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IntroductionClassical Hodgkin lymphoma (cHL) is the most common pediatric lymphoma. Approximately 10% of patients develop refractory or recurrent disease. These patients are treated with intensive chemotherapy followed by consolidation with radiotherapy or high-dose chemotherapy and autologous stem cell reinfusion. Although this treatment is effective, it comes at the cost of severe long-term adverse events, such as reduced fertility and an increased risk of secondary cancers. Recently, promising results of inducing remission with the immune checkpoint inhibitor nivolumab (targeting PD-1) and the anti-CD30 antibody-drug conjugate Brentuximab vedotin (BV) +/- bendamustine were published.MethodsHere we describe a cohort of 10 relapsed and refractory pediatric cHL patients treated with nivolumab + BV +/- bendamustine to induce remission prior to consolidation with standard treatment.Results and discussionAll patients achieved complete remission prior to consolidation treatment and are in ongoing complete remission with a median follow-up of 25 months (range: 12 to 42 months) after end-of-treatment. Only one adverse event of CTCAE grade 3 or higher due to nivolumab + BV was identified. Based on these results we conclude that immunotherapy with nivolumab + BV +/- bendamustine is an effective and safe treatment to induce remission in pediatric R/R cHL patients prior to standard consolidation treatment. We propose to evaluate this treatment further to study putative long-term toxicity and the possibility to reduce the intensity of consolidation treatment.

Background Interim FDG-PET is used for treatment tailoring in lymphoma. Deauville response criteria consist of five ordinal categories based on visual comparison of residual tumor uptake to physiological reference uptakes. However, PET-response is a continuum and visual assessments can be distorted by optical illusions. Objectives With a novel semi-automatic quantification tool we eliminate optical illusions and extend the Deauville score to a continuous scale. Patients and methods SUV peak of residual tumors and average uptake of the liver is measured with standardized volumes of interest. The qPET value is the quotient of these measurements. Deauville scores and qPET-values were determined in 898 pediatric Hodgkin’s lymphoma patients after two OEPA chemotherapy cycles. Results Deauville categories translate to thresholds on the qPET scale: Categories 3, 4, 5 correspond to qPET values of 0.95, 1.3 and 2.0, respectively. The distribution of qPET values is unimodal with a peak representing metabolically normal responses and a tail of clearly abnormal outliers. In our patients, the peak is at qPET = 0.95 coinciding with the border between Deauville 2 and 3. qPET cut values of 1.3 or 2 (determined by fitting mixture models) select abnormal metabolic responses with high sensitivity, respectively, specificity. Conclusions qPET methodology provides semi-automatic quantification for interim FDG-PET response in lymphoma extending ordinal Deauville scoring to a continuous scale. Deauville categories correspond to certain qPET cut values. Thresholds between normal and abnormal response can be derived from the qPET-distribution without need for follow-up data. In our patients, qPET < 1.3 excludes abnormal response with high sensitivity.

Objectives To assess the concordance of whole-body MRI (WB-MRI) and an FDG-PET/CT-based reference standard for the initial staging in children with Hodgkin lymphoma (HL) Methods Children with newly diagnosed HL were included in this prospective, multicentre, international study and underwent WB-MRI and FDG-PET/CT at staging. Two radiologists and a nuclear medicine physician independently evaluated all images. Discrepancies between WB-MRI and FDG-PET/CT were assessed by an expert panel. All FDG-PET/CT errors were corrected to derive the FDG-PET/CT-based reference standard. The expert panel corrected all reader errors in the WB-MRI DWI dataset to form the intrinsic MRI data. Inter-observer agreement for WB-MRI DWI was calculated using overall agreement, specific agreements and kappa statistics. Concordance for correct classification of all disease sites and disease stage between WB-MRI (without DWI, with DWI and intrinsic WB-MRI DWI) and the reference standard was calculated as primary outcome. Secondary outcomes included positive predictive value, negative predictive value and kappa statistics. Clustering within patients was accounted for using a mixed-effect logistic regression model with random intercepts and a multilevel kappa analysis. Results Sixty-eight children were included. Inter-observer agreement between WB-MRI DWI readers was good for disease stage ( κ = 0.74). WB-MRI DWI agreed with the FDG-PET/CT-based reference standard for determining disease stage in 96% of the patients versus 88% for WB-MRI without DWI. Agreement between WB-MRI DWI and the reference standard was excellent for both nodal (98%) and extra-nodal (100%) staging. Conclusions WB-MRI DWI showed excellent agreement with the FDG-PET/CT-based reference standard. The addition of DWI to the WB-MRI protocol improved the staging agreement. Key Points • This study showed excellent agreement between WB-MRI DWI and an FDG-PET/CT-based reference standard for staging paediatric HL. • Diffusion-weighted imaging is a useful addition to WB-MRI in staging paediatric HL. • Inter-observer agreement for WB-MRI DWI was good for both nodal and extra-nodal staging and determining disease stage.

Objectives To compare WB-MRI with an [ 18 F]FDG-PET/CT-based reference for early response assessment and restaging in children with Hodgkin’s lymphoma (HL). Methods Fifty-one children (ages 10–17) with HL were included in this prospective, multicentre study. All participants underwent WB-MRI and [ 18 F]FDG-PET/CT at early response assessment. Thirteen of the 51 patients also underwent both WB-MRI and [ 18 F]FDG-PET/CT at restaging. Two radiologists independently evaluated all WB-MR images in two separate readings: without and with DWI. The [ 18 F]FDG-PET/CT examinations were evaluated by a nuclear medicine physician. An expert panel assessed all discrepancies between WB-MRI and [ 18 F]FDG-PET/CT to derive the [ 18 F]FDG-PET/CT-based reference standard. Inter-observer agreement for WB-MRI was calculated using kappa statistics. Concordance, PPV, NPV, sensitivity and specificity for a correct assessment of the response between WB-MRI and the reference standard were calculated for both nodal and extra-nodal disease presence and total response evaluation. Results Inter-observer agreement of WB-MRI including DWI between both readers was moderate ( κ 0.46–0.60). For early response assessment, WB-MRI DWI agreed with the reference standard in 33/51 patients (65%, 95% CI 51–77%) versus 15/51 (29%, 95% CI 19–43%) for WB-MRI without DWI. For restaging, WB-MRI including DWI agreed with the reference standard in 9/13 patients (69%, 95% CI 42–87%) versus 5/13 patients (38%, 95% CI 18–64%) for WB-MRI without DWI. Conclusions The addition of DWI to the WB-MRI protocol in early response assessment and restaging of paediatric HL improved agreement with the [ 18 F]FDG-PET/CT-based reference standard. However, WB-MRI remained discordant in 30% of the patients compared to standard imaging for assessing residual disease presence. Key Points • Inter-observer agreement of WB-MRI including DWI between both readers was moderate for (early) response assessment of paediatric Hodgkin’s lymphoma. • The addition of DWI to the WB-MRI protocol in early response assessment and restaging of paediatric Hodgkin’s lymphoma improved agreement with the [18F]FDG-PET/CT-based reference standard. • WB-MRI including DWI agreed with the reference standard in respectively 65% and 69% of the patients for early response assessment and restaging.

Immunohistochemical markers are associated with treatment outcome in adults with classical Hodgkin Lymphoma (cHL). Studies in children are scarce and inconsistent. We investigated in 67 children with cHL, whether the expression of CD15, CD30, PAX5, PD-1, PD-L1, CD68, CD163 and TARC at diagnosis is associated with disease free survival (DFS) and with interim remission status. Low CD15 and low TARC expression were associated with relapsed disease. Low expression of PD-L1 was associated with complete remission at interim PET-scan. Our data suggest a difference between pediatric and adult cHL. This underlines the importance of future research into specific prognostic factors in pediatric cHL, indispensable for improvement of treatment in this population.

Twenty percent of children with T‐cell lymphoblastic lymphoma (T‐LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low‐risk subgroup in pediatric T‐LBL, yet these high‐risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high‐risk T‐LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T‐LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high‐risk biological subgroup of children with T‐LBL. This subgroup is characterized by NOTCH1 gene fusions, found in 21% of our T‐LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C‐C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with NOTCH1 gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T‐cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy‐related acute myeloid leukemia during maintenance therapy. These data indicate that T‐LBL patients with a NOTCH1 fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through NOTCH1 gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.

Purpose The purpose of this study was to determine the most optimal central venous catheter (CVC) for pediatric patients with Hodgkin lymphoma (HL) in terms of complications. Methods A retrospective study including patients diagnosed with HL from 2015 to 2021 at the Princess Máxima Center was performed. Patients were followed from CVC insertion until removal or 06–2021, whichever came first. The primary outcome was the CVC-related complication incidence rate (IR) per 1000 CVC-days. Furthermore, the incidence rate ratio (IRR) was calculated by comparing complication IRs between peripherally inserted central catheters (PICC) and totally implantable venous access ports (TIVAP). Additionally, risk factors for central venous thrombosis (CVT) were identified. Results A total of 98 patients were included. The most frequently observed complications were local irritation/infections (18%; IR 0.93), malfunctions (15%; IR 0.88), and CVC-related CVTs (10%; IR 0.52). Single lumen PICCs were associated with a higher risk of complications (49% vs. 26%; IRR 5.12, CI 95% 2.76–9.50), severe complications (19% vs. 7%; IRR 11.96, CI 95% 2.68–53.42), and early removal (18% vs. 7%; IRR 9.96, CI 95% 2.18–45.47). A single lumen PICC was identified as a risk factor for CVC-related CVT when compared to TIVAPs (12% vs. 7%, IRR 6.98, CI 95% 1.45–33.57). Conclusion The insertion of a TIVAP rather than a PICC should be recommended for pediatric patients with HL, especially in the presence of CVT-related risk factors. Future trials should evaluate the efficacy and safety of direct oral anticoagulants for the primary prevention of CVT in pediatric patients with a PICC and other CVT-related risk factors.

While cervical lymphadenopathy is common in children, a decision model for detecting high-grade lymphoma is lacking. Previously reported individual lymphoma-predicting factors and multivariate models were not sufficiently discriminative for clinical application. To develop a diagnostic scoring tool, we collected data from all children with cervical lymphadenopathy referred to our national pediatric oncology center within 30 months (n = 182). Thirty-nine putative lymphoma-predictive factors were investigated. The outcome groups were classical Hodgkin lymphoma (cHL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), non-Hodgkin lymphoma (NHL), other malignancies, and a benign group. We integrated the best univariate predicting factors into a multivariate, machine learning model. Logistic regression allocated each variable a weighing factor. The model was tested in a different patient cohort (n = 60). We report a 12-factor diagnostic model with a sensitivity of 95% (95% CI 89–98%) and a specificity of 88% (95% CI 77–94%) for detecting cHL and NHL. Our 12-factor diagnostic scoring model is highly sensitive and specific in detecting high-grade lymphomas in children with cervical lymphadenopathy. It may enable fast referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals and unnecessary invasive procedures in children with benign lymphadenopathy.

To compare WB-MRI with an [18F]FDG-PET/CT-based reference for early response assessment and restaging in children with Hodgkin's lymphoma (HL).OBJECTIVESTo compare WB-MRI with an [18F]FDG-PET/CT-based reference for early response assessment and restaging in children with Hodgkin's lymphoma (HL).Fifty-one children (ages 10-17) with HL were included in this prospective, multicentre study. All participants underwent WB-MRI and [18F]FDG-PET/CT at early response assessment. Thirteen of the 51 patients also underwent both WB-MRI and [18F]FDG-PET/CT at restaging. Two radiologists independently evaluated all WB-MR images in two separate readings: without and with DWI. The [18F]FDG-PET/CT examinations were evaluated by a nuclear medicine physician. An expert panel assessed all discrepancies between WB-MRI and [18F]FDG-PET/CT to derive the [18F]FDG-PET/CT-based reference standard. Inter-observer agreement for WB-MRI was calculated using kappa statistics. Concordance, PPV, NPV, sensitivity and specificity for a correct assessment of the response between WB-MRI and the reference standard were calculated for both nodal and extra-nodal disease presence and total response evaluation.METHODSFifty-one children (ages 10-17) with HL were included in this prospective, multicentre study. All participants underwent WB-MRI and [18F]FDG-PET/CT at early response assessment. Thirteen of the 51 patients also underwent both WB-MRI and [18F]FDG-PET/CT at restaging. Two radiologists independently evaluated all WB-MR images in two separate readings: without and with DWI. The [18F]FDG-PET/CT examinations were evaluated by a nuclear medicine physician. An expert panel assessed all discrepancies between WB-MRI and [18F]FDG-PET/CT to derive the [18F]FDG-PET/CT-based reference standard. Inter-observer agreement for WB-MRI was calculated using kappa statistics. Concordance, PPV, NPV, sensitivity and specificity for a correct assessment of the response between WB-MRI and the reference standard were calculated for both nodal and extra-nodal disease presence and total response evaluation.Inter-observer agreement of WB-MRI including DWI between both readers was moderate (κ 0.46-0.60). For early response assessment, WB-MRI DWI agreed with the reference standard in 33/51 patients (65%, 95% CI 51-77%) versus 15/51 (29%, 95% CI 19-43%) for WB-MRI without DWI. For restaging, WB-MRI including DWI agreed with the reference standard in 9/13 patients (69%, 95% CI 42-87%) versus 5/13 patients (38%, 95% CI 18-64%) for WB-MRI without DWI.RESULTSInter-observer agreement of WB-MRI including DWI between both readers was moderate (κ 0.46-0.60). For early response assessment, WB-MRI DWI agreed with the reference standard in 33/51 patients (65%, 95% CI 51-77%) versus 15/51 (29%, 95% CI 19-43%) for WB-MRI without DWI. For restaging, WB-MRI including DWI agreed with the reference standard in 9/13 patients (69%, 95% CI 42-87%) versus 5/13 patients (38%, 95% CI 18-64%) for WB-MRI without DWI.The addition of DWI to the WB-MRI protocol in early response assessment and restaging of paediatric HL improved agreement with the [18F]FDG-PET/CT-based reference standard. However, WB-MRI remained discordant in 30% of the patients compared to standard imaging for assessing residual disease presence.CONCLUSIONSThe addition of DWI to the WB-MRI protocol in early response assessment and restaging of paediatric HL improved agreement with the [18F]FDG-PET/CT-based reference standard. However, WB-MRI remained discordant in 30% of the patients compared to standard imaging for assessing residual disease presence.• Inter-observer agreement of WB-MRI including DWI between both readers was moderate for (early) response assessment of paediatric Hodgkin's lymphoma. • The addition of DWI to the WB-MRI protocol in early response assessment and restaging of paediatric Hodgkin's lymphoma improved agreement with the [18F]FDG-PET/CT-based reference standard. • WB-MRI including DWI agreed with the reference standard in respectively 65% and 69% of the patients for early response assessment and restaging.KEY POINTS• Inter-observer agreement of WB-MRI including DWI between both readers was moderate for (early) response assessment of paediatric Hodgkin's lymphoma. • The addition of DWI to the WB-MRI protocol in early response assessment and restaging of paediatric Hodgkin's lymphoma improved agreement with the [18F]FDG-PET/CT-based reference standard. • WB-MRI including DWI agreed with the reference standard in respectively 65% and 69% of the patients for early response assessment and restaging.