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Cell-free DNA sequencing allows the identification of the mutational profile of TFH lymphomas and has a predictive value: a LYSA study
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International audience. Introduction: TFH lymphomas (TFHL) commonly harbor mutations in TET2, RHOA, DNMT3A and IDH2. While RHOA and IDH2 appear restricted to the neoplastic cells, TET2 and DNMT3A mutations occur in a significant proportion of cases in a hematopoietic progenitor cell and can also be detected in B or myeloid cells. Cell-free DNA (cfDNA) sequencing allows the detection of circulating tumor DNA in solid cancers or B-cell lymphomas, with predictive value, but few data exist on cfDNA sequencing in TFHL.Methods: In the frame of the ORACLE study, a phase 3 trial comparing oral azacitidine to investigator choice treatment in relapsed or refractory TFHL patients, we collected tumor biopsies and plasma in streck tube at inclusion, after 3 cycles, and at progression. Tumour and cfDNA were sequenced by NGS using 9 genes, amplicon-based libraries. Median sequencing depth was 2386X in tumor and 3519X in cfDNA.Results: Among patients with confirmed TFHL treated in LYSA centers, we collected 45 samples at inclusion, 16 after cycle 3, and 14 at progression. The median cfDNA concentration at each time point was respectively 7507 (IQR 3418–19414), 5182 (3438–12429), and 15750 (7316–26953) hEG/mL. Results of cfDNA at inclusion and tumor sequencing were compared in 43 patients. Common TET2 mutations were detected in the tumor of 36/43 (84%) and in cfDNA of 33/43 (77%) patients, with a median variant allele frequency (VAF) of 17.75% vs. 9.8% respectively. RHOAG17V was detected in 29/43 (67%, VAF 10%) and in 24/43 (59%, VAF 4.4%), DNMT3A in 13/43 (30%, VAF 17.9%) and 15/73 (35%, VAF 17.9%), and IDH2 in 12/43 (28%, VAF 5.9%) and 8/43 (19%, VAF 5.4%) of tumor biopsies and cfDNA samples respectively. Only one patient had detectable TET2, DNMT3A, IDH2, and RHOA mutations in the cfDNA and not in the tumor biopsy, corresponding to a tumor with low neoplastic cell content. By contrast, 3 patients had DNMT3A mutations, not affecting the R882 residue, detected in the cfDNA but not in the tumor likely corresponding to clonal hematopoiesis not related to the TFHL. We also compared 25 paired cfDNA samples collected at inclusion and after cycle 3 (including progression sample if occurring at cycle 3 or before). In all but one patient, we observed the persistence of TET2 and DNMT3A mutations, even in responding patients, confirming that these mutations are not restricted to neoplastic cells, and suggesting that treatment, especially with 5-azacitidine, does not affect the clonal hematopoiesis. By contrast, among the 14/25 patients with a detectable RHOA mutation in cfDNA at inclusion, progression-free survival was longer in the 4 patients with the disappearance of the RHOA mutations in cfDNA at cycle 3 than in the 10 others (median 29 vs. 3 months, p = 0.01).Conclusion: cfDNA sequencing allowed the detection of the RHOA mutation in 77% of mutated patients, and the disappearance of RHOA mutation at cycle 3 predict prolonged PFS.
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