TYROSINE KINASE FUSION GENES IN PEDIATRIC BCR-ABL1-LIKE ACUTE LYMPHOBLASTIC LEUKEMIA
(Abstract release date: 05/21/15)
EHA Library. Boer J. 06/13/15; 103107; S436
Disclosure(s): Erasmus MCPediatric Oncology/Hematology
Dr. Judith Boer
Contributions
Contributions
Abstract
Abstract: S436
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45
Location: Room C1
Background
Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the BCR-ABL1 fusion gene forms a small high-risk patient group with a poor prognosis. Approximately 15% of BCP-ALL shows gene expression similar to BCR-ABL1-positive disease and a similar unfavorable prognosis. This group shows a high frequency of B-cell development gene aberrations, especially IKZF1 deletions and tyrosine kinase activating lesions (Den Boer et al. Lancet Oncol 2009; Mullighan et al. N Engl J Med 2009; Roberts et al. Cancer Cell 2012, N Engl J Med 2014; Van der Veer et al. Blood 2013).
Aims
To detect the clinical value (frequency, prognosis and drugability) of tyrosine kinase fusions in childhood B-cell precursor ALL.
Methods
This study comprised 204 children with BCP-ALL in 3 Dutch trials (DCOG ALL-8, 9, 10) and 2 German trials (COALL 06-97, 07-03) including 92 previously described BCR-ABL1-like cases identified by hierarchical clustering and 112 non-BCR-ABL1-like B-other cases. Characterization included RT-PCR and FISH to detect fusions involving ABL1, PDGFRB, JAK2 and CSF1R, copy number analysis, and Sanger sequencing of JAK1 exons 13, 14 and JAK2 exons 16, 20, 21.
Results
We identified 12 tyrosine kinase activating fusion genes among 73 BCR-ABL1-like cases tested (16%) and none among 87 B-other cases. Four EBF1-PDGFRB, two PAX5-JAK2, ZMIZ1-ABL1, and SSBP1-CSF1R fusions were confirmed by RT-PCR. Four cases showed split FISH and/or breaks on DNA copy number arrays for PDGFRB, ABL1, or JAK2 with unknown fusion partners. IKZF1 deletions occurred more frequently in tyrosine kinase fusion cases compared with B-other (55% vs. 32%), and were enriched for rare, i.e. other than exon 4-7 or full deletion, variants (46% vs. 18%). JAK2 mutations (mainly in exon 16) were present in 7/70 B-other and 2/82 BCR-ABL1-like cases. JAK2 mutations co-occurred with high CRLF2 expression and had no prognostic impact. The cumulative incidence of relapse (CIR) in the BCR-ABL1-like group with tyrosine kinase fusions (5-yr CIR 25% ± 13%) was comparable with the remaining BCR-ABL1-like group (5-yr CIR 33% ± 5%), and worse than the B-other group (5-yr CIR 18% ± 4%; overall Gray p-value 0.06). Of the 12 tyrosine kinase fusion cases, 4 were late responders who only achieved remission after day 33 of induction therapy. Of 8 patients receiving a prednisone window before start of induction therapy, 3 showed a poor prednisone response on day 8. Day 15 punctures showed M2 or M3 marrows in 7/9 cases. Minimal residual disease PCR at the end of induction was high (TP1 and TP2 ≥10-3) in 5 and intermediate (TP1 ≥10-3, TP2 <10-3) in 2/8 cases. Leukemic cells from 3 EBF1-PDGFRB patients were sensitive to imatinib in ex vivo cultures, compared with lack of cytotoxic response in 4 EBF1-PDGFRB-negative samples, 2 of which even showed growth on imatinib. Combination of imatinib with prednisolone resulted in further growth inhibition in ex vivo cultures from 2/3 EBF1-PDGFRB patients.
Summary
Tyrosine kinase fusion genes were found in 16% of DCOG/COALL BCR-ABL1-like cases, representing ~3% of total BCP-ALL. JAK2 mutations were infrequent and not associated with BCR-ABL1-like in our cohort. Tyrosine kinase fusion cases were characterized by poor initial response to treatment, had an unfavorable clinical outcome compared to remaining non-BCR-ABL1-like B-other ALL cases but had a comparable unfavorable outcome to BCR-ABL1-like ALL without tyrosine kinase fusions. Imatinib worked additive to prednisolone in EBF1-PDGFRB patient cells, indicating that this inhibitor may be clinically used in combination with at least prednisone.
Keyword(s): B cell acute lymphoblastic leukemia, Imatinib, Pediatric, Tyrosine kinase
Session topic: Translational studies in ALL
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45
Location: Room C1
Background
Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the BCR-ABL1 fusion gene forms a small high-risk patient group with a poor prognosis. Approximately 15% of BCP-ALL shows gene expression similar to BCR-ABL1-positive disease and a similar unfavorable prognosis. This group shows a high frequency of B-cell development gene aberrations, especially IKZF1 deletions and tyrosine kinase activating lesions (Den Boer et al. Lancet Oncol 2009; Mullighan et al. N Engl J Med 2009; Roberts et al. Cancer Cell 2012, N Engl J Med 2014; Van der Veer et al. Blood 2013).
Aims
To detect the clinical value (frequency, prognosis and drugability) of tyrosine kinase fusions in childhood B-cell precursor ALL.
Methods
This study comprised 204 children with BCP-ALL in 3 Dutch trials (DCOG ALL-8, 9, 10) and 2 German trials (COALL 06-97, 07-03) including 92 previously described BCR-ABL1-like cases identified by hierarchical clustering and 112 non-BCR-ABL1-like B-other cases. Characterization included RT-PCR and FISH to detect fusions involving ABL1, PDGFRB, JAK2 and CSF1R, copy number analysis, and Sanger sequencing of JAK1 exons 13, 14 and JAK2 exons 16, 20, 21.
Results
We identified 12 tyrosine kinase activating fusion genes among 73 BCR-ABL1-like cases tested (16%) and none among 87 B-other cases. Four EBF1-PDGFRB, two PAX5-JAK2, ZMIZ1-ABL1, and SSBP1-CSF1R fusions were confirmed by RT-PCR. Four cases showed split FISH and/or breaks on DNA copy number arrays for PDGFRB, ABL1, or JAK2 with unknown fusion partners. IKZF1 deletions occurred more frequently in tyrosine kinase fusion cases compared with B-other (55% vs. 32%), and were enriched for rare, i.e. other than exon 4-7 or full deletion, variants (46% vs. 18%). JAK2 mutations (mainly in exon 16) were present in 7/70 B-other and 2/82 BCR-ABL1-like cases. JAK2 mutations co-occurred with high CRLF2 expression and had no prognostic impact. The cumulative incidence of relapse (CIR) in the BCR-ABL1-like group with tyrosine kinase fusions (5-yr CIR 25% ± 13%) was comparable with the remaining BCR-ABL1-like group (5-yr CIR 33% ± 5%), and worse than the B-other group (5-yr CIR 18% ± 4%; overall Gray p-value 0.06). Of the 12 tyrosine kinase fusion cases, 4 were late responders who only achieved remission after day 33 of induction therapy. Of 8 patients receiving a prednisone window before start of induction therapy, 3 showed a poor prednisone response on day 8. Day 15 punctures showed M2 or M3 marrows in 7/9 cases. Minimal residual disease PCR at the end of induction was high (TP1 and TP2 ≥10-3) in 5 and intermediate (TP1 ≥10-3, TP2 <10-3) in 2/8 cases. Leukemic cells from 3 EBF1-PDGFRB patients were sensitive to imatinib in ex vivo cultures, compared with lack of cytotoxic response in 4 EBF1-PDGFRB-negative samples, 2 of which even showed growth on imatinib. Combination of imatinib with prednisolone resulted in further growth inhibition in ex vivo cultures from 2/3 EBF1-PDGFRB patients.
Summary
Tyrosine kinase fusion genes were found in 16% of DCOG/COALL BCR-ABL1-like cases, representing ~3% of total BCP-ALL. JAK2 mutations were infrequent and not associated with BCR-ABL1-like in our cohort. Tyrosine kinase fusion cases were characterized by poor initial response to treatment, had an unfavorable clinical outcome compared to remaining non-BCR-ABL1-like B-other ALL cases but had a comparable unfavorable outcome to BCR-ABL1-like ALL without tyrosine kinase fusions. Imatinib worked additive to prednisolone in EBF1-PDGFRB patient cells, indicating that this inhibitor may be clinically used in combination with at least prednisone.
Keyword(s): B cell acute lymphoblastic leukemia, Imatinib, Pediatric, Tyrosine kinase
Session topic: Translational studies in ALL
Abstract: S436
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45
Location: Room C1
Background
Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the BCR-ABL1 fusion gene forms a small high-risk patient group with a poor prognosis. Approximately 15% of BCP-ALL shows gene expression similar to BCR-ABL1-positive disease and a similar unfavorable prognosis. This group shows a high frequency of B-cell development gene aberrations, especially IKZF1 deletions and tyrosine kinase activating lesions (Den Boer et al. Lancet Oncol 2009; Mullighan et al. N Engl J Med 2009; Roberts et al. Cancer Cell 2012, N Engl J Med 2014; Van der Veer et al. Blood 2013).
Aims
To detect the clinical value (frequency, prognosis and drugability) of tyrosine kinase fusions in childhood B-cell precursor ALL.
Methods
This study comprised 204 children with BCP-ALL in 3 Dutch trials (DCOG ALL-8, 9, 10) and 2 German trials (COALL 06-97, 07-03) including 92 previously described BCR-ABL1-like cases identified by hierarchical clustering and 112 non-BCR-ABL1-like B-other cases. Characterization included RT-PCR and FISH to detect fusions involving ABL1, PDGFRB, JAK2 and CSF1R, copy number analysis, and Sanger sequencing of JAK1 exons 13, 14 and JAK2 exons 16, 20, 21.
Results
We identified 12 tyrosine kinase activating fusion genes among 73 BCR-ABL1-like cases tested (16%) and none among 87 B-other cases. Four EBF1-PDGFRB, two PAX5-JAK2, ZMIZ1-ABL1, and SSBP1-CSF1R fusions were confirmed by RT-PCR. Four cases showed split FISH and/or breaks on DNA copy number arrays for PDGFRB, ABL1, or JAK2 with unknown fusion partners. IKZF1 deletions occurred more frequently in tyrosine kinase fusion cases compared with B-other (55% vs. 32%), and were enriched for rare, i.e. other than exon 4-7 or full deletion, variants (46% vs. 18%). JAK2 mutations (mainly in exon 16) were present in 7/70 B-other and 2/82 BCR-ABL1-like cases. JAK2 mutations co-occurred with high CRLF2 expression and had no prognostic impact. The cumulative incidence of relapse (CIR) in the BCR-ABL1-like group with tyrosine kinase fusions (5-yr CIR 25% ± 13%) was comparable with the remaining BCR-ABL1-like group (5-yr CIR 33% ± 5%), and worse than the B-other group (5-yr CIR 18% ± 4%; overall Gray p-value 0.06). Of the 12 tyrosine kinase fusion cases, 4 were late responders who only achieved remission after day 33 of induction therapy. Of 8 patients receiving a prednisone window before start of induction therapy, 3 showed a poor prednisone response on day 8. Day 15 punctures showed M2 or M3 marrows in 7/9 cases. Minimal residual disease PCR at the end of induction was high (TP1 and TP2 ≥10-3) in 5 and intermediate (TP1 ≥10-3, TP2 <10-3) in 2/8 cases. Leukemic cells from 3 EBF1-PDGFRB patients were sensitive to imatinib in ex vivo cultures, compared with lack of cytotoxic response in 4 EBF1-PDGFRB-negative samples, 2 of which even showed growth on imatinib. Combination of imatinib with prednisolone resulted in further growth inhibition in ex vivo cultures from 2/3 EBF1-PDGFRB patients.
Summary
Tyrosine kinase fusion genes were found in 16% of DCOG/COALL BCR-ABL1-like cases, representing ~3% of total BCP-ALL. JAK2 mutations were infrequent and not associated with BCR-ABL1-like in our cohort. Tyrosine kinase fusion cases were characterized by poor initial response to treatment, had an unfavorable clinical outcome compared to remaining non-BCR-ABL1-like B-other ALL cases but had a comparable unfavorable outcome to BCR-ABL1-like ALL without tyrosine kinase fusions. Imatinib worked additive to prednisolone in EBF1-PDGFRB patient cells, indicating that this inhibitor may be clinically used in combination with at least prednisone.
Keyword(s): B cell acute lymphoblastic leukemia, Imatinib, Pediatric, Tyrosine kinase
Session topic: Translational studies in ALL
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45
Location: Room C1
Background
Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the BCR-ABL1 fusion gene forms a small high-risk patient group with a poor prognosis. Approximately 15% of BCP-ALL shows gene expression similar to BCR-ABL1-positive disease and a similar unfavorable prognosis. This group shows a high frequency of B-cell development gene aberrations, especially IKZF1 deletions and tyrosine kinase activating lesions (Den Boer et al. Lancet Oncol 2009; Mullighan et al. N Engl J Med 2009; Roberts et al. Cancer Cell 2012, N Engl J Med 2014; Van der Veer et al. Blood 2013).
Aims
To detect the clinical value (frequency, prognosis and drugability) of tyrosine kinase fusions in childhood B-cell precursor ALL.
Methods
This study comprised 204 children with BCP-ALL in 3 Dutch trials (DCOG ALL-8, 9, 10) and 2 German trials (COALL 06-97, 07-03) including 92 previously described BCR-ABL1-like cases identified by hierarchical clustering and 112 non-BCR-ABL1-like B-other cases. Characterization included RT-PCR and FISH to detect fusions involving ABL1, PDGFRB, JAK2 and CSF1R, copy number analysis, and Sanger sequencing of JAK1 exons 13, 14 and JAK2 exons 16, 20, 21.
Results
We identified 12 tyrosine kinase activating fusion genes among 73 BCR-ABL1-like cases tested (16%) and none among 87 B-other cases. Four EBF1-PDGFRB, two PAX5-JAK2, ZMIZ1-ABL1, and SSBP1-CSF1R fusions were confirmed by RT-PCR. Four cases showed split FISH and/or breaks on DNA copy number arrays for PDGFRB, ABL1, or JAK2 with unknown fusion partners. IKZF1 deletions occurred more frequently in tyrosine kinase fusion cases compared with B-other (55% vs. 32%), and were enriched for rare, i.e. other than exon 4-7 or full deletion, variants (46% vs. 18%). JAK2 mutations (mainly in exon 16) were present in 7/70 B-other and 2/82 BCR-ABL1-like cases. JAK2 mutations co-occurred with high CRLF2 expression and had no prognostic impact. The cumulative incidence of relapse (CIR) in the BCR-ABL1-like group with tyrosine kinase fusions (5-yr CIR 25% ± 13%) was comparable with the remaining BCR-ABL1-like group (5-yr CIR 33% ± 5%), and worse than the B-other group (5-yr CIR 18% ± 4%; overall Gray p-value 0.06). Of the 12 tyrosine kinase fusion cases, 4 were late responders who only achieved remission after day 33 of induction therapy. Of 8 patients receiving a prednisone window before start of induction therapy, 3 showed a poor prednisone response on day 8. Day 15 punctures showed M2 or M3 marrows in 7/9 cases. Minimal residual disease PCR at the end of induction was high (TP1 and TP2 ≥10-3) in 5 and intermediate (TP1 ≥10-3, TP2 <10-3) in 2/8 cases. Leukemic cells from 3 EBF1-PDGFRB patients were sensitive to imatinib in ex vivo cultures, compared with lack of cytotoxic response in 4 EBF1-PDGFRB-negative samples, 2 of which even showed growth on imatinib. Combination of imatinib with prednisolone resulted in further growth inhibition in ex vivo cultures from 2/3 EBF1-PDGFRB patients.
Summary
Tyrosine kinase fusion genes were found in 16% of DCOG/COALL BCR-ABL1-like cases, representing ~3% of total BCP-ALL. JAK2 mutations were infrequent and not associated with BCR-ABL1-like in our cohort. Tyrosine kinase fusion cases were characterized by poor initial response to treatment, had an unfavorable clinical outcome compared to remaining non-BCR-ABL1-like B-other ALL cases but had a comparable unfavorable outcome to BCR-ABL1-like ALL without tyrosine kinase fusions. Imatinib worked additive to prednisolone in EBF1-PDGFRB patient cells, indicating that this inhibitor may be clinically used in combination with at least prednisone.
Keyword(s): B cell acute lymphoblastic leukemia, Imatinib, Pediatric, Tyrosine kinase
Session topic: Translational studies in ALL
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