The diagnosis of classic Hodgkin lymphoma is made by detecting characteristic tumor cells in an equally characteristic and even dominant accompanying infiltrate. While the morphological subtype is not relevant to the treatment decision, it is all the more important to rule out "imitators" of Hodgkin lymphoma in the differential diagnosis. These are differential diagnoses that can only be recognized when the clinical context is taken into account and often only show subtle deviations in the immune profile of the neoplastic cells or the accompanying infiltrate. In younger patients, these differential diagnoses include primary infection with Epstein-Barr virus, immunodeficiency-associated lymphoproliferative disorders, and nodular lymphocyte-predominant Hodgkin lymphoma. In addition, in cases of mediastinal manifestation, a distinction must be made between primary mediastinal B‑cell lymphoma and gray zone lymphoma. In older patients, the most important "imitators" of classic Hodgkin lymphoma are T‑cell lymphomas and immunodeficiency-associated lymphoproliferative disorders.

Die Diagnose des klassischen Hodgkin-Lymphoms erfolgt über den Nachweis charakteristischer Tumorzellen in einem ebenso charakteristischen und das histologische Bild sogar dominierenden Begleitinfiltrat. Während die Angabe des morphologischen Subtyps in der Therapieentscheidung keine Rolle spielt, ist es umso wichtiger, Imitatoren eines Hodgkin-Lymphoms differenzialdiagnostisch auszuschließen. Es handelt sich dabei um Differenzialdiagnosen, die nur bei Berücksichtigung des klinischen Kontexts und der oft nur dezenten Abweichungen im Immunprofil der neoplastischen Zellen oder des Begleitinfiltrats erkennbar sind. Bei jüngeren Patientinnen und Patienten sind diese Differenzialdiagnosen vor allem die Primärinfektion mit Epstein-Barr-Virus, immundefizienzassoziierte Lymphoproliferationen und das noduläre lymphozytenprädominante Hodgkin-Lymphom. Zudem müssen bei mediastinaler Manifestation ein primär mediastinales B‑Zell-Lymphom und ein Grauzonenlymphom abgegrenzt werden. Bei älteren Patientinnen und Patienten sind die wichtigsten Imitatoren des klassischen Hodgkin-Lymphoms T‑Zell-Lymphome und immundefizienzassoziierte Lymphoproliferationen.

The R2 (lenalidomide-rituximab) and R2 with bendamustine (R2B) regimens are both feasible in relapsed/refractory follicular lymphoma (R/R FL), but prospective phase II data on R2B are lacking. In this multinational, prospective, randomised, non-comparative trial, patients with R/R FL were randomised 1:1 to R2 (arm A) or R2B (arm B). Patients achieving CT-based partial or complete remission (PR/CR) received rituximab maintenance every 3 months for 2 years. Co-primary endpoints were investigator-assessed CR rates at end-of-induction (EOI) and severe toxicity rates. Between December 2014 and July 2019, 92 patients were randomized. The trial was stopped prematurely due to slow accrual. CR rates at EOI were 11.4% (95% CI [3.8, 24.6%]) for R2 and 15.2% (CI [6.3, 28.9%]) for R2B. With a median follow-up of 74 months, predefined severe toxicities occurred in 3 (6.8%; CI [1.4, 18.7%]) and 6 pts (13.0%, CI [4.9, 26.3%]) in Arm A and Arm B respectively, with 2 pneumonia-related deaths in arm A and no treatment-related deaths in arm B; 43% and 66% experienced any grade 3-4 AE (2%/7% grade 4). At 60 months, in arms A and B event free survival (EFS) was 39.5% (CI [25.1, 53.6%]) and 56.4% (CI [40.1, 69.3%]). Overall survival (OS) was excellent at 72.1% and 86.3%, respectively. R2 and R2B are both effective treatment regimens for R/R FL. While CT-based CR rates were low, treatment with R2B resulted in numerically longer median EFS and OS, but this was associated with higher toxicity.

MIR142 is the most frequently mutated microRNA (miRNA) gene in cancer, with recurrent alterations observed particularly in hematologic malignancies of lymphoid origin. It is expressed at very high levels in blood cells and plays an essential role in the development, differentiation, and maturation of various lymphopoietic and hematopoietic lineages. To gain a deeper understanding of MIR142 mutations, we summarize all data on these mutations, including their frequency in different cancers, their location within the miR-142 precursor, and their functional consequences. We also analyzed MIR142 mutations within a broader genomic context in thousands of cancers, including hundreds of blood neoplasms. Our results show that the most prevalent mutations in the MIR142 gene originate from a clearly distinct hotspot in hematologic malignancies, concentrated mainly within the sequence of the secondary miR-142 precursor. We found substantial differences in mutation frequency and distribution across cancer types. This indicates that MIR142 alterations are not random consequences of an increased mutational load but are likely subject to positive selection, underscoring their biological and clinical significance.

Abstract Mantle cell lymphoma (MCL) is characterized by t(11;14)-driven Cyclin D1 (encoded by CCND1) overexpression and recurrent alterations affecting SOX11, ATM, and TP53. Yet, how these lesions cooperate to drive lymphomagenesis in vivo remains incompletely understood. Here, we established conditional autochthonous genetically engineered mouse models integrating CD19 Cre -mediated B cell–specific overexpression of Ccnd1 and Sox11, and loss of Atm and Trp53 to reflect MCL hallmarks and investigate its evolution. Ccnd1 overexpression led to lymphoproliferative disease with long latency that progressed to systemic lymphoma, supporting a role as an initiating lesion. Additional loss of Atm and Trp53 markedly accelerated disease onset and lymphoma penetrance. Sox11 overexpression alone less frequently resulted in lymphoma, but combination with Ccnd1 overexpression increased disease penetrance and accelerated lymphomagenesis, further indicating cooperative effects. Across genotypes, mice developed systemic lymphoma involving lymphoid and non-lymphoid tissues, including bone marrow, blood, liver, and gastrointestinal tract. Tumors displayed a canonical MCL-like immunophenotype characterized by expansion of CD19+ B cells with aberrant CD5 expression, absence of CD23, and an IgM+, non–class-switched state. Blinded histopathological evaluation by an expert hematopathologist confirmed morphologic and immunophenotypic features consistent with human MCL. B cell receptor sequencing revealed oligo- to monoclonal disease lacking somatic hypermutation and class-switch recombination, consistent with a germinal center–inexperienced origin. Additionally, whole-exome sequencing showed acquired genetic alterations commonly observed in human MCL, including non-synonymous mutations in Trp53 and Map3k14, as well as copy number variations affecting Card11 and Cdkn2a. Transcriptome analyses supported Sox11-associated transcriptional programs and suppression of germinal center–associated genes. Strikingly, primary lymphomas were readily transplantable in mice with high engraftment rates and serial passaging capacity, enabling their use in in vivo functional and therapeutic studies. Together, these findings support that Ccnd1 overexpression initiates a pre–germinal center B cell state that undergoes clonal evolution and is shaped by additional genetic lesions to drive overt lymphoma. These MCL in vivo models provide a basis for studying disease biology and for evaluating therapeutic approaches in genetically defined settings in an immunocompetent environment. Citation Format: Nicolas Moenig, Paul J. Bröckelmann, Claus Moritz. Gräf, Charlotte Bruzeau, Moritz Reese, Arvid Becker, Tim Schlierkamp-Voosen, Wolfram Klapper, Gero Knittel, H. Christian Reinhardt, Melanie Thelen, Ron D. Jachimowicz. Ccnd1 initiates mantle cell lymphoma–like disease and cooperates with Sox11 expression and loss of Atm/Trp53 in autochthonous mouse models [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr IA011.

Abstract Children and adolescents with early-stage nodular lymphocyte–predominant Hodgkin lymphoma (nLPHL) have a 5-year event-free survival (EFS) of ∼77% after complete lymph node resection and ∼89% with anthracycline-containing chemotherapy. We investigated whether those patients can be successfully treated with surgical resection alone or with low-intensity, anthracycline-free CVP (cyclophosphamide, vinblastine, and prednisone) chemotherapy. EuroNet-PHL-LP1 was a prospective phase 3 trial enrolling patients aged <18 years with stage IA/IIA nLPHL. Complete resection led to active surveillance. Patients with unresectable disease received 3 cycles CVP. In CVP cohort 1, treatment cessation required negative 2-deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (18F-FDG PET). An amendment in 2014 omitted PET for end-of-treatment response; computed tomography and/or magnetic resonance imaging alone defined response in CVP cohort 2. The primary endpoint was 5-year EFS, with death, relapse, second malignancy, and PET positivity counting as events; for CVP cohort 2, progression-free survival (PFS) was primary. Among 267 registered patients, 247 were evaluable. Seventy-eight underwent resection only; their 5-year EFS/PFS was 79.5%. Six of 18 patients who relapsed after surgical resection reentered the CVP arm. In CVP cohort 1, 51 of 82 (62%) achieved complete metabolic response (CMR). Five-year EFS was 56.4%, whereas 5-year PFS in the CMR group was 91.3%. In contrast, PFS in 84 patients in CVP cohort 2 was 64.7%. During CVP, 68.3% of patients experienced grade 3 to 4 neutropenia. No treatment-related deaths were reported. Excellent outcomes were achieved after complete resection and with low-intensity, anthracycline-free chemotherapy if in CMR after chemotherapy. This strategy now constitutes the EuroNet-PHL standard of care for early-stage nLPHL. The trial was registered at www.clinicaltrialsregister.eu as EudraCT 2007-004092-19.

Implant-associated lymphomas of the breast are rare. Among breast-implant-associated lymphomas, anaplastic large cell lymphoma (BIA-ALCL) has gained significant attention in recent years and is recognized as a distinct entity. While ALCL is a well-known T-cell lymphoma, there are only a few reports concerning breast-implant-associated B-cell lymphomas. In our report, the lymphoma showed large blasts which were positive for CD20, highly proliferative and associated with Epstein-Barr-Virus. There was no tumor mass present, the cells were seroma associated. BIA-DLCBL has only been known for a few years. They are limited to lymphoma by definition and, unlike DLCBL, BIA-DLCBL is always EBV-positive. A comprehensive evaluation of immunohistochemical markers is crucial for establishing a differential diagnosis between BIA-ALCL and BIA-DLBCL, as overlapping features, particularly CD30 positivity, may lead to misdiagnosis. Other than ALCL, DLCBL typically do not show ALK, CD2, CD3, and other B-cell markers but are positive to CD20, CD5, BCL-2, CD21, CD23, IgD and IgM. This underscores the importance of referring patients to specialized centers to ensure accurate diagnosis and appropriate treatment. The subsequent therapy of BIA-DLCBL should include an en-bloc-resection of the capsule-implant-unit. There is currently no consensus on the optimal therapy for these cases, highlighting the need for further research and expert collaborationWe report on a case of breast-implant-associated diffuse large cell B-cell lymphoma, a review of the literature and a diagnostic algorithm based on the available data in the literature.

Maschinelle Lernverfahren (ML) haben in den letzten Jahren deutlich an Bedeutung gewonnen und sind heute ein fester Bestandteil der biomedizinischen Forschung. Sie unterstützen die Identifikation von Biomarkern und ermöglichen deren Kombination zu Vorhersagemodellen. Anders ausgedrückt: ML erlauben die effiziente Entwicklung von Biomarkersignaturen. In diesem Beitrag wird das Anwendungsspektrum von ML anhand ausgewählter Beispiele aus der Forschung an malignen Lymphomen veranschaulicht.

Prediction of the outcome of large B-cell lymphomas/high-grade B-cell lymphomas (DLBCLs/HGBCLs) is based on clinical parameters and molecular testing, for example, for rearrangements of MYC (MYC-R) and MYC-R in combination with BCL2 and BCL6 translocations (double/triple hit). However, the group of DLBCL/HGBCL with poor outcome is not confined to MYC-R lymphomas, and fluorescence in situ hybridization (FISH) testing for MYC-R misses several high-risk lymphomas. We aimed to understand if artificial intelligence (AI) trained to identify MYC-R will delineate a poor prognostic subgroup. We generated a collection of digital hematoxylin and eosin (H&E)-stained slides of DLBCL/HGBCL (N = 2018) annotated for MYC, BCL2, and BCL6 translocations. A multiple-instance deep learning AI model for the identification of MYC-R alone or as double/triple hit was established using 1035 H&E-stained slides and evaluated on an external test cohort (N = 499). A pretrained tumor tissue classifier improved reliability and interpretability by focusing the model on tumor areas. Our model score reflects a morphological "MYCness" in DLBCL/HGBCL and demonstrates a strong association with overall survival (OS) and progression-free survival (PFS) in the external test cohort. This was confirmed with an additional clinical test cohort (N = 484) without FISH labels. The AI model scores correlate with various molecular features of DLBCL/HGBCL, including BCL2 and MYC gene expression, and the high-grade gene expression signature, but also features of the tumor microenvironment. Multivariate analysis, adjusted for International Prognostic Index (IPI) factors, demonstrated the prognostic significance of our model in identifying high-risk cases for both PFS and OS.

The LP-IPS including four (age, stage, splenic involvement, hemoglobin; 1 point for each factor) and the GHSG score comprising three (sex, albumin, variant histopathological growth pattern (GP); 2 points for sex, 1 point for albumin and variant GP) risk factors represent prognostic tools for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). A comparison of the scores has not been conducted until now. We thus performed an analysis comprising 583 NLPHL patients treated within GHSG studies. In addition to the LP-IPS and the original GHSG score, a modified GHSG score (GP DE replacing GP CDEF as risk factor variant GP) was also investigated. Low-risk vs high-risk groups were defined as 0-1 vs 2-4 points for the LP-IPS and 0-2 vs 3-4 points for the GHSG scores. Regarding progression-free survival (PFS) and overall survival (OS), Cox regression analyses revealed hazard ratios (HR) for the high-risk vs low-risk groups of 2.71 (95%-CI: 1.76-4.18) and 8.24 (95%-CI: 3.7-18.34) for the LP-IPS, 1.59 (95%-CI: 1.04-2.45) and 2.45 (95%-CI: 1.1-5.45) for the original and 1.97 (95%-CI: 1.25-3.09) and 4.15 (95%-CI: 1.86-9.23) for the modified GHSG score. The combination of the LP-IPS and the modified GHSG score (low-risk/low-risk vs high-risk/high-risk) resulted in high HR for the high-risk/high-risk group in terms of both PFS (HR: 3.74; 95%-CI: 2.09-6.7) and OS (HR: 13.52; 95%-CI: 5.03-36.35). Thus, the LP-IPS represents the most reliable standalone risk score for NLPHL. The combination of the LP-IPS and the modified GHSG score may help to further characterize specific risk groups.

IntroductionThe potential risk of eliminating or reducing CD19 expression following CD19-targeted therapies has raised questions about the optimal treatment sequencing strategies for B-cell malignancies. This study assessed CD19 expression and mutational status in samples from patients with relapsed or refractory B-cell malignancies who received tafasitamab, an anti-CD19 monoclonal antibody.MethodsBiopsy and peripheral blood samples were collected from a total of 100 patients with relapsed or refractory B-cell malignancies who received tafasitamab in a clinical trial or a real-world setting. Post-treatment samples collected from 66 patients were available for assessment of CD19 protein expression; six samples were excluded from the analyses as CD19 expression could not be assessed due to lack of residual lymphoma cells. The remaining 60 samples were assessed by either immunohistochemistry (n=46) or flow cytometry (n=14). Next-generation sequencing (NGS) was used to assess CD19 mutational status (n=39) and transcript expression (n=4). CD19 retention in lymphoma cell lines treated with tafasitamab was assessed by immunohistochemistry and flow cytometry.ResultsOf 46 patient samples assessed by immunohistochemistry, 45 (98%) were CD19 positive after tafasitamab treatment. CD19 expression was retained in all 14 samples analyzed by flow cytometry. NGS of 39 samples revealed no somatic CD19 mutations. CD19 expression was transiently masked in lymphoma cells treated with tafasitamab when assessed by flow cytometry; however, expression was detectable by immunohistochemistry at all time points assessed.ConclusionThese data suggest that tafasitamab treatment, even in the most recent line, may not preclude subsequent treatment with other CD19-targeting agents.

Im vorliegenden Artikel wird das aktuelle Verständnis zur Pathogenese des klassischen Hodgkin-Lymphoms vorgestellt. Ein Schwerpunkt liegt auf der Landschaft der somatischen Mutationen in den Hodgkin- und Reed/Sternberg-Tumorzellen des Lymphoms. Aktuelle Studien zu zirkulierender Tumor-DNA im Blutplasma von Hodgkin-Lymphom-Patienten haben dabei zur Identifizierung genetischer Subgruppen des Hodgkin-Lymphoms geführt. Wir beleuchten ebenfalls das komplexe Mikromilieu des Hodgkin-Lymphoms und seine Relevanz für immunologische Therapieansätze, insbesondere mit Checkpointinhibitoren.

Intensive multiagent treatment regimens have substantially improved outcomes in advanced-stage classic Hodgkin lymphoma (cHL). Brentuximab vedotin (BV), etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone (BrECADD) demonstrated the highest efficacy in cHL reported to date in a randomised phase III trial. Cytotoxic agents are conventionally administered during the first 4 days of a 21-day cycle. A total of four cycles are applied to patients with a complete response after two cycles, otherwise six cycles. We developed a condensed BrECADD protocol, reducing intravenous administration days to only three (-25%). Between January 2024 and July 2026, 30 patients received 132 cycles of 3-day BrECADD at our institution. Primary objective was to describe feasibility and safety; secondary objectives included response, progression-free survival (PFS) and overall survival (OS). Grade ≥3 adverse events occurred in 23 patients (77%), predominantly haematological. Six patients (20%) had grade ≥3 infections (four viral, two bacterial) and six (20%) had pathogen-unspecified febrile neutropenia. Twenty-four patients (80%) required only four BrECADD cycles. There were no treatment discontinuations. After a median follow-up of 18 months (range 4-29), 1-year PFS and OS rates were both 100%. Based on these encouraging results, the condensed 3-day protocol is considered feasible and we recommend it for future BrECADD use.

BACKGROUND:Adding ibrutinib to standard, first-line immunochemotherapy improves failure-free survival in adult patients aged 18-65 years with mantle cell lymphoma, according to the first results from the TRIANGLE trial. With prolonged follow-up, we investigated whether the addition of autologous stem-cell transplantation (ASCT) to an ibrutinib-containing regimen improves failure-free survival, and evaluated effects on overall survival. METHODS:We conducted a three-arm, randomised, open-label, phase 3 superiority trial (TRIANGLE) in 165 secondary or tertiary clinical centres, with experience in mantle cell lymphoma treatment and the capability to perform ASCT or an association with such a centre, in 13 European countries and Israel. Patients aged 18-65 years with untreated, stage II-IV mantle cell lymphoma and suitable for ASCT were randomly assigned (1:1:1) to control group A or experimental groups A + I or I. Randomisation was done using computer-generated random numbers and stratified by study groups and Mantle Cell Lymphoma International Prognostic Index risk groups. Treatment in group A consisted of six alternating, 21-day cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1·4 mg/m2 on day 1 [up to a maximum of 2 mg], and oral prednisone 100 mg on days 1-5) and R-DHAP or R-DHAOx (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, high-dose intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, plus either intravenous cisplatin 100 mg/m2 over 24 h on day 1 [R-DHAP] or intravenous oxaliplatin 130 mg/m2 on day 1 [R-DHAOx]), followed by ASCT. In group A + I, oral ibrutinib (560 mg daily) was added on days 1-19 of R-CHOP cycles and as 2-year maintenance after ASCT. In group I, ibrutinib was given the same way, but ASCT was omitted. Rituximab maintenance was allowed in all treatment groups according to national guidelines. Three pairwise, one-sided, log-rank tests for the primary outcome (failure-free survival) were statistically monitored. The primary analysis was by intention to treat and included all randomly assigned patients, ignoring protocol deviations. Safety was assessed in randomly assigned patients who started any trial treatment component of the respective treatment phase. The trial is registered with ClinicalTrials.gov (NCT02858258) and is complete. FINDINGS:Between July 29, 2016, and Dec 28, 2020, 870 patients (662 [76%] were male, 208 [24%] were female) were randomly assigned to group A (n=288), group A + I (n=292), or group I (n=290). After median follow-up of 54·9 months (95% CI 54·4-56·0), group A + I did not show superiority over group I, with 4-year failure-free survival of 82% (95% CI 78-87) versus 81% (76-86; hazard ratio [HR] 0·86 [one-sided 98·33% CI 0·00-1·27]; one-sided p=0·21). Group A + I remained superior to group A (82% [78-87] vs 70% [65-76]; HR 0·63 [one-sided 98·33% CI 0·00-0·89]; one-sided p=0·0026) and, as before, group A did not show superiority over group I (70% [65-76] vs 81% [76-86]; HR 1·45 [one-sided 98·33% CI 0·00-2·02]; one-sided p=0·99). 4-year overall survival was 88% (95% CI 84-92) in group A + I versus 81% (76-85) in group A (HR 0·59 [95% CI 0·38-0·92], p=0·0036) and 90% (87-94) in group I versus 81% (76-85) in group A (0·57 [0·36-0·90], p=0·0019). During maintenance or follow-up, the most common grade 3-5 adverse events were haematological disorders, reported in 127 (54%) of 234 patients in group A + I versus 74 (28%) of 269 in group I and 56 (23%) of 240 patients in group A, and infections, reported in 80 (34%) of 234 patients in group A + I versus 71 (26%) of 269 in group I and 37 (15%) of 240 patients in group A. Infections and infestations were the most common fatal adverse events during maintenance or follow-up, occurring in four (2%) of 234 patients in group A + I and five (2%) of 269 patients in group I. INTERPRETATION:After a prolonged follow-up of 55 months, both ibrutinib-containing groups showed relevant improvements not only in failure-free survival-a modified form of progression-free survival-but also in overall survival. In contrast, the addition of ASCT to an ibrutinib-containing regimen had no supplementary benefit but increased toxicity. Induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx), followed by 2 years of maintenance treatment with ibrutinib, should be considered as a new standard of care for younger patients with mantle cell lymphoma. FUNDING:Janssen.

High-grade B-cell lymphoma with 11q-aberration (HGBCL-11q) is a rare pediatric non-Hodgkin lymphoma. This study assessed outcome in 90 children with HGBCL-11q. With survival rates ≥95%, patients with HGBCL-11q and no predisposition are candidates for deescalated therapy in future prospective trials.

The TRIANGLE trial established an ibrutinib-containing therapy without autologous stem-cell transplantation (ASCT) as the new standard for younger, treatment-naïve patients with mantle cell lymphoma (MCL). However, the benefit of rituximab maintenance (RM) within this novel standard is unclear. We investigated whether RM improves progression-free survival (PFS) and overall survival (OS) with acceptable toxicity when added to the experimental arms of TRIANGLE. This secondary analysis of TRIANGLE included patients randomly assigned to ibrutinib-containing therapy without (I) or with (A + I) ASCT who responded to induction/ASCT. RM was given per national and center practice. PFS and OS of patients with and without RM were compared with inverse probability of treatment weighted Kaplan-Meier curves and log-rank tests. Among responders after induction/ASCT (I: 274; A + I: 237), RM was given to 61% (I) and 64% (A + I). RM prolonged PFS in ibrutinib-containing treatment arms (I: log-rank test: P = .003, 4-year PFS probability RM v no RM, 85% v 73%; A + I: P < .001, 90% v 75%). There were trends toward prolonged OS in RM groups. RM groups were at higher risk of grade 3 to 5 infectious toxicity (I: 34% v 11%; A + I: 41% v 18%). Our findings support adding RM to BTK inhibitor treatments in younger, untreated patients with MCL to achieve prolonged remission.

INTRODUCTION The German Hodgkin Study Group (GHSG) HD21 trial for adult patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (AS-cHL) was designed to reduce treatment-related morbidity (TRMB) and improve efficacy by comparing the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to the standard eBEACOPP protocol. Here, we report the final efficacy and safety including long-term progression-free survival (PFS), overall survival (OS), and late toxicity outcomes. METHODS This open-label, international, randomized phase III trial included adults aged 18-60 with newly diagnosed AS-cHL, randomized 1:1 to treatment with 4–6 cycles of eBEACOPP or BrECADD, guided by positron emission tomography after two cycles (PET2). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Co-primary objectives were reduction of TRMB and superiority of PFS with BrECADD vs. eBEACOPP, both of which were met previously. The final analysis focused on long-term PFS, overall survival (OS), and second primary malignancies (SPMs). Kaplan-Meier estimates and Cox regression were used for time-to-event analysis in the intention-to-treat (ITT) population. Additionally, we describe prognostic factors for PET2 response among baseline characteristics including metabolic tumor volume (MTV) and the prognostic value of international prognostic score (IPS) variables and MTV at baseline for PFS, respectively, in the BrECADD arm. Univariate logistic regressions were used to identify associations with interim PET response (p<=.001), which were then compared using multivariate analyses. RESULTS A total of 1,500 patients were enrolled between July 2016 and August 2020 across 233 sites in nine countries. Baseline demographics and disease characteristics were well balanced between arms. After 2 cycles of BrECADD, 235/664 patients (35%) with centrally reviewed PET2 were classified as PET-positive. ECOG > 0 (Odds Ratio [OR] 1.62, 95% CI 1.03-2.55) and higher MTV (OR 1.14 per 100 mL, 95% CI 1.06-1.22) at baseline were associated with positive PET after 2x BrECADD in multivariate analysis. Median follow-up for this final analysis was 60 months and seven new PFS-events occurred after the previous analysis at 48 months: Five in the eBEACOPP arm and two in the BrECADD arm. Confirming earlier analysis, the hazard ratio (HR) for PFS was 0.64 (95% CI 0.44–0.93) favoring BrECADD. The absolute 5-year PFS for BrECADD was 93.6% (95% CI 91.7–95.5) vs. 90.6% (95% CI 88.4-92.8) with eBEACOPP, with a particularly pronounced 5y PFS benefit in PET2-negative patients of 96.2% vs. 92.4% (HR 0.46, 95% CI 0.25–0.83;). Among the IPS variables, male sex (HR 2.68, CI 95% 1.37-5.27) and hemoglobin < 10.5 g/dL (HR 2.41, 95% CI 1.25-4.68) were associated with higher risk for PFS events in multivariate cox regression, whereas MTV at baseline in univariate cox regression was not (HR 0.95 per 100 mL, 95% CI 0.81-1.11). Salvage therapies were similar across treatment arms: most patients with progression or relapse received autologous stem cell transplantation (52/61 (82%) after eBEACOPP vs 29/38 (76%) after BrECADD). With four (two in each treatment group) new death events since the previous analysis, OS remained at 98% in both arms. The cumulative incidence of SPMs at 60 months was 2.1% after eBEACOPP and 2.8% after BrECADD, with differing patterns: more secondary MDS/AML occurred in the eBEACOPP arm (six vs. one), while more secondary NHL cases were observed in the BrECADD arm (two vs. eight). No new sMDS/AML events occurred beyond the primary analysis. CONCLUSION With 5 years follow-up, this analysis confirms the unprecedented primary cure-rate and long-term safety profile of BrECADD. While higher baseline lymphoma burden associates with incomplete remission at PET2, the risk for treatment failure seems mitigated through response-adaptation. Taken together, our results establish individualized BrECADD as a standard treatment option for adult patients with newly diagnosed AS-cHL.