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FREQUENCY AND CLINICAL IMPACT OF CDKN2A/B GENE LOCUS IN AN ADULT T-ALL COHORT OF PATIENTS ENROLLED IN THE SPANISH PETHEMA GROUP PROTOCOLS
Author(s): ,
Eulalia Genescà
Affiliations:
All Research Group,Josep Carreras Leukaemia Research Institute (IJC),Badalona,Spain
,
Aleksey Lazarenkof
Affiliations:
All Research Group,Josep Carreras Leukaemia Research Institute (IJC),Badalona,Spain
,
Mireia Morgades
Affiliations:
ICO-Germans Trias i Pujol Hospital,Badalona,Spain
,
Guillem Berbis
Affiliations:
All Research Group,Josep Carreras Leukaemia Research Institute (IJC),Badalona,Spain
,
Neus Ruíz-Xivillé
Affiliations:
ICO-Germans Trias i Pujol Hospital,Badalona,Spain
,
Paula Gómez-Marzo
Affiliations:
Josep Carreras Leukaemia Research Institute (IJC),Badalona,Spain
,
Jordi Ribera
Affiliations:
All Research Group,Josep Carreras Leukaemia Research Institute (IJC),Badalona,Spain
,
Santiago Mercadal
Affiliations:
ICO-Duran i Reynals Hospital,Hospitalet del LLobregat,Spain
,
Ramon Guardia
Affiliations:
ICO-Josep Trueta Hospital,Girona,Spain
,
María Teresa Artola
Affiliations:
Donostia University Hospital,Donostia,Spain
,
Maria José Moreno
Affiliations:
Virgen de la Victoria Hospital,Málaga,Spain
,
Joaquin Martínez-López
Affiliations:
12 October Hospital,Madrid,Spain
,
Lurdes Zamora
Affiliations:
ICO-Germans Trias i Pujol Hospital,Badalona,Spain
,
Pere Barba
Affiliations:
Vall de Hebron Hospital,Barcelona,Spain
,
Cristina Gil
Affiliations:
Alicante General Hospital,Alicante,Spain
,
Mar Tormo
Affiliations:
Valencia Clinic Hospital,Valencia,Spain
,
Antonia Cladera
Affiliations:
Son LLàtzer Hospital,Mallorca,Spain
,
Andrés Novo
Affiliations:
Son Espases Hospital,Mallorca,Spain
,
Jordi Esteve
Affiliations:
Barcelona Clinic Hospital,Barcelona,Spain
,
José González-Campos
Affiliations:
Virgen del Rocío Hospital,Sevilla,Spain
,
María Almeida
Affiliations:
USAL-BNADN,Salamanca,Spain
,
Jose-Vicente Cervera
Affiliations:
La Fe Hospital-Biobanco de la Fe,Valencia,Spain
,
Pau Montesinos
Affiliations:
La Fe Hospital,Valencia,Spain
,
Isabel Granada
Affiliations:
ICO-Germans Trias i Pujol Hospital,Badalona,Spain
,
Montserrat Batlle
Affiliations:
ICO-Germans Trias i Pujol Hospital,Badalona,Spain
,
Susana Vives
Affiliations:
ICO-Germans Trias i Pujol Hospital,Badalona,Spain
,
Evarist Feliu
Affiliations:
Josep Carreras Leukaemia Research Institute (IJC),Badalona,Spain
,
Alberto Orfao
Affiliations:
USAL-BNADN,Salamanca,Spain
,
Francesc Solé
Affiliations:
Josep Carreras Leukaemia Research Institute (IJC),Badalona,Spain
Josep Maria Ribera
Affiliations:
ICO-Germans Trias i Pujol Hospital,Badalona,Spain
(Abstract release date: 05/18/17) EHA Library. Genescà E. 05/18/17; 182330; PB1616
Eulàlia Genescà
Eulàlia Genescà
Contributions
Abstract

Abstract: PB1616

Type: Publication Only

Background

Recurrent 9p21 deletions involving CDKN2A/CDKN2B locus are frequent in ALL. The very few data regarding their prognostic significance in adult T-ALL have shown that homozygous deletions of the CDKN2A/CDKN2B locus are associated with improved overall survival (OS).

Aims

We precisely characterized the copy number status (CNA) of CDKN2A/CDKN2B locus by discriminating deletions in A or B gene in order to elucidate its clinical impact separately.

Methods

Samples from 30 adult T-ALL cases included in high-risk protocols from the PETHEMA group were analyzed by CytoScan array (Affymetrix). Additionally, we set up a genomic qPCR to screen for CDKN2A and CDKN2B deletions in samples with few or not enough quality DNA (n=53). We corrected our CNA values for the normal cells (2N) contaminant present in the diagnosis samples. In addition, the results obtained by the array and/or qPCR were checked by FISH, when samples were available. Cumulative incidence of relapse (CIR) and OS were analyzed after censoring the patients at the time of allogeneic hematopoietic stem cell transplantation.

Results
qPCR results showed that most of the 9p21 losses corresponded to homozygous deletions in both genes (36%, 19/53), while heterozygosis deletions corresponded to 5.7% (3/53) and different CNA status between CDKN2A and B to 28% (15/53) of the samples. Globally alterations in CDKN2A/B locus were observed in 70% (37/53) of patients. Results obtained by the array corroborate the findings obtained by qPCR. The resolution of the array allowed us to distinguish between homozygosis in CDKN2A and heterozygosis on CDKN2B. The FISH analysis corroborated the homozygous deletion in the CDKN2A/B locus in all the cases analyzed. With that, we ask for clinical implications of CDKN2A/B CNA status in 49 cases with adequate follow-up. Median age (range) was 34 (16-68) years, 76% males, median WBC count 34 (0.6-431.0) x109/L. Immunophenotype: pro-T+pre-T (n=21), cortical T (n=21), mature T (n=7). CR was achieved in 92% (45/49) and MRD levels <0.1% at the end of induction were attained in 81% of patients. A trend for better OS was observed for patients with heterozygous or homozygous deletion of CDKN2B (61% [40%>82%]) vs. non deleted patients (25% [0%>54%],(p=0.084), whereas no clinical impact was observed for the CNA status in the CDKN2A gene. No influence of CDKN2A or CDKN2B CNA status on CIR was observed. By multivariate analysis only the MRD level at the end of induction influenced on OS (p=0.028, HR=5.58 [1.21 ; 25.79]) and on CIR (p=0.07, HR= 3.67 [0.90-15.63]).

Conclusion

CDKN2A/B locus abnormalities, mainly homozygous deletions, were found in 70% of adult T-ALL patients. Different CNA status was found for CDKN2A and CDKN2B. Although homozygous deletion in CDKN2B was associated with a trend for better OS, the level of MRD was the only prognostic factor for OS in these patients.
Supported by 2014 SGR225 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds from Josep Carreras International Foundation, “la Caixa” Foundation and Celgene Spain.

Session topic: 1. Acute lymphoblastic leukemia - Biology

Keyword(s): adult, T-ALL, prognosis, Gene deletion

Abstract: PB1616

Type: Publication Only

Background

Recurrent 9p21 deletions involving CDKN2A/CDKN2B locus are frequent in ALL. The very few data regarding their prognostic significance in adult T-ALL have shown that homozygous deletions of the CDKN2A/CDKN2B locus are associated with improved overall survival (OS).

Aims

We precisely characterized the copy number status (CNA) of CDKN2A/CDKN2B locus by discriminating deletions in A or B gene in order to elucidate its clinical impact separately.

Methods

Samples from 30 adult T-ALL cases included in high-risk protocols from the PETHEMA group were analyzed by CytoScan array (Affymetrix). Additionally, we set up a genomic qPCR to screen for CDKN2A and CDKN2B deletions in samples with few or not enough quality DNA (n=53). We corrected our CNA values for the normal cells (2N) contaminant present in the diagnosis samples. In addition, the results obtained by the array and/or qPCR were checked by FISH, when samples were available. Cumulative incidence of relapse (CIR) and OS were analyzed after censoring the patients at the time of allogeneic hematopoietic stem cell transplantation.

Results
qPCR results showed that most of the 9p21 losses corresponded to homozygous deletions in both genes (36%, 19/53), while heterozygosis deletions corresponded to 5.7% (3/53) and different CNA status between CDKN2A and B to 28% (15/53) of the samples. Globally alterations in CDKN2A/B locus were observed in 70% (37/53) of patients. Results obtained by the array corroborate the findings obtained by qPCR. The resolution of the array allowed us to distinguish between homozygosis in CDKN2A and heterozygosis on CDKN2B. The FISH analysis corroborated the homozygous deletion in the CDKN2A/B locus in all the cases analyzed. With that, we ask for clinical implications of CDKN2A/B CNA status in 49 cases with adequate follow-up. Median age (range) was 34 (16-68) years, 76% males, median WBC count 34 (0.6-431.0) x109/L. Immunophenotype: pro-T+pre-T (n=21), cortical T (n=21), mature T (n=7). CR was achieved in 92% (45/49) and MRD levels <0.1% at the end of induction were attained in 81% of patients. A trend for better OS was observed for patients with heterozygous or homozygous deletion of CDKN2B (61% [40%>82%]) vs. non deleted patients (25% [0%>54%],(p=0.084), whereas no clinical impact was observed for the CNA status in the CDKN2A gene. No influence of CDKN2A or CDKN2B CNA status on CIR was observed. By multivariate analysis only the MRD level at the end of induction influenced on OS (p=0.028, HR=5.58 [1.21 ; 25.79]) and on CIR (p=0.07, HR= 3.67 [0.90-15.63]).

Conclusion

CDKN2A/B locus abnormalities, mainly homozygous deletions, were found in 70% of adult T-ALL patients. Different CNA status was found for CDKN2A and CDKN2B. Although homozygous deletion in CDKN2B was associated with a trend for better OS, the level of MRD was the only prognostic factor for OS in these patients.
Supported by 2014 SGR225 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds from Josep Carreras International Foundation, “la Caixa” Foundation and Celgene Spain.

Session topic: 1. Acute lymphoblastic leukemia - Biology

Keyword(s): adult, T-ALL, prognosis, Gene deletion

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