Pieternella Johanna Lugtenburg

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

Epcoritamab is a subcutaneous CD3×CD20 bispecific antibody approved as monotherapy for relapsed/refractory (R/R) follicular lymphoma (FL). We evaluated fixed-duration epcoritamab with rituximab plus lenalidomide (R2) in R/R FL in arm 2 of EPCORE NHL-2 (phase 1b/2). Patients received epcoritamab (2 step-up doses, then 48-mg full doses) for up to 2 years, and R2 for up to 12 cycles (28 days per cycle). The primary end point was overall response rate (ORR) per investigator assessment (Lugano criteria). As of 21 September 2024, 108 patients received ≥1 epcoritamab dose in expansion (median follow-up, 28.2 months). Median age was 65 years; 57% had 1 previous line of therapy. ORR and complete response (CR) rate were 96% and 88%, respectively; CR rates in patients with high-risk features were 90% (primary refractory), 82% (refractory to anti-CD20 and an alkylating agent), and 83% (disease progression within 24 months of first-line therapy). Two-year estimates for remaining in CR, progression-free survival, overall survival, and not starting next antilymphoma therapy were 82%, 76%, 90%, and 84%, respectively. Minimal residual disease negativity was observed in 86% of evaluable patients (clonoSEQ assay). Common treatment-emergent adverse events (TEAEs) included neutropenia (65%), COVID-19 (59%), and cytokine release syndrome (CRS; 51%). Grade ≥3 TEAEs occurred in 87% of patients; 5 had grade 5 TEAEs (all COVID-19). CRS events were mostly low grade (grade 1, 38%; grade 2, 11%; grade 3, 2%), all resolved, and none led to epcoritamab discontinuation. Fixed-duration epcoritamab plus R2 demonstrated deep, durable responses with manageable safety and favorable outcomes in R/R FL, irrespective of risk features. This trial was registered at www.ClinicalTrials.gov as #NCT04663347.

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.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes (complete response [CR] rates with standard salvage therapy gemcitabine plus oxaliplatin [GemOx], ∼30%; median overall survival [OS], 10 to 13 months). Patients with refractory disease fare worse (CR rate with salvage therapy, 7%; median OS, 6 months). Epcoritamab, a CD3×CD20 bispecific antibody approved for R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE NHL-2 trial evaluating epcoritamab plus GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL. Patients received 48 mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given once every 2 weeks for 8 doses. The primary end point was overall response rate (ORR). As of 15 December 2023, 103 patients were enrolled (median follow-up, 13.2 months; median age, 72 years). Patients had challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior chimeric antigen receptor T-cell therapy, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR and CR rate were 85% and 61%, respectively. Median duration of CR and OS were 23.6 and 21.6 months, respectively. Common treatment-emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab plus GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT-ineligible R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT04663347.

Background: Bleomycin is an oncolytic and antibiotic agent used to treat various human cancers because of its antitumor activity. Unfortunately, up to 46% of the patients treated with bleomycin develop drug-induced interstitial lung disease (DIILD) and potentially life-threatening interstitial pulmonary fibrosis. Tools and biomarkers for predicting and detecting DIILD are limited. Therefore, we aimed to evaluate the feasibility of ¹⁸F-FDG PET/CT, PET radiomics, and machine learning in distinguishing DIILD in an explorative pilot study. Methods: Eighteen Hodgkin’s lymphoma (HL) patients, of whom 10 developed DIILD after treatment with bleomycin, were retrospectively included. Five diffuse large B-cell lymphoma (DLBCL) patients were included as a control group since they were not treated with bleomycin. All patients underwent ¹⁸F-FDG PET/CT scans before (baseline) and during treatment (interim). Structural changes were assessed by changes in Hounsfield Units (HUs). The ¹⁸F-FDG PET scans were used to assess metabolic changes by examining the feasibility of 504 radiomics features, including the mean activity of the lungs (SUVmean). A Random Forest (RF) classifier evaluated the identification and prediction of DIILD based on PET radiomics features. Results: HL patients who developed DIILD showed a significant increase in standard SUV metrics (SUVmean; p = 0.012, median increase 37.4%), and in some regional PET radiomics features (texture strength; p = 0.009, median increase 101.6% and zone distance entropy; p = 0.019, median increase 18.5%), while this was not found in HL patients who did not develop DIILD and DLBCL patients. The RF classifier correctly identified DIILD in 72.2% of the patients and predicted the development of DIILD correctly in 50% of the patients. There were no significant differences in HUs over time within all three patient groups. Conclusions: Our explorative longitudinal pilot study suggests that certain regional ¹⁸F-FDG PET radiomics features can effectively identify DIILD in HL patients treated with bleomycin, as significant longitudinal increases were observed in SUVmean, texture strength, and zone distance entropy after the development of DIILD. The metabolic activity of these features did not significantly increase over time in DLBCL patients and HL patients who did not develop DIILD. This indicates that ¹⁸F-FDG PET radiomics, with and without machine learning, might serve as potential biomarkers for detecting DIILD.

PURPOSE: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages. METHODS: We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses. RESULTS: After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m² had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m² doxorubicin ( P_trend = .004). The risk increase associated with doxorubicin (yes v no) was not modified by age at first treatment (hazard ratio [HR]_{age , 1.5 [95% CI, 0.9 to 2.6]; HRage ≥21 years, 1.3 [95% CI, 0.9 to 1.9) or chest RT (HRwithout mantle/axillary field RT, 1.9 [95% CI, 1.06 to 3.3]; HRwith mantle/axillary field RT, 1.2 [95% CI, 0.8 to 1.8]). CONCLUSION: This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.}

The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020–May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.

Emma Elisabeth Geerdes, Müjde Durmaz, Ms, Pieternella J. Lugtenburg, Martine E.D. Chamuleau, Otto Visser, Djamila E. Issa, Rolf E. Brouwer, Eduardus F.M. Posthu