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1580 Longitudinal Monitoring of Circulating Tumor DNA to Predict Survival in Newly Diagnosed Peripheral T-Cell Lymphoma Patients

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Lymphomas, T Cell lymphoma, Diseases, Lymphoid Malignancies, Measurable Residual Disease
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Cristiana Carniti1*, Sadhana Jonnalagadda1*, Giada Zanirato1*, Martina Magni1*, Eugenio Fardella, MD2*, Claudia Castellino3*, Alessandro Re, MD4*, Chiara Ghiggi5*, Filippo Ballerini6*, Rosanna Ciancia7*, Lorella Orsucci8*, Antonio Pinto9,10*, Sara Usai11*, Francesca Gaia Rossi, MD12*, Annalisa Arcari13*, Fiorella Ilariucci14*, Vittorio Ruggero Zilioli15*, Leonardo Flenghi16*, Melania Celli17*, Fabio Benedetti18*, Caterina Patti19*, Caterina Plenteda20*, Manuela Zanni21*, Gerardo Musuraca22*, Riccardo Bruna23*, Luca Arcaini24*, Federica Cavallo25*, Annalisa Chiappella1, Anna Dodero, MD26* and Paolo Corradini, MD27

1Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
2Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3A.O. S. Croce e Carle - S.C. di Ematologia e Trapianto di Midollo Osseo, Cuneo, Italy
4Lymphoma Unit, Division of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
5UO Ematologia e Terapie Cellulari, IRCCS Ospedale Policlinico San Martino, Genova, Italy
6Hematology, IRCCS Ospedale Policlinico San Martino, Genova, Italy
7Onco-hematology and Stem Cell Transplantation and Cellular Therapies,, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
8Hematology Division, A.O.U Città della Salute e della Scienza, Ospedale S. Giovanni Battista Molinette, Torino, Italy
9Hematology-Oncology & Stem Cell Transplantation Unit, IRCCS Istituto Nazionale Tumori, Fondazione G. Pascale, Napoli, Italy
10Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
11SC Ematologia e CTMO ARNAS G. Brotzu, Cagliari, Italy
12Ospedale Maggiore Policlinico - Fondazione IRCCS Ca Granda – Ematologia, Milano, Italy
13UO Ematologia, Ospedale Guglielmo da Saliceto, Piacenza, Italy
14Hematology, Azienda USL-IRCCS di Reggio Emilia,, Reggio Emilia, Italy
15Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, Milano, IT-MI, Italy
16Hematology, Azienda Ospedaliera di Perugia, Perugia, Italy
17Ospedale Degli Infermi Di Rimini, Rimini, Italy
18Department of Engineering for Innovation Medicine, Section of Medicine and Bone Marrow Transplant Unit, Verona University, Verona, Italy
19Onco-Hematology Unit, Azienda Ospedaliera Riunita Villa Sofia-Vincenzo Cervello, Palermo, Italy
20Hematology and CTMO, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy
21Department of Translational Medicine, Università del Piemonte Orientale SCDU Ematologia, AO SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
22Hematology unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
23Division of Hematology, Ospedale Maggiore Della Carità, Novara, Italy
24Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
25Division of Hematology, AOU Città della Salute e della Scienza di Torino, Torino, Italy
26Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
27Fondazione IRCCS Istituto Nazionale dei Tumori Milano, University of Milano, Milano, Italy

Introduction

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of Non-Hodgkin lymphomas characterized by poor prognosis and represent 10% to 15% of all lymphoid malignancies. Given the complex biology and pathogenesis of PTCLs, there is a need to find new biomarkers that can possibly predict prognosis. In recent years, liquid biopsy has emerged as a novel molecular tool to genotype circulating tumor DNA (ctDNA), however, little is known about its role in PTCLs. In this study, we aimed at understanding the relevance of liquid biopsy in PTCL genomics and the potential role of ctDNA in predicting survival and monitoring minimal residual disease (MRD).

Methods

Formalin-fixed, paraffin-embedded (FFPE) tissue and plasma samples of 51 newly diagnosed patients with different PTCL histologies [nodal T-follicular helper lymphoma (nTFHL; n=18); Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; n=21); Anaplastic Lymphoma Kinase-negative Anaplastic large-cell lymphoma (ALKneg ALCL;n=12)], were analyzed. Patients were part of the PTCL13 Fondazione Italiana Linfomi prospective study aimed at assessing the role of romidepsin addition to anthracycline-based chemotherapy followed by stem cell transplantation (SCT) (NCT02223208, Chiappella et al, Leukemia 2023). The FFPE samples were collected at baseline, while based on the availability, the plasma samples were collected at baseline, cycle 3, cycle 6, SCT and relapse. We extracted DNA from FFPE tissue and cell-free DNA (cfDNA) from plasma to prepare libraries. The libraries were then sequenced using a targeted panel of 60 genes (Roche) to identify somatic mutations. Sequencing was performed on NextSeq 550 (Illumina). Variants were called and annotated with a bioinformatic pipeline.

Results

Somatic mutations were detected in 43 out of 51 (84.3%) FFPE samples and 38 out of 51 (74.5%) plasma samples at baseline. Liquid biopsies were able to identify tumor mutations with a sensitivity of 68.3% [95% CI: 59.69% - 75.74%]. TET2 was found to be the most frequently mutated gene (35%) in plasma, followed by IDH2 (20%), RHOA (18%), DNMT3A (16%) and TP53 (14%). Mutations in TET2 were found to be significantly associated with nTFHL histology (11/18, p=0.008) and TP53 mutations were found exclusively in PTCL-NOS patients (7/21, p=0.003). Interestingly, patients with TET2/IDH2 had a better progression free survival (PFS) probability as compared to patients with only TET2 mutations (p=0.015). Circulating tumor DNA levels, calculated as human Genome Equivalents (hGE)/mL, associated with high International Prognostic Index (IPI) score (>2, p<0.0001), high Prognostic Index for T-cell lymphoma (PIT) score (≥2, p=0.02) and increased lactate dehydrogenase (LDH) levels (greater than upper normal limit, p=0.0003). By receiver operating characteristic (ROC) curve, a cut-off value of ctDNA was identified at baseline (1650 hGE/mL) which was able to predict survival (PFS p=0.0022; Overall Survival (OS) p=0.0004). In patients with a complete clinical response, ctDNA levels significantly decreased after end-of-treatment (EOT) with respect to baseline (p=0.0004), however, for patients with a partial clinical response/progressive disease, no significant differences were observed between baseline and EOT ctDNA levels. Notably, irrespective of the clinical response status, the presence of detectable ctDNA (hGE/mL>0) at EOT was able to predict survival (PFS p=0.05; OS p=0.009). At the time point of relapse, the genetic landscape of PTCLs was characterized by the emergence of mutations in CHEK2, FYN and STAT5B genes.

Conclusions

Considering the high sensitivity of detection, liquid biopsy could be used as a reliable tool to identify somatic mutations in PTCLs. Plasma DNA genotyping unveiled the complex genomics of PTCLs, with the presence of TET2/IDH2 co-mutations in plasma conferring a better prognosis. Baseline ctDNA level was representative of disease burden, but more importantly, it was able to predict long term survival, indicating its potential role as a novel prognostic biomarker to tailor future treatments. Moreover, irrespective of clinical response status, the association of detectable ctDNA at EOT with survival suggests that it could also be used to monitor the presence of MRD. The change in the mutational profile of PTCLs at relapse likely suggests a genetic evolution during disease progression.

Disclosures: Re: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Sobi: Speakers Bureau. Pinto: Incyte: Honoraria; BeiGene: Honoraria; Eli Lilly: Honoraria; Kite-Gilead: Honoraria; Merck Sharp and Dohme: Honoraria; IGM Biosciences: Current holder of stock options in a privately-held company; Autolus Therapeutics: Current holder of stock options in a privately-held company; Bristol Myers Squibb: Honoraria; Hoffmann-La Roche AG: Consultancy, Honoraria. Rossi: Takeda: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Zilioli: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Other: Consultancy; Janssen: Speakers Bureau; Lilly: Speakers Bureau. Patti: MSD: Research Funding. Arcaini: EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Kile/Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Chiappella: INCYTE: Honoraria; JANNSEN-CILAG: Honoraria; NOVARTIS: Honoraria; ASTRAZENECA: Honoraria; TAKEDA: Honoraria; IDEOGEN: Honoraria; ROCHE: Honoraria; GILEAD-SCIENCES: Honoraria. Dodero: gilled: Research Funding. Corradini: Bristol Myers Squibb: Other: Support for travel and accommodations; Celgene: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Takeda: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Janssen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Novartis: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Daiichi Sankyo: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Sanofi: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Pfizer: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Kyowa Kirin: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); GlaxoSmithKline: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Incyte: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Gilead/Kite: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Amgen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; AbbVie: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Roche: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; SOBI: Other: Honoraria (for consultancy, participation in advisory boards, or lectures).

*signifies non-member of ASH