Josee M. Zijlstra

The Lugano Imaging Committee recently refined the Deauville Score (DS), subdividing DS5 into DS5a (>2x liver uptake without new lesions) and DS5b (new lesions). We investigated whether this improves prognostic discrimination at interim positron emission tomography after two cycles (PET-2) in patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) treated in recent GHSG randomized phase III trials. The primary analysis cohort was HD18 post-amendment standard arms (uniform treatment with six cycles of eBEACOPP); sensitivity cohorts were HD18 intention-to-treat, and HD21 eBEACOPP and BrECADD arms. Progression-free survival (PFS) was analyzed by landmark Cox models starting at PET2. DS5a was infrequent (4-6% across cohorts: 39/639; 67/1745; 33/568; 29/560). In the primary cohort, DS5 vs DS1-3 was associated with inferior PFS (hazard ratio [HR] 3.00, 95% confidence interval [CI] 1.25-7.23) and vs DS1-4 (HR 2.35, 95% CI 1.01-5.50). Across sensitivity cohorts, DS5a remained adverse compared with DS1-4 (HR range 2.57-5.47), while DS4 according to the new definition did not consistently separate from DS1-3, which is likely a result of PET-adapted treatment. Overall survival trends were concordant, but interpretation is limited by few events. To our knowledge, this is the first prognostic validation of the refined DS in prospectively randomized trial populations. The newly introduced DS5a isolates a small high-risk AS-cHL, which further supports risk assessment and adaptation using quantitative biomarkers from PET. HD18 NCT00515554; HD21 NCT02661503

Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient’s individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor DNA (ctDNA) sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling time points, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista, a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma, to samples obtained from the German Hodgkin Study Group (GHSG) HD21 trial after 2 cycles of treatment (MRD-2) using a case-cohort design. Patients with positive MRD-2 result were at higher risk for relapse, progression, or death compared with MRD-2–negative patients (4-year progression-free survival [PFS], 36.7% vs 82.2%; hazard ratio, 5.3; 95% confidence interval, 2.0-13.8; P = .0008). After inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 results had 4-year PFS rates of 72.2% vs 95.3%. Combining MRD-2 with positron emission tomography after 2 cycles of BrECADD/eBEACOPP (PET-2) can identify patients at very low and patients at very high risk of relapse, progression, or death. In summary, these results suggest that MRD-2 assessment by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.

Large-axial field of view (LAFOV) PET/CT systems have improved whole-body dynamic 18F-FDG imaging, enabling improved quantitative assessment of tracer kine

Background: Few studies examined treatment-specific long-term risks of cardiovascular diseases (CVD) in diffuse large B-cell lymphoma survivors treated with potentially cardiotoxic radiotherapy and/or chemotherapy with or without rituximab after the 1990s. Methods: Long-term CVD risk was examined in a multicenter cohort comprising 2356 diffuse large B-cell lymphoma survivors who survived at least 5 years and who were treated at ages 15-61 years in 1989-2012. CVD data were acquired from medical records, general practitioners, and disease registries. Observed CVD numbers were compared with expected CVD incidence in the Dutch population to estimate standardized incidence ratios (SIRs) and absolute excess risks (10 000 person-years). Treatment-specific CVD risks were assessed using multivariable Cox regression. Results: During a median follow-up of 14.2 years (IQR = 10.1-18.9 years), 312 survivors were diagnosed with a first CVD at least 5 years after treatment. Compared with the general population, diffuse large B-cell lymphoma survivors had increased risks of heart failure ([HF]; SIR = 3.9, 95% confidence interval [CI] = 3.4 to 4.6; absolute excess risk = 62.8) and cerebrovascular accident (SIR = 1.3, 95% CI = 1.0 to 1.7; absolute excess risk = 9.8), while risk of coronary artery disease was decreased (SIR = 0.7, 95% CI = 0.5 to 0.9; absolute excess risk = −30.9). HF risk was higher among females (SIR = 5.3, 95% CI = 4.2 to 6.5) than males (SIR = 3.2, 95% CI = 2.6 to 4.0, P for heterogeneity < .001), and among survivors aged 40 years and younger at diffuse large B-cell lymphoma treatment (SIR = 10.5, 95% CI = 7.2 to 14.8; P for trend < .001). Exposure to more than 300 mg/m2 doxorubicin was associated with a 2.8-fold (95% CI = 1.7 to 4.5) increased risk of cardiomyopathy or HF, while radiotherapy involving the heart was associated with a 1.9-fold (95% CI = 1.1 to 3.1) increased risk of valvular heart disease. Conclusion: Those surviving at least 5 years after diffuse large B-cell lymphoma have increased risks of developing CVDs, especially HF. Physicians and patients should recognize this risk, and individualized cardiac screening should be considered.

Background: Patients with Hodgkin lymphoma are at increased risk of developing lung cancer, especially after chest radiation therapy. No tools are currently available, however, to predict lung cancer risk for different Hodgkin lymphoma treatments. Methods: In a cohort of 5370 individuals who had survived Hodgkin lymphoma for at least 5 years, were 15 to 50 years of age at the time of Hodgkin lymphoma diagnosis, and who were treated in the Netherlands between 1965 and 2012, we used radiation therapy fields and prescribed dose to estimate mean lung dose. The twinning method was used to divide the cohort into homogenous parts: 80% for model development and 20% for validation using inverse probability of censoring weighting area under the curve. Cox proportional hazards models allowing for time-dependent coefficients were used to model time from Hodgkin lymphoma diagnosis to lung cancer and lung cancer–free death as the competing event for predicting absolute lung cancer risk up to 30 years after Hodgkin lymphoma diagnosis. Results: Treatment information consisted of supradiaphragmatic radiation therapy in 75.2% of patients with a mean lung dose of 15.8 Gy. During follow-up, 218 survivors developed lung cancer. Older age, male sex, smoking at the time of Hodgkin lymphoma diagnosis, and higher mean lung dose were associated with higher lung cancer risk. The median Inter Quartile Range (IQR) estimated 30-year absolute lung cancer risk in our cohort was 1.2% (0.8%-1.9%) in nonsmokers and 6.9% (4.6%-10.9%) in smokers at the time of Hodgkin lymphoma diagnosis. The 20-year and 30-year inverse probability of censoring weighting areas under the curve values were 0.79 (95% Confidence Interval (CI) = 0.73 to 0.85) and 0.75 (95% CI = 0.69 to 0.81), respectively. Conclusion: We developed a well-calibrated prediction tool that estimates long-term risk of lung cancer with good discrimination based on patient characteristics and mean lung dose, allowing application in Hodgkin lymphoma survivors and contemporary patients with Hodgkin lymphoma.

Purpose: SUV4.0-based thresholding is widely used for baseline [¹⁸F]FDG PET-based metabolic tumor volume (MTV) assessment in diffuse large B-cell lymphoma (DLBCL), but its suitability at interim and end-of-treatment (EoT) PET, when residual uptake is heterogeneous and tumor-to-background contrast is lower, is uncertain. We aimed to define a lesion-adaptive decision rule approach for selecting the optimal segmentation method based on lesion-level features and treatment phase and, exploratorily, to compare its performance with ML-based selection models. Methods: A total of 598 lesions from 33 DLBCL patients (HOVON-84 trial) were segmented at baseline, interim, and EoT [¹⁸F]FDG PET/CT using six semi-automated methods: SUV2.5, SUV4.0, 41%max, A50peak, MV2, and MV3. Segmentation quality was independently rated for each lesion by two observers (scale 1–5; 3 = preferred), with adjudication by a third reviewer. The influence of lesional SUVpeak, tumor-to-background ratio (TBRpeak), background uptake (SUVbg), treatment phase, and location on segmentation quality was assessed. Over six million rule-based combinations of key features were evaluated to derive a lesion-adaptive decision rule for preferred method selection. Exploratorily, ML classifiers were trained and compared with the decision-rule strategy. Results: Segmentation quality varied across lesions and methods. SUVpeak, TBRpeak, and SUVbg were key predictors of method performance. The final lesion-adaptive rule, applying SUV4.0 if SUVpeak > 8, MV3 if SUVbg > 0.8, and otherwise MV2, achieved a lesion-wise accuracy of 0.82 for preferred method selection, matching the best-performing ML models. Versus SUV4.0 alone (benchmark), the Decision Rule improved lesion-level MTV agreement with the reference (ρ = 0.85 vs. 0.82 vs. best ML ρ = 0.81) and reduced the proportion of lesions with > 10% MTV deviation (46.2% vs. 63.5%; best ML 50.2%). Total-MTV agreements with the reference were uniformly high across all strategies (all ρ ≥ 0.94), with modest gains for the decision rule at interim and EoT PET. Conclusion: A straightforward decision-rule approach using SUVpeak and SUVbg successfully selects the preferred method for individual DLBCL lesions across treatment phases and matches ML performance with greater simplicity and clinical applicability. Although supervision remains necessary, this approach helps address the current gap in segmentation methodology for interim and EoT PET, where SUV4.0 may not always be appropriate. Graphical

Background/Objectives: There is a need for prediction models which enable weighing benefits against risks of different treatment strategies for individual Hodgkin lymphoma (HL) patients. Therefore, we aimed to predict absolute risk of progression, first relapse or death (PRD) with and without incorporating HL treatment. Methods: The prognostic and treatment information of 2343 patients treated for classical HL at ages 15–60 years between 2008 and 2018 in the Netherlands was used to predict absolute risk of PRD up to 5 years after diagnosis using Cox proportional hazard models allowing for time-varying coefficients. Models were externally validated in 1675 patients treated for classical HL in Denmark between 2000 and 2018. Results: In early stages, gender, leukocyte, and lymphocyte counts were associated with risk of PRD. Additionally, receiving >4 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or ABVD plus radiotherapy predicted lower risk of relapse compared with receiving ≤4 cycles of ABVD. In advanced stages, age, albumin and leukocyte counts predicted PRD risk. Receiving (escalated) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) predicted lower PRD risk compared to ABVD. In Danish patients treated between 2008 and 2018, adding treatment information improved 5-year Inverse Probability of Censoring Weighted (IPCW) Area Under the Curve (AUC) values from 0.63 (95% Confidence Interval (CI): 0.55–0.72) to 0.71 (95% CI: 0.63–0.79) in early stages (p-value = 0.04) and from 0.59 (95% CI: 0.52–0.65) to 0.62 (95% CI: 0.55–0.68) in advanced stages (p-value = 0.33). Conclusions: We developed well calibrated models with reasonable discrimination, not only incorporating pre-treatment prognostic factors but also treatment effect enabling the prediction of absolute risk of first relapse/progression.

Purpose: Diffuse large B-cell lymphoma (DLBCL) patients often experience relapse or progression after treatment, emphasizing the need for better prognostic markers. This study investigated baseline FDG uptake and volume of healthy tissues and tumours, to assess their association with time-to-progression (TTP) in DLBCL. Methods: This study included 259 newly diagnosed DLBCL patients. Outcome was two-year TTP after treatment initiation. Automatic segmentation of tissues was performed on the low dose CT scans. Tumour lesions were outlined with a semi-automated segmentation method (standardised uptake value ≥ 4) and subtracted from the tissues. Mean standardised uptake value (SUVmean), tissue-to-blood SUVmean ratio, volume, and total lesion glycolysis (TLG) were determined for the spleen, liver, kidneys, lungs, and brain. Only SUVmean and SUVmean ratio were assessed for fat, bone, and skeletal muscle. Intercorrelations among all tissues and correlations with tumour TLG were calculated. Volume and uptake measures were compared between patients with and without progression using the Wilcoxon signed-rank test. Any measure significantly associated with two-year TTP was added to an existing logistic regression model based on baseline tumour characteristics to assess its added prognostic value. Results: Patients with progression showed a significantly higher spleen-to-blood SUVmean ratio, lower SUVmean and TLG in the brain, lower SUVmean in skeletal muscle, and a larger liver volume. Liver volume and spleen-to-blood SUVmean ratio did not significantly improve the prediction of two-year TTP compared to the original model only based on tumour characteristics. Conclusion: Healthy tissue PET/CT measures were significantly associated with two-year TTP in DLBCL patients. However, these measures did not improve the prediction of two-year TTP compared to models using only tumour characteristics. Trial registration number and date of registration: HOVON-84: EudraCT: 2006-005, 174 − 42, retrospectively registered 01-08-2008.