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CHRONIC LYMPHOCYTIC LEUKEMIA

Incidence of Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma in the targeted therapy era

Leukemia volume 39, pages 503–507 (2025)Cite this article

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Richter transformation (RT) is the histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RT has devastating consequences with survival after transformation typically <1 year [1]. Estimates of RT frequency vary by study design, setting, and duration of follow-up. In several large studies from time periods when chemoimmunotherapy (CIT) was used to treat patients with CLL, RT rates have been reported between 2 and 10% after a median follow-up of 4–6 years from the time of diagnosis; these studies included patients with both newly diagnosed CLL and treated CLL [2,3,4,5,6]. Targeted therapies, including Bruton tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL2i), are now standard of care treatment for patients with CLL. High RT rates (up to 25%) reported in early studies with BTKi and BCL2i in relapsed CLL patients likely reflect increased RT risk among heavily pre-treated patients rather than risk due to these therapies themselves [7, 8]. Comparison of risk after specific treatment exposures from first-line clinical trials with CIT and targeted therapy arms is limited by the low numbers of RT events reported [9,10,11,12,13]. As the treatment paradigm for CLL has changed and CLL patients are living longer, we aimed to assess the current risk of developing RT and the potential impact of targeted therapies on that risk by comparing cohorts of patients with newly diagnosed CLL across different time periods.

Following IRB approval, we identified patients with previously untreated CLL in the Mayo Clinic CLL Database who were seen within 12 months of diagnosis. Only cases of biopsy proven DLBCL with histopathologic confirmation at Mayo Clinic were considered an RT event. Cumulative incidence methodology was used to display the time to development of RT, both from time of initial CLL diagnosis and from start of CLL-directed therapy, with death as a competing risk. We defined the period prior to February 2014 (FDA approval of ibrutinib for CLL) as the pre-targeted therapy era and the period after February 2014 as the targeted therapy era. Using Cox proportional hazards regression analysis, we compared the incidence of RT between patients diagnosed with CLL in the pre-targeted therapy era versus the targeted therapy era. Cox regression analysis was also used to investigate the association of effects of type of treatment exposure (time-dependent variable) on risk of RT. Statistical analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC, USA).

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Fig. 1: Rate of Richter transformation (RT) in patients diagnosed in the pre-targeted therapy era (prior to February 2014) and the targeted therapy era (after February 2014).

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Acknowledgements

The conduct of this research was supported in part by the Henry J. Predolin Foundation.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Paul J. Hampel, Yucai Wang, Steven R. Hwang, Saad S. Kenderian, Eli Muchtar, Amber B. Koehler, Rachel J. Bailen, Susan M. Schwager, Susan L. Slager, Timothy G. Call, Neil E. Kay, Wei Ding & Sameer A. Parikh

  2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Kari G. Rabe & Susan L. Slager

  3. Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA

    Jose F. Leis, Mazie Tsang, Talal Hilal & Esteban Braggio

  4. Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA

    Ricardo Parrondo

  5. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Curtis A. Hanson, Min Shi, Cinthya J. Zepeda-Mendoza, Daniel L. Van Dyke & Rebecca L. King

  6. Division of Hematology, Department of Medicine, Stanford University, Palo Alto, CA, USA

    Tait D. Shanafelt

  7. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Neil E. Kay

Authors
  1. Paul J. Hampel
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  2. Kari G. Rabe
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  22. Timothy G. Call
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  23. Neil E. Kay
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  25. Sameer A. Parikh
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Contributions

PJH, KGR, YW, WD, and SAP designed the research, collected, analyzed, and interpreted data, and wrote the manuscript; SRH, SSK, EM, JFL, ABK, MT, TH, RP, RJB, CAH, EB, MS, CJZM, DLV, TDS, TGC, RBK, and NEK cared for the patients, interpreted the results, and critically reviewed/revised the manuscript; SMS acquired data and critically reviewed/revised the manuscript; SLS and KGR analyzed data, conducted statistical analyses, and critically reviewed/revised the manuscript; All authors approved the manuscript in its final format.

Corresponding author

Correspondence to Sameer A. Parikh.

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Competing interests

The authors declare no competing financial interests in direct relation to the work reported. The following authors also declare no competing financial interests otherwise: PJH, KGR, SRH, JFL, RP, RJB, SMS, MT, CAH, MS, CJZM, DLV, EB, SLS, RBK, TGC. In the interest of transparency, additional potential conflicts of interest for the remaining authors are included below. TH: Consultancy for BeiGene. Research funding provided to the institution from BeiGene. YW: Membership on Board of Directors or advisory committees for Incyte, InnoCare, LOXO Oncology, Eli Lilly, TG Therapeutics, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie (compensation to institution). Research funding (to institution) from Incyte, InnoCare, LOXO Oncology, Eli Lilly, Novartis, Genentech, MorphoSys, GenMab, AbbVie. Honorarium (to institution) from Kite. SSK: Patents and royalties from Novartis, Humanigen, Mettafforgr, Sendero, and MustangBio; Research funding from Kite, Gilead, Juno, BMS, Novartis, Humanigen, MorphoSys, Tolero, Sunesis/Viracta, LifEngine Animal Health Laboratories Inc, and Lentigen; Scientific advisory boards in Kite/Gilead, Calibr, Luminary Therapeutics, Humanigen, Juno/BMS, Capstan Bio, and Novartis; DSMB: Humanigen, Carisma; Consultancy: Torque, Calibr, Novartis, Capstan Bio, and Humanigen. EM: Honorarium from Janssen. Consultation fee from Protego (paid to the institution). SA: Consultancy for BMS, Janssen, Amgen, Pharmacyclics, GSK, Takeda, Genentech, AbbVie, Karyopharm, Beigene, Sanofi. Research funding from BMS, Janssen, Amgen, Pharmacyclics, Ascentage, Medimmune, Cellectar, Xencor, GSK. ABK: Membership on Board of Directors or advisory committees for AbbVie and TG Therapeutics. TDS: Research funding from Abbvie, Genentech, and Pharmacyclics. NEK: Membership on Board of Directors or advisory committees for Abbvie, BMS, Celgene, Pharmacyclics, AstraZeneca, Behring, CytomX Therapeutics, Dava Oncology, Janssen, Juno Therapeutics, Oncotracker, Targeted Oncology, Agios Pharm, Morpho-sys, Rigel. Research funding from Abbvie, Acerta Pharma, BMS, Celgene, Genentech, MEI Pharma, Sunesis, TG Therapeutics, Tolero Pharmaceuticals. WD: Employment with BeiGene. Research funding has been provided to the institution from Merck and DTRM. Participation in advisory board meetings for Merck and Octapharma. SAP: Research funding has been provided to the institution from Janssen, AstraZeneca, Merck, and Genentech for clinical studies in which Sameer A. Parikh is a principal investigator. Honoraria has been provided to the institution from Pharmacyclics, Merck, AstraZeneca, Janssen, BeiGene, Genentech, Amgen, MingSight Pharmaceuticals, Ascentage Pharma, Eli Lilly, TG Therapeutics, Novalgen Limited, Kite Pharma, and AbbVie for Sameer A. Parikh’s participation in consulting activities/advisory board meetings.

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Hampel, P.J., Rabe, K.G., Wang, Y. et al. Incidence of Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma in the targeted therapy era. Leukemia 39, 503–507 (2025). https://doi.org/10.1038/s41375-024-02492-4

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