Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.

Autor: Toksvang LN; Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark., De Pietri S; Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark., Nielsen SN; Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark., Nersting J; Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark., Albertsen BK; Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark., Wehner PS; Department of Pediatric Hematology and Oncology, H. C. Andersen Children's Hospital, Odense University Hospital, Odense, Denmark., Rosthøj S; Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark., Lähteenmäki PM; Department of Pediatric and Adolescent Medicine, Turku University Hospital, Turku, Finland., Nilsson D; Department of Pediatrics, Astrid Lindgrens Hospital, Stockholm, Sweden., Nystad TA; Department of Pediatrics, University Hospital North Norway, Tromsø, Norway., Grell K; Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.; Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark., Frandsen TL; Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark., Schmiegelow K; Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.; Institute of Clinical Medicine, The Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Pediatric blood & cancer [Pediatr Blood Cancer] 2017 Sep; Vol. 64 (9). Date of Electronic Publication: 2017 Apr 19.
DOI: 10.1002/pbc.26519
Abstrakt: Background: Hepatic 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.
Procedure: In 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.
Results: Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 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).
Conclusions: PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.
(© 2017 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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