Heterogeneity in patients with Richter transformation (RT) and chronic lymphocytic leukemia (CLL)
Tian S, Wang H, Parikh SA, et al. Leuk Res. 2026;160:108133.
Summary. In this study, researchers compared the genomic profiles of 5 patients with chronic lymphocytic leukemia (CLL) and 7 patients with Richter transformation (RT). Cases were divided into two major clusters with distinct expression profiles: C1, which contained 5 RT cases, and C2, which contained 2 RT and all CLL cases. In C2, one CLL case developed RT, and this case had a more similar expression profile to RT than CLL cases. There was a higher expression of differentially expressed genes (DEGs) in C1 versus C2. DEGs in C1 were mostly enriched in immune response-related pathways, whereas DEGs in C2 were enriched in WNT signaling. The abundance of macrophages (M1) and CD8+ T cells was significantly higher in C1, and tumor B cell composition differed significantly between cohorts. Median overall survival (OS) was shorter in C1 vs C2 (11 vs 36 months). Fifty-one genes carrying copy number alterations were identified across both cohorts.
* PMID: 41260131
Monoclonal gammopathy defines distinct clinical subsets in chronic lymphocytic leukemia across therapeutic eras
Yan Y, Yuan B, Qiu T, et al. Blood Adv. 2025;9(24):6279–6291.
Summary. Among 1,223 patients with CLL and immunofixation electrophoresis data, 226 (18.47%) had monoclonal gammopathy (MG), most commonly immunoglobulin M (IgM) (n=110, 8.18%) and IgG (n=99, 8.09%) types. The proportion of patients with unmutated IGHV was significantly higher in the IgM MG group, compared to other MG or no MG groups. IgM MG was associated with TP53, BIRC3, and DDX3X mutations, and IgG, IgA, and light-chain MG were associated with MYD88 mutations. Time to first treatment (TTFT), progression-free survival (PFS), and OS were shorter in the IgM MG group vs the no MG group. In the IgM MG group, PFS was similar across treatment modalities, indicating no survival benefit with targeted therapy over chemotherapy or immunochemotherapy.
* PMID: 40902084, PMCID: PMC12744275
Mutational landscape and clinical impact of SPEN mutations in patients with chronic lymphocytic leukemia
Nirmalanantham P, Quesada AE, Ghosh A, et al. Cancers (Basel). 2025;17(21):3586.
Summary. Among 1,617 patients with CLL, 48 (2.9%) patients harbored 53 SPEN mutations (10 patients with >1 SPEN mutation). Most mutations (n=49) were deleterious, and the remaining 4 were missense mutations. The most frequently comutated gene was NOTCH1 (n=21, 43.7%), followed by TP53 (n=11, 22.9%) and BIRC3 (n=6, 12.5%). The frequency of unmutated IGHV, CD38 positivity, trisomy 12, ZAP70 expression were significantly higher in SPEN-mutant CLL compared to SPEN-wildtype CLL. On univariate analysis, SPEN mutation was associated with shorter TTFT (hazard ratio [HR]: 1.47; p=0.02), but significance was not maintained upon multivariable analysis (HR: 1.26; p=0.25).
* PMID: 41228377, PMCID: PMC12607580
Association of galectin-9 soluble immune checkpoint with clinical prognostic markers in patients with chronic lymphocytic leukemia
Ntsethe A, Dludla PV, Nkambule BB. Int J Mol Sci. 2025;27(1):98.
Summary. In this study, researchers assessed the association between soluble immune checkpoint levels and prognostic markers in treatment-naïve patients with CLL. Compared to controls (n=12), patients with CLL (n=21) had significantly increased levels of soluble interleukin-2 receptor alpha, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and galectin-9. Additionally, programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) were significantly elevated in patients with CLL compared to controls. Multivariable analysis showed a significant positive association between β2 microglobulin and galectin-9 levels (β=0.65; p=0.012).
* PMID: 41515978, PMCID: PMC12785695
Clinical and transcriptomic characterization of patients with chronic lymphocytic leukemia harboring t(14;19): an ERIC study
Visentin A, Gaffo E, Fürstenau M, et al. Leukemia. 2025;39(12):2957–2967.
Summary. Compared to patients with CLL without t(14;19)(q32;q13) (oCLL), patients with CLL harboring t(14;19)(q32;q13) (tCLL) were younger and more frequently had unmutated IGHV and trisomy 12. Prognosis was worse in tCLL compared to oCLL; median TTFT was 1.92 vs 6.94 years (p<0.0001), and median OS was 12.6 years vs not reached (p<0.0001). In Binet stage A and unmutated IGHV subgroups, tCLL retained its prognostic significance. Patients with tCLL exhibited overexpression of BCL3 messenger ribonucleic acid (mRNA). In tCLL, BTK and CD79B were upregulated and BCL2L11 was downregulated, and apoptosis-related pathways were downregulated. Bruton tyrosine kinase inhibitor treatment trended toward a longer time to next treatment compared to venetoclax-based regimens (p=0.058).
* PMID: 40973766, PMCID: PMC12634426
Optimizing markers for chronic lymphocytic leukemia diagnosis by flow cytometry: results from the Nationwide Thai Lymphoma Study Group
Sathitakorn O, Kobbuaklee S, Chanswangphuwana C, et al. J Clin Lab Anal. 2025;39(22):e70116.
Summary. Analyzing flow cytometry data from 228 patients with persistent lymphocytosis, 206 with CLL and 22 with a non‐CLL lymphoproliferative disorder, researchers found that CD19 had the highest expression in CLL (99.5%), followed by CD5 (95.6%) and CD200 (88.6%). Model 1, which combined CD5, CD200, and CD19, had a sensitivity and specificity of 82.5% and 90.9%, respectively; positive (PPV) and negative predictive value (NPV) were 98.8% and 35.7%, respectively. Model 4, which combined CD5, CD200, CD19, CDCD31, and CD11c, had a specificity and PPV approaching 100%, but sensitivity and NPV were low (38.8% and 14.9%, respectively). Area under the curve (AUC) was higher for Model 1 (0.87) compared to Model 4 (0.69). According to multivariate analysis, CD38 was associated with increased risk of relapse, whereas leukocyte‐associated immunoglobulin‐like receptor was protective against relapse.
* PMID: 41059584, PMCID: PMC12640788
Expression of TIM-3 and Gal-9 immune checkpoints in chronic lymphocytic leukemia: the potential role of interleukin-27
Wędrowska E, Wandtke T, Ulaszewski B, et al. Curr Issues Mol Biol. 2025;47(11):881.
Summary. Researchers cultured peripheral blood mononuclear cells from 20 treatment-naïve patients with CLL with or without interleukin (IL)-27 to determine the impact of IL-27 on immune checkpoint expression. CD4+ T helper cell levels were significantly decreased in IL-27-treated cells compared to nontreated cells (mean±standard error of the mean [SEM]: 22.01±3.23% vs 26.71±4.19%; p=0.010). TIM-3 expression on CD8+ T cells was significantly increased with IL-27 treatment (3.09±0.49% vs 2.18±0.32%; p=0.009). Furthermore, the proportion of galectin-9-positive lymphocytes was significantly higher in IL-27-treated cells compared to nontreated cells (96.55±0.67% vs 93.91±1.17%; p=0.005).
* PMID: 41296385, PMCID: PMC12650853