Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement

Simon Bomken; Amir Enshaei; Ed Schwalbe; Aneta Mikulasova; Yunfeng Dai; Masood Zaka; Kent Tm Fung; Matthew Bashton; Huezin Lim; Lisa Jones; Nefeli Karataraki; Emily Winterman; Cody Ashby; Andishe Attarbaschi; Yves Bertrand; Jutte Bradtke; Barbara Buldini; G.A. Amos Burke; Giovanni Cazzaniga; Gudrun Gohring; Hesta A. De Groot-Kruseman; Claudia Haferlach; Luca Lo Nigro; Mayur Parihar; Adriana Plesa; Emma Seaford; Edwin Sonneveld; Sabine Strehl; Vincent H.J. Van der Velden; Vikki Rand; Stephen P. Hunger; Christine J. Harrison; Chris M. Bacon; Frederik W. Van Delft; Mignon L. Loh; John Moppett; Josef Vormoor; Brian A. Walker; Anthony Vincent Moorman; Lisa J. Russell

doi:10.3324/haematol.2021.280557

Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement

Simon Bomken, Amir Enshaei, Ed Schwalbe, Aneta Mikulasova, Yunfeng Dai, Masood Zaka, Kent Tm Fung, Matthew Bashton, Huezin Lim, Lisa Jones, Nefeli Karataraki, Emily Winterman, Cody Ashby, Andishe Attarbaschi, Yves Bertrand, Jutte Bradtke, Barbara Buldini, G.A. Amos Burke, Giovanni Cazzaniga, Gudrun GohringHesta A. De Groot-Kruseman, Claudia Haferlach, Luca Lo Nigro, Mayur Parihar, Adriana Plesa, Emma Seaford, Edwin Sonneveld, Sabine Strehl, Vincent H.J. Van der Velden, Vikki Rand, Stephen P. Hunger, Christine J. Harrison, Chris M. Bacon, Frederik W. Van Delft, Mignon L. Loh, John Moppett, Josef Vormoor, Brian A. Walker, Anthony Vincent Moorman, Lisa J. Russell

Applied Sciences

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Abstract

Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukaemia and use of unproven individualised treatment schedules. Here we contrast the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered on a national BCP-ALL clinical trial/registry. Where present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analysis. Outcome was analysed to define 3-year event free survival (EFS) and overall survival (OS). IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either: established BCP-ALL specific abnormalities (high hyperdiploidy n=3, KMT2A-rearrangement n=6, iAMP21 n=1, BCR-ABL n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J rearranged cases, clearly distinct from Burkitt leukaemia/lymphoma. Children with IG-MYC-r within that subgroup had 3-year EFS of 47% and OS of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this patient group must be allowed access to contemporary, minimal residual disease adapted, prospective clinical trial protocols.

Original language	English
Pages (from-to)	717-731
Journal	Haematologica
Volume	108
Issue number	3
Early online date	28 Apr 2022
DOIs	https://doi.org/10.3324/haematol.2021.280557
Publication status	Published - 1 Mar 2023

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10624-Article Text-78143-1-10-20220428Accepted author manuscript, 8.7 MBLicence: CC BY-NC
10624-Article Text-78143-3-10-20230222Final published version, 2.06 MBLicence: CC BY-NC

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Bomken, S., Enshaei, A., Schwalbe, E., Mikulasova, A., Dai, Y., Zaka, M., Fung, K. T., Bashton, M., Lim, H., Jones, L., Karataraki, N., Winterman, E., Ashby, C., Attarbaschi, A., Bertrand, Y., Bradtke, J., Buldini, B., Burke, G. A. A., Cazzaniga, G., ... Russell, L. J. (2023). Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement. Haematologica, 108(3), 717-731. https://doi.org/10.3324/haematol.2021.280557

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title = "Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement",

abstract = "Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukaemia and use of unproven individualised treatment schedules. Here we contrast the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered on a national BCP-ALL clinical trial/registry. Where present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analysis. Outcome was analysed to define 3-year event free survival (EFS) and overall survival (OS). IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either: established BCP-ALL specific abnormalities (high hyperdiploidy n=3, KMT2A-rearrangement n=6, iAMP21 n=1, BCR-ABL n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J rearranged cases, clearly distinct from Burkitt leukaemia/lymphoma. Children with IG-MYC-r within that subgroup had 3-year EFS of 47% and OS of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this patient group must be allowed access to contemporary, minimal residual disease adapted, prospective clinical trial protocols.",

author = "Simon Bomken and Amir Enshaei and Ed Schwalbe and Aneta Mikulasova and Yunfeng Dai and Masood Zaka and Fung, {Kent Tm} and Matthew Bashton and Huezin Lim and Lisa Jones and Nefeli Karataraki and Emily Winterman and Cody Ashby and Andishe Attarbaschi and Yves Bertrand and Jutte Bradtke and Barbara Buldini and Burke, {G.A. Amos} and Giovanni Cazzaniga and Gudrun Gohring and {De Groot-Kruseman}, {Hesta A.} and Claudia Haferlach and Nigro, {Luca Lo} and Mayur Parihar and Adriana Plesa and Emma Seaford and Edwin Sonneveld and Sabine Strehl and {Van der Velden}, {Vincent H.J.} and Vikki Rand and Hunger, {Stephen P.} and Harrison, {Christine J.} and Bacon, {Chris M.} and {Van Delft}, {Frederik W.} and Loh, {Mignon L.} and John Moppett and Josef Vormoor and Walker, {Brian A.} and Moorman, {Anthony Vincent} and Russell, {Lisa J.}",

year = "2023",

month = mar,

day = "1",

doi = "10.3324/haematol.2021.280557",

language = "English",

volume = "108",

pages = "717--731",

journal = "Haematologica",

issn = "0390-6078",

publisher = "Ferrata Storti Foundation",

number = "3",

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Bomken, S, Enshaei, A, Schwalbe, E, Mikulasova, A, Dai, Y, Zaka, M, Fung, KT, Bashton, M, Lim, H, Jones, L, Karataraki, N, Winterman, E, Ashby, C, Attarbaschi, A, Bertrand, Y, Bradtke, J, Buldini, B, Burke, GAA, Cazzaniga, G, Gohring, G, De Groot-Kruseman, HA, Haferlach, C, Nigro, LL, Parihar, M, Plesa, A, Seaford, E, Sonneveld, E, Strehl, S, Van der Velden, VHJ, Rand, V, Hunger, SP, Harrison, CJ, Bacon, CM, Van Delft, FW, Loh, ML, Moppett, J, Vormoor, J, Walker, BA, Moorman, AV & Russell, LJ 2023, 'Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement', Haematologica, vol. 108, no. 3, pp. 717-731. https://doi.org/10.3324/haematol.2021.280557

TY - JOUR

T1 - Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement

AU - Bomken, Simon

AU - Enshaei, Amir

AU - Schwalbe, Ed

AU - Mikulasova, Aneta

AU - Dai, Yunfeng

AU - Zaka, Masood

AU - Fung, Kent Tm

AU - Bashton, Matthew

AU - Lim, Huezin

AU - Jones, Lisa

AU - Karataraki, Nefeli

AU - Winterman, Emily

AU - Ashby, Cody

AU - Attarbaschi, Andishe

AU - Bertrand, Yves

AU - Bradtke, Jutte

AU - Buldini, Barbara

AU - Burke, G.A. Amos

AU - Cazzaniga, Giovanni

AU - Gohring, Gudrun

AU - De Groot-Kruseman, Hesta A.

AU - Haferlach, Claudia

AU - Nigro, Luca Lo

AU - Parihar, Mayur

AU - Plesa, Adriana

AU - Seaford, Emma

AU - Sonneveld, Edwin

AU - Strehl, Sabine

AU - Van der Velden, Vincent H.J.

AU - Rand, Vikki

AU - Hunger, Stephen P.

AU - Harrison, Christine J.

AU - Bacon, Chris M.

AU - Van Delft, Frederik W.

AU - Loh, Mignon L.

AU - Moppett, John

AU - Vormoor, Josef

AU - Walker, Brian A.

AU - Moorman, Anthony Vincent

AU - Russell, Lisa J.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukaemia and use of unproven individualised treatment schedules. Here we contrast the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered on a national BCP-ALL clinical trial/registry. Where present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analysis. Outcome was analysed to define 3-year event free survival (EFS) and overall survival (OS). IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either: established BCP-ALL specific abnormalities (high hyperdiploidy n=3, KMT2A-rearrangement n=6, iAMP21 n=1, BCR-ABL n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J rearranged cases, clearly distinct from Burkitt leukaemia/lymphoma. Children with IG-MYC-r within that subgroup had 3-year EFS of 47% and OS of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this patient group must be allowed access to contemporary, minimal residual disease adapted, prospective clinical trial protocols.

AB - Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukaemia and use of unproven individualised treatment schedules. Here we contrast the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered on a national BCP-ALL clinical trial/registry. Where present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analysis. Outcome was analysed to define 3-year event free survival (EFS) and overall survival (OS). IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either: established BCP-ALL specific abnormalities (high hyperdiploidy n=3, KMT2A-rearrangement n=6, iAMP21 n=1, BCR-ABL n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J rearranged cases, clearly distinct from Burkitt leukaemia/lymphoma. Children with IG-MYC-r within that subgroup had 3-year EFS of 47% and OS of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this patient group must be allowed access to contemporary, minimal residual disease adapted, prospective clinical trial protocols.

U2 - 10.3324/haematol.2021.280557

DO - 10.3324/haematol.2021.280557

M3 - Article

C2 - 35484682

SN - 0390-6078

VL - 108

SP - 717

EP - 731

JO - Haematologica

JF - Haematologica

IS - 3

ER -

Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement

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