At the 2026 European Hematology Association (EHA) Annual Meeting, experts including Professor Paolo Ghia from Università Vita-Salute San Raffaele, Professor Barbara Eichhorst from the University Hospital of Cologne, and Professor Elżbieta Kalicińska from Wroclaw Medical University jointly released and interpreted the latest version of the "EHA Guidelines for the Management of Chronic Lymphocytic Leukemia (CLL) and Richter Transformation (RT)". This update not only incorporates data from multiple cutting-edge targeted studies but also includes "Richter Transformation" in the title for the first time, aiming to provide a more practical clinical pathway for hematologists worldwide. 01 Standards and Unification: Alignment of CLL/SLL/MBL Definitions with WHO/iwCLL Standards
The guidelines first emphasize the importance of standardizing disease definitions. To ensure consistency in clinical diagnosis, the new version of the guidelines has fully aligned the classifications of CLL, Small Lymphocytic Lymphoma (SLL), and Monoclonal B-cell Lymphocytosis (MBL) with the standards of the World Health Organization (WHO) and the International Workshop on CLL (iwCLL). • Core Boundary: The key cutoff for distinguishing CLL from SLL/MBL remains the peripheral blood monoclonal B-lymphocyte count. It is clearly stated that if the peripheral blood monoclonal B-cell count is ≥ 5 × 10^9/L, it is diagnosed as CLL regardless of the presence of lymphadenopathy or organomegaly. • MBL Classification: For patients with a monoclonal B-cell count < 5 × 10^9/L and no lymphadenopathy/organ involvement, they must be further distinguished into “High-count MBL” (close to CLL characteristics) and “Low-count MBL” (with a cutoff of 0.5 × 10^9/L), where low-count MBL generally does not require routine clinical monitoring.
02 A New Dimension for Benefit Assessment: Inclusion of the ESMO-MCBS Grading System
This guideline update introduces the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). This is a standardized tool for evaluating the clinical value of anti-tumor drugs. In the context of non-curative diseases like CLL, the score ranges from 1 to 5. • Scoring Logic: The scale comprehensively considers the magnitude of improvement in Progression-Free Survival (PFS), Overall Survival (OS) benefit, Hazard Ratio (HR value), and the impact of drug toxicity on the patient’s Quality of Life (QoL). • Clinical Significance: The guidelines point out that current mainstream targeted regimens in the CLL field (such as BTK inhibitors and BCL-2 inhibitor-related combinations) mostly score in the high range of 4-5 points. The introduction of this scoring system helps clinicians scientifically select from available options based on evidence strength and value.
03 Shift in First-line Treatment Paradigm: From “Age-Driven” to “Biology-Driven”
In previous guidelines, age (65 years) and fitness status were the primary stratification factors for regimen selection. The new guidelines achieve a major paradigm shift: Fitness status is no longer the decisive indicator; biological characteristics (TP53 status, IGHV mutation status) have become the core drivers. • Patients with TP53 Abnormalities (del(17p) or TP53 mutation): o Preferred Regimen: Continuous administration of second-generation BTK inhibitors (BTKi), such as Acalabrutinib and Zanubrutinib, carries the highest level of evidence. o Fixed-duration Regimens: Although some studies explore combinations of BCL-2 inhibitors (such as Venetoclax) and CD20 monoclonal antibodies for this group, continuous BTKi therapy remains the most robust choice for very high-risk populations at present. • Patients without TP53 Abnormalities: o IGHV Unmutated: Based on data from the AMPLIFY study and others, the EMA has approved Acalabrutinib plus Venetoclax (+/- Obinutuzumab) for these patients. The guidelines recommend prioritizing double or triple targeted regimens of “Acalabrutinib + Venetoclax” or Venetoclax combined with Obinutuzumab for these patients. o IGHV Mutated: The guidelines lean towards recommending Time-limited therapy, with Venetoclax + Obinutuzumab as the primary preference, aiming to allow patients to achieve deep remission (uMRD) while attaining long-term treatment cessation.
04 Individualized Selection “Heatmap”: Precision in Comorbidity and Safety Management
To resolve the “selection difficulty” clinicians face among various targeted drugs, the guidelines have added a treatment strategy selection heatmap based on patient characteristics. • Cardiovascular Risk: For patients with a history of atrial fibrillation or hypertension, the first-generation BTKi (Ibrutinib) should be avoided, and second-generation BTKi with a lower incidence of atrial fibrillation are preferred. • Infection Risk: When using CD20 monoclonal antibodies or specific targeted drugs long-term, the patient’s baseline immune status and history of previous infections must be assessed. • Convenience of Medication: For patients who cannot cooperate with frequent intravenous infusions or laboratory monitoring, all-oral regimens (such as BTKi monotherapy or the oral portion of BTKi + Venetoclax) offer significant advantages.
05 Sequential Strategies for Relapsed/Refractory (R/R) Stages
The guidelines provide clear pathways for sequential treatment after progression on different first-line regimens: • After First-line Chemoimmunotherapy (CIT) Progression: Sequential use of BTKi (such as Zanubrutinib, Acalabrutinib) or Venetoclax + Rituximab (VenR). • After First-line Continuous BTKi Progression: It is suggested to switch to a BCL-2 inhibitor-based regimen (VenR) or consider a non-covalent BTKi (such as Pirtobrutinib). Pirtobrutinib has been approved by the EMA for patients previously treated with covalent BTKi. • After First-line Fixed-duration Regimen (Ven+CD20 mAb) Progression: o Late Relapse (off-treatment > 24 months): Re-treatment with the original regimen can be considered. o Early Relapse (off-treatment < 24 months): It is recommended to switch the mechanism of action to a BTKi class drug.
06 Richter Transformation (RT): Standardized Diagnosis and Exploration in the New Targeted Era
As a major highlight of this guideline, the diagnosis and treatment of Richter Transformation (CLL progressing to Diffuse Large B-cell Lymphoma, DLBCL) have been elevated to a position of importance. • Diagnostic Criteria: Confirmation via pathological biopsy is mandatory. The guidelines emphasize that clonal relationship analysis (IGHV sequencing) must be performed. Clonal-related RT has an extremely poor prognosis, with median survival usually less than one year; clonal-unrelated RT is closer to de novo DLBCL. • Treatment Pathway: o First-line: R-CHOP and similar chemotherapy regimens remain the mainstay, but the addition of BTKi or Venetoclax in clinical trials can be considered. o Novel Therapies: The guidelines mention the application prospects of bispecific antibodies and CAR-T cell therapy in RT. Although not yet fully approved for RT, they have shown positive signals in clinical trials. o Consolidation Therapy: For RT patients with good fitness status, allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be considered as early as possible after achieving remission through chemotherapy or targeted therapy.
Professor Barbara Eichhorst concluded by pointing out that the treatment of CLL has fully entered the era of targeted drugs, and the role of chemotherapy has been marginalized. The future challenge lies in how to precisely guide treatment cessation through MRD (measurable residual disease) monitoring and how to overcome difficult-to-treat progressions like RT through novel drug combinations (such as bispecific antibodies or non-covalent BTKi). The update of these guidelines establishes a new benchmark for the standardized management of CLL globally.
