Personalized baseline and residual TMTV influence treatment response and outcomes in relapsed/refractory lymphomas: results from the GATA study.

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

The Prognostic Value of MTV Is Retained in New Proposed SUV 4 Threshold: An International Comparison of Follicular and Hodgkin Patient Survival

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.

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

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.

Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma

Evaluating the PET Parameters SUVmax and TMTV in the Setting of Autologous Stem Cell Transplantation for DLBCL

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.

Total metabolic tumor volume (TMTV) segmentation has significant value enabling quantitative imaging biomarkers for lymphoma management. In this work, we tackle the challenging task of automated tumor delineation in lymphoma from PET/CT scans using a cascaded approach. Our study included 1418 2-[18F]FDG PET/CT scans from four different centers. The dataset was dividedinto 900 scans for development/validation/testing phasesand 518 for multi-center external testing. The former consisted of 450 lymphoma, lung cancer, and melanoma scans, along with 450 negative scans, while the latter consisted of lymphoma patients from different centers with diffuse large B cell, primary mediastinal large B cell, and classic Hodgkin lymphoma cases. Our approach involves resampling PET/CT images into different voxel sizes in the first step, followed by training multi-resolution 3D U-Nets on each resampled dataset using a fivefold cross-validation scheme. The models trained on different data splits were ensemble. After applying soft voting to the predicted masks, in the second step, we input the probability-averaged predictions, along with the input imaging data, into another 3D U-Net. Models were trained with semi-supervised loss. We additionally considered the effectiveness of using test time augmentation (TTA) to improve the segmentation performance after training. In addition to quantitative analysis including Dice score (DSC) and TMTV comparisons, the qualitative evaluation was also conducted by nuclear medicine physicians. Our cascaded soft-voting guided approach resulted in performance with an average DSC of 0.68 ± 0.12 for the internal test data from developmental dataset, and an average DSC of 0.66 ± 0.18 on the multi-site external data (n = 518), significantly outperforming (p < 0.001) state-of-the-art (SOTA) approaches including nnU-Net and SWIN UNETR. While TTA yielded enhanced performance gains for some of the comparator methods, its impact on our cascaded approach was found to be negligible (DSC: 0.66 ± 0.16). Our approach reliably quantified TMTV, with a correlation of 0.89 with the ground truth (p < 0.001). Furthermore, in terms of visual assessment, concordance between quantitative evaluations and clinician feedback was observed in the majority of cases. The average relative error (ARE) and the absolute error (AE) in TMTV prediction on external multi-centric dataset were ARE = 0.43 ± 0.54 and AE = 157.32 ± 378.12 (mL) for all the external test data (n = 518), and ARE = 0.30 ± 0.22 and AE = 82.05 ± 99.78 (mL) when the 10% outliers (n = 53) were excluded. TMTV-Net demonstrates strong performance and generalizability in TMTV segmentation across multi-site external datasets, encompassing various lymphoma subtypes. A negligible reduction of 2% in overall performance during testing on external data highlights robust model generalizability across different centers and cancer types, likely attributable to its training with resampled inputs. Our model is publicly available, allowing easy multi-site evaluation and generalizability analysis on datasets from different institutions.

The purpose of this study was to determine the prognostic value of metabolic volumetric parameters as a quantitative index on pre-treatment 18F-FDG PET/CT in addition to the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) in patients with diffuse large B-cell lymphoma (DLBCL). A total of 103 consecutive patients with DLBCL and baseline FDG PET/CT were retrospectively evaluated. Quantitative metabolic parameters, including total metabolic tumour volume (TMTV) using a standardized uptake value (SUV) of ≥2.5 as the threshold, were estimated. Receiver operating characteristic curve analysis was used to determine the optimal cut-off values for the metabolic parameters. The relationships between study variables and patient survival were tested using Cox regression analysis. Patient survival rates were derived from Kaplan-Meier curves and compared using the log-rank test. Median follow-up was 34months. In patients with a low TMTV (<249cm3), the 3-year progression free survival (PFS) rate was 83% and the overall survival (OS) rate was 92%, in contrast to 41% and 57%, respectively, in those with a high TMTV (≥249cm3). In univariate analysis, a high TMTV and NCCN-IPI ≥4 were associated with inferior PFS and OS (P < 0.0001 for all), as was a high total lesion glycolysis (P= 0.004 and P= 0.005, respectively). In multivariate analysis, TMTV and NCCN-IPI were independent predictors of PFS (hazard ratio, HR, 3.11, 95% confidence interval, CI, 1.37-7.07, P= 0.007, and HR 3.42, 95% CI 1.36-8.59, P= 0.009, respectively) and OS (HR 3.41, 95% CI 1.24-9.38, P= 0.017, and HR 5.06, 95% CI 1.46-17.60, P= 0.014, respectively). TMTV was able to separate patients with a high-risk NCCN-IPI of ≥4 (n= 62) into two groups with significantly different outcomes; patients with low TMTV (n= 16) had a 3-year PFS rate of 75% and an OS rate of 88%, while those with a high TMTV had a 3-year PFS rate of 32% and an OS rate of 47% (χ2= 7.92, P= 0.005, and χ2= 8.26, P= 0.004, respectively). However, regardless of TMTV, patients with a low-risk NCCN-IPI of <4 (n= 41) had excellent outcomes (3-year PFS and OS rates of 85% and 95%, respectively). Pretreatment TMTV was an independent predictor of survival in patients with DLBCL. Importantly, TMTV had an additive prognostic value in patients with a high-risk NCCN-IPI. Thus, the combination of baseline TMTV with NCCN-IPI may improve the prognostication and may be helpful guide the decision for intensive therapy and clinical trials, especially in DLBCL patients with a high-risk NCCN-IPI.

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

A Comparative Analysis of Individual Readers and an Autonomous Deep-Learning-Based Algorithm for Assessing Total Metabolic Tumor Volume from Positron Emission Tomography/Computed Tomography Scans

The total metabolic tumor volume (TMTV) measured from fluorine-18 fluorodeoxyglucose (18F-FDG) PET can be useful for determining the prognosis of patients with lymphoma. Stratifying patients into high- and low-TMTV risk groups requires a cutoff point, which is determined through the dichotomization method. This study investigated whether different TMTV dichotomization methods influenced survival prediction in patients with lymphoma. We retrospectively enrolled 129 patients with lymphoma who had undergone baseline 18F-FDG PET. TMTV was calculated using a fixed standardized uptake value threshold of 4.0. A total of six methods were employed to determine the optimal TMTV cutoff point using receiver-operating characteristic curve analyses, X-Tile bioinformatics software, and the Cutoff Finder web application. The prognostic performance of each method in survival prediction was examined. The median (interquartile range) TMTV was 123 cm3 (21-335 cm3). The optimal TMTV cutoff values for predicting progression-free survival (PFS) and overall survival (OS) were in the range of 144-748 cm3. The cutoff points were used to dichotomize patients into two groups with distinct prognoses. All TMTV dichotomizations were significantly predictive of PFS and OS. The survival curves showed significant differences between the high- and low-TMTV groups. The C-indices of the survival models did not significantly differ in any of the dichotomizations. The prognostic significance of TMTV was maintained regardless of the methodological aspects of dichotomization. However, the optimal TMTV cutoff point varied according to the chosen dichotomization method. Care should be taken when establishing an optimal TMTV cutoff point for clinical use.

Interim PET-Adapted De-Escalation Chemotherapy Regimen for Advanced Stage Classical Hodgkin Lymphoma Using Brentuximab Vedotin, Pembrolizumab, Doxorubicin, and Dacarbazine: Phase 2 Safety and Efficacy Study