Mrd‐negativity after frontline dlbcl therapy: pooled analysis of 6 clinical trials

Introduction: Current lymphoma response criteria rely on metabolic imaging with moderate predictive value. Prior studies showed prognostic utility of circulating tumor DNA (ctDNA) early during therapy. However, accurate MRD detection at the end of therapy (EOT) is difficult using 1st-generation assays with plasma detection limits of ∼1e-4. We tested performance of phased variant enrichment and detection by sequencing (PhasED-Seq), an ultrasensitive ctDNA MRD method (LOD ∼1e-6), focusing on EOT disease detection. Methods: We integrated PhasED-Seq MRD from LBCL studies using curative intent 1st-line regimens. We considered 6 prospective trials including investigational combinations of CHOP or EPOCH with rituximab, acalabrutinib, lenalidomide, obinutuzumab, polatuzumab, and/or tafasitimab [ACTRN12609001077257;NCT04002947;NCT00398177;NCT02529852;NCT04231877;NCT04134936]. Samples were profiled by PhasED-Seq at Foresight Diagnostics or Stanford University. Tumor or pretreatment plasma samples were used to identify Phased Variants, which were tracked at MRD timepoints (C2D1, C3D1, C4D1, and EOT). Results: 407 specimens from 151 pts were evaluable, with 148 pts (97%) successfully genotyped. Plasma samples were available from 119 pts pretreatment, 52 at C2D1, 53 at C3D1, 51 at C4D1, and 93 at EOT. While MRD clearance during therapy stratified PFS, persistent MRD at EOT identified highest risk (p < 0.0001, HR = 90, Figure A). EOT MRD+ had 95% Sn for predicting future PFS events, with lead times up to 30 mo before radiologic PD. In total, 23 cases (25%) were MRD+ at EOT, with 18/23 experiencing PFS events to date. Among 5 pts without PFS events to date, 1 received subsequent RT for FDG-avid residual disease, while 2 others have <1-yr follow-up. In contrast, 70 cases were MRD-neg at EOT, with 99% (69/70) remaining alive without progression to date. The 1 MRD-neg case at EOT that experienced later progression presented with isolated CNS relapse at 10 mo. MRD status predicted PFS in multivariate models after adjusting for regimen and ctDNA profiling lab (p < 0.01). Clinical Sn, Sp, PPV, and NPV of EOT MRD for subsequent events were 95.0%, 94.5%, 83%, and 99%, respectively. While analytical Sn of 1e-4 has been used in CLL and myeloma for MRD, detection below this threshold was needed for adequate clinical Sn in DLBCL. When using a threshold of 1e-4 for MRD-detection, performance deteriorated, with clinical Sn dropping to 60% (Figure B), and corresponding degradation in PFS stratification ([email protected], HR = 16; MRD-Full, HR = 90). Although EOT PET/CT response also predicted PFS (p < 0.0001, HR = 8.5), PhasED-seq showed higher Sn (95% vs. 50%, p = 0.008). Keywords: aggressive b-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, minimal residual disease The research was funded by: Grants from the NCI/NIH, Foresight Diagnostics. Conflicts of interests pertinent to the abstract D. M. Kurtz Other remuneration: Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Genentech: Consultancy. J. Westin Other remuneration: Research funding: Genentech, Kite, BMS, Novartis, Morphosys/incyte, AstraZeneca, ADC Therapeutics; Consulting: Genentech, Kite, BMS, Novartis, Morphosys/Incyte, AstraZeneca, ADC Therapeutics, Monterosa, AbbVie, Seagen, Foresight R. C. Lynch Other remuneration: Research Funding: TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, Rapt; Consultant/Advisory: Cancer Study Group, SeaGen, Foresight Diagnostics C. Kuffer Other remuneration: MorphoSys AG: Current Employment, Current equity holder in publicly-traded company G. J. Hogan Other remuneration: Foresight Diagnostics: Current Employment; Freenome: Other: Equity holder. A. Schultz Other remuneration: Foresight Diagnostics: Current Employment, Current holder of stock options in a privately-held company. S. Close Other remuneration: Foresight Diagnostics: Current Employment, Current holder of stock options in a privately-held company. J. J. Chabon Other remuneration: Foresight Diagnostics: Current Employment, Current holder of stock options in a privately-held company. D. Rossi Other remuneration: Gilead: Other: honoraria, advisory board fees, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; BeiGene: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD: Other: advisory board fees; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding. S. Opat Conflicts of interests pertinent to the abstract Other remuneration: Pharmacyclics, LLC an AbbVie Company: Research Funding; Antegene: Consultancy, Honoraria, Research Funding; CSL: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Belgene: Research Funding. R. Hicks Conflicts of interests pertinent to the abstract Stock ownership: Telix Pharmaceuticals M. S Hertzberg Other remuneration: Beigene: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria M. Diehn Other remuneration: Foresight Diagnostics: Consultancy, Current equity holder in private company. W. Wilson Other remuneration: Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Gilead: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties; Syncopation: Current equity holder in private company, Patents & Royalties; Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Genentech: Consultancy; Cibermed Inc: Consultancy, Current equity holder in private company, Patents & Royalties. A. A Alizadeh Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Gilead: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties; Syncopation: Current equity holder in private company, Patents & Royalties; Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Genentech: Consultancy; Cibermed Inc: Consultancy, Current equity holder in private company, Patents & Royalties.