NOTCH1, TP53, SF3B1, ATM AND BIRC3 GENE MUTATIONS ARE ASSOCIATED WITH A WORSE OUTCOME IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS WITH 13Q LOSSES
Author(s): ,
Claudia Pérez Carretero
Affiliations:
IBSAL, IBMCC, Universidad de Salamanca, CSIC, Centro de Investigación del Cáncer,Salamanca,Spain;Servicio de hematología, Hospital Universitario de Salamanca,Salamanca,Spain
,
Ana E Rodríguez-Vicente
Affiliations:
IBSAL, IBMCC, Universidad de Salamanca, CSIC, Centro de Investigación del Cáncer,Salamanca,Spain;Servicio de hematología, Hospital Universitario de Salamanca,Salamanca,Spain
,
María Hernández-Sánchez
Affiliations:
IBSAL, IBMCC, Universidad de Salamanca, CSIC, Centro de Investigación del Cáncer,Salamanca,Spain;Servicio de hematología, Hospital Universitario de Salamanca,Salamanca,Spain
,
Miguel Quijada-Álamo
Affiliations:
IBSAL, IBMCC, Universidad de Salamanca, CSIC, Centro de Investigación del Cáncer,Salamanca,Spain;Servicio de hematología, Hospital Universitario de Salamanca,Salamanca,Spain
,
Rocío Benito
Affiliations:
IBSAL, IBMCC, Universidad de Salamanca, CSIC, Centro de Investigación del Cáncer,Salamanca,Spain;Servicio de hematología, Hospital Universitario de Salamanca,Salamanca,Spain
,
Jesús Hernández-Sánchez
Affiliations:
IBSAL, IBMCC, Universidad de Salamanca, CSIC, Centro de Investigación del Cáncer,Salamanca,Spain;Servicio de hematología, Hospital Universitario de Salamanca,Salamanca,Spain
,
Marta Martín-Izquierdo
Affiliations:
IBSAL, IBMCC, Universidad de Salamanca, CSIC, Centro de Investigación del Cáncer,Salamanca,Spain;Servicio de hematología, Hospital Universitario de Salamanca,Salamanca,Spain
,
Teresa González
Affiliations:
Servicio de hematología,Hospital Universitario de Salamanca,Salamanca,Spain
,
María Jesús Vidal-Manceñido
Affiliations:
Servicio de hematología,Hospital Virgen Blanca,León,Spain
,
Alfonso García de Coca
Affiliations:
Servicio de hematología,Hospital Clínico Universitario,Valladolid,Spain
,
María Pilar Delgado-Beltrán
Affiliations:
Servicio de hematología,Hospital Miguel Servet,Zaragoza,Spain
,
Juan Nicolás Rodríguez
Affiliations:
Servicio de hematología,Hospital Juan Ramón Jiménez,Huelva,Spain
,
Manuel Vargas
Affiliations:
Servicio de hematología,Hospital de Jarrio,Asturias,Spain
,
José Antonio Queizán
Affiliations:
Servicio de hematología,Hospital General,Segovia,Spain
,
Ignacio de la Fuente
Affiliations:
Servicio de hematología,Hospital Río Hortega,Valladolid,Spain
,
Jorge Labrador
Affiliations:
Servicio de hematología,Hospital Universitario,Burgos,Spain
,
Beatriz Albarrán Servero
Affiliations:
Servicio de hematología,Hospital Río Carrión,Palencia,Spain
,
José-Ángel Hernández
Affiliations:
Servicio de hematología,Hospital Universitario Infanta Leonor,Madrid,Spain
Jesús-María Hernández Rivas
Affiliations:
IBSAL, IBMCC, Universidad de Salamanca, CSIC, Centro de Investigación del Cáncer,Salamanca,Spain;Servicio de hematología, Hospital Universitario de Salamanca,Salamanca,Spain
EHA Library. E Rodríguez-Vicente A. Jun 15, 2018; 214803; PF328
Ana E Rodríguez-Vicente
Ana E Rodríguez-Vicente
Contributions
Abstract

Abstract: PF328

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
13q deletion (13q-) is the most common cytogenetic aberration in chronic lymphocytic leukemia (CLL) associated with a favorable prognosis. However, CLL patients showing 13q- can have a variable outcome. Although the use of next-generation sequencing (NGS) has expanded our knowledge of the genomic alterations in CLL, the mutational background of 13q- patients has not been analyzed in detail so far.

Aims
To analyze the mutational status of CLL patients with 13q- by NGS in order to improve our understanding of the genetic underpinnings of this subgroup of CLL.

Methods
A total of 213 untreated CLL patients were selected for the study. Clinical and biological data were recorded. CD19 positive B cells were isolated and DNA extracted to perform NGS. The mutational status of 54 genes (8,952 probes, 416 Mb) was evaluated using a custom-designed gene panel (MiSeq, Illumina) including recurrent mutated genes in CLL associated with CLL pathogenesis. 95% of regions were sufficiently covered (>100X) and a mean depth of 343 reads/base within the regions of interest was obtained, allowing us to identify variants at low allele frequencies (down to 3%).

Results

A total of 117 patients (54.9%) had 13q- as a sole abnormality. Most patients (82.9%) were in Binets stage A. The median follow-up for the CLL patients was 60 months.

A total of 172 mutations were detected in 39 genes in seventy-three 13q- CLL patients (13q- mut). The median of mutations detected per patient was 1 (0-7).  63% of the 13q- mut cases presented more than one mutation. Surprisingly, the most frequently mutated genes were NOTCH1 (16.7%), TP53 (14.3%), SF3B1 (11.9%) ATM (7.1%) and BIRC3 (4.7%), genes previously associated with bad prognosis. The presence of mutations was associated with Binet B/C (p <0.001), unmutated IGHV gene (p =0.001), CD38 positivity (p =0.05) and need for treatment (p=0.004).

Of note, in 13q- patients with mutations in NOTCH, TP53, SF3B1, ATM or BIRC3 (32 cases, 27.35%), OS was 136 months (CI95% 98–174) whereas in the group without any mutation, OS has not been reached (CI95% 216–254) (p=0.039). In the univariate analysis, Binet B/C (p<0.001), unmutated IGHV status (p<0.001), B symptoms (p=0.002), hepatomegaly (p<0.0001), splenomegaly (p=0.01), lymphocyte count>20·109/L (p<0.001) and b2M high levels (p=0.048) were significant associated with a short OS. In the multivariate analysis, only unmutated IGVH status resulted significant in predicting OS (HR 5.89, CI95% 1.15–30.13, p=0.033).

Regarding TFT, in 13q- mut patients the median TFT was 36 months (CI95% 0–87.7), whereas in the group without any mutation TFT has not been reached (p<0.001). In the univariate analysis, significant variables were Binet B/C (p<0.001), unmutated IGHV status (p<0.001), b2M levels (p<0.001), splenomegaly (p=0.015), lymphocyte count>2020·109/L (p<0.001), the percentage of cells >80% with 13q- (p=0.008) and B symptoms (p<0.001). In the Cox analysis, Binet stage (HR 10.1, CI95% 2.83–26.89,p<0.0001), B symptoms (HR 0.17, CI95% 0.05–0.54, p=0.003), lymphocytes count >20·109/L (HR 0.38, CI95% 0.18–0.81,p=0.012) and the presence of mutations in NOTCH, TP53, SF3B1, ATM or BIRC3 (HR 0.45, CI95% 0.21–0.96,p=0.039) resulted significant in predicting TFT.

Conclusion
13q- CLL patients with mutations in NOTCH1, TP53, SF3B1, ATM or BIRC3 have shorter overall survival (OS) and time to first treatment (TFT).

Session topic: 5. Chronic lymphocytic leukemia and related disorders – Biology & Translational Research

Keyword(s): Chromosomal abnormality, Chronic Lymphocytic Leukemia, Clinical outcome, Mutation status

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