DIFFERENT PROGNOSTIC ROLE OF RECURRENT COPY NUMBER ABERRATIONS IN B-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA WITHOUT RECURRENT FUSION GENES IN 3 CONSECUTIVE AGE COHORTS
(Abstract release date: 05/19/16)
EHA Library. Messina M. 06/09/16; 132396; E847
Dr. Monica Messina
Contributions
Contributions
Abstract
Abstract: E847
Type: Eposter Presentation
Background
In B-lineage acute lymphoblastic leukemia negative (B-NEG ALL) for recurrent fusion genes (BCR-ABL1, MLL-rearrangements, TCF3-PBX1, ETV6-RUNX1), the most common copy number aberrations (CNAs) - i.e. IKZF1, PAX5, EBF1, BTG1, CDKN2A, RB1, CRLF2 deletions - increase with age progression (Messina et al, 2016). While the prognostic role of IKZF1 deletion (ΔIKZF1) has been extensively studied, novel data on the potential role of other CNAs are currently emerging. With the number of novel prognostic markers increasing exponentially, ALL risk assessment is becoming complex; thus, it is crucial to provide a simplified, integrated predictor, possibly adjusted for age-cohort.
Aims
1) To correlate the most common CNAs with the clinico-biological features of B-NEG ALL patients; 2) to assess their prognostic role; 3) to evaluate whether their impact on outcome varies across age-cohorts.
Methods
CNAs of the above mentioned genes were studied by Multiplex Ligation-dependent Probe Amplification (Salsa MLPA P335 ALL-IKZF1 kit, MRC-Holland) in 157 B-NEG ALL, including 56 adults, 56 adolescents/young adults (AYA) and 45 children. CNAs were correlated with age, gender, Hb levels, white blood cell (WBC) and platelets counts, and with RAS and JAK/STAT pathway mutations. The impact of CNAs on disease free survival (DFS) was analyzed.
Results
Overall, 46.6% of children, 82.4% of AYA and 87.5% of adults, carried at least 1 CNA. In particular, deletions of IKZF1 were detected in 41.4%, of CDKN2A in 36.9%, of PAX5 in 25.5%, of ETV6 in 17.8%, of EBF1 in 12.1% and of BTG1 in 10.2% of patients, with IKZF1, CDKN2A, PAX5 and BTG1 deletions being significantly more frequent in adults and AYA than in children, as already mentioned. EBF1 and CDKN2A-deleted patients had a significantly higher WBC count. BTG1 deletions occurred exclusively in males (p=0.002). Furthermore, JAK/STAT mutations were significantly associated with EBF1 (p=0.033) and CDKN2A deletions (p=0.026). Survival analyses on the whole cohort with clinical data available (N=133) showed that CDKN2A-deleted patients had a significantly worse DFS than CDKN2A-WT cases at 5 years (39.7% vs 64.1%, p=0.005); EBF1-deleted patients also had a significantly poorer DFS than EBF1-WT cases (33.3% vs 60.1%, p=0.003). A trend towards a worse DFS was observed for BTG1-deleted cases, with its negative impact being more evident when considering only AYA (30% vs 61.4%, p=0.095). CDKN2A and EBF1 deletions retained their negative impact on DFS also when considering the adult cohort only. Indeed, CDKN2A-deleted had a shorter DFS than CDKN2A-WT cases (12.8% vs 54%, p=0.03); similarly, DFS of EBF1-deleted was inferior than EBF1-WT cases (0% vs 38.3, p=0.002); a trend was observed combining adults with AYA, while no impact was found in children. At variance, a trend towards a better DFS for ETV6-deleted vs ETV6-WT cases was observed (100% vs 65%, p=0.065) in children, recalling the favorable prognostic impact of ETV6-RUNX1. In the present cohort, the role of ΔIKZF1 remains controversial: nevertheless, by combining adults and AYA, patients harboring ΔIKZF1-only or no CNAs had a trend towards a longer DFS than the remaining cases (62.6% vs 39.1%, p=0.068).
Conclusion
Besides the heterogeneous distribution, we also found a different impact on prognosis of CNAs across age cohorts, with CDKN2A and EBF1 deletions influencing adult patients’ outcome and BTG1 negatively impacting on AYA survival; notably, these lesions did not impact on the outcome of childhood ALL. These findings indicate that, apart from the mutational status, risk assessment of ALL should also include the evaluation of selected CNAs.
Session topic: E-poster
Keyword(s): B cell acute lymphoblastic leukemia, Clinical outcome, Gene deletion
Type: Eposter Presentation
Background
In B-lineage acute lymphoblastic leukemia negative (B-NEG ALL) for recurrent fusion genes (BCR-ABL1, MLL-rearrangements, TCF3-PBX1, ETV6-RUNX1), the most common copy number aberrations (CNAs) - i.e. IKZF1, PAX5, EBF1, BTG1, CDKN2A, RB1, CRLF2 deletions - increase with age progression (Messina et al, 2016). While the prognostic role of IKZF1 deletion (ΔIKZF1) has been extensively studied, novel data on the potential role of other CNAs are currently emerging. With the number of novel prognostic markers increasing exponentially, ALL risk assessment is becoming complex; thus, it is crucial to provide a simplified, integrated predictor, possibly adjusted for age-cohort.
Aims
1) To correlate the most common CNAs with the clinico-biological features of B-NEG ALL patients; 2) to assess their prognostic role; 3) to evaluate whether their impact on outcome varies across age-cohorts.
Methods
CNAs of the above mentioned genes were studied by Multiplex Ligation-dependent Probe Amplification (Salsa MLPA P335 ALL-IKZF1 kit, MRC-Holland) in 157 B-NEG ALL, including 56 adults, 56 adolescents/young adults (AYA) and 45 children. CNAs were correlated with age, gender, Hb levels, white blood cell (WBC) and platelets counts, and with RAS and JAK/STAT pathway mutations. The impact of CNAs on disease free survival (DFS) was analyzed.
Results
Overall, 46.6% of children, 82.4% of AYA and 87.5% of adults, carried at least 1 CNA. In particular, deletions of IKZF1 were detected in 41.4%, of CDKN2A in 36.9%, of PAX5 in 25.5%, of ETV6 in 17.8%, of EBF1 in 12.1% and of BTG1 in 10.2% of patients, with IKZF1, CDKN2A, PAX5 and BTG1 deletions being significantly more frequent in adults and AYA than in children, as already mentioned. EBF1 and CDKN2A-deleted patients had a significantly higher WBC count. BTG1 deletions occurred exclusively in males (p=0.002). Furthermore, JAK/STAT mutations were significantly associated with EBF1 (p=0.033) and CDKN2A deletions (p=0.026). Survival analyses on the whole cohort with clinical data available (N=133) showed that CDKN2A-deleted patients had a significantly worse DFS than CDKN2A-WT cases at 5 years (39.7% vs 64.1%, p=0.005); EBF1-deleted patients also had a significantly poorer DFS than EBF1-WT cases (33.3% vs 60.1%, p=0.003). A trend towards a worse DFS was observed for BTG1-deleted cases, with its negative impact being more evident when considering only AYA (30% vs 61.4%, p=0.095). CDKN2A and EBF1 deletions retained their negative impact on DFS also when considering the adult cohort only. Indeed, CDKN2A-deleted had a shorter DFS than CDKN2A-WT cases (12.8% vs 54%, p=0.03); similarly, DFS of EBF1-deleted was inferior than EBF1-WT cases (0% vs 38.3, p=0.002); a trend was observed combining adults with AYA, while no impact was found in children. At variance, a trend towards a better DFS for ETV6-deleted vs ETV6-WT cases was observed (100% vs 65%, p=0.065) in children, recalling the favorable prognostic impact of ETV6-RUNX1. In the present cohort, the role of ΔIKZF1 remains controversial: nevertheless, by combining adults and AYA, patients harboring ΔIKZF1-only or no CNAs had a trend towards a longer DFS than the remaining cases (62.6% vs 39.1%, p=0.068).
Conclusion
Besides the heterogeneous distribution, we also found a different impact on prognosis of CNAs across age cohorts, with CDKN2A and EBF1 deletions influencing adult patients’ outcome and BTG1 negatively impacting on AYA survival; notably, these lesions did not impact on the outcome of childhood ALL. These findings indicate that, apart from the mutational status, risk assessment of ALL should also include the evaluation of selected CNAs.
Session topic: E-poster
Keyword(s): B cell acute lymphoblastic leukemia, Clinical outcome, Gene deletion
Abstract: E847
Type: Eposter Presentation
Background
In B-lineage acute lymphoblastic leukemia negative (B-NEG ALL) for recurrent fusion genes (BCR-ABL1, MLL-rearrangements, TCF3-PBX1, ETV6-RUNX1), the most common copy number aberrations (CNAs) - i.e. IKZF1, PAX5, EBF1, BTG1, CDKN2A, RB1, CRLF2 deletions - increase with age progression (Messina et al, 2016). While the prognostic role of IKZF1 deletion (ΔIKZF1) has been extensively studied, novel data on the potential role of other CNAs are currently emerging. With the number of novel prognostic markers increasing exponentially, ALL risk assessment is becoming complex; thus, it is crucial to provide a simplified, integrated predictor, possibly adjusted for age-cohort.
Aims
1) To correlate the most common CNAs with the clinico-biological features of B-NEG ALL patients; 2) to assess their prognostic role; 3) to evaluate whether their impact on outcome varies across age-cohorts.
Methods
CNAs of the above mentioned genes were studied by Multiplex Ligation-dependent Probe Amplification (Salsa MLPA P335 ALL-IKZF1 kit, MRC-Holland) in 157 B-NEG ALL, including 56 adults, 56 adolescents/young adults (AYA) and 45 children. CNAs were correlated with age, gender, Hb levels, white blood cell (WBC) and platelets counts, and with RAS and JAK/STAT pathway mutations. The impact of CNAs on disease free survival (DFS) was analyzed.
Results
Overall, 46.6% of children, 82.4% of AYA and 87.5% of adults, carried at least 1 CNA. In particular, deletions of IKZF1 were detected in 41.4%, of CDKN2A in 36.9%, of PAX5 in 25.5%, of ETV6 in 17.8%, of EBF1 in 12.1% and of BTG1 in 10.2% of patients, with IKZF1, CDKN2A, PAX5 and BTG1 deletions being significantly more frequent in adults and AYA than in children, as already mentioned. EBF1 and CDKN2A-deleted patients had a significantly higher WBC count. BTG1 deletions occurred exclusively in males (p=0.002). Furthermore, JAK/STAT mutations were significantly associated with EBF1 (p=0.033) and CDKN2A deletions (p=0.026). Survival analyses on the whole cohort with clinical data available (N=133) showed that CDKN2A-deleted patients had a significantly worse DFS than CDKN2A-WT cases at 5 years (39.7% vs 64.1%, p=0.005); EBF1-deleted patients also had a significantly poorer DFS than EBF1-WT cases (33.3% vs 60.1%, p=0.003). A trend towards a worse DFS was observed for BTG1-deleted cases, with its negative impact being more evident when considering only AYA (30% vs 61.4%, p=0.095). CDKN2A and EBF1 deletions retained their negative impact on DFS also when considering the adult cohort only. Indeed, CDKN2A-deleted had a shorter DFS than CDKN2A-WT cases (12.8% vs 54%, p=0.03); similarly, DFS of EBF1-deleted was inferior than EBF1-WT cases (0% vs 38.3, p=0.002); a trend was observed combining adults with AYA, while no impact was found in children. At variance, a trend towards a better DFS for ETV6-deleted vs ETV6-WT cases was observed (100% vs 65%, p=0.065) in children, recalling the favorable prognostic impact of ETV6-RUNX1. In the present cohort, the role of ΔIKZF1 remains controversial: nevertheless, by combining adults and AYA, patients harboring ΔIKZF1-only or no CNAs had a trend towards a longer DFS than the remaining cases (62.6% vs 39.1%, p=0.068).
Conclusion
Besides the heterogeneous distribution, we also found a different impact on prognosis of CNAs across age cohorts, with CDKN2A and EBF1 deletions influencing adult patients’ outcome and BTG1 negatively impacting on AYA survival; notably, these lesions did not impact on the outcome of childhood ALL. These findings indicate that, apart from the mutational status, risk assessment of ALL should also include the evaluation of selected CNAs.
Session topic: E-poster
Keyword(s): B cell acute lymphoblastic leukemia, Clinical outcome, Gene deletion
Type: Eposter Presentation
Background
In B-lineage acute lymphoblastic leukemia negative (B-NEG ALL) for recurrent fusion genes (BCR-ABL1, MLL-rearrangements, TCF3-PBX1, ETV6-RUNX1), the most common copy number aberrations (CNAs) - i.e. IKZF1, PAX5, EBF1, BTG1, CDKN2A, RB1, CRLF2 deletions - increase with age progression (Messina et al, 2016). While the prognostic role of IKZF1 deletion (ΔIKZF1) has been extensively studied, novel data on the potential role of other CNAs are currently emerging. With the number of novel prognostic markers increasing exponentially, ALL risk assessment is becoming complex; thus, it is crucial to provide a simplified, integrated predictor, possibly adjusted for age-cohort.
Aims
1) To correlate the most common CNAs with the clinico-biological features of B-NEG ALL patients; 2) to assess their prognostic role; 3) to evaluate whether their impact on outcome varies across age-cohorts.
Methods
CNAs of the above mentioned genes were studied by Multiplex Ligation-dependent Probe Amplification (Salsa MLPA P335 ALL-IKZF1 kit, MRC-Holland) in 157 B-NEG ALL, including 56 adults, 56 adolescents/young adults (AYA) and 45 children. CNAs were correlated with age, gender, Hb levels, white blood cell (WBC) and platelets counts, and with RAS and JAK/STAT pathway mutations. The impact of CNAs on disease free survival (DFS) was analyzed.
Results
Overall, 46.6% of children, 82.4% of AYA and 87.5% of adults, carried at least 1 CNA. In particular, deletions of IKZF1 were detected in 41.4%, of CDKN2A in 36.9%, of PAX5 in 25.5%, of ETV6 in 17.8%, of EBF1 in 12.1% and of BTG1 in 10.2% of patients, with IKZF1, CDKN2A, PAX5 and BTG1 deletions being significantly more frequent in adults and AYA than in children, as already mentioned. EBF1 and CDKN2A-deleted patients had a significantly higher WBC count. BTG1 deletions occurred exclusively in males (p=0.002). Furthermore, JAK/STAT mutations were significantly associated with EBF1 (p=0.033) and CDKN2A deletions (p=0.026). Survival analyses on the whole cohort with clinical data available (N=133) showed that CDKN2A-deleted patients had a significantly worse DFS than CDKN2A-WT cases at 5 years (39.7% vs 64.1%, p=0.005); EBF1-deleted patients also had a significantly poorer DFS than EBF1-WT cases (33.3% vs 60.1%, p=0.003). A trend towards a worse DFS was observed for BTG1-deleted cases, with its negative impact being more evident when considering only AYA (30% vs 61.4%, p=0.095). CDKN2A and EBF1 deletions retained their negative impact on DFS also when considering the adult cohort only. Indeed, CDKN2A-deleted had a shorter DFS than CDKN2A-WT cases (12.8% vs 54%, p=0.03); similarly, DFS of EBF1-deleted was inferior than EBF1-WT cases (0% vs 38.3, p=0.002); a trend was observed combining adults with AYA, while no impact was found in children. At variance, a trend towards a better DFS for ETV6-deleted vs ETV6-WT cases was observed (100% vs 65%, p=0.065) in children, recalling the favorable prognostic impact of ETV6-RUNX1. In the present cohort, the role of ΔIKZF1 remains controversial: nevertheless, by combining adults and AYA, patients harboring ΔIKZF1-only or no CNAs had a trend towards a longer DFS than the remaining cases (62.6% vs 39.1%, p=0.068).
Conclusion
Besides the heterogeneous distribution, we also found a different impact on prognosis of CNAs across age cohorts, with CDKN2A and EBF1 deletions influencing adult patients’ outcome and BTG1 negatively impacting on AYA survival; notably, these lesions did not impact on the outcome of childhood ALL. These findings indicate that, apart from the mutational status, risk assessment of ALL should also include the evaluation of selected CNAs.
Session topic: E-poster
Keyword(s): B cell acute lymphoblastic leukemia, Clinical outcome, Gene deletion
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