Richter Transformation in Chronic Lymphocytic Leukemia: Current Treatment Challenges and Evolving Therapies

  • Int J Mol Sci. 2025 Sep 8;26(17):8747. doi: 10.3390/ijms26178747.
Zi-Chi Lin  1 ,  Ming-Jen Chan  2  3 ,  Tang-Her Jaing  3  4 ,  Tung-Liang Lin  1 ,  Yu-Shin Hung  1  3 ,  Yi-Jiun Su  1  3
Affiliations
  • 1. Division of Hematology-Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan.
  • 2. Department of Nephrology, Kidney Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan.
  • 3. College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan.
  • 4. Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital in Linkou, Taoyuan 333423, Taiwan.
PMID: 40943662 DOI: 10.3390/ijms26178747
Abstract

Richter transformation (RT) affects 2-10% of Chronic Lymphocytic Leukemia (CLL) patients, evolving into an aggressive lymphoma-most often diffuse large B-cell lymphoma-with poor prognosis, especially when clonally related to CLL. Key risk factors include unmutated IGHV, TP53 and Notch1 mutations, stereotyped B-cell receptors, and complex cytogenetics. This review summarizes RT biology, clinical predictors, and treatment outcomes. Traditional chemoimmunotherapy (e.g., R-CHOP) yields complete response rates around 20-30% and median overall survival of 6-12 months; intensified regimens (R-EPOCH, hyper-CVAD) offer only modest gains. Allogeneic hematopoietic stem cell transplantation is potentially curative but limited to fit patients due to high treatment-related mortality. Emerging therapies now include Bruton's tyrosine kinase and Bcl-2 inhibitors, which achieve partial responses but short progression-free survival. CD19-directed chimeric antigen receptor T-cell therapies produce overall response rates of 60-65%, though relapses remain frequent. Bispecific Antibodies (e.g., CD3×CD20 agents epcoritamab and mosunetuzumab) show promising activity and tolerable toxicity in relapsed/refractory RT. Ongoing trials are exploring combinations with checkpoint inhibitors, triplet regimens, and novel targets such as ROR1, CD47, and CDK9. Continued research into optimized induction, consolidation, and innovative immunotherapies is essential to improve outcomes in this biologically distinct, high-risk CLL-related lymphoma.

Keywords
BCL-2 inhibitors; BTK inhibitors; CAR T-cell therapy; Richter transformation; allogeneic hematopoietic stem cell transplantation; bispecific antibodies; chemoimmunotherapy; chronic lymphocytic leukemia.