Disease evolution and outcomes in familial AML with germline CEBPA mutations

Kiran Tawana; Jun Wang; Aline Renneville; Csaba Bödör; Robert Hills; Chey Loveday; Aleksandar Savic; Frederik W Van Delft; Jennifer Treleaven; Panayiotis Georgiades; Elizabeth Uglow; Norio Asou; Naokuni Uike; Maruša Debeljak; Janez Jazbec; Philip Ancliff; Rosemary Gale; Xavier Thomas; Valerie Mialou; Konstanze Döhner; Lars Bullinger; Beatrice Mueller; Thomas Pabst; Matthias Stelljes; Brigitte Schlegelberger; Eva Wozniak; Sameena Iqbal; Jessica Okosun; Shamzah Araf; Anne-Katrine Frank; Felicia B Lauridsen; Bo Porse; Claus Nerlov; Carolyn Owen; Inderjeet Dokal; John Gribben; Matthew Smith; Claude Preudhomme; Claude Chelala; Jamie Cavenagh; Jude Fitzgibbon

doi:10.1182/blood-2015-05-647172

Disease evolution and outcomes in familial AML with germline CEBPA mutations

Kiran Tawana, Jun Wang, Aline Renneville, Csaba Bödör, Robert Hills, Chey Loveday, Aleksandar Savic, Frederik W Van Delft, Jennifer Treleaven, Panayiotis Georgiades, Elizabeth Uglow, Norio Asou, Naokuni Uike, Maruša Debeljak, Janez Jazbec, Philip Ancliff, Rosemary Gale, Xavier Thomas, Valerie Mialou, Konstanze DöhnerLars Bullinger, Beatrice Mueller, Thomas Pabst, Matthias Stelljes, Brigitte Schlegelberger, Eva Wozniak, Sameena Iqbal, Jessica Okosun, Shamzah Araf, Anne-Katrine Frank, Felicia B Lauridsen, Bo Porse, Claus Nerlov, Carolyn Owen, Inderjeet Dokal, John Gribben, Matthew Smith, Claude Preudhomme, Claude Chelala, Jamie Cavenagh, Jude Fitzgibbon

79 Citations (Scopus)

Abstract

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

Original language	English
Journal	Blood
Volume	126
Issue number	10
Pages (from-to)	1214-23
Number of pages	10
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2015-05-647172
Publication status	Published - 3 Sept 2015

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Tawana, K., Wang, J., Renneville, A., Bödör, C., Hills, R., Loveday, C., Savic, A., Van Delft, F. W., Treleaven, J., Georgiades, P., Uglow, E., Asou, N., Uike, N., Debeljak, M., Jazbec, J., Ancliff, P., Gale, R., Thomas, X., Mialou, V., ... Fitzgibbon, J. (2015). Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood, 126(10), 1214-23. https://doi.org/10.1182/blood-2015-05-647172

Tawana, K, Wang, J, Renneville, A, Bödör, C, Hills, R, Loveday, C, Savic, A, Van Delft, FW, Treleaven, J, Georgiades, P, Uglow, E, Asou, N, Uike, N, Debeljak, M, Jazbec, J, Ancliff, P, Gale, R, Thomas, X, Mialou, V, Döhner, K, Bullinger, L, Mueller, B, Pabst, T, Stelljes, M, Schlegelberger, B, Wozniak, E, Iqbal, S, Okosun, J, Araf, S, Frank, A-K, Lauridsen, FB, Porse, B, Nerlov, C, Owen, C, Dokal, I, Gribben, J, Smith, M, Preudhomme, C, Chelala, C, Cavenagh, J & Fitzgibbon, J 2015, 'Disease evolution and outcomes in familial AML with germline CEBPA mutations', Blood, vol. 126, no. 10, pp. 1214-23. https://doi.org/10.1182/blood-2015-05-647172

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title = "Disease evolution and outcomes in familial AML with germline CEBPA mutations",

abstract = "In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.",

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T1 - Disease evolution and outcomes in familial AML with germline CEBPA mutations

AU - Tawana, Kiran

AU - Wang, Jun

AU - Renneville, Aline

AU - Bödör, Csaba

AU - Hills, Robert

AU - Loveday, Chey

AU - Savic, Aleksandar

AU - Van Delft, Frederik W

AU - Treleaven, Jennifer

AU - Georgiades, Panayiotis

AU - Uglow, Elizabeth

AU - Asou, Norio

AU - Uike, Naokuni

AU - Debeljak, Maruša

AU - Jazbec, Janez

AU - Ancliff, Philip

AU - Gale, Rosemary

AU - Thomas, Xavier

AU - Mialou, Valerie

AU - Döhner, Konstanze

AU - Bullinger, Lars

AU - Mueller, Beatrice

AU - Pabst, Thomas

AU - Stelljes, Matthias

AU - Schlegelberger, Brigitte

AU - Wozniak, Eva

AU - Iqbal, Sameena

AU - Okosun, Jessica

AU - Araf, Shamzah

AU - Frank, Anne-Katrine

AU - Lauridsen, Felicia B

AU - Porse, Bo

AU - Nerlov, Claus

AU - Owen, Carolyn

AU - Dokal, Inderjeet

AU - Gribben, John

AU - Smith, Matthew

AU - Preudhomme, Claude

AU - Chelala, Claude

AU - Cavenagh, Jamie

AU - Fitzgibbon, Jude

PY - 2015/9/3

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N2 - In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

AB - In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

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DO - 10.1182/blood-2015-05-647172

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Disease evolution and outcomes in familial AML with germline CEBPA mutations

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