Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Larry Mansouri; Birna Thorvaldsdottir; Lesley Ann Sutton; Georgios Karakatsoulis; Manja Meggendorfer; Helen Parker; Ferran Nadeu; Christian Brieghel; Stamatia Laidou; Riccardo Moia; Davide Rossi; Mark Catherwood; Jana Kotaskova; Julio Delgado; Ana E. Rodríguez-Vicente; Rocío Benito; Gian Matteo Rigolin; Silvia Bonfiglio; Lydia Scarfo; Mattias Mattsson; Zadie Davis; Ajay Gogia; Lata Rani; Panagiotis Baliakas; Hassan Foroughi-Asl; Cecilia Jylhä; Aron Skaftason; Inmaculada Rapado; Fatima Miras; Joaquín Martinez-Lopez; Javier de la Serna; Jesús María Hernández Rivas; Patrick Thornton; María José Larráyoz; María José Calasanz; Viktória Fésüs; Zoltán Mátrai; Csaba Bödör; Karin E. Smedby; Blanca Espinet; Anna Puiggros; Ritu Gupta; Lars Bullinger; Francesc Bosch; Bárbara Tazón-Vega; Fanny Baran-Marszak; David Oscier; Florence Nguyen-Khac; Thorsten Zenz; Maria Jose Terol; Antonio Cuneo; María Hernández-Sánchez; Sarka Pospisilova; Ken Mills; Gianluca Gaidano; Carsten U. Niemann; Elias Campo; Jonathan C. Strefford; Paolo Ghia; Kostas Stamatopoulos; Richard Rosenquist

doi:10.1038/s41375-022-01802-y

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Larry Mansouri
, Birna Thorvaldsdottir
, Lesley Ann Sutton
, Georgios Karakatsoulis
, Manja Meggendorfer
, Helen Parker
, Ferran Nadeu
, Christian Brieghel
, Stamatia Laidou
, Riccardo Moia
, Davide Rossi
, Mark Catherwood
, Jana Kotaskova
, Julio Delgado
, Ana E. Rodríguez-Vicente
, Rocío Benito
, Gian Matteo Rigolin
, Silvia Bonfiglio
, Lydia Scarfo
, Mattias Mattsson

Zadie Davis, Ajay Gogia, Lata Rani, Panagiotis Baliakas, Hassan Foroughi-Asl, Cecilia Jylhä, Aron Skaftason, Inmaculada Rapado, Fatima Miras, Joaquín Martinez-Lopez, Javier de la Serna, Jesús María Hernández Rivas, Patrick Thornton, María José Larráyoz, María José Calasanz, Viktória Fésüs, Zoltán Mátrai, Csaba Bödör, Karin E. Smedby, Blanca Espinet, Anna Puiggros, Ritu Gupta, Lars Bullinger, Francesc Bosch, Bárbara Tazón-Vega, Fanny Baran-Marszak, David Oscier, Florence Nguyen-Khac, Thorsten Zenz, Maria Jose Terol, Antonio Cuneo, María Hernández-Sánchez, Sarka Pospisilova, Ken Mills, Gianluca Gaidano, Carsten U. Niemann, Elias Campo, Jonathan C. Strefford, Paolo Ghia, Kostas Stamatopoulos, Richard Rosenquist

Dipartimento di Medicina Traslazionale

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

Abstract

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

Lingua originale	Inglese
pagine (da-a)	339-347
Numero di pagine	9
Rivista	Leukemia
Volume	37
Numero di pubblicazione	2
DOI	https://doi.org/10.1038/s41375-022-01802-y
Stato di pubblicazione	Pubblicato - feb 2023

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Mansouri, L., Thorvaldsdottir, B., Sutton, L. A., Karakatsoulis, G., Meggendorfer, M., Parker, H., Nadeu, F., Brieghel, C., Laidou, S., Moia, R., Rossi, D., Catherwood, M., Kotaskova, J., Delgado, J., Rodríguez-Vicente, A. E., Benito, R., Rigolin, G. M., Bonfiglio, S., Scarfo, L., ... Rosenquist, R. (2023). Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY. Leukemia, 37(2), 339-347. https://doi.org/10.1038/s41375-022-01802-y

@article{6782668ebffd4272b880d114cbd709f1,

title = "Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY",

abstract = "Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7\%) patients at frequencies ranging from 2.3–9.8\% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.",

author = "Larry Mansouri and Birna Thorvaldsdottir and Sutton, \{Lesley Ann\} and Georgios Karakatsoulis and Manja Meggendorfer and Helen Parker and Ferran Nadeu and Christian Brieghel and Stamatia Laidou and Riccardo Moia and Davide Rossi and Mark Catherwood and Jana Kotaskova and Julio Delgado and Rodr{\'i}guez-Vicente, \{Ana E.\} and Roc{\'i}o Benito and Rigolin, \{Gian Matteo\} and Silvia Bonfiglio and Lydia Scarfo and Mattias Mattsson and Zadie Davis and Ajay Gogia and Lata Rani and Panagiotis Baliakas and Hassan Foroughi-Asl and Cecilia Jylh{\"a} and Aron Skaftason and Inmaculada Rapado and Fatima Miras and Joaqu{\'i}n Martinez-Lopez and \{de la Serna\}, Javier and Rivas, \{Jes{\'u}s Mar{\'i}a Hern{\'a}ndez\} and Patrick Thornton and Larr{\'a}yoz, \{Mar{\'i}a Jos{\'e}\} and Calasanz, \{Mar{\'i}a Jos{\'e}\} and Vikt{\'o}ria F{\'e}s{\"u}s and Zolt{\'a}n M{\'a}trai and Csaba B{\"o}d{\"o}r and Smedby, \{Karin E.\} and Blanca Espinet and Anna Puiggros and Ritu Gupta and Lars Bullinger and Francesc Bosch and B{\'a}rbara Taz{\'o}n-Vega and Fanny Baran-Marszak and David Oscier and Florence Nguyen-Khac and Thorsten Zenz and Terol, \{Maria Jose\} and Antonio Cuneo and Mar{\'i}a Hern{\'a}ndez-S{\'a}nchez and Sarka Pospisilova and Ken Mills and Gianluca Gaidano and Niemann, \{Carsten U.\} and Elias Campo and Strefford, \{Jonathan C.\} and Paolo Ghia and Kostas Stamatopoulos and Richard Rosenquist",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2023",

month = feb,

doi = "10.1038/s41375-022-01802-y",

language = "English",

volume = "37",

pages = "339--347",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

number = "2",

}

Mansouri, L, Thorvaldsdottir, B, Sutton, LA, Karakatsoulis, G, Meggendorfer, M, Parker, H, Nadeu, F, Brieghel, C, Laidou, S, Moia, R, Rossi, D, Catherwood, M, Kotaskova, J, Delgado, J, Rodríguez-Vicente, AE, Benito, R, Rigolin, GM, Bonfiglio, S, Scarfo, L, Mattsson, M, Davis, Z, Gogia, A, Rani, L, Baliakas, P, Foroughi-Asl, H, Jylhä, C, Skaftason, A, Rapado, I, Miras, F, Martinez-Lopez, J, de la Serna, J, Rivas, JMH, Thornton, P, Larráyoz, MJ, Calasanz, MJ, Fésüs, V, Mátrai, Z, Bödör, C, Smedby, KE, Espinet, B, Puiggros, A, Gupta, R, Bullinger, L, Bosch, F, Tazón-Vega, B, Baran-Marszak, F, Oscier, D, Nguyen-Khac, F, Zenz, T, Terol, MJ, Cuneo, A, Hernández-Sánchez, M, Pospisilova, S, Mills, K, Gaidano, G, Niemann, CU, Campo, E, Strefford, JC, Ghia, P, Stamatopoulos, K & Rosenquist, R 2023, 'Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY', Leukemia, vol. 37, n. 2, pagg. 339-347. https://doi.org/10.1038/s41375-022-01802-y

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY. / Mansouri, Larry; Thorvaldsdottir, Birna; Sutton, Lesley Ann et al.
In: Leukemia, Vol. 37, N. 2, 02.2023, pag. 339-347.

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

TY - JOUR

T1 - Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status

T2 - a study by ERIC in HARMONY

AU - Mansouri, Larry

AU - Thorvaldsdottir, Birna

AU - Sutton, Lesley Ann

AU - Karakatsoulis, Georgios

AU - Meggendorfer, Manja

AU - Parker, Helen

AU - Nadeu, Ferran

AU - Brieghel, Christian

AU - Laidou, Stamatia

AU - Moia, Riccardo

AU - Rossi, Davide

AU - Catherwood, Mark

AU - Kotaskova, Jana

AU - Delgado, Julio

AU - Rodríguez-Vicente, Ana E.

AU - Benito, Rocío

AU - Rigolin, Gian Matteo

AU - Bonfiglio, Silvia

AU - Scarfo, Lydia

AU - Mattsson, Mattias

AU - Davis, Zadie

AU - Gogia, Ajay

AU - Rani, Lata

AU - Baliakas, Panagiotis

AU - Foroughi-Asl, Hassan

AU - Jylhä, Cecilia

AU - Skaftason, Aron

AU - Rapado, Inmaculada

AU - Miras, Fatima

AU - Martinez-Lopez, Joaquín

AU - de la Serna, Javier

AU - Rivas, Jesús María Hernández

AU - Thornton, Patrick

AU - Larráyoz, María José

AU - Calasanz, María José

AU - Fésüs, Viktória

AU - Mátrai, Zoltán

AU - Bödör, Csaba

AU - Smedby, Karin E.

AU - Espinet, Blanca

AU - Puiggros, Anna

AU - Gupta, Ritu

AU - Bullinger, Lars

AU - Bosch, Francesc

AU - Tazón-Vega, Bárbara

AU - Baran-Marszak, Fanny

AU - Oscier, David

AU - Nguyen-Khac, Florence

AU - Zenz, Thorsten

AU - Terol, Maria Jose

AU - Cuneo, Antonio

AU - Hernández-Sánchez, María

AU - Pospisilova, Sarka

AU - Mills, Ken

AU - Gaidano, Gianluca

AU - Niemann, Carsten U.

AU - Campo, Elias

AU - Strefford, Jonathan C.

AU - Ghia, Paolo

AU - Stamatopoulos, Kostas

AU - Rosenquist, Richard

PY - 2023/2

Y1 - 2023/2

N2 - Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

AB - Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

UR - https://www.scopus.com/pages/publications/85144854271

U2 - 10.1038/s41375-022-01802-y

DO - 10.1038/s41375-022-01802-y

M3 - Article

SN - 0887-6924

VL - 37

SP - 339

EP - 347

JO - Leukemia

JF - Leukemia

IS - 2

ER -

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

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