TARGETED GENOTYPING OF CIRCULATING TUMOR DNA FOR CLASSICAL HODGKIN LYMPHOMA MONITORING: A PROSPECTIVE STUDY
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Introduction: The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin Lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed.
Methods: We developed a targeted Next‐Generation sequencing (NGS) panel for fast analysis (AmpliSeq® technology) of nine commonly mutated genes in biopsy and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow up at diagnosis and after 2 cycles of chemotherapy (C2). A dedicated bioinformatics pipeline to optimize detections of variants with low rates and minimize artefactual misinterpretations was built. Sixty cHL patients treated by first line conventional chemotherapy (BEACOPPescalated [21.3%], ABVD/ABVD‐like [73.5%] and other regimens [5.2%, for elderly patients] were included in this non‐interventional study (NCT02815137).
Results: Median age of the patients was 33.5 years (range 20‐86) with a predominance of male patients, scleronodular subtype and ECOG 0‐1 (53.3%, 70% and 88.3%, respectively). Variants were identified in 33 (55%) patients, precisely in 16/30 (53.3%) and 30/60 (50%) of available biopsy and ctDNA samples respectively. Concordance between genetic profiles of biopsy and ctDNA was accurate for 22/30 patients (73.3%). Mutations of NFKBIE, TNFAIP3, STAT6, PTPN1, B2M, XPO1, ITPKB, GNA13 and SOCS1were found in 11.7% (mean number of variants by sample [range]: 1 [0‐1]), 25% (1.1 [0‐2]), 21.7% (1.4 [0‐2]), 1.7% (1 [0‐1]), 25% (1.3 [0‐3]), 6.7% (1 [0‐1]), 15% (1.4 [0‐3]), 5% (1.3 [0‐2]) and 31.7% (1.8 [0‐7]) of all patients, respectively. Unsupervised hierarchical clustering was performed among the 9 genes to represent the association of alterations (See Figure 1).
Higher level of [ctDNA] at diagnosis was associated with adverse characteristics: age ≥45 years, presence of anemia (hemoglobin <10.5g/dl), albuminemia <40g/l, sedimentation rate ≥50mm, stage III‐IV, lymphocytes count <0.6 G/L, presence of B symptoms, International prognostic Index ≥3, elevated LDH. The ITPKB and B2M mutated patients displayed more disseminated disease (≥ 4 median nodal areas versus [vs] 3 for non‐mutated patients, p = 0.005) and XPO1 mutations were associated with female sex (p = 0.042). Median VAF were higher in ctDNA than in biopsy (3.23% vs 2.15%, p = 0.023) and there was a moderate correlation between higher metabolic tumor volume (MTV) and higher [ctDNA] (r = 0.36, p = 0.005).
Regarding early therapeutic response, 45 patients (83%, NA = 6) had a negative positron emission tomography (PET) after C2 (Deauville Score 1‐3). Mean of DeltaSUVmax after C2 was ‐78.8%. We analyzed ctDNA after C2 for 45 patients (70%). A rapid clearance of ctDNA in all cases was observed after C2.
Conclusions: Variants detection in ctDNA is suitable to depict the genetic features of cHL at diagnosis and may help to assess early treatment response, in complement to PET. [ctDNA] level and genotype are correlated with clinical characteristics and presentation.
Keywords: classical Hodgkin lymphoma (cHL); minimal residual disease (MRD); molecular genetics.
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