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Prognostic score including gene mutations in chronic myelomonocytic leukemia

Prognostic score including gene mutations in chronic myelomonocytic leukemia
Prognostic score including gene mutations in chronic myelomonocytic leukemia
PURPOSESeveral prognostic scoring systems have been proposed for chronic myelomonocytic leukemia (CMML), a disease in which some gene mutations-including ASXL1-have been associated with poor prognosis in univariable analyses. We developed and validated a prognostic score for overall survival (OS) based on mutational status and standard clinical variables. PATIENTS AND METHODSWe genotyped ASXL1 and up to 18 other genes including epigenetic (TET2, EZH2, IDH1, IDH2, DNMT3A), splicing (SF3B1, SRSF2, ZRSF2, U2AF1), transcription (RUNX1, NPM1, TP53), and signaling (NRAS, KRAS, CBL, JAK2, FLT3) regulators in 312 patients with CMML. Genotypes and clinical variables were included in a multivariable Cox model of OS validated by bootstrapping. A scoring system was developed using regression coefficients from this model.ResultsASXL1 mutations (P < .0001) and, to a lesser extent, SRSF2 (P = .03), CBL (P = .003), and IDH2 (P = .03) mutations predicted inferior OS in univariable analysis. The retained independent prognostic factors included ASXL1 mutations, age older than 65 years, WBC count greater than 15 ×109/L, platelet count less than 100 ×109/L, and anemia (hemoglobin < 10 g/dL in female patients, < 11g/dL in male patients). The resulting five-parameter prognostic score delineated three groups of patients with median OS not reached, 38.5 months, and 14.4 months, respectively (P < .0001), and was validated in an independent cohort of 165 patients (P < .0001). CONCLUSIONA new prognostic score including ASXL1 status, age, hemoglobin, WBC, and platelet counts defines three groups of CMML patients with distinct outcomes. Based on concordance analysis, this score appears more discriminative than those based solely on clinical parameters.
1527-7755
2428-2436
Itzykson, Raphaël
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Kosmider, Olivier
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Renneville, Aline
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Gelsi-Boyer, Véronique
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Meggendorfer, Manja
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Morabito, Margot
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Berthon, Céline
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Adès, Lionel
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Fenaux, Pierre
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Beyne-Rauzy, Odile
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Vey, Norbert
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Braun, Thorsten
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Haferlach, Torsten
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Dreyfus, François
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Cross, Nicholas C.P.
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Preudhomme, Claude
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Bernard, Oliver A.
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Fontenay, Michaela
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Vainchenker, William
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Schnittger, Susanne
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Birnbaum, Daniel
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Droin, Nathalie
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Solary, Eric
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Itzykson, Raphaël
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Kosmider, Olivier
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Renneville, Aline
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Gelsi-Boyer, Véronique
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Meggendorfer, Manja
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Morabito, Margot
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Berthon, Céline
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Adès, Lionel
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Fenaux, Pierre
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Beyne-Rauzy, Odile
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Vey, Norbert
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Braun, Thorsten
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Haferlach, Torsten
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Dreyfus, François
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Cross, Nicholas C.P.
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Preudhomme, Claude
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Bernard, Oliver A.
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Fontenay, Michaela
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Vainchenker, William
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Schnittger, Susanne
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Birnbaum, Daniel
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Droin, Nathalie
c07f89fc-9bc2-47ac-a29d-4f130638b149
Solary, Eric
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Itzykson, Raphaël, Kosmider, Olivier, Renneville, Aline, Gelsi-Boyer, Véronique, Meggendorfer, Manja, Morabito, Margot, Berthon, Céline, Adès, Lionel, Fenaux, Pierre, Beyne-Rauzy, Odile, Vey, Norbert, Braun, Thorsten, Haferlach, Torsten, Dreyfus, François, Cross, Nicholas C.P., Preudhomme, Claude, Bernard, Oliver A., Fontenay, Michaela, Vainchenker, William, Schnittger, Susanne, Birnbaum, Daniel, Droin, Nathalie and Solary, Eric (2013) Prognostic score including gene mutations in chronic myelomonocytic leukemia. Journal of Clinical Oncology, 31 (19), 2428-2436. (doi:10.1200/JCO.2012.47.3314). (PMID:23690417)

Record type: Article

Abstract

PURPOSESeveral prognostic scoring systems have been proposed for chronic myelomonocytic leukemia (CMML), a disease in which some gene mutations-including ASXL1-have been associated with poor prognosis in univariable analyses. We developed and validated a prognostic score for overall survival (OS) based on mutational status and standard clinical variables. PATIENTS AND METHODSWe genotyped ASXL1 and up to 18 other genes including epigenetic (TET2, EZH2, IDH1, IDH2, DNMT3A), splicing (SF3B1, SRSF2, ZRSF2, U2AF1), transcription (RUNX1, NPM1, TP53), and signaling (NRAS, KRAS, CBL, JAK2, FLT3) regulators in 312 patients with CMML. Genotypes and clinical variables were included in a multivariable Cox model of OS validated by bootstrapping. A scoring system was developed using regression coefficients from this model.ResultsASXL1 mutations (P < .0001) and, to a lesser extent, SRSF2 (P = .03), CBL (P = .003), and IDH2 (P = .03) mutations predicted inferior OS in univariable analysis. The retained independent prognostic factors included ASXL1 mutations, age older than 65 years, WBC count greater than 15 ×109/L, platelet count less than 100 ×109/L, and anemia (hemoglobin < 10 g/dL in female patients, < 11g/dL in male patients). The resulting five-parameter prognostic score delineated three groups of patients with median OS not reached, 38.5 months, and 14.4 months, respectively (P < .0001), and was validated in an independent cohort of 165 patients (P < .0001). CONCLUSIONA new prognostic score including ASXL1 status, age, hemoglobin, WBC, and platelet counts defines three groups of CMML patients with distinct outcomes. Based on concordance analysis, this score appears more discriminative than those based solely on clinical parameters.

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More information

e-pub ahead of print date: 20 May 2013
Published date: 1 July 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 353021
URI: http://eprints.soton.ac.uk/id/eprint/353021
ISSN: 1527-7755
PURE UUID: 6d785906-bbfd-421c-8274-f6352301718b
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 24 May 2013 10:29
Last modified: 28 Apr 2022 01:49

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Contributors

Author: Raphaël Itzykson
Author: Olivier Kosmider
Author: Aline Renneville
Author: Véronique Gelsi-Boyer
Author: Manja Meggendorfer
Author: Margot Morabito
Author: Céline Berthon
Author: Lionel Adès
Author: Pierre Fenaux
Author: Odile Beyne-Rauzy
Author: Norbert Vey
Author: Thorsten Braun
Author: Torsten Haferlach
Author: François Dreyfus
Author: Claude Preudhomme
Author: Oliver A. Bernard
Author: Michaela Fontenay
Author: William Vainchenker
Author: Susanne Schnittger
Author: Daniel Birnbaum
Author: Nathalie Droin
Author: Eric Solary

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