Editor's Note: Recently, the European Hematology Association (EHA) released its highly anticipated "Management of Aggressive Large B-cell Lymphoma (LBCL) Guidelines," providing comprehensive and authoritative clinical guidance for this highly heterogeneous malignancy. The guidelines were formulated by 23 top European experts spanning multiple disciplines, including hematology, pathology, nuclear medicine, and radiation oncology, and for the first time, were co-developed with patient representatives. At a recent 2025 EHA conference, Professor Catherine Thieblemont from France, a core member of the project, provided an interpretation of these guidelines. This article, based on Professor Thieblemont's report, will systematically review the core principles and changes in the new guidelines regarding diagnosis, staging, first-line treatment, and subsequent strategies.Precision Diagnosis and Risk Stratification: The Cornerstone of Individualized Treatment
The new EHA guidelines first emphasize the central role of precise diagnosis and comprehensive risk assessment in the management of LBCL. Professor Thieblemont noted, “Our consensus is that all diagnoses must be based on review by an expert hematopathologist and employ comprehensive immunohistochemistry (IHC) and molecular testing standards.” The guidelines recommend that IHC should, at a minimum, include markers such as CD20, BCL6, CD10, MUM1, MYC, BCL2, Ki-67, and CD5 to accurately define LBCL subtypes.
On a molecular level, the guidelines clearly establish Fluorescence In Situ Hybridization (FISH) testing for MYC rearrangement as a critical step. If MYC is positive, FISH testing for BCL2 and BCL6 becomes mandatory to identify “double-hit” or “triple-hit” lymphomas, which have a very poor prognosis. Professor Thieblemont added, “Although Cell of Origin (COO) subtyping, such as Germinal Center B-cell-like (GCB) and Activated B-cell-like (ABC), holds significant prognostic value, there is currently insufficient evidence to support its direct use in guiding first-line treatment choices.”
In terms of staging and risk assessment, the guidelines establish Positron Emission Tomography (PET) as the “gold standard.” Professor Thieblemont stressed, “PET is far superior to traditional bone marrow biopsy in assessing extranodal lesions and has independent prognostic value. Therefore, routine bone marrow biopsy is no longer necessary unless there is suspicion of a concomitant hematological disorder.” Furthermore, the International Prognostic Index (IPI) remains a mandatory assessment tool, while the CNS-IPI is strongly recommended to guide CNS prophylaxis strategies in high-risk patients. The guidelines also look forward to the application of emerging biomarkers, such as Metabolic Tumor Volume (MTV) and circulating tumor DNA (ctDNA), which are considered to have stronger prognostic predictive power than the traditional IPI.
A New Paradigm in First-line Treatment: A Risk-Stratified, Stepped-Care Strategy
One of the main highlights of these guidelines is the establishment of a refined, risk-factor-based first-line treatment pathway for patients under 80, moving beyond the previous “one-size-fits-all” model dominated by the R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone).
For low-risk patients (Stage I/II, 0 risk factors), the guidelines recommend 4 cycles of the R-CHOP-21 regimen. Professor Thieblemont explained, “For this patient population, our goal is to achieve a cure while minimizing treatment toxicity. If there is bulky disease (diameter >7.5 cm), an increase to 6 cycles may be considered. Importantly, if a patient achieves a complete metabolic response after adequate chemotherapy, consolidative radiotherapy is generally not required.”
For intermediate-risk patients (1 risk factor), the standard treatment is 6 cycles of the R-CHOP-21 regimen. These patients should undergo PET assessments both mid-treatment (after 2-4 cycles) and at the end of treatment to dynamically monitor efficacy.
For high-risk patients (≥2 risk factors), the guidelines, for the first time, list the Pola-R-CHP regimen (Polatuzumab vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone) as the preferred recommendation, with 6 cycles of R-CHOP-21 as an alternative. This change is based on the groundbreaking results of the POLARIX study, which demonstrated that Pola-R-CHP significantly improves progression-free survival compared to R-CHOP.
Management Strategies for Special Subtypes and Complex Scenarios
The guidelines provide detailed guidance for several common “special situations,” reflecting a high degree of clinical practicality.
High risk of Central Nervous System (CNS) relapse: For patients with a CNS-IPI score of 4-6 or involvement of specific sites (e.g., testes, breast, adrenal glands), the guidelines recommend a baseline brain Magnetic Resonance Imaging (MRI) and cerebrospinal fluid analysis. Professor Thieblemont specifically pointed out, “Intrathecal methotrexate is no longer recommended due to lack of efficacy. While the effectiveness of high-dose methotrexate (HD-MTX) remains controversial, if it is to be used, we recommend administering at least 2 cycles after a complete response to systemic chemotherapy is achieved.”
Primary Mediastinal Large B-cell Lymphoma (PMBCL): The guidelines recommend intensified regimens such as R-CHOP-14 or DA-EPOCH-R and explicitly state that the standard R-CHOP-21 regimen should be avoided. For patients who achieve a complete metabolic response after chemotherapy, mediastinal radiotherapy can be omitted.
Primary Testicular Lymphoma: The treatment strategy is 6 cycles of R-CHOP combined with contralateral testicular irradiation and CNS prophylaxis. Elderly/frail patients (>80 years): The guidelines emphasize the importance of a Geriatric Assessment and recommend the R-mini-CHOP regimen for patients who are otherwise fit. For patients with cardiac dysfunction, anthracycline-free regimens should be considered.
Second-line and Beyond: CAR-T and Innovative Drugs Lead the Future
For relapsed/refractory LBCL, the guidelines delineate clear treatment pathways based on the timing of relapse.
Early relapse/refractory (within 12 months of first-line therapy): For patients eligible for Chimeric Antigen Receptor T-cell (CAR-T) therapy, the guidelines recommend approved CAR-T products (e.g., Axi-cel, Liso-cel) as the standard second-line treatment. Professor Thieblemont stated, “This is a major advancement in the field of LBCL treatment. CAR-T therapy offers new hope for a cure for this patient group with the worst prognosis.” For patients who are ineligible for or cannot access CAR-T therapy, Glofitamab (a CD20xCD3 bispecific antibody), GemOx chemotherapy, or participation in clinical trials may be considered.
Late relapse (after 12 months of first-line therapy): For transplant-eligible patients, traditional salvage chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of care. For patients ineligible for transplant, treatment options are similar to those for non-CAR-T candidates with early relapse.
In third-line and subsequent settings, the guidelines list multiple options, including CAR-T cell therapy, Loncastuximab tesirine (an antibody-drug conjugate), and Tafasitamab in combination with lenalidomide, emphasizing that decisions must be highly individualized and strongly recommending a biopsy to confirm the pathology upon relapse
Long-term Management and Survivorship Care: From Cure to Healthy Living
The final section of the guidelines focuses on long-term patient follow-up and quality of life, proposing systematic management recommendations. Professor Thieblemont concluded, “The end of treatment is just a new beginning. We strongly recommend a comprehensive end-of-treatment consultation for every patient.” The guidelines advise against routine imaging surveillance in asymptomatic patients but suggest one PET scan one year after the end of initial therapy for high-risk patients who would be eligible for CAR-T therapy. Additionally, the guidelines cover the long-term monitoring and management of secondary malignancies, cardiotoxicity, neuropathy, fatigue, and mental health, truly achieving comprehensive patient care throughout their journey.
Conclusion and Outlook
The release of these new EHA LBCL management guidelines marks a significant milestone for the lymphoma community in Europe and globally. Based on rigorous evidence-based medicine, and through the intellectual collaboration of multidisciplinary experts and the active participation of patients, it constructs a comprehensive, refined, and individualized clinical decision-making framework that covers the entire patient journey from diagnosis and treatment to long-term survival. As Professor Thieblemont stated, these guidelines, the result of a six-month consensus-building effort, not only provide a clear roadmap for clinicians but also demonstrate the leadership of the European hematology community in collaborative innovation in global cancer care. Ultimately, they will bring improved survival outcomes and a better quality of life to the vast number of LBCL patients.
