Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.
Pediatr Blood Cancer
; 64(9)2017 Sep.
Article
em En
| MEDLINE
| ID: mdl-28423235
ABSTRACT
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 × 109 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.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Hepatopatia Veno-Oclusiva
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Protocolos de Quimioterapia Combinada Antineoplásica
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Leucemia-Linfoma Linfoblástico de Células Precursoras
Tipo de estudo:
Clinical_trials
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Guideline
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Prognostic_studies
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Risk_factors_studies
Limite:
Adolescent
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Pediatr Blood Cancer
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
/
PEDIATRIA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Dinamarca