RISK FACTORS IN PEDIATRIC T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA: A COLLABORATIVE STUDY OF THE BIOLOGICAL COMMITTEE OF THE LEUKEMIA GROUP OF THE SPANISH HEMATOLOGY AND ONCOLOGY PEDIATRIC SOCIETY
(Abstract release date: 05/19/16)
EHA Library. Camós M. 06/09/16; 132419; E870
Mireia Camós
Contributions
Contributions
Abstract
Abstract: E870
Type: Eposter Presentation
Background
Useful biomarkers for risk stratification in pediatric T-ALL are still needed. Several biological variables have been proposed as new prognostic biomarkers, including NOTCH1, FBXW7, PTEN & RAS mutations, expression of myeloid antigens and presence of copy number alterations (CNAs) of certain genes, but published results are controversial.
Aims
To analyze the prognostic impact of mutations, CNAs and myeloid antigens expression in a series of 56 pediatric T-ALL patients.
Methods
Pediatric patients (0-18 years) diagnosed with T-ALL, treated according to SEHOP (Spanish Hematology and Oncology Pediatric Society) and PETHEMA Cooperative Groups from 2001 to 2015. Mutations of NOTCH1, FBXW7, PTEN, NRAS & KRAS were screened by Sanger sequencing. CNAs were studied by MLPA technique with SALSA-P383 T-ALL kit (MRC-Holland) and Coffalyser software.
Results
Median age was 7 years (range, 0.3-15.4 years), 72% males. Central nervous system infiltration was present in 3 cases. Median WBC count was 56x109/L (range, 1.1-588). Twenty-four cases showed a cortical phenotype and 3 were classified as early T-cell precursor leukemia. Myeloid antigen expression (CD13 and/or CD33) was observed in 5 cases (14%). Twenty-three (41%) cases harbored NOTCH1 mutations, including 18 single NOTCH1 mutations (NOTCH1single) and 5 cases with more than one mutation, located in different domains (NOTCH1double). FBXW7 was mutated in 9 cases (16%) and NRAS in 5 (9%). Overall, we observed NOTCH1/FBXW7 mutations in 28 cases (50%). Six cases harbored PTEN abnormalities (mutations and/or deletions). Thirty-one of 41 analyzed cases (76%) showed ≥1 CNAs: CDKN2A/B deletions were the most frequent (28 cases, 60%) and were homozygous in 17 cases (CDKN2A/Bhomo). We also observed LEF1 deletions (n=4), MYB duplications (n=4), CASP8AP2 deletions (n=4), and deletions (n=2) and duplications (n=1) of EZH2 gene. NUP214/ABL fusion gene was detected in 2 cases. CDKN2A/Bhomo was associated with higher WBC count (p=0.04). After a median follow-up of 4 years (range, 0.09-14.24), 10 patients relapsed and 12 died. The 5 years overall survival (OS) was 70±8%. All patients achieved morphological complete remission (CR) after induction. Minimal residual disease levels (≥0.01%) were detected by flow cytometry in 8 cases (28%). Five patients underwent allogeneic stem cell transplantation. The univariate analysis showed a better OS for patients with cortical phenotype (90±7% vs 50±20%, p=0.035) and a worse OS for CDKN2A/Bhomo (44±16% vs 78±10%, p=0.048) and mutations in FBXW7, NRAS or PTEN abnormalities (FBXW7mut/NRASmut/PTENabn) (50±14% vs 78±8%, p=0.027). In the multivariate analysis, CDKN2A/Bhomo and FBXW7mut/NRASmut/PTENabn retained their statistical significance (HR 5.5, p=0.013 and HR 6.4, p=0.006, respectively). For event free survival (EFS), hyperleukocytosis >200x109/L and FBXW7mut/NRASmut/PTENabn independently predicted a worse outcome (HR 5.3, p=0.034 and HR 8.9, p=0.007, respectively).
Conclusion
In our series, the presence of FBXW7mut/NRASmut/PTENabn predicted a worse OS and EFS, and the homozygous deletion of CDKN2A/B genes were independently associated with an inferior OS. Larger series of patients are needed to confirm our results.GRANTS: PI12/2417, PN I+D+I, ISCIII (SGE, FIS), CIBERER, AMPILE, Fundación AECC, Asociación Pablo Ugarte, Fundación Uno entre cienmil, Fundación Sandra Ibarra, Fundación Cris contra el cáncer, “Força Miquel”, “Candela” & “Mua” projects.
Session topic: E-poster
Keyword(s): Acute lymphoblastic leukemia, Notch, Pediatric, Risk factor
Type: Eposter Presentation
Background
Useful biomarkers for risk stratification in pediatric T-ALL are still needed. Several biological variables have been proposed as new prognostic biomarkers, including NOTCH1, FBXW7, PTEN & RAS mutations, expression of myeloid antigens and presence of copy number alterations (CNAs) of certain genes, but published results are controversial.
Aims
To analyze the prognostic impact of mutations, CNAs and myeloid antigens expression in a series of 56 pediatric T-ALL patients.
Methods
Pediatric patients (0-18 years) diagnosed with T-ALL, treated according to SEHOP (Spanish Hematology and Oncology Pediatric Society) and PETHEMA Cooperative Groups from 2001 to 2015. Mutations of NOTCH1, FBXW7, PTEN, NRAS & KRAS were screened by Sanger sequencing. CNAs were studied by MLPA technique with SALSA-P383 T-ALL kit (MRC-Holland) and Coffalyser software.
Results
Median age was 7 years (range, 0.3-15.4 years), 72% males. Central nervous system infiltration was present in 3 cases. Median WBC count was 56x109/L (range, 1.1-588). Twenty-four cases showed a cortical phenotype and 3 were classified as early T-cell precursor leukemia. Myeloid antigen expression (CD13 and/or CD33) was observed in 5 cases (14%). Twenty-three (41%) cases harbored NOTCH1 mutations, including 18 single NOTCH1 mutations (NOTCH1single) and 5 cases with more than one mutation, located in different domains (NOTCH1double). FBXW7 was mutated in 9 cases (16%) and NRAS in 5 (9%). Overall, we observed NOTCH1/FBXW7 mutations in 28 cases (50%). Six cases harbored PTEN abnormalities (mutations and/or deletions). Thirty-one of 41 analyzed cases (76%) showed ≥1 CNAs: CDKN2A/B deletions were the most frequent (28 cases, 60%) and were homozygous in 17 cases (CDKN2A/Bhomo). We also observed LEF1 deletions (n=4), MYB duplications (n=4), CASP8AP2 deletions (n=4), and deletions (n=2) and duplications (n=1) of EZH2 gene. NUP214/ABL fusion gene was detected in 2 cases. CDKN2A/Bhomo was associated with higher WBC count (p=0.04). After a median follow-up of 4 years (range, 0.09-14.24), 10 patients relapsed and 12 died. The 5 years overall survival (OS) was 70±8%. All patients achieved morphological complete remission (CR) after induction. Minimal residual disease levels (≥0.01%) were detected by flow cytometry in 8 cases (28%). Five patients underwent allogeneic stem cell transplantation. The univariate analysis showed a better OS for patients with cortical phenotype (90±7% vs 50±20%, p=0.035) and a worse OS for CDKN2A/Bhomo (44±16% vs 78±10%, p=0.048) and mutations in FBXW7, NRAS or PTEN abnormalities (FBXW7mut/NRASmut/PTENabn) (50±14% vs 78±8%, p=0.027). In the multivariate analysis, CDKN2A/Bhomo and FBXW7mut/NRASmut/PTENabn retained their statistical significance (HR 5.5, p=0.013 and HR 6.4, p=0.006, respectively). For event free survival (EFS), hyperleukocytosis >200x109/L and FBXW7mut/NRASmut/PTENabn independently predicted a worse outcome (HR 5.3, p=0.034 and HR 8.9, p=0.007, respectively).
Conclusion
In our series, the presence of FBXW7mut/NRASmut/PTENabn predicted a worse OS and EFS, and the homozygous deletion of CDKN2A/B genes were independently associated with an inferior OS. Larger series of patients are needed to confirm our results.GRANTS: PI12/2417, PN I+D+I, ISCIII (SGE, FIS), CIBERER, AMPILE, Fundación AECC, Asociación Pablo Ugarte, Fundación Uno entre cienmil, Fundación Sandra Ibarra, Fundación Cris contra el cáncer, “Força Miquel”, “Candela” & “Mua” projects.
Session topic: E-poster
Keyword(s): Acute lymphoblastic leukemia, Notch, Pediatric, Risk factor
Abstract: E870
Type: Eposter Presentation
Background
Useful biomarkers for risk stratification in pediatric T-ALL are still needed. Several biological variables have been proposed as new prognostic biomarkers, including NOTCH1, FBXW7, PTEN & RAS mutations, expression of myeloid antigens and presence of copy number alterations (CNAs) of certain genes, but published results are controversial.
Aims
To analyze the prognostic impact of mutations, CNAs and myeloid antigens expression in a series of 56 pediatric T-ALL patients.
Methods
Pediatric patients (0-18 years) diagnosed with T-ALL, treated according to SEHOP (Spanish Hematology and Oncology Pediatric Society) and PETHEMA Cooperative Groups from 2001 to 2015. Mutations of NOTCH1, FBXW7, PTEN, NRAS & KRAS were screened by Sanger sequencing. CNAs were studied by MLPA technique with SALSA-P383 T-ALL kit (MRC-Holland) and Coffalyser software.
Results
Median age was 7 years (range, 0.3-15.4 years), 72% males. Central nervous system infiltration was present in 3 cases. Median WBC count was 56x109/L (range, 1.1-588). Twenty-four cases showed a cortical phenotype and 3 were classified as early T-cell precursor leukemia. Myeloid antigen expression (CD13 and/or CD33) was observed in 5 cases (14%). Twenty-three (41%) cases harbored NOTCH1 mutations, including 18 single NOTCH1 mutations (NOTCH1single) and 5 cases with more than one mutation, located in different domains (NOTCH1double). FBXW7 was mutated in 9 cases (16%) and NRAS in 5 (9%). Overall, we observed NOTCH1/FBXW7 mutations in 28 cases (50%). Six cases harbored PTEN abnormalities (mutations and/or deletions). Thirty-one of 41 analyzed cases (76%) showed ≥1 CNAs: CDKN2A/B deletions were the most frequent (28 cases, 60%) and were homozygous in 17 cases (CDKN2A/Bhomo). We also observed LEF1 deletions (n=4), MYB duplications (n=4), CASP8AP2 deletions (n=4), and deletions (n=2) and duplications (n=1) of EZH2 gene. NUP214/ABL fusion gene was detected in 2 cases. CDKN2A/Bhomo was associated with higher WBC count (p=0.04). After a median follow-up of 4 years (range, 0.09-14.24), 10 patients relapsed and 12 died. The 5 years overall survival (OS) was 70±8%. All patients achieved morphological complete remission (CR) after induction. Minimal residual disease levels (≥0.01%) were detected by flow cytometry in 8 cases (28%). Five patients underwent allogeneic stem cell transplantation. The univariate analysis showed a better OS for patients with cortical phenotype (90±7% vs 50±20%, p=0.035) and a worse OS for CDKN2A/Bhomo (44±16% vs 78±10%, p=0.048) and mutations in FBXW7, NRAS or PTEN abnormalities (FBXW7mut/NRASmut/PTENabn) (50±14% vs 78±8%, p=0.027). In the multivariate analysis, CDKN2A/Bhomo and FBXW7mut/NRASmut/PTENabn retained their statistical significance (HR 5.5, p=0.013 and HR 6.4, p=0.006, respectively). For event free survival (EFS), hyperleukocytosis >200x109/L and FBXW7mut/NRASmut/PTENabn independently predicted a worse outcome (HR 5.3, p=0.034 and HR 8.9, p=0.007, respectively).
Conclusion
In our series, the presence of FBXW7mut/NRASmut/PTENabn predicted a worse OS and EFS, and the homozygous deletion of CDKN2A/B genes were independently associated with an inferior OS. Larger series of patients are needed to confirm our results.GRANTS: PI12/2417, PN I+D+I, ISCIII (SGE, FIS), CIBERER, AMPILE, Fundación AECC, Asociación Pablo Ugarte, Fundación Uno entre cienmil, Fundación Sandra Ibarra, Fundación Cris contra el cáncer, “Força Miquel”, “Candela” & “Mua” projects.
Session topic: E-poster
Keyword(s): Acute lymphoblastic leukemia, Notch, Pediatric, Risk factor
Type: Eposter Presentation
Background
Useful biomarkers for risk stratification in pediatric T-ALL are still needed. Several biological variables have been proposed as new prognostic biomarkers, including NOTCH1, FBXW7, PTEN & RAS mutations, expression of myeloid antigens and presence of copy number alterations (CNAs) of certain genes, but published results are controversial.
Aims
To analyze the prognostic impact of mutations, CNAs and myeloid antigens expression in a series of 56 pediatric T-ALL patients.
Methods
Pediatric patients (0-18 years) diagnosed with T-ALL, treated according to SEHOP (Spanish Hematology and Oncology Pediatric Society) and PETHEMA Cooperative Groups from 2001 to 2015. Mutations of NOTCH1, FBXW7, PTEN, NRAS & KRAS were screened by Sanger sequencing. CNAs were studied by MLPA technique with SALSA-P383 T-ALL kit (MRC-Holland) and Coffalyser software.
Results
Median age was 7 years (range, 0.3-15.4 years), 72% males. Central nervous system infiltration was present in 3 cases. Median WBC count was 56x109/L (range, 1.1-588). Twenty-four cases showed a cortical phenotype and 3 were classified as early T-cell precursor leukemia. Myeloid antigen expression (CD13 and/or CD33) was observed in 5 cases (14%). Twenty-three (41%) cases harbored NOTCH1 mutations, including 18 single NOTCH1 mutations (NOTCH1single) and 5 cases with more than one mutation, located in different domains (NOTCH1double). FBXW7 was mutated in 9 cases (16%) and NRAS in 5 (9%). Overall, we observed NOTCH1/FBXW7 mutations in 28 cases (50%). Six cases harbored PTEN abnormalities (mutations and/or deletions). Thirty-one of 41 analyzed cases (76%) showed ≥1 CNAs: CDKN2A/B deletions were the most frequent (28 cases, 60%) and were homozygous in 17 cases (CDKN2A/Bhomo). We also observed LEF1 deletions (n=4), MYB duplications (n=4), CASP8AP2 deletions (n=4), and deletions (n=2) and duplications (n=1) of EZH2 gene. NUP214/ABL fusion gene was detected in 2 cases. CDKN2A/Bhomo was associated with higher WBC count (p=0.04). After a median follow-up of 4 years (range, 0.09-14.24), 10 patients relapsed and 12 died. The 5 years overall survival (OS) was 70±8%. All patients achieved morphological complete remission (CR) after induction. Minimal residual disease levels (≥0.01%) were detected by flow cytometry in 8 cases (28%). Five patients underwent allogeneic stem cell transplantation. The univariate analysis showed a better OS for patients with cortical phenotype (90±7% vs 50±20%, p=0.035) and a worse OS for CDKN2A/Bhomo (44±16% vs 78±10%, p=0.048) and mutations in FBXW7, NRAS or PTEN abnormalities (FBXW7mut/NRASmut/PTENabn) (50±14% vs 78±8%, p=0.027). In the multivariate analysis, CDKN2A/Bhomo and FBXW7mut/NRASmut/PTENabn retained their statistical significance (HR 5.5, p=0.013 and HR 6.4, p=0.006, respectively). For event free survival (EFS), hyperleukocytosis >200x109/L and FBXW7mut/NRASmut/PTENabn independently predicted a worse outcome (HR 5.3, p=0.034 and HR 8.9, p=0.007, respectively).
Conclusion
In our series, the presence of FBXW7mut/NRASmut/PTENabn predicted a worse OS and EFS, and the homozygous deletion of CDKN2A/B genes were independently associated with an inferior OS. Larger series of patients are needed to confirm our results.GRANTS: PI12/2417, PN I+D+I, ISCIII (SGE, FIS), CIBERER, AMPILE, Fundación AECC, Asociación Pablo Ugarte, Fundación Uno entre cienmil, Fundación Sandra Ibarra, Fundación Cris contra el cáncer, “Força Miquel”, “Candela” & “Mua” projects.
Session topic: E-poster
Keyword(s): Acute lymphoblastic leukemia, Notch, Pediatric, Risk factor
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