l(-1)) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01).ConclusionsPEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.
BackgroundHepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.ProcedureIn children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.ResultsAmong 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain 2.5%, unexplained thrombocytopenia <75 x 10(9) l(-1)) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01).ConclusionsPEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.
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