Educational content on VJHemOnc is intended for healthcare professionals only. By visiting this website and accessing this information you confirm that you are a healthcare professional.
The Chronic Lymphocytic Leukemia Channel on VJHemOnc is an independent medical education platform, supported with funding from AstraZeneca (Diamond), AbbVie (Platinum), BeOne Medicines (Silver) and Lilly (Silver). Supporters have no influence on the production of content. The levels of sponsorship listed are reflective of the amount of funding given.
The Community Focus Channel on VJHemOnc is an independent medical education platform, supported with funding from Johnson & Johnson (Gold). Supporters have no influence on the production of content. The levels of sponsorship listed are reflective of the amount of funding given.
Introduction
Richter’s transformation (RT) is the development of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL).1
“Richter’s transformation continues to be the unmet need of patients with CLL where the overall survival has been described as anywhere between six months to 24 months post-diagnosis” – Adam Kittai, MD, Icahn School of Medicine at Mount Sinai, New York, NY. To address this, the European Research Initiative on CLL (ERIC) has published updated consensus recommendations to improve diagnosis, management, and research in RT.2
Updated ERIC consensus recommendations
Prioritize early and accurate diagnosis
RT should be suspected in patients with CLL who have rapid clinical decline, new systemic B-symptoms, elevated lactate dehydrogenase (LDH), or discordant/enlarging lymphadenopathy. PET-CT is essential, and biopsy of the most avid accessible lesion is recommended to confirm diagnosis. Fine needle aspiration is inadequate, excisional biopsy is strongly recommended, with review by an expert hematopathologist if possible.2
Assess clonality to guide prognosis
Determining whether RT is clonally related or unrelated to the original CLL is strongly recommended and affects prognosis significantly. Patients with clonally unrelated RT typically have a better prognosis. The gold standard for clonality assessment is immunoglobulin gene rearrangement testing, per ERIC and EuroClonality guidelines.2
Enroll patients in clinical trials when possible
R-CHOP-based therapy remains the standard, but with limited efficacy. All patients should be enrolled in clinical trials when possible; flexible eligibility criteria (e.g., allowance for one prior cycle of debulking treatment and active or symptomatic CLL) are encouraged to improve access. Trials should assess both CLL and RT response and prioritize overall survival (OS) and progression-free survival (PFS) as endpoints.2
Use PET-CT and bone marrow biopsy for staging and response assessment
Pre-treatment PET-CT is recommended to evaluate the extent of the disease, and again to assess response or confirm progression in suspected cases. Bone marrow biopsy is recommended at baseline to assess bone marrow disease and CLL involvement, and post-treatment in patients with prior marrow disease to confirm CLL response. If peripheral blood flow cytometry shows residual CLL at end of treatment, biopsy may be omitted but is warranted when distinguishing between residual CLL and RT is unclear.2
Support biobanking and translational research
RT tissue and associated CLL samples should be biobanked for future genetic and molecular studies. TP53 abnormalities correlate with worse outcomes, but further research is needed to integrate genomics into risk stratification. Emerging tools such as circulating tumor DNA (ctDNA), multiomics, and single-cell analyses hold promise for earlier detection, better disease monitoring, and personalized treatment strategies in RT.2
Treatment advances: ongoing trials
While chemoimmunotherapy (CIT) remains the consensus approach for treatment, outcomes are typically poor, emphasizing the need for clinical trial enrollment and research into novel strategies.1
Venetoclax + CIT
In a Phase II trial (NCT03054896), the combination of venetoclax with dose-adjusted R-EPOCH (VR-EPOCH) demonstrated promising activity in patients with RT. Among 26 treated patients, 50% achieved complete response (CR), and 42% achieved undetectable measurable residual disease (MRD) in the bone marrow for the CLL component. The overall response rate (ORR) was 62%, with a median PFS of 10.1 months and OS of 19.6 months. However, the regimen was associated with notable hematologic toxicity, including grade ≥3 neutropenia (65%), thrombocytopenia (50%), and febrile neutropenia (38%). No cases of tumor lysis syndrome occurred during venetoclax ramp-up.3 Reflecting on these findings, Matthew Davids, MD, Dana-Farber Cancer Institute, Boston, MA, notes, “this was an effective regimen but had significant toxicity due to the intensity of the chemotherapy.”
In this video, Dr Davids introduces data from a new cohort receiving a reduced-intensity regimen combining venetoclax with R-CHOP, aiming to mitigate toxicity while preserving efficacy.
BTK inhibitors (BTKis): monotherapy and combinations
In a Phase II international trial (NCT04271956), patients with RT were treated with the PD-1 inhibitor tislelizumab plus the BTKi zanubrutinib. Among 48 evaluable patients, the ORR after six cycles was 58.3%, including 18.8% CRs, meeting the primary endpoint (p = 0.008). Median PFS was 10.0 months, and 12-month OS was 74.7%. The combination was generally well tolerated, with the most common adverse events being infections (18%), gastrointestinal disorders (13%), and hematologic toxicities (11.4%), highlighting the potential of this combination which is under further evaluation in a Phase III trial.4
Pirtobrutinib monotherapy has shown encouraging activity for the treatment of RT. An analysis of the RT subgroup from the Phase I/II BRUIN study (NCT03740529) revealed an ORR of 50.0% among 82 patients, including 13% complete and 37% partial responses. Most patients (90%) had received prior RT-directed therapy, and 74% had been treated with covalent BTKis. Pirtobrutinib was generally well tolerated, with neutropenia being the most common grade ≥3 adverse event; no treatment-related deaths were reported.5
Bispecific antibodies and CAR T-cells
CD3×CD20 bispecific antibodies, including epcoritamab, glofitamab, and mosunetuzumab, are emerging as treatment options in RT. Epcoritamab is being investigated in the Phase Ib/II EPCORE CLL-1 trial (NCT04623541), in which 35 enrolled patients with RT achieved an ORR and CR of 50% and 35%, respectively. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event (TEAE), occurring in 80% (any grade) of patients.1 Mosunetuzumab monotherapy has also shown activity in relapsed/refractory (R/R) RT in a Phase I/II trial (NCT02500407), achieving an investigator-assessed ORR of 40% and CR of 20%. CRS was predominantly low grade (65% any grade; 5% grade 3), supporting use in patients less fit for intensive therapy.1 Novel strategies are testing glofitamab-based combinations (e.g., with polatuzumab vedotin or atezolizumab; NCT06043674).1
The CAR-T experience is well-established in R/R DLBCL, but more limited in RT. An international multicenter retrospective study of 69 heavily pretreated patients with RT receiving commercial CAR-T products found ORR and CR rates of 63% and 46%, respectively; CRs were durable (median duration of response 27.6 months). Grade ≥3 CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed in 16% and 37% of patients, respectively.8 Multiple Phase II studies evaluating lisocabtagene maraleucel (liso-cel) as monotherapy or in combinations are underway, including liso-cel with nivolumab and ibrutinib (NCT05672173) and liso-cel with zanubrutinib (NCT05873712).1
Conclusion
RT carries a poor prognosis despite standard CIT.1 The updated ERIC guidelines offer a framework for earlier detection, optimal management, and timely clinical trial referral. Novel strategies, including targeted agents, bispecific antibodies, and CAR-T, are under investigation, bringing hope for improved survival in this high-risk population.
References
- Rippel N, Sheppard R, Kittai AS. Updates in the management of Richter transformation. Cancers (Basel). 2024 Dec 31;17(1):95.
- Kittai AS, Marchetti M, Al-Sawaf O, et al. International consensus statement on diagnosis, evaluation, and research of Richter transformation: the ERIC recommendations. Blood. 2025 Jul;146(3):291-303.
- Davids MS, Rogers KA, Tyekucheva S, et al. Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome. Blood. 2022 Feb;139(5):686-689.
- Al-Sawaf O, Ligtvoet R, Robrecht S, et al. Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Nat Med. 2023 Dec;30:240–248.
- Wierda WG, Shah NN, Cheah CY, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study. Lancet Haematol. 2024 Sep;11(9):e682–e692.
- Kater AP, Janssens A, Eradat H, et al. Epcoritamab induces deep responses in patients with Richter transformation (RT): primary results from the EPCORE CLL-1 trial. Clin Lymphoma Myeloma Leuk. 2024 Sep;24(Suppl 1):S350–S351.
- Cheah CY, Assouline S, Baker R, et al. Mosunetuzumab monotherapy demonstrates activity and a manageable safety profile in patients with relapsed or refractory Richter’s transformation. 2023 Nov;142(Suppl 1):614.
- Kittai AS, Bond D, Huang Y, et al. Anti-CD19 chimeric antigen receptor T-cell therapy for Richter transformation: an international, multicenter, retrospective study. J Clin Oncol. 2024 Jun 10;42(17):2071-2079.
Reviewed by Solyana Yohannes
