Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers

Stine N. Nielsen; Frank Eriksson; Susanne Rosthoej; Mette K. Andersen; Erik Forestier; Henrik Hasle; Lisa L. Hjalgrim; Ann Aasberg; Jonas Abrahamsson; Mats Heyman; Ólafur G. Jónsson; Kaie Pruunsild; Goda E. Vaitkeviciené; Kim Vettenranta; Kjeld Schmiegelow

doi:10.1002/pbc.26518

Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers

Stine N. Nielsen, Frank Eriksson, Susanne Rosthoej, Mette K. Andersen, Erik Forestier, Henrik Hasle, Lisa L. Hjalgrim, Ann Aasberg, Jonas Abrahamsson, Mats Heyman, Ólafur G. Jónsson, Kaie Pruunsild, Goda E. Vaitkeviciené, Kim Vettenranta, Kjeld Schmiegelow

1 Citationer (Scopus)

Abstract

Background: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. Procedure: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. Results: After median 9.5 years (interquartile range, 5.4–15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06−0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02−0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69−5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54−3.76, P = 0.47). Conclusions: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

Originalsprog	Engelsk
Artikelnummer	e26518
Tidsskrift	Pediatric Blood & Cancer
Vol/bind	64
Udgave nummer	10
Sider (fra-til)	1-9
Antal sider	9
ISSN	1545-5009
DOI	https://doi.org/10.1002/pbc.26518
Status	Udgivet - okt. 2017

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10.1002/pbc.26518

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Nielsen, S. N., Eriksson, F., Rosthoej, S., Andersen, M. K., Forestier, E., Hasle, H., Hjalgrim, L. L., Aasberg, A., Abrahamsson, J., Heyman, M., Jónsson, Ó. G., Pruunsild, K., Vaitkeviciené, G. E., Vettenranta, K., & Schmiegelow, K. (2017). Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers. Pediatric Blood & Cancer, 64(10), 1-9. Artikel e26518. https://doi.org/10.1002/pbc.26518

Nielsen, SN, Eriksson, F , Rosthoej, S, Andersen, MK, Forestier, E, Hasle, H, Hjalgrim, LL, Aasberg, A, Abrahamsson, J, Heyman, M, Jónsson, ÓG, Pruunsild, K, Vaitkeviciené, GE, Vettenranta, K & Schmiegelow, K 2017, 'Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers', Pediatric Blood & Cancer, bind 64, nr. 10, e26518, s. 1-9. https://doi.org/10.1002/pbc.26518

@article{77ecce29e1a44949961c6cc7e0be401d,

title = "Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers",

abstract = "Background: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. Procedure: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. Results: After median 9.5 years (interquartile range, 5.4–15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06−0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02−0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69−5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54−3.76, P = 0.47). Conclusions: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.",

keywords = "Adolescent, Antineoplastic Combined Chemotherapy Protocols, Child, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Female, Follow-Up Studies, Humans, Male, Methyltransferases, Neoplasms, Second Primary, Ploidies, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Retrospective Studies, Risk Factors, Translocation, Genetic, Journal Article",

author = "Nielsen, {Stine N.} and Frank Eriksson and Susanne Rosthoej and Andersen, {Mette K.} and Erik Forestier and Henrik Hasle and Hjalgrim, {Lisa L.} and Ann Aasberg and Jonas Abrahamsson and Mats Heyman and J{\'o}nsson, {{\'O}lafur G.} and Kaie Pruunsild and Vaitkevicien{\'e}, {Goda E.} and Kim Vettenranta and Kjeld Schmiegelow",

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

year = "2017",

month = oct,

doi = "10.1002/pbc.26518",

language = "English",

volume = "64",

pages = "1--9",

journal = "Pediatric Blood & Cancer",

issn = "1545-5009",

publisher = "JohnWiley & Sons, Inc.",

number = "10",

}

TY - JOUR

T1 - Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers

AU - Nielsen, Stine N.

AU - Eriksson, Frank

AU - Rosthoej, Susanne

AU - Andersen, Mette K.

AU - Forestier, Erik

AU - Hasle, Henrik

AU - Hjalgrim, Lisa L.

AU - Aasberg, Ann

AU - Abrahamsson, Jonas

AU - Heyman, Mats

AU - Jónsson, Ólafur G.

AU - Pruunsild, Kaie

AU - Vaitkeviciené, Goda E.

AU - Vettenranta, Kim

AU - Schmiegelow, Kjeld

PY - 2017/10

Y1 - 2017/10

N2 - Background: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. Procedure: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. Results: After median 9.5 years (interquartile range, 5.4–15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06−0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02−0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69−5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54−3.76, P = 0.47). Conclusions: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

AB - Background: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. Procedure: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. Results: After median 9.5 years (interquartile range, 5.4–15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06−0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02−0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69−5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54−3.76, P = 0.47). Conclusions: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

KW - Adolescent

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Child

KW - Chromosomes, Human, Pair 12

KW - Chromosomes, Human, Pair 21

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Male

KW - Methyltransferases

KW - Neoplasms, Second Primary

KW - Ploidies

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Retrospective Studies

KW - Risk Factors

KW - Translocation, Genetic

KW - Journal Article

U2 - 10.1002/pbc.26518

DO - 10.1002/pbc.26518

M3 - Journal article

C2 - 28500740

SN - 1545-5009

VL - 64

SP - 1

EP - 9

JO - Pediatric Blood & Cancer

JF - Pediatric Blood & Cancer

IS - 10

M1 - e26518

ER -

Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers

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