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

Introduction: High total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT before R-CHOP has been shown to be significantly associated with inferior progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma. The REMARC study (NCT01122472) showed a significantly better progression-free survival (PFS) in 650 patients responding to R-CHOP treated with maintenance therapy with lenalidomide (LEN) versus placebo (PBO), but no difference in OS was observed. The aim was to analyze the prognostic impact of baseline TMTV together with biological profile. Methods: TMTV was computed on baseline PET/CT using the 41% SUVmax method. The optimal TMTV cut-off for PFS and OS was determined by Receiver Operating Curve and X-tile analyses and confirmed by a training validation method. A subset of patients (n = 192) was classified as GCB or non-GCB profile, and with MYC or BCL2 by FISH. Survival was estimated using Kaplan Meier (KM) curves. Analyses were performed on the evaluable population (n=301/650) and each arm, with 146 pts on PBO and 155 pts on LEN. Results: Clinical characteristics were similar to the overall population. After a median 5 years follow-up, 4y-PFS was 73% and 4y-OS was 85%. Median baseline TMTV was 238 cm3 (Q1-Q3;78,523). The optimal TMTV cut-off was 220 cm3 for PFS and OS. Patients with TMTV >220 vs ≤220 cm3 presented with worse ECOG performance status (ECOG ≥2: 21% vs 11.5%, p=0.029), higher Ann Arbor stage (stage III-IV: 94% vs 87%, p=0.043), more extra-nodal sites (>1: 63.5% vs 39%, p<0.001), more frequently elevated LDH (74% vs 45%, p<0.001), higher IPI (IPI 3-5: 85% vs 58%, p=10-3), and higher aaIPI (score 2-3: 74% vs 40%, p=10-3). In all evaluated patients, a significant impact of TMTV was observed for PFS (p=2.10-4) and OS (p=10-4). Patients with high TMTV>220 vs low TMTV≤220, had a 4-year PFS of 56% vs 82% and OS of 74% vs 92% respectively. This prognostic impact of a high baseline TMTV on PFS (HR=2.2; 95% CI, 1.4-3.5) and OS (HR=3.2; 95% CI, 1.5-6.6) was maintained in both PBO and LEN arms. As demonstrated in the original report, GCB/nonGCB profile had no significant impact on PFS and OS, regardless of TMTV. BCL2 impacted PFS and could be stratified by TMTV. MYC had no impact on PFS and OS. In multivariate analysis, baseline TMTV was the most powerful parameter associated with inferior PFS and OS, compared to aaIPI and treatment arm. Conclusion: TMTV measured on baseline PET/CT is the strongest prognosticator of outcome in DLBCL, even in patients in responding after R-CHOP. High TMTV at baseline was significantly associated with inferior PFS and OS in patients receiving either PBO or LEN. Keywords: diffuse large B-cell lymphoma (DLBCL); positron emission tomography (PET).

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV41max ) and SUV4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUVmax approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm3 using SUV41max and 460 cm3 using SUV4 . For iPET response, the respective thresholds were 46.9% SUVmax reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV41max and SUV4 , and 29% and 25% for iPET response by ΔSUVmax and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV41max and 3.206 (1.524-6.743) for SUV4 . At iPET, it was 3.910 (1.891-8.087) for ΔSUVmax and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.

PurposeThe purpose of this study was to investigate the prognostic significance of total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) in patients with follicular lymphoma (FL) at baseline and mid-treatment with 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans.MethodsThe study analyzed data from 48 patients with FL who were treated in Jiangsu Province Hospital and reviewed their baseline PET-CT scans. TMTV and TLG were computed by using the absolute value of 2.0, 2.5, and 3.0 thresholding method, respectively.ResultsMedian age was 53 years, 75.0% of patients had stage III to IV disease, 43.8% had a Follicular Lymphoma International Prognostic Index 1 (FLIPI1) score of 3 to 5 and 20.8% had a FLIPI2 score of 3 to 5. Receiver operating characteristic (ROC) curve analysis showed the optimal cut-off values for TMTV3.0 and TLG3.0 were 476.4 (sensitivity, 85.7%; specificity, 78.0%; area under the curve [AUC], 0.760; p=0.003) and 2,676.9 (sensitivity, 71.4%; specificity, 78.0%; AUC, 0.760; p=0.003). On multivariable analysis, TMTV3.0 and TLG3.0 were independent predictors of both progression-free survival (PFS) (hazard ratio [HR], 5.406; 95% confidence interval [CI], 1.326 to 22.040; p=0.019 and HR, 6.502; 95% CI, 1.079 to 39.182; p=0.042) and overall survival (OS) (HR, 4.111; 95% CI, 1.125 to 15.027; p=0.033 and HR, 5.885; 95% CI, 1.014 to 34.148; p=0.049). ROC curve analysis showed the optimal cut-off values for ΔTMTV3.0 and ΔTLG3.0 were 66.3% (sensitivity, 85.7%; specificity, 63.4%; AUC, 0.774; p < 0.001) and 64.5% (sensitivity, 85.7%; specificity, 65.9%; AUC, 0.777; p < 0.001).ConclusionBaseline TMTV and TLG are strong predictors of PFS and OS in FL. Furthermore, interim TMTV (ΔTMTV > 66.3%) and TLG (ΔTLG > 64.5%) reduction are valuable tools for early treatment response assessment in FL patients.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare aggressive lymphoma characterized by a paucity of neoplastic B-cells and a majority of reactive T-cells with or without histiocytes. In the ‘Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas’ trial (clinicaltrials.gov NCT00554164; EudraCT 2006-001641-33), its frequency was less than 3%. While cancer cell content by quantitative histology was 10-times lower, baseline total metabolic tumor volume (TMTV) by 18-fluorodesoxyglucose positron emission tomography was 10-times higher in THRLBCL than in diffuse large B-cell lymphoma (DLBCL). When THRLBCL and DLBCL populations were matched for TMTV, the survival curves were superimposable. However, when the populations were matched for cancer cell volume by multiplying TMTV by cancer cell fraction, outcome in THRLBCL was worse than in DLBCL. Whether genetic differences between cancer cells, tumor-promoting properties of non-neoplastic cells, or both are responsible for inferior cancer cell volume-related outcome in THRLBCL, remains to be elucidated.

Simultaneous Assessment of Total Metabolic Tumor Volume and Intratumoral CD4+ T-Cell Infiltration Identifies Early Progression of Follicular Lymphoma on Watch-and-Wait Approach

Total metabolic tumor volume (TMTV) at baseline becomes a key biomarker in several lymphoma subtypes. Variability in segmentation methods such as 41%SUVmax and SUVmax > 4 has limited its clinical application. Additionally, immune-checkpoint-inhibitors introduced challenges in response assessment due to pseudoprogression, complicating the use of traditional metrics. This study investigates the prognostic impact of baseline- and residual-TMTV and introduces a novel personalized-liver-based-threshold (pTMTVliver) to enhance precision in patient stratification. We analyzed 91 patients with relapsed/refractory diffuse-large-B-cell lymphoma and follicular lymphoma from the GATA trial, comparing patient's outcome according to three segmentation methods: TMTV41%, TMTV4, and pTMTVliver. pTMTVliver used a threshold of 200%SUVmeanliver aligning with 125%SUVmaxliver to enhance standardization and reduce variability. Baseline-TMTV significantly influenced prognosis with higher TMTV correlating with shorter PFS and OS (p < 0.0001 for all methods). Residual-TMTV, particularly with pTMTVliver and TMTV4, stratified no-CMR patients with the lowest predictive errors and better predictive accuracy compared to TMTV41% Multivariate analyses confirmed residual-pTMTVliver as superior for prognostic performance for PFS (HR:5.10; C-index:0.724) and OS (HR:4.00; C-index:0.853) compared to TMTV4 and Deauville Score (DS). The DS alone did not fully capture the heterogeneity of outcomes of DS4-5 patients. Baseline- and residual-TMTV strongly influence prognosis and response in lymphoma patients. The novel personalized pTMTVliver method offers improved accuracy of patient stratification, particularly for those with DS4-5, providing more reliable risk assessment. Larger cohorts are needed to validate these findings and optimize residual-TMTV-based clinical applications.

Baseline and interim functional imaging with PET effectively risk stratifies patients with peripheral T-cell lymphoma

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Overestimated Value of Baseline Total Metabolic Tumor Volume at 18F-Labeled Fluorodeoxyglucose Positron Emission Tomography in Follicular Lymphoma.

Longitudinal Noninvasive Surveillance & Fragmentomic Characterization of Follicular Lymphoma

Phased Variants Allow Robust Profiling of Circulating Tumor DNA in Untreated Follicular Lymphomas

Baseline Suvmax Did Not Predict Histological Transformation from Follicular Lymphoma to Aggressive Lymphoma in the Phase III GALLIUM Study

Dynamics of Circulating Tumor DNA in Relapsed/Refractory DLBCL Patients