Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol

B. O. Wolthers, Thomas L. Frandsen, Jonas Abrahamsson, B. K. Albertsen, L. R. Helt, Mats Heyman, Olafur G. Jonsson, L. T. Korgvee, B. Lund, R. A. Raja, K. K. Rasmussen, M. Taskinen, M. Tulstrup, G. E. Vaitkeviciene, Rachita Yadav, R. Gupta, K. Schmiegelow

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence = 6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting 472 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P = 0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P = 5.8x10(-7); odds ratio (OR) = 6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P = 0.015) and had lower risk of AAP-related complications (15% vs 43%; P = 0.13) compared with cases without this variant. Among 45 cases and 517 controls
    Original languageEnglish
    JournalLeukemia
    Volume31
    Issue number2
    Pages (from-to)325-332
    ISSN0887-6924
    DOIs
    Publication statusPublished - 2016

    Cite this

    Wolthers, B. O., Frandsen, T. L., Abrahamsson, J., Albertsen, B. K., Helt, L. R., Heyman, M., ... Schmiegelow, K. (2016). Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. Leukemia, 31(2), 325-332. https://doi.org/10.1038/leu.2016.203
    Wolthers, B. O. ; Frandsen, Thomas L. ; Abrahamsson, Jonas ; Albertsen, B. K. ; Helt, L. R. ; Heyman, Mats ; Jonsson, Olafur G. ; Korgvee, L. T. ; Lund, B. ; Raja, R. A. ; Rasmussen, K. K. ; Taskinen, M. ; Tulstrup, M. ; Vaitkeviciene, G. E. ; Yadav, Rachita ; Gupta, R. ; Schmiegelow, K. / Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. In: Leukemia. 2016 ; Vol. 31, No. 2. pp. 325-332.
    @article{b0f296bd56d5457da0687029b77a590b,
    title = "Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol",
    abstract = "Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence = 6.8{\%}) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting 472 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P = 0.001). Pseudocysts developed in 28{\%}. Of the 20 re-exposed to ASP, 9 (45{\%}) developed a second AAP. After a median follow-up of 2.3 years, 8{\%} needed permanent insulin therapy, and 7{\%} had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P = 5.8x10(-7); odds ratio (OR) = 6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P = 0.015) and had lower risk of AAP-related complications (15{\%} vs 43{\%}; P = 0.13) compared with cases without this variant. Among 45 cases and 517 controls",
    author = "Wolthers, {B. O.} and Frandsen, {Thomas L.} and Jonas Abrahamsson and Albertsen, {B. K.} and Helt, {L. R.} and Mats Heyman and Jonsson, {Olafur G.} and Korgvee, {L. T.} and B. Lund and Raja, {R. A.} and Rasmussen, {K. K.} and M. Taskinen and M. Tulstrup and Vaitkeviciene, {G. E.} and Rachita Yadav and R. Gupta and K. Schmiegelow",
    year = "2016",
    doi = "10.1038/leu.2016.203",
    language = "English",
    volume = "31",
    pages = "325--332",
    journal = "Leukemia",
    issn = "0887-6924",
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    Wolthers, BO, Frandsen, TL, Abrahamsson, J, Albertsen, BK, Helt, LR, Heyman, M, Jonsson, OG, Korgvee, LT, Lund, B, Raja, RA, Rasmussen, KK, Taskinen, M, Tulstrup, M, Vaitkeviciene, GE, Yadav, R, Gupta, R & Schmiegelow, K 2016, 'Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol', Leukemia, vol. 31, no. 2, pp. 325-332. https://doi.org/10.1038/leu.2016.203

    Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. / Wolthers, B. O.; Frandsen, Thomas L.; Abrahamsson, Jonas; Albertsen, B. K.; Helt, L. R.; Heyman, Mats; Jonsson, Olafur G.; Korgvee, L. T.; Lund, B.; Raja, R. A.; Rasmussen, K. K.; Taskinen, M.; Tulstrup, M.; Vaitkeviciene, G. E.; Yadav, Rachita; Gupta, R.; Schmiegelow, K.

    In: Leukemia, Vol. 31, No. 2, 2016, p. 325-332.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol

    AU - Wolthers, B. O.

    AU - Frandsen, Thomas L.

    AU - Abrahamsson, Jonas

    AU - Albertsen, B. K.

    AU - Helt, L. R.

    AU - Heyman, Mats

    AU - Jonsson, Olafur G.

    AU - Korgvee, L. T.

    AU - Lund, B.

    AU - Raja, R. A.

    AU - Rasmussen, K. K.

    AU - Taskinen, M.

    AU - Tulstrup, M.

    AU - Vaitkeviciene, G. E.

    AU - Yadav, Rachita

    AU - Gupta, R.

    AU - Schmiegelow, K.

    PY - 2016

    Y1 - 2016

    N2 - Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence = 6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting 472 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P = 0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P = 5.8x10(-7); odds ratio (OR) = 6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P = 0.015) and had lower risk of AAP-related complications (15% vs 43%; P = 0.13) compared with cases without this variant. Among 45 cases and 517 controls

    AB - Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence = 6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting 472 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P = 0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P = 5.8x10(-7); odds ratio (OR) = 6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P = 0.015) and had lower risk of AAP-related complications (15% vs 43%; P = 0.13) compared with cases without this variant. Among 45 cases and 517 controls

    U2 - 10.1038/leu.2016.203

    DO - 10.1038/leu.2016.203

    M3 - Journal article

    VL - 31

    SP - 325

    EP - 332

    JO - Leukemia

    JF - Leukemia

    SN - 0887-6924

    IS - 2

    ER -

    Wolthers BO, Frandsen TL, Abrahamsson J, Albertsen BK, Helt LR, Heyman M et al. Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. Leukemia. 2016;31(2):325-332. https://doi.org/10.1038/leu.2016.203