Abstract Hodgkin lymphoma (HL) is a B‐cell‐derived malignancy often affecting young adults. Allocation into risk groups is based on staging with positron emission tomography and computed tomography (PET/CT) and the presence or absence of risk factors. Standard treatment for early‐stage favorable classic HL (cHL) consists of two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), followed by 20 Gy involved‐site radiotherapy (IS‐RT). Two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) or a procarbazine‐free eBEACOPP variant plus two cycles of ABVD, followed by 30 Gy IS‐RT in the case of PET/CT positivity and no further treatment in the case of PET/CT negativity after chemotherapy should be considered in patients with early‐stage unfavorable cHL ≤ 60 years. If a less intensive approach is preferred and in individuals > 60 years, four cycles of A(B)VD followed by 30 Gy IS‐RT can be given. In advanced cHL, brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) for four (in the case of PET/CT negativity after two cycles) or six cycles (in the case of PET/CT positivity after two cycles), followed by PET/CT‐guided 30 Gy IS‐RT should be considered in patients ≤ 60 years. Six cycles of nivolumab and AVD (N‐AVD) followed by PET/CT‐guided 30 Gy IS‐RT represents a less intensive alternative for younger patients and the preferred approach for patients > 60 years. Patients with cHL recurrence should receive checkpoint inhibitor‐containing salvage treatment followed by high‐dose chemotherapy and autologous stem cell transplantation if eligible. Treatment of nodular lymphocyte‐predominant HL differs from cHL in some situations and may contain an anti‐CD20 antibody. This guideline aims at providing recommendations for diagnosis, staging, treatment, and follow‐up of HL.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

AIMS:Cardiac exposure to radiation is associated with an increased risk of cardiovascular morbidity. Radiation therapy technologies have developed to provide target dose coverage with less exposure to adjacent organs. We investigated trends in cardiac exposure among patients treated with curative-intent radiotherapy from a single institution. MATERIALS AND METHODS:A total of 10,215 treatment courses were analyzed from 9,966 patients treated for intrathoracic or breast cancers in 2009-2020. Hearts were redelineated using an artificial intelligence model to ensure consistency. Cardiac doses were extracted in 3D and converted, voxel-by-voxel, to equi-effective doses in 2 Gy fractions (EQD2) using α/β = 2 Gy. The mean heart dose (in EQD2) and volume exposed to 5 and 40 Gy, respectively, were extracted. Time trends were investigated for each diagnosis. RESULTS:Patients with esophageal cancer had the highest mean heart dose (median = 11.67 Gy; IQR = 2.85-18.18), while patients treated for right-sided breast cancer (median = 0.34 Gy; IQR = 0.21-0.51) and lymphoma (median = 0.01 Gy; IQR = 0.00-0.38) had the lowest. A decreasing trend over time was seen most clearly for patients with esophageal and lung cancers (P < .05). For left-sided/bilateral breast cancer, volume exposed to 5 Gy increased over time (P = .032). CONCLUSION:Radiation exposure to the heart decreased significantly in patients treated between 2009 and 2020, likely due to increased awareness of cardiovascular toxicity and technological developments. For left-sided/bilateral breast cancer, V5 increased significantly, possibly related to increased prioritization of target coverage.

BACKGROUND:Intensity-modulated radiation therapy (IMRT) is widely used for lymphoma because a multileaf collimator (MLC) can sculpt dose around irregular targets. Planning, however, is time-consuming and difficult to standardize. Fluence map prediction (FMP) using deep learning (DL) could potentially be used to automate planning, but it has not been evaluated in full-body lymphoma, where prescriptions, organ-at-risk (OAR) sets, and anatomical presentations vary substantially. Here, we evaluate multiple DL configurations to determine whether they can be adapted to lymphoma and generate IMRT plans that are deliverable in a clinical treatment planning system (TPS). PURPOSE:To investigate the feasibility and limitations of DL-based dose and fluence prediction methods in the heterogeneous setting of lymphoma. METHODS:A single-institution lymphoma cohort (571 patients, 619 plans) was replanned from clinical volumetric modulated arc therapy (VMAT) to a consistent 15-field IMRT reference using the Eclipse Scripting API (ESAPI), yielding 9285 beam-level pairs. We implemented a two-stage DL pipeline that first predicts beam-wise dose from CT and planning target volume (PTV), then maps dose to fluence, and finally computes the corresponding dose in the TPS after leaf sequencing. We evaluated several architectural and training variants, from replication-focused models to configurations with a clinical loss based on dose-volume histogram (DVH) aimed at moving beyond simple plan replication. For each configuration, we analysed how these choices influenced predicted dose realism and the quality of the resulting plans. RESULTS:In Stage 1 (dose prediction), replication-focused DL models were numerically inferior to the IMRT and VMAT references, while DVH-driven variants yielded superior target DVHs. After fluence mapping and TPS sequencing, all configurations produced machine-deliverable IMRT plans but with lower target coverage and higher hot spots than the references; fluence was largely preserved by MLC sequencing, indicating that current limitations mainly stem from the predicted dose distributions and the learned dose-to-fluence mapping. CONCLUSIONS:DL-based dose and fluence prediction can generate fast, machine-deliverable IMRT plans for heterogeneous lymphoma that lie in the clinical ballpark, but they remain dosimetrically inferior to manual IMRT and VMAT, highlighting the current limitations of these methods for automated planning in this setting.

The European Group for Blood and Bone Marrow transplantation Practice Harmonization and Guidelines Committee together with the Lymphoma Working Party convened 23 experts in Hodgkin lymphoma, transplantation, and radiation oncology, to develop consensus recommendations on the use of autologous and allogeneic haematopoietic cell transplantation (HCT) in relapsed or refractory Hodgkin lymphoma. Through a structured literature review and a 2-day workshop in Berlin, Germany, on Sept 29 and 30, 2025, the panel established guidance across major clinical decision points. The outcome of this review and workshop include the following recommendations. Salvage therapy should include brentuximab vedotin or checkpoint inhibitors, or both, with metabolic complete response preferred before autologous HCT. BEAM (carmustine, etoposide, cytarabine and melphalan) remains the most commonly used conditioning regimen, and autologous HCT continues to be the standard for chemosensitive relapse. Peri-transplantation radiotherapy could be considered for PET-positive or residual disease. Brentuximab vedotin consolidation is recommended for patients at high-risk. Allogeneic HCT is advised for eligible patients who relapse after autologous HCT, ideally with reduced intensity conditioning and post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Routine maintenance after allogeneic HCT is not recommended; relapse management should be tailored and can involve donor lymphocyte infusion, brentuximab vedotin, checkpoint inhibitors, chemotherapy, radiotherapy, or clinical trial enrolment.

Primary cutaneous lymphomas are highly radiosensitive. X-rays work well for localized cutaneous lymphomas. However, if disseminated in the skin and covering larger areas, as is commonly the case with the most common type, mycosis fungoides, x-ray therapy is not suited because the dose to underlying organs exceeds their tolerance. By contrast, electrons have a limited range of penetration, and are ideal for treating superficial lesions. Techniques have been developed to yield a fairly uniform dose to the entire skin surface and treating to a depth of about 1-1½ cm. Total skin electron beam therapy (TSEBT) is probably the most effective skin directed therapy for widespread primary cutaneous lymphomas. For many years the total dose used for mycosis fungoides was 30-36 Gy, given in small fractions. This treatment could only be repeated once. However, total doses of 10-12 Gy have now been shown to offer excellent response rates, and the treatment can be repeated up to 6 times, offering as much or probably even more palliation than the high-dose treatment. Today, most patients are treated with low-dose TSEBT, the higher doses reserved for patients with more resistant disease. Attempts have been made to use photon therapy for total skin irradiation, e.g., tomotherapy. However, even with the most meticulous of techniques there is too much dose in deeper structures, resulting in bone marrow toxicity even with low-dose treatment. This is never seen with electrons, even with high-dose therapy. Further research into optimizing TSEBT and exploring combinations with systemic treatments is ongoing.

Current epidemiological thinking is that classic Hodgkin lymphoma (cHL) comprises multiple aetiologically distinct disease entities that may in part be defined by either histological subtype or the presence of Epstein-Barr virus (EBV) in the malignant cells, or by both. This study aimed to advance our understanding of epidemiological differences between cHL subtypes, in particular EBV-positive and EBV-negative cHL. We retrospectively collected and EBV-typed 1992 cHL primary tumour tissues from among all 2811 patients diagnosed with incident HL in Denmark in the period 1990 through 2010 'Hodgkin lymphoma in Denmark' [HOLYDAN] project. Based on characteristics of retrieved samples combined with additional information from national registers, we projected nationwide age-, sex-, histology- and EBV-specific cHL incidence rates. The analyses demonstrated age- and sex-dependent variation in histology- and EBV-tumour status-specific cHL incidence rates, details of which yielded new aetiological clues. cHL incidence increased markedly around the age of puberty, irrespective of histological subtype and EBV status. The incidence of all subtypes of cHL increased with age after age 50 years, with the exception of EBV-negative nodular sclerosis cHL in females, which therefore showed a single peak in incidence and was higher than in males among young adults. These results were obtained in a small homogeneous population and might, therefore, only apply to rich, industrialised, Western populations. Nevertheless, we propose that puberty creates an immunological host environment conducive to cHL development irrespective of EBV status and histology, and that age-related decline in immune function facilitates the development of both EBV-positive and EBV-negative cHL.

ABSTRACT Background A previously published failure‐type specific risk model showed good performance in the original cohort. Aim: to validate the model and separate patients with high‐ and low‐risk loco‐regional failure (LRF). Goal: to identify patients potentially suitable for treatment intensification trials. Methods Validation data: 756 patients from two institutions (different countries). Predictive performance was evaluated by Brier scores and AUCs. Discriminatory performance was compared to Union for International Cancer Control (UICC) staging (versions 7 and 8). Results The model's 3‐year AUC for LRF was 65%, significantly better than UICC7 staging, but no significant difference to UICC8. Model‐based risk stratification and UICC8 both identified high‐risk patient groups with 3‐year LRF ≈30%. The population mean was 18%. Conclusions The model performed well on a group level. UICC8 staging performed equally well. Although developed for the endpoint of OS, an improvement from UICC version 7 to version 8 was evident also for the prediction of LRF.

BACKGROUND AND PURPOSE:During the COVID19 pandemic, shorter radiation therapy (RT) courses were needed to minimize patient exposure, ensure staff safety, and conserve healthcare resources. In response, guidelines were published by the International Lymphoma Radiation Oncology Group (ILROG) to guide treatment of hematologic malignancies patients with hypofractionated radiation therapy (hRT) regimens. However, outcomes for these hypofractionated dose/fractionation regimens in terms of efficacy and toxicity are unknown. MATERIALS AND METHODS:In collaboration with ILROG, we performed a retrospective multinational, multicenter study. We included patients treated from 01 January 2020 to 01 September 2020 with hRT given according to the published ILROG guidelines or hRT given at > 3 Gy per fraction. We abstracted patient and treatment data from institutional databases. CTCAE v5.0 was used to grade toxicity. RESULTS:We included 219 patients from 8 different institutions treated with 255 RT courses. Median RT dose was 12 Gy (range 4-39) in a median of 3 fractions (range 1-13). Median follow up was 232 days, with 151 patients (69 %) alive at last follow up. Response within the RT field was assessed in 210 sites, and 127 sites (60 %) had a confirmed complete response. Maximal toxicities (per site) reported were Grade 1 (n = 48), Grade 2 (n = 25), Grade 3 (n = 3) and Grade 4 (n = 1). Grade 3/4 toxicities included dermatitis, pain, and hematologic toxicity. CONCLUSIONS:Treatment of hematologic malignancies patients with hRT was generally well tolerated with few unexpected toxicities. These data provide guidance for emergencies, and hRT may be useful and could be considered even in routine settings, especially for certain patient subgroups.

Cutaneous T-cell lymphomas (CTCL) are a rare collection of diseases, frequently associated with diagnostic challenges and complex management dilemmas. The multidisciplinary team is vital for accurate clinico-pathological diagnoses and for collaborative therapeutic decisions throughout the management journey, which frequently involves multiple lines of therapy. Radiotherapy (RT) is a highly effective skin-directed therapy for CTCL, commonly delivered as localised fields or as total skin electron beam therapy (TSEBT). Mycosis fungoides (MF) is the most common of the CTCL, and patients typically experience high rates of morbidity and long natural histories of relapse and progression. Patients with MF typically present with incurable disease; in these patients, RT has an established role in symptom- and disease-control, achieving excellent response rates and proven therapeutic benefits. The role of RT continues to evolve, with modern practices favouring lower doses to reduce toxicity risks and allow for re-irradiation. Less commonly, there are situations where RT has an integral role in the potential cure of patients with MF: firstly, in the setting of unilesional MF where localised RT alone may be curative, and secondly, in the setting of preconditioning prior to curative-intent allogeneic hematopoietic stem cell transplant for patients with advanced MF/Sezary syndrome, where conventional-dose TSEBT is indicated as the most effective single agent for maximal debulking of skin disease. Radiotherapy also has an important role in the management of the less common CTCL, including the curative treatment of localised primary cutaneous anaplastic large cell lymphoma. Despite proven efficacy and quality of life benefits, disparity exists in access to RT and TSEBT. World-wide, stronger multidisciplinary collaborations and greater patient advocacy are required to increase access to RT and improve equity of care for our patients with CTCL.

Late cardiac toxicity after radiation therapy and/or systemic therapy with anthracyclines for lymphomas is a serious concern. To estimate the risks with different treatment combinations, reliable estimates of the dose-response relationships are needed. We performed a literature-based regression analysis of long-term cardiac events after lymphoma treatment. The objective was to identify dose-response relationships for anthracycline and radiotherapy regarding congestive heart failure (CHF), ischemic heart disease (IHD), and valvular heart disease (VHD). We included papers published January 2000-December 2022 with data on long term cardiac outcomes in lymphoma patients, radiation doses to the heart, and anthracycline doses. Papers without dose/response information were excluded. We identified six eligible papers including 22,916 patients. The excess relative risk (ERR) of CHF for anthracyclines per 100 mg/m2 (corresponding to 2 cycles of ABVD or CHOP chemotherapy) was 92% (CI: 74%-101%), and for radiotherapy per Gray (Gy) of mean heart dose it was 6.1% (CI: 4.4%-7.6%). Corresponding numbers for the other endpoints were: IHD: No effect of anthracyclines, ERR = 4.4%/Gy (CI: 2.7%-6.1%) and VHD: ERR = 25%/100 mg/m2 (CI: 13%-37%) and ERR = 10%/Gy (CI: 6%-13%). Data agree with a linear no threshold dose-response relationship for related endpoints, that is, there are no "safe" lower doses of either anthracyclines or radiotherapy. Late cardiac toxicity risks for all three endpoints can be assessed in each patient by a combined estimate from the cumulative doses of anthracyclines and radiation to the heart. This estimate can guide future treatment allocation in lymphoma patients.

BACKGROUND:Total body irradiation (TBI) is a pivotal part of conditioning prior to hematopoietic stem cell transplantation (HSCT) for childhood acute lymphoblastic leukemia (ALL), yet evidence is sparse regarding the effect of TBI delivery techniques on acute and late toxicities. DESIGN:In a national cohort of pediatric HSCT-recipients, we compared three TBI schedules; 12 Gray (Gy) delivered as (i) 4 Gy daily fractions from 2008 to 2011 (n = 12); (ii) 2 Gy fractions twice daily with two-dimensional (2D) planning technology from 2012 to 2015 (n = 16); and (iii) 2 Gy twice daily with three-dimensional (3D) planning intensity-modulated radiotherapy (IMRT) from 2016 to 2020 (n = 14). RESULTS:The 5-year event-free survival was 75.0%, 81.3%, and 81.3% in Cohorts 1, 2, and 3, respectively. Acute toxicity assessed as maximum ferritin and C-reactive protein during the first 3 months post HSCT did not differ between cohorts, nor did the time to first hospital discharge (median 28, 32, and 31 days, p = .25). The incidences of acute graft-versus-host disease (GvHD) (66%, 56%, 71%) and chronic GvHD (25%, 31%, 14%) were comparable. Pulmonary function assessed by spirometry did not differ significantly. The 5-year cataract-free survival was 33.3%, 79%, and 100% in Cohorts 1, 2, and 3, respectively. We found a nonsignificant tendency toward more endocrinopathies in Cohort 1 compared to Cohorts 2 and 3. CONCLUSION:The change of modality did not result in more relapses. More fractionation led to improvement with a lower incidence of cataract and a tendency toward fewer endocrinopathies. The effect of 3D-planning-IMRT technology requires further evaluation in larger studies.

PURPOSE Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

SummaryLate toxicities can impact survivorship in patients with classical Hodgkin lymphoma (cHL) with pulmonary toxicity after bleomycin‐containing chemotherapy being a concern. The incidence of pulmonary diseases was examined in this Danish population‐based study. A total of 1474 adult patients with cHL treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, vincristine, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisone) between 2000 and 2018 were included along with 7370 age‐ and sex‐matched comparators from the background population. Median follow‐up was 8.6 years for the patients. Patients with cHL had increased risk of incident pulmonary diseases (HR 2.91 [95% CI 2.30–3.68]), with a 10‐year cumulative risk of 7.4% versus 2.9% for comparators. Excess risks were observed for interstitial lung diseases (HR 15.84 [95% CI 9.35–26.84]) and chronic obstructive pulmonary disease (HR 1.99 [95% CI 1.43–2.76]), with a 10‐year cumulative risk of 4.1% and 3.5% respectively for patients. No excess risk was observed for asthma (HR 0.82 [95% CI 0.43–1.56]). Risk factors for interstitial lung diseases were age ≥60 years, the presence of B‐symptoms and low albumin. These findings document a significant burden of pulmonary diseases among patients with cHL and emphasize the importance of diagnostic work‐up of pulmonary symptoms.