Session: 627. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Retrospective/Observational Studies: Biomarkers and Prognostication in Aggressive B-Cell Non-Hodgkin Lymphomas
Hematology Disease Topics & Pathways:
Adult, Diseases, Therapies, DLBCL, B-Cell Lymphoma, Technology and Procedures, Lymphoid Malignancies, Study Population, Clinically relevant, molecular testing
Methods: Samples from 3 cohorts were analyzed. Pts in cohort 1 (C1) underwent ASCT at Dana-Farber Cancer Institute (DFCI) from 2003-2013 (Herrera, ASH 2015). Archival tumor tissue and ASC samples were retrospectively collected for analysis. Pts in cohort 2 (C2) were prospectively enrolled on a banking protocol at DFCI and underwent ASCT from 2014-2016. Pts in cohort 3 (C3) underwent ASCT from 2015-2016 and participated in a multicenter phase II trial of post-ASCT pembrolizumab maintenance (PM) (Frigault, Blood Adv 2020). Pts in C2/C3 had tumor tissue and serially collected post-ASCT PBMC and plasma samples as mandated by protocol, and a subset had available pre-ASCT PB or ASC samples. Because PM did not demonstrate a clear benefit in the trial, all cohorts were analyzed together. IgNGS (Adaptive Biotechnologies; Seattle, WA) was performed, as previously described (Armand, BJH 2013). In all cases, ctDNA testing was not performed in real-time or used to drive clinical decisions.
Results: 152 pts were enrolled. Among 141 pts with sufficient DNA for testing, a clonotype was identified in 112 (78%) with a higher detection rate in more recent cohorts – C2 (93%) and C3 (90%) vs C1 (67%).
Among 97 pts with an available ASC sample, 23 (24%) were ctDNA-positive (pos). With a median follow-up among survivors of 69 months (m) (range 13-185), the 5-year (y) progression-free survival (PFS) for ASC ctDNA-pos and ASC ctDNA-negative (neg) pts were 13% (95% CI 3-30%) and 52% (95% CI 40-63%), respectively (HR 2.8, p<0.001), while the 5y cumulative incidences of relapse were 83% (95% CI 66-99%) and 39% (95% CI 27-50%), respectively (HR 3.1, p<0.001). The sensitivity and specificity of ASC ctDNA for progression or death were 36% and 95%, respectively. ASC ctDNA (HR 2.5, p=0.002) was the only significant predictor of PFS in a multivariable model that included pre-ASCT positron emission tomography (PET), lines of therapy, age, and primary refractory status. Inferior overall survival was observed for ASC ctDNA-pos pts (HR 2.1 p=0.037). In an exploratory analysis, we examined 14 pts with an available pre-ASCT plasma sample. 2/14 were ctDNA-pos (14%) and both pts relapsed (HR for PFS 9.4, p=0.03). Among 13 pts with both pre-ASCT PB and ASC samples (drawn a median of 19 days apart [range 11-47]), results were concordant in 12/13 pts (92%).
56 pts had a median of 3 (range 1-8) post-ASCT plasma samples available for analysis. Within this cohort, 25 pts relapsed and 2 pts died in remission. 21 pts (38%) had detectable ctDNA in a median of 2 post-ASCT samples (range 1-5); among them, 18 (86%) relapsed with a median lead time from first ctDNA detection to relapse of 52 days (range 0-518). Among the 3 ctDNA-pos pts who did not relapse, 2 had detectable ctDNA at a single time point and subsequently became ctDNA-neg, and 1 developed acute myeloid leukemia and underwent allogeneic transplantation. Among 20 pts who relapsed and had ≥1 plasma sample available within 100 days of relapse, 18 (90%) had detectable ctDNA. PBMC testing had inferior performance characteristics (Table).
Conclusions: Identification of ctDNA using IgNGS within an ASC sample is a powerful predictor of post-ASCT relapse and provides (at least in this cohort) a better way to predict relapse than pre-ASCT PET. Detection of ctDNA in pre-ASCT plasma also appears to be predictive of relapse. In ctDNA-pos pts, given the dismal PFS, strong consideration could be given to alternative treatment strategies, e.g. CAR-T cell therapy. Furthermore, detection of ctDNA in post-ASCT plasma samples is closely associated with impending relapse, which provides an attractive platform for pre-emptive therapeutic intervention.
Disclosures: Brown: Dynamo Therapeutics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Octapharma: Consultancy; Pfizer: Consultancy; Acerta: Consultancy; Sun: Research Funding; Genentech: Consultancy; Rigel Pharmaceuticals: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Gilead: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Janssen: Honoraria; Sunesis: Consultancy; Novartis: Consultancy; Loxo: Consultancy, Research Funding; Nextcea: Consultancy; MEI Pharma: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy. Crombie: AbbVie: Research Funding; Bayer: Research Funding. Davids: Eli Lilly: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Merck: Consultancy; Research to Practice: Honoraria; Syros Pharmaceuticals: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Research Funding; AbbVie: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding. Fisher: Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Jacobsen: Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Takeda: Honoraria; Acerta, AstraZeneca, Merck: Consultancy. LaCasce: BMS: Consultancy; Research to Practice: Speakers Bureau; UptoDate: Patents & Royalties. Dahi: Kite: Consultancy. Nieto: Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Astra Zeneca: Other: Grant Support. Chen: Incyte Corporation: Consultancy; Takeda: Consultancy; Magenta: Consultancy; Kiadis: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; AbbVie: Other: Data and Safety Monitoring Board Member. Herrera: Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding. Armand: IGM: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Genentech: Research Funding; Roche: Research Funding; Tensha: Research Funding; Merck: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Research Funding; Sigma Tau: Research Funding.
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