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

Linea Natalie Toksvang; Silvia De Pietri; Stine N Nielsen; Jacob Nersting; Birgitte K Albertsen; Peder S Wehner; Steen Rosthøj; Päivi M Lähteenmäki; Daniel Nilsson; Tove A Nystad; Kathrine Grell; Thomas L Frandsen; Kjeld Schmiegelow

doi:10.1002/pbc.26519

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

Linea Natalie Toksvang, Silvia De Pietri, Stine N Nielsen, Jacob Nersting, Birgitte K Albertsen, Peder S Wehner, Steen Rosthøj, Päivi M Lähteenmäki, Daniel Nilsson, Tove A Nystad, Kathrine Grell, Thomas L Frandsen, Kjeld Schmiegelow

Afdeling for Børn og Unge

26 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Pediatric Blood and Cancer
Vol/bind	64
Udgave nummer	9
Sider (fra-til)	e26519
ISSN	1545-5009
DOI	https://doi.org/10.1002/pbc.26519
Status	Udgivet - sep. 2017

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10.1002/pbc.26519

Citationsformater

Toksvang, L. N., De Pietri, S., Nielsen, S. N., Nersting, J., Albertsen, B. K., Wehner, P. S., Rosthøj, S., Lähteenmäki, P. M., Nilsson, D., Nystad, T. A., Grell, K., Frandsen, T. L., & Schmiegelow, K. (2017). Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites. Pediatric Blood and Cancer, 64(9), e26519. https://doi.org/10.1002/pbc.26519

Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites. / Toksvang, Linea Natalie; De Pietri, Silvia; Nielsen, Stine N et al.
I: Pediatric Blood and Cancer, Bind 64, Nr. 9, 09.2017, s. e26519.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Toksvang, LN, De Pietri, S, Nielsen, SN, Nersting, J, Albertsen, BK, Wehner, PS, Rosthøj, S, Lähteenmäki, PM, Nilsson, D, Nystad, TA, Grell, K, Frandsen, TL & Schmiegelow, K 2017, 'Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites', Pediatric Blood and Cancer, bind 64, nr. 9, s. e26519. https://doi.org/10.1002/pbc.26519

@article{c4845c80416b4d9db102ca8a09bf85d5,

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

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.",

keywords = "Adolescent, Antineoplastic Combined Chemotherapy Protocols, Asparaginase, Child, Child, Preschool, Drug Interactions, Female, Hepatic Veno-Occlusive Disease, Humans, Infant, Kaplan-Meier Estimate, Maintenance Chemotherapy, Male, Mercaptopurine, Methotrexate, Polyethylene Glycols, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proportional Hazards Models, Clinical Trial, Journal Article",

author = "Toksvang, {Linea Natalie} and {De Pietri}, Silvia and Nielsen, {Stine N} and Jacob Nersting and Albertsen, {Birgitte K} and Wehner, {Peder S} and Steen Rosth{\o}j and L{\"a}hteenm{\"a}ki, {P{\"a}ivi M} and Daniel Nilsson and Nystad, {Tove A} and Kathrine Grell and Frandsen, {Thomas L} and Kjeld Schmiegelow",

note = "{\textcopyright} 2017 Wiley Periodicals, Inc.",

year = "2017",

month = sep,

doi = "10.1002/pbc.26519",

language = "English",

volume = "64",

pages = "e26519",

journal = "Pediatric Blood and Cancer",

issn = "1545-5009",

publisher = "Wiley-Liss Inc.",

number = "9",

}

TY - JOUR

T1 - Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites

AU - Toksvang, Linea Natalie

AU - De Pietri, Silvia

AU - Nielsen, Stine N

AU - Nersting, Jacob

AU - Albertsen, Birgitte K

AU - Wehner, Peder S

AU - Rosthøj, Steen

AU - Lähteenmäki, Päivi M

AU - Nilsson, Daniel

AU - Nystad, Tove A

AU - Grell, Kathrine

AU - Frandsen, Thomas L

AU - Schmiegelow, Kjeld

PY - 2017/9

Y1 - 2017/9

N2 - 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.

AB - 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.

KW - Adolescent

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Asparaginase

KW - Child

KW - Child, Preschool

KW - Drug Interactions

KW - Female

KW - Hepatic Veno-Occlusive Disease

KW - Humans

KW - Infant

KW - Kaplan-Meier Estimate

KW - Maintenance Chemotherapy

KW - Male

KW - Mercaptopurine

KW - Methotrexate

KW - Polyethylene Glycols

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Proportional Hazards Models

KW - Clinical Trial

KW - Journal Article

U2 - 10.1002/pbc.26519

DO - 10.1002/pbc.26519

M3 - Journal article

C2 - 28423235

SN - 1545-5009

VL - 64

SP - e26519

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

IS - 9

ER -

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

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