Limited Survival in CLL With CNS Richter Transformation

For patients who have chronic lymphocytic leukemia (CLL), experiencing Richter transformation with central nervous system involvement (RT-CNS) confers a generally poor prognosis. The disease state has a clinically heterogeneous makeup, and can be seen in isolation or concurrent with systemic disease, report authors in Blood Cancer Journal.1

These patients also often do not have long-term survival following diagnosis, with a median overall survival of just 13 months, and there is a noted lack of guidance due to the rarity of the condition. “In the absence of established guidelines, most clinicians rely on treatment strategies extrapolated from primary CNS lymphoma and secondary CNS DLBCL [diffuse large B-cell lymphoma],” the authors wrote.

To better define this disease environment, they conducted a retrospective analysis for patients with confirmed RT to either DLBCL or high-grade B-cell lymphoma and CNS involvement diagnosed between January 2005 and August 2024. Their patient population (N = 36) was primarily male (58.3%) with a median age of 63 years (range, 34-78). Common findings were IGHV unmutated status (53.3%); positivity for del(17p) (34.6%), trisomy 12 (23.1%), TP53 mutation (63.6%); and being treatment-naïve prior to RT. Among the 12 previously treated patients, their median lines of treatment were 1.5 (range, 1-5).

IGHV mutation status was shown to not be related to overall survival (OS) (P = .19), but there was a positive correlation between TP53 alterations and shorter OS (P = .0198).

The patients who underwent RT had a median time to transformation of 17.3 months (0-277.4) and a median age at RT diagnosis of 69 years (range, 46-80). At that time, most had progressed to DLBCL (91.7%) vs 8.3% who had progressed to high-grade B-cell lymphoma. The primary cell of origin was germinal center B-cell-like (61.9%), and most (80%) were positive via immunohistochemistry (IHC) for the MYC gene, which is typically overexpressed in many cancers2 and has recently been implicated in CLL.3 However, 61.9% also were negative for MYC via fluorescence in situ hybridization (FISH).

Even with this study being the largest to date on Richter transformation of chronic lymphocytic leukemia, according to the authors, they also note more data and multicenter collaborations are needed to validate their observations. | Image Credit: © Saiful52-stock.adobe.com

Also, 81.2% of patients were negative for BCL2 and 100% negative for BCL6 via FISH, 93.7% were negative for the Epstein–Barr virus via IHC, and 66.6% had an MYD88 mutation. Elevated levels of lactate dehydrogenase were seen in 91.7% of the patients, another biomarker implicated in leukemia development.4

For the period from RT diagnosis to CNS involvement, only 15 patients had a treatment history, and among them, the median number of lines of treatment was 1 (range, 1-5). Results on clonal relatedness with CLL were positive in 75% and negative in 25%. Their median time to transformation was just 11.1 months (range, 1.0-41.6), with most diagnoses confirmed via tissue biopsy (44.4%) and imaging (33.3%). More patients had CNS involvement at RT diagnosis vs RT progression (61.1% vs 38.9%) and isolated CNS involvement vs CNS and systemic involvement (52.8% vs 47.2%). Sites of CNS involvement were very mixed: 30.6% were parenchymal and leptomeningeal, cranial nerve roots, or ocular disease; 33.3% were parenchymal only; and 36.1% were nonparenchymal (leptomeningeal, ocular, cranial or spinal nerve roots, and skull base lesions).

Treatment regimens for RT-CNS were high-dose (HD) methotrexate (MTX)-based therapy in 15 patients and steroids only or rituximab and temozolomide in 1 patient each; another patient died, and 1 patient’s treatment was unknown. Six of these patients also underwent autologous stem cell transplant (ASCT) consolidation. Therapies for patients with concurrent systemic and CNS disease were MTX-based therapy (n = 6), anthracycline-based regimens plus CNS-directed therapy (n = 8), and steroids/obinutuzumab/venetoclax (n = 1); 2 patients died. Two of these patients also underwent ASCT.

Over a median follow-up of 62.7 months (95% CI, 45.9-79.5), median OS following CNS involvement was 13.0 months (95% CI, 1.4-24.6). Although survival rates were longer in patients with isolated CNS involvement vs patients with concurrent systemic and CNS disease (34.7 vs 3.1 months; P < .001) and CLL treatment-naïve vs treatment-experienced patients (32.0 vs 1.8 months; P < .001), OS did not vary much among patients whose CNS involvement sites differed.

The authors explain that their findings echo previous studies, showing worse outcomes among patients with systemic disease and prior CLL-directed therapy and TP53 alterations.

There are limitations on their results, however, including the small sample size, retrospective design, treatment heterogeneity, and incomplete clonal and molecular data from the very long study period. They also did not include patients who received newer-generation therapeutics, such as chimeric antigen receptor T-cell therapy.

“Prospective and larger studies, which would be facilitated by multicenter collaborations, are needed to validate these observations,” the authors concluded, “and guide optimal and novel treatment strategies for this challenging population.”

References

1. Baccon D, Atallah-Yunes SA, Hampel PJ, et al. Central nervous system involvement in patients with Richter transformation of chronic lymphocytic leukemia (CLL): the Mayo Clinic experience. Blood Cancer J. 2026;16(1):7. doi:10.1038/s41408-025-01446-y
2. Zhou X, Moreira M, Wang H, et al. Activating a non-genetic MYC-regulating pathway sensitizes acute myeloid leukemia to bromodomain inhibition. Blood. Published online November 15, 2022. doi:10.1182/blood-2022-167049
3. Giuyedi K, Parquet M, Aoufouchi S, et al. Increased c-MYC expression associated with active IGH locus rearrangement: an emerging role for c-MYC in chronic lymphocytic leukemia. Cancers (Basel). 2024;16(22):3749. doi:10.3390/cancers16223749
4. LDH test. Cleveland Clinic. Reviewed April 15, 2022. Accessed January 16, 2026. https://my.clevelandclinic.org/health/diagnostics/22736-lactate-dehydrogenase-ldh-test