Contributions
Abstract: EP856
Type: E-Poster Presentation
Session title: Lymphoma Biology & Translational Research
Background
Inadequate molecular recognition of high-risk diffuse large B-cell lymphoma (DLBCL) hampers the discovery of novel treatments for the patients with poor outcome. Clinical significance and prognostic impact of circulating tumor DNA (ctDNA) warrants establishment in prospectively collected samples from homogeneous patient populations.
Aims
We aimed to delineate molecular determinants of outcome within the ctDNA of the patients with aggressive B-cell lymphoma.
Methods
We applied whole-genome and targeted duplex DNA sequencing to serially sampled plasma cell-free DNA of 101 patients less than 65 years with high-risk (aaIPI 2-3 and/or site-specific risk factors for central nervous system (CNS) progression) aggressive B-cell lymphoma. The patients were treated in a Nordic Lymphoma Group phase II trial with dose-dense immunochemotherapy and early CNS prophylaxis (Leppä et al., Blood Advances 4(9):1906-1915, 2020).
Results
We found that the patients with high pretreatment ctDNA burden (log hGE/ml) were at high risk of relapse and early death from lymphoma. In contrast, non-lymphoma related treatment failures were mainly seen in the patients with low to moderate ctDNA levels. High ctDNA burden overcame the conventional measures of high tumor burden and other high-risk features including double-hit lymphomas, revealing that additional clinically meaningful heterogeneity exists within the established clinical and biological risk factors.
Treatment refractoriness exhibited diverging ctDNA kinetics during therapy, whereas late molecular responses, and end-of-treatment negativity for minimal residual disease characterized cured patients. As a proof-of-concept, we show that advanced ctDNA tools based on hypermutation patterns and fragmentome disparities can complement prediction of progression at the end of therapy, and provide tools to clinical challenges, including false residual PET positivity.
Lastly, we analyzed the potential of non-invasive ctDNA interrogation for somatic drivers, hypermutation signatures and variant haplotypes to offer novel translational information for diagnostics and understanding of treatment-refractoriness in patients with aggressive B-cell lymphoma. Genomic dissection of pretreatment ctDNA revealed a strong association between TP53-loss and high ctDNA burden – a duo that in the context of high-risk biology rendered lymphomas refractory to frontline treatment. In contrast, subclonal MYC lesions that were not detectable at diagnosis were positively selected at late relapses following complete responses to the initial therapy. We further identified that the limitations of tissue biopsies can culminate in diagnosis-changing discoveries in plasma ctDNA, including progression-driving transformation to high-grade B-cell lymphoma.
Conclusion
Our integrative approach with prospectively collected serial plasma samples reveals that quantitative, mutational and fragmentome features of ctDNA can be utilized as novel diagnostic and prognostic tools in aggressive B-cell lymphomas.
Keyword(s): Diffuse large B cell lymphoma, Prognosis, Risk factor
Abstract: EP856
Type: E-Poster Presentation
Session title: Lymphoma Biology & Translational Research
Background
Inadequate molecular recognition of high-risk diffuse large B-cell lymphoma (DLBCL) hampers the discovery of novel treatments for the patients with poor outcome. Clinical significance and prognostic impact of circulating tumor DNA (ctDNA) warrants establishment in prospectively collected samples from homogeneous patient populations.
Aims
We aimed to delineate molecular determinants of outcome within the ctDNA of the patients with aggressive B-cell lymphoma.
Methods
We applied whole-genome and targeted duplex DNA sequencing to serially sampled plasma cell-free DNA of 101 patients less than 65 years with high-risk (aaIPI 2-3 and/or site-specific risk factors for central nervous system (CNS) progression) aggressive B-cell lymphoma. The patients were treated in a Nordic Lymphoma Group phase II trial with dose-dense immunochemotherapy and early CNS prophylaxis (Leppä et al., Blood Advances 4(9):1906-1915, 2020).
Results
We found that the patients with high pretreatment ctDNA burden (log hGE/ml) were at high risk of relapse and early death from lymphoma. In contrast, non-lymphoma related treatment failures were mainly seen in the patients with low to moderate ctDNA levels. High ctDNA burden overcame the conventional measures of high tumor burden and other high-risk features including double-hit lymphomas, revealing that additional clinically meaningful heterogeneity exists within the established clinical and biological risk factors.
Treatment refractoriness exhibited diverging ctDNA kinetics during therapy, whereas late molecular responses, and end-of-treatment negativity for minimal residual disease characterized cured patients. As a proof-of-concept, we show that advanced ctDNA tools based on hypermutation patterns and fragmentome disparities can complement prediction of progression at the end of therapy, and provide tools to clinical challenges, including false residual PET positivity.
Lastly, we analyzed the potential of non-invasive ctDNA interrogation for somatic drivers, hypermutation signatures and variant haplotypes to offer novel translational information for diagnostics and understanding of treatment-refractoriness in patients with aggressive B-cell lymphoma. Genomic dissection of pretreatment ctDNA revealed a strong association between TP53-loss and high ctDNA burden – a duo that in the context of high-risk biology rendered lymphomas refractory to frontline treatment. In contrast, subclonal MYC lesions that were not detectable at diagnosis were positively selected at late relapses following complete responses to the initial therapy. We further identified that the limitations of tissue biopsies can culminate in diagnosis-changing discoveries in plasma ctDNA, including progression-driving transformation to high-grade B-cell lymphoma.
Conclusion
Our integrative approach with prospectively collected serial plasma samples reveals that quantitative, mutational and fragmentome features of ctDNA can be utilized as novel diagnostic and prognostic tools in aggressive B-cell lymphomas.
Keyword(s): Diffuse large B cell lymphoma, Prognosis, Risk factor