Contributions
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:00 to 13.06.2015 16:15
Location: Room A7
Background
The introduction of intensive cycles of high-dose immunotherapy with rituximab has improved the outcome and survival rates in patients with Burkitt lymphoma (BL). However, early relapse and refractoriness are current limitations of BL treatment and new biological factors affecting the outcome of the patients treated with dose-intensive chemotherapy including Rituximab have not been explored.
Aims
To characterize by array-based comparative genomic hybridization (aCGH) and next generation sequencing (NGS) the presence of genetic changes that could be predictive of the clinical response to Rituximab in a selected group of BL patients included in the Dose-Intensive Chemotherapy Including Rituximab (Burkimab trial) from the Spanish PETHEMA cooperative group.
Methods
Forty adolescent and adult BL patients were included. All of them were homogeneously treated according to Burkimab trial established by the PETHEMA group. The inclusion criteria were: a) diagnosis of BL or Burkitt-like lymphoma according to WHO criteria, b) MYC-rearrangement demonstrated by karyotype and/or fluorescence in situ hybridization c) age greater than 14 years. The segmentation analysis was performed using CGHweb tool. In addition, amplicon-based NGS was carried out to investigate the mutational status of TP53 gene (4 to 11 exons). The 454 Life Sciences, a Roche company GS Junior system was used. The variant analysis was performed using Amplicon Variant Analyzer (AVA-Roche 454) and Sequence Pilot (JSI Medical Systems) software. The genomic alterations were associated with clinical, biological and survival parameters.
Results
CNAs were present in 97.5% of patients. The most common aberrations were gains on chromosomes 1q (33%), 7q (31%) and 8q (18%), whereas the losses predominantly involved chromosomes 9p (23%), 13q (23%), 15q (21%), 11q (15%) and 6q (10%). The losses on 11q, 13q, 15q or 17p (p=0.028) and poor performance status (ECOG≥2) (p=0.016) was associated with the poor response Burkimab. These losses were also associated with shorter four-year progression free survival (PSF) (50% vs 93%, p=0.012). Shorter DFS was observed in BL patients with losses on 11q (p=0.003), 15q (p=0.002) or 17p (p=0.03). The four-year DFS of patients with these losses was 56% versus 93% for patients without losses. Likewise, BL patients with losses on 11q (p=0.001) or 15q (p=0.02) had shorter OS than patients without these abnormalities; the four-year OS of patients with these losses was 60% vs 96% for patients without them. The ECOG≥2 was associated with a shorter PFS (p=0.02), DFS (p=0.036) and OS (p=0.012). The losses on 11q, 13q, 15q or 17p (HR, 5.506; 95%CI, 1.283–23.624; p=0.022) and ECOG≥2 (HR, 8.605; 95%CI: 1.044–70.900; p=0.045) were independent risk factors associated with shorter PFS. Losses in 11q, 15q or 17p were identified as risk factors independently associated with shorter DFS (HR, 4.921; 95%CI: 1.0-22.4; p=0.040) and OS (HR, 7.2; 95%CI: 1.2-41.5; p=0.026). In addition, the integrative analysis of aCGH and NGS showed that 26% (5/19) of patients carried at least one alteration in TP53 gene, two cases had loss of 17p and three cases had missense mutations. TP53alt was associated with a poor response to Burkimab therapy (p=0.044) and a shorter four-year PFS: 84.6% vs 25% (p=0.022).
Summary
Losses of 11q, 13q, 15q, or 17p, as well as TP53alt are associated with a poor response to Dose-Intensive Chemotherapy Including Rituximab (Burkimab trial). These non-random losses could be used for the risk stratification of BL patients treated with Rituximab.
Keyword(s): Array based comparative genomic hybridization, Burkitt's lymphoma, Mutation analysis, Rituximab
Session topic: Optimization and innovation in treating aggressive lymphomas
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:00 to 13.06.2015 16:15
Location: Room A7
Background
The introduction of intensive cycles of high-dose immunotherapy with rituximab has improved the outcome and survival rates in patients with Burkitt lymphoma (BL). However, early relapse and refractoriness are current limitations of BL treatment and new biological factors affecting the outcome of the patients treated with dose-intensive chemotherapy including Rituximab have not been explored.
Aims
To characterize by array-based comparative genomic hybridization (aCGH) and next generation sequencing (NGS) the presence of genetic changes that could be predictive of the clinical response to Rituximab in a selected group of BL patients included in the Dose-Intensive Chemotherapy Including Rituximab (Burkimab trial) from the Spanish PETHEMA cooperative group.
Methods
Forty adolescent and adult BL patients were included. All of them were homogeneously treated according to Burkimab trial established by the PETHEMA group. The inclusion criteria were: a) diagnosis of BL or Burkitt-like lymphoma according to WHO criteria, b) MYC-rearrangement demonstrated by karyotype and/or fluorescence in situ hybridization c) age greater than 14 years. The segmentation analysis was performed using CGHweb tool. In addition, amplicon-based NGS was carried out to investigate the mutational status of TP53 gene (4 to 11 exons). The 454 Life Sciences, a Roche company GS Junior system was used. The variant analysis was performed using Amplicon Variant Analyzer (AVA-Roche 454) and Sequence Pilot (JSI Medical Systems) software. The genomic alterations were associated with clinical, biological and survival parameters.
Results
CNAs were present in 97.5% of patients. The most common aberrations were gains on chromosomes 1q (33%), 7q (31%) and 8q (18%), whereas the losses predominantly involved chromosomes 9p (23%), 13q (23%), 15q (21%), 11q (15%) and 6q (10%). The losses on 11q, 13q, 15q or 17p (p=0.028) and poor performance status (ECOG≥2) (p=0.016) was associated with the poor response Burkimab. These losses were also associated with shorter four-year progression free survival (PSF) (50% vs 93%, p=0.012). Shorter DFS was observed in BL patients with losses on 11q (p=0.003), 15q (p=0.002) or 17p (p=0.03). The four-year DFS of patients with these losses was 56% versus 93% for patients without losses. Likewise, BL patients with losses on 11q (p=0.001) or 15q (p=0.02) had shorter OS than patients without these abnormalities; the four-year OS of patients with these losses was 60% vs 96% for patients without them. The ECOG≥2 was associated with a shorter PFS (p=0.02), DFS (p=0.036) and OS (p=0.012). The losses on 11q, 13q, 15q or 17p (HR, 5.506; 95%CI, 1.283–23.624; p=0.022) and ECOG≥2 (HR, 8.605; 95%CI: 1.044–70.900; p=0.045) were independent risk factors associated with shorter PFS. Losses in 11q, 15q or 17p were identified as risk factors independently associated with shorter DFS (HR, 4.921; 95%CI: 1.0-22.4; p=0.040) and OS (HR, 7.2; 95%CI: 1.2-41.5; p=0.026). In addition, the integrative analysis of aCGH and NGS showed that 26% (5/19) of patients carried at least one alteration in TP53 gene, two cases had loss of 17p and three cases had missense mutations. TP53alt was associated with a poor response to Burkimab therapy (p=0.044) and a shorter four-year PFS: 84.6% vs 25% (p=0.022).
Summary
Losses of 11q, 13q, 15q, or 17p, as well as TP53alt are associated with a poor response to Dose-Intensive Chemotherapy Including Rituximab (Burkimab trial). These non-random losses could be used for the risk stratification of BL patients treated with Rituximab.
Keyword(s): Array based comparative genomic hybridization, Burkitt's lymphoma, Mutation analysis, Rituximab
Session topic: Optimization and innovation in treating aggressive lymphomas