Contributions
Abstract: S825
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 12:00 - 12:15
Location: Room A6
Background
Ph-like (or BCR/ABL-like) ALL subtype encompasses 10-15% of BCP-ALL patients, predicts high incidence of relapses and defines a candidate subgroup for targeted treatment.
Aims
(i) To identify BCP-ALL Ph-like cases in patients treated in Study Protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP); (ii) to assess their prognosis; and (iii) to characterize their genetics basis, in terms of CNV and fusion genes.
Methods
Gene expression profiling was successfully performed on 400 Italian childhood BCP-ALL cases enrolled in AIEOP-BFM ALL2000/R2006 protocols. Of them, 142 negative for common fusion transcripts, non-high hyperdiploid and non-Down Syndrome, were defined as B-others. We implemented IKZF1-P335 MLPA kit (MRC Holland), in combination with ERG PCR to identify cases with an ‘IKZF-plus’ profile. RNA-target-NGS (panel with 1385 cancer-associated genes, Trusight RNA Pan Cancer, Illumina) has been setup to identify fusion genes involving recurrent genes with novel partners.
Results
Out of 142 B-other cases, 43 (30.3%, and 11% of the total BCP-ALL cohort) presented as a cluster with a gene expression signature close to the BCR/ABL signature, therefore referred to as Ph-like. Among B-others, Ph-like cases had a significantly increased proportion of males, age>10 years and WBC>20x109/L. The 5y event-free survival (EFS) of Ph-like patients was 54.8% (SE 8.2) vs 83.1% (3.9) in the remaining B-others patients (p<0.001), mostly due to an increased cumulative incidence of relapse (CIR: 33.9% (7.4) vs. 14.9% (3.7); p=0.009). Overall, 33 out of 142 cases experienced relapse, 14 Ph-like (33%) and 19 B-others not Ph-like (19%).
We analyzed 138/142 B-others by MLPA (in 59 cases also by DNA array), and detected 11/142 IKZF-plus patients (7/11 Ph-like and 6/7 experienced relapse). Regarding the CLRF2 status, 15/142 cases resulted rearranged, 11/15 within Ph-like and 4/15 relapsed (exclusively in the Ph-like group). By NGS, we analyzed 61/142 patients, including all the Ph-like cases plus relapsed cases B-other not Ph-like.
Among the 14 Ph-like relapsed cases, 11 were positive for a fusion gene, while the three cases negative were IKZF-plus. We detected four cases carrying P2RY8/CLRF2, 1 case with TCF3/HLF, 1 with EBF1-fusion, 1 with IKZF1-fusion, 1 with a TTYH3-fusion and 3 cases with PAX5-fusions. Considering the 28 Ph-like not relapsed patients, we detected 10 cases with various fusion genes and 4 additional cases with PAX5-fusion genes. Moreover, we detected two cases with EBF1/PDGFRB, 1 carrying MEF2D/BCL9, 1 positive for RB1-fusion, 1 with DOT1L-fusion and 1 patients with a non-canonical MLL fusion. Strikingly, the PAX5rearrangements are overrepresented in the Ph-like subgroup (N=7), followed by P2RY8/CRLF2 (N=6). We further identified IgH-CRLF2 (FISH) in two cases, one with a concomitant PAX5-fusion. Overall, 21/43 Ph-like cases were carrying a pathogenetic relevant fusion gene.
Among relapsed B-others not Ph-like patients, only one carried a fusion gene, ZNF384/CREBBP originated from translocation t(12;16).
Conclusion
We dissected the Ph-like subgroup in the Italian cohort of children with BCP-ALL Ph-like patients, showing that, independently of other known risk features, these patients have a poor outcome and can be considered eligible for alternative treatments, in particular when they have high levels of MRD after induction. The genetic characterization of this subgroup revealed a high recurrence of fusion genes, this finding underlining the urgent need to define the pathogenetic mechanisms, with the aim to identify novel, maybe targeted, therapies.
Session topic: 1. Acute lymphoblastic leukemia – Biology & Translational Research
Keyword(s): Acute lymphoblastic leukemia, Childhood, Fusion
Abstract: S825
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 12:00 - 12:15
Location: Room A6
Background
Ph-like (or BCR/ABL-like) ALL subtype encompasses 10-15% of BCP-ALL patients, predicts high incidence of relapses and defines a candidate subgroup for targeted treatment.
Aims
(i) To identify BCP-ALL Ph-like cases in patients treated in Study Protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP); (ii) to assess their prognosis; and (iii) to characterize their genetics basis, in terms of CNV and fusion genes.
Methods
Gene expression profiling was successfully performed on 400 Italian childhood BCP-ALL cases enrolled in AIEOP-BFM ALL2000/R2006 protocols. Of them, 142 negative for common fusion transcripts, non-high hyperdiploid and non-Down Syndrome, were defined as B-others. We implemented IKZF1-P335 MLPA kit (MRC Holland), in combination with ERG PCR to identify cases with an ‘IKZF-plus’ profile. RNA-target-NGS (panel with 1385 cancer-associated genes, Trusight RNA Pan Cancer, Illumina) has been setup to identify fusion genes involving recurrent genes with novel partners.
Results
Out of 142 B-other cases, 43 (30.3%, and 11% of the total BCP-ALL cohort) presented as a cluster with a gene expression signature close to the BCR/ABL signature, therefore referred to as Ph-like. Among B-others, Ph-like cases had a significantly increased proportion of males, age>10 years and WBC>20x109/L. The 5y event-free survival (EFS) of Ph-like patients was 54.8% (SE 8.2) vs 83.1% (3.9) in the remaining B-others patients (p<0.001), mostly due to an increased cumulative incidence of relapse (CIR: 33.9% (7.4) vs. 14.9% (3.7); p=0.009). Overall, 33 out of 142 cases experienced relapse, 14 Ph-like (33%) and 19 B-others not Ph-like (19%).
We analyzed 138/142 B-others by MLPA (in 59 cases also by DNA array), and detected 11/142 IKZF-plus patients (7/11 Ph-like and 6/7 experienced relapse). Regarding the CLRF2 status, 15/142 cases resulted rearranged, 11/15 within Ph-like and 4/15 relapsed (exclusively in the Ph-like group). By NGS, we analyzed 61/142 patients, including all the Ph-like cases plus relapsed cases B-other not Ph-like.
Among the 14 Ph-like relapsed cases, 11 were positive for a fusion gene, while the three cases negative were IKZF-plus. We detected four cases carrying P2RY8/CLRF2, 1 case with TCF3/HLF, 1 with EBF1-fusion, 1 with IKZF1-fusion, 1 with a TTYH3-fusion and 3 cases with PAX5-fusions. Considering the 28 Ph-like not relapsed patients, we detected 10 cases with various fusion genes and 4 additional cases with PAX5-fusion genes. Moreover, we detected two cases with EBF1/PDGFRB, 1 carrying MEF2D/BCL9, 1 positive for RB1-fusion, 1 with DOT1L-fusion and 1 patients with a non-canonical MLL fusion. Strikingly, the PAX5rearrangements are overrepresented in the Ph-like subgroup (N=7), followed by P2RY8/CRLF2 (N=6). We further identified IgH-CRLF2 (FISH) in two cases, one with a concomitant PAX5-fusion. Overall, 21/43 Ph-like cases were carrying a pathogenetic relevant fusion gene.
Among relapsed B-others not Ph-like patients, only one carried a fusion gene, ZNF384/CREBBP originated from translocation t(12;16).
Conclusion
We dissected the Ph-like subgroup in the Italian cohort of children with BCP-ALL Ph-like patients, showing that, independently of other known risk features, these patients have a poor outcome and can be considered eligible for alternative treatments, in particular when they have high levels of MRD after induction. The genetic characterization of this subgroup revealed a high recurrence of fusion genes, this finding underlining the urgent need to define the pathogenetic mechanisms, with the aim to identify novel, maybe targeted, therapies.
Session topic: 1. Acute lymphoblastic leukemia – Biology & Translational Research
Keyword(s): Acute lymphoblastic leukemia, Childhood, Fusion