Circulating Tumor DNA Predicts Time to First Treatment in Previously Untreated Follicular Lymphoma: Analysis from a Prospective Clonal Evolution Study

Lakhotia, Rahul

Oral and Poster Abstracts
621. Lymphomas: Translational – Molecular and Genetic: Poster II

Research, Clinical trials, Adult, Translational Research, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Diseases, Indolent lymphoma, Lymphoid Malignancies, Study Population, Human, Measurable Residual Disease

Rahul Lakhotia, MBBS¹, Stefania Pittaluga, MD, PhD²^*, James D. Phelan, PhD¹^*, Allison Graeter, MD³, Christopher Melani, MD⁴, Max J Gordon, MD¹^*, Jagan R. Muppidi, MD, PhD⁵^*, Sam Y. Ng, MD, PhD¹, Sumaya Berg, RN¹^*, Sarah Evans, RN¹^*, Amynah Pradhan, NP¹^*, Atekelt Tadese, PA¹^*, Candis Morrison, NP, PhD¹^*, Bonita Bryant¹^*, Yandan Yang, PhD¹^*, Theresa Davies-Hill²^*, Liza Lindenberg, MD⁶^*, Mark Ahlman⁷^*, Esther Mena, MD⁶^*, Ethan Bergvall⁸^*, Nick Micheletti, MS⁹^*, Laura M Yee⁹^*, Allison P. Jacob, MSc¹⁰, Monica Gallucci¹⁰^*, Heidi Simmons, PhD¹⁰, Alexander Bagaev, PhD¹¹^*, Mark Meerson, MSc¹²^*, Ekaterina Postovalova, PhD¹²^*, Olga Kudryashova¹²^*, Nikita Kotlov, PhD¹¹^*, Nathan H. Fowler, MD¹³^*, Elaine S. Jaffe, MD¹⁴, Louis M. Staudt, MD, PhD¹⁵, Wyndham H. Wilson, MD, PhD¹^* and Mark Roschewski, MD¹⁶

¹Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
²Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
³University of South Florida, Tampa, FL
⁴Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Derwood, MD
⁵Lymphoid Malignancies Branch, National Institutes of Health, Bethesda, MD
⁶Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
⁷Radiology and Imaging, Medical College of Georgia, Augusta, GA, Augusta, GA
⁸Section of Nuclear Medicine, University of Virginia, Charlottesville, VA, Bethesda, MD
⁹Office of Collaborative Biostatistics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
¹⁰Adaptive Biotechnologies, Seattle, WA
¹¹BostonGene Corp., Waltham, MA
¹²BostonGene, Corp., Waltham, MA
¹³BostonGene, Waltham, MA
¹⁴Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Great Falls, VA
¹⁵Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
¹⁶National Cancer Institute, Bethesda, MD

Background:

Follicular lymphoma (FL) shows marked heterogeneity in clinical course including spontaneous regression and histologic transformation (HT). Watchful waiting (W&W) is routinely employed, but monitoring is not standardized. A subset of pts require treatment early after diagnosis, but biologic basis is unclear. Improved classifiers and monitoring tools are needed. Circulating tumor DNA (ctDNA) is a highly tumor-specific biomarker that is prognostic in aggressive B-cell lymphomas. We previously showed that ctDNA in plasma can be identified in >90% FL pts with next-generation sequencing of Ig heavy- and light-chain loci. Here, we present updated results from serial ctDNA monitoring of pts on a prospective clinical trial [NCT03190928].

Methods: Adult pts with grade 1-3A FL were eligible if evaluable disease, no HT, and no prior systemic therapy. Pts underwent W&W until they met uniform protocol-defined treatment criteria and then monitored until 2^nd line therapy. Baseline testing included plasma, CT and PET, and biopsy. Clinic visits were every 4m for 2y, every 6m in years 3-5, then annually with CT scans every other clinic visit. PET scans were repeated at 2y, or at suspected disease progression. Cell-stabilizing tubes (plasma) and PBMCs were drawn at each visit. Analysis of ctDNA was performed using the research version of clonoSEQ blinded to clinical outcomes. The primary endpoint was progression requiring treatment within 2 years of enrollment. Pts who required treatment in first 2 years were labeled early progressors and those without treatment were labeled non-progressors.

Results: 78 pts enrolled between July 2017 and Aug 2021, of which 77 had baseline plasma samples. Of 58 pts with available FFPE tumor biopsies, all (100%) had ≥1 dominant clonotype(s) identified from tumor. Of 19 pts without FFPE, ≥1 dominant clonotype was identified from plasma in 7 (37%). These 65 pts with trackable clonotype(s) comprised the study population. Median age of the study population was 57y (range 24-84), including 12 (18%) low-risk, 25 (39%) intermediate-risk, and 28 (43%) high-risk by FLIPI. Baseline ctDNA was detectable in 60 (92%) pts with median (interquartile range [IQR]) level of 34 (6-114) lymphoma molecules per mL. Four (80%) pts with undetectable ctDNA at baseline had stage 1-2 disease. Baseline ctDNA levels correlated with both FLIPI (p<0.01) and total metabolic tumor volume (TMTV) on PET (p<0.001).

Three pts were unevaluable for progression at 2y due to non-progression events including a second malignancy, sudden death, and hemolytic anemia requiring rituximab. Thirty-three (53%) pts were early progressors and 29 (47%) were non-progressors at 2y. Median time to treatment (TTT) was 20m (95% CI, 10-68). Early progressors had median (IQR) baseline ctDNA level of 38.2 (13-189.4) compared to 18.7 (1.2-56.8) lymphoma molecules per mL for non-progressors. Pts with >median baseline ctDNA levels had median TTT of 9.7m (95% CI, 2.8-NE) compared to 37m (95% CI, 17-NE) for pts with <median ctDNA (p=0.06). All 5 pts with undetectable baseline ctDNA remained treatment free after median 5.4y of follow-up.

Median (IQR) baseline TMTV was 138 (39-388) cm³. Pts with >median baseline TMTV had median TTT of 5.3m (95% CI, 2.1-28) compared to 54m (95% CI, 26-NE) for pts with <median TMTV (p<0.001). Serial ctDNA samples were available for 37 pts. Rising ctDNA levels were observed in 10 (83%) of 12 pts prior to or at the time of treatment. Fluctuating ctDNA patterns were observed in 25 pts without progression which corresponded to changes on serial CTs.

Ten (15%) pts had HT. Neither baseline ctDNA levels (p=0.85) nor TMTV (p=0.65) were associated with increased risk of subsequent HT. Twenty-three (39%) pts had spontaneous regression of tumor lesions by ≥25% on CT. Lower baseline ctDNA levels (p=0.02) and TMTV (p<0.01) were associated with subsequent spontaneous regression. Twenty pts with spontaneous regression had serial samples and 13 (65%) had decrease in ctDNA levels corresponding to CTs.

Conclusions: Circulating tumor DNA is detectable in baseline plasma of >90% pts with untreated FL. Quantitative ctDNA levels correlate with both FLIPI and TMTV and are associated with earlier need for treatment. Serial ctDNA monitoring shows fluctuating levels that correlate with tumor burden on CT which provides a non-invasive method to monitor disease. Baseline ctDNA levels and TMTV do not predict future histologic transformation.

2958 Circulating Tumor DNA Predicts Time to First Treatment in Previously Untreated Follicular Lymphoma: Analysis from a Prospective Clonal Evolution Study