Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia

Chiara Elena, Anna Gallì, Esperanza Such, Manja Meggendorfer, Ulrich Germing, Ettore Rizzo, Jose Cervera, Elisabetta Molteni, Annette Fasan, Esther Schuler, Ilaria Ambaglio, Maria Lopez-Pavia, Silvia Zibellini, Andrea Kuendgen, Erica Travaglino, Reyes Sancho-Tello, Silvia Catricalà, Ana I. Vicente, Torsten Haferlach, Claudia HaferlachGuillermo F. Sanz, Luca Malcovati, Mario Cazzola

Research output: Contribution to journalArticle

Abstract

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.

Original languageEnglish
Pages (from-to)1408-1417
Number of pages10
JournalBlood
Volume128
Issue number10
DOIs
Publication statusPublished - 2016

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Leukemia, Myelomonocytic, Chronic
Risk assessment
Mutation
Genes
Hazards
Blood
Cells
Survival
Linear Models
Linear regression
Phenotype
Erythrocyte Transfusion
Decision making
Incidence
Leukocyte Count
Cytogenetics
Chromosome Aberrations
Bone Marrow
Regression Analysis
Clinical Trials

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

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Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. / Elena, Chiara; Gallì, Anna; Such, Esperanza; Meggendorfer, Manja; Germing, Ulrich; Rizzo, Ettore; Cervera, Jose; Molteni, Elisabetta; Fasan, Annette; Schuler, Esther; Ambaglio, Ilaria; Lopez-Pavia, Maria; Zibellini, Silvia; Kuendgen, Andrea; Travaglino, Erica; Sancho-Tello, Reyes; Catricalà, Silvia; Vicente, Ana I.; Haferlach, Torsten; Haferlach, Claudia; Sanz, Guillermo F.; Malcovati, Luca; Cazzola, Mario.

In: Blood, Vol. 128, No. 10, 2016, p. 1408-1417.

Research output: Contribution to journalArticle

Elena, C, Gallì, A, Such, E, Meggendorfer, M, Germing, U, Rizzo, E, Cervera, J, Molteni, E, Fasan, A, Schuler, E, Ambaglio, I, Lopez-Pavia, M, Zibellini, S, Kuendgen, A, Travaglino, E, Sancho-Tello, R, Catricalà, S, Vicente, AI, Haferlach, T, Haferlach, C, Sanz, GF, Malcovati, L & Cazzola, M 2016, 'Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia', Blood, vol. 128, no. 10, pp. 1408-1417. https://doi.org/10.1182/blood-2016-05-714030
Elena, Chiara ; Gallì, Anna ; Such, Esperanza ; Meggendorfer, Manja ; Germing, Ulrich ; Rizzo, Ettore ; Cervera, Jose ; Molteni, Elisabetta ; Fasan, Annette ; Schuler, Esther ; Ambaglio, Ilaria ; Lopez-Pavia, Maria ; Zibellini, Silvia ; Kuendgen, Andrea ; Travaglino, Erica ; Sancho-Tello, Reyes ; Catricalà, Silvia ; Vicente, Ana I. ; Haferlach, Torsten ; Haferlach, Claudia ; Sanz, Guillermo F. ; Malcovati, Luca ; Cazzola, Mario. / Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. In: Blood. 2016 ; Vol. 128, No. 10. pp. 1408-1417.
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AU - Elena, Chiara

AU - Gallì, Anna

AU - Such, Esperanza

AU - Meggendorfer, Manja

AU - Germing, Ulrich

AU - Rizzo, Ettore

AU - Cervera, Jose

AU - Molteni, Elisabetta

AU - Fasan, Annette

AU - Schuler, Esther

AU - Ambaglio, Ilaria

AU - Lopez-Pavia, Maria

AU - Zibellini, Silvia

AU - Kuendgen, Andrea

AU - Travaglino, Erica

AU - Sancho-Tello, Reyes

AU - Catricalà, Silvia

AU - Vicente, Ana I.

AU - Haferlach, Torsten

AU - Haferlach, Claudia

AU - Sanz, Guillermo F.

AU - Malcovati, Luca

AU - Cazzola, Mario

PY - 2016

Y1 - 2016

N2 - Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.

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