EHA 2025 Congress on June 12–15, 2025, in Milan, Italy.
A real-world comparison of hypertension and cardiovascular adverse events with acalabrutinib vs. ibrutinib in patients with treatment-naïve chronic lymphocytic leukemia or small lymphocytic leukemia. Acalabrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, has demonstrated comparable efficacy and improved safety over ibrutinib in the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL). However, these treatments have not been compared in a randomized trial of treatment-naïve patients. As such, researchers conducted a real-world analysis to compare the risk of new/worsening hypertension and cardiovascular medical events of interest (MEOI) with acalabrutinib versus ibrutinib in treatment-naïve patients with CLL/SLL. Baseline characteristics were similar between acalabrutinib and ibrutinib groups (both n=227); median age was 72 and 73 years, respectively, and median Charlson comorbidity score was 3 in both groups. Median systolic and diastolic blood pressure were similar, at 130mmHg and 72mmHg in the acalabrutinib group and 127mmHg and 71mmHg in the ibrutinib group, respectively. A total of 67.8 percent of acalabrutinib-treated patients and 66.5 percent of ibrutinib-treated patients had a history of hypertension. At median 28-month follow-up, the rate of discontinuation due to intolerability was significantly higher in the ibrutinib group compared to the acalabrutinib group (46.7% vs. 19.4%, p<0.001). In both groups, median time to new/worsening hypertension was not reached. Median time to cardiovascular MEOI was not reached in the acalabrutinib group, compared to 44.8 months in the ibrutinib group. Compared to ibrutinib, acalabrutinib was associated with significantly decreased risk of new worsening hypertension (hazard ratio [HR]: 0.27, 95% confidence interval [CI]: 0.14–0.55; p<0.001) and significantly longer time to cardiovascular MEOI (HR: 0.47, 95% CI: 0.33–0.68; p<0.001), according to multivariable analysis. Sensitivity analyses confirmed the stability of these findings. This real-world study suggests that acalabrutinib has an improved cardiovascular safety profile over ibrutinib in treatment-naïve patients with CLL/SLL.
Access abstract here: https://library.ehaweb.org/eha/2025/eha2025-congress/4161700/
Assessing the utility of NGS-detected CNVs as an alternative to FISH for cytogenetic analysis in chronic lymphocytic leukemia. In this retrospective study, researchers evaluated the utility of next-generation sequencing (NGS) to detect cytogenetic abnormalities in patients with CLL, comparing it to fluorescence in situ hybridization (FISH). Data from 64 patients with CLL who underwent NGS and FISH between August 2023 and December 2024 were included for analysis; samples were analyzed for del17p13, del11q22, del13q14.3, and trisomy 12. Fifty-five samples (85.9%) were from peripheral blood and nine (14.1%) were from bone marrow. Thirty-three samples (51.6%) were collected at diagnosis and 31 (48.4%) during follow-up. In total, 256 events were analyzed per technique, 60 (23.4%) of which showed a cytogenetic abnormality; 47 cytogenetic abnormalities were detected by both NGS and FISH. Trisomy 12 showed very good concordance across methods, and the remaining cytogenetic abnormalities showed good concordance. Copy number variations (CNVs) detected through NGS had high sensitivity, ranging from 83.3 to 100 percent, and high specificity, ranging from 85.3 to 98.4 percent. Thirteen discrepancies in 10 samples, nine detected by CNVs and four by FISH, were identified. Eight of the nine CNV discrepancies involved single-gene alterations, and one demonstrated gains in KRAS and ATF1. These findings indicate that NGS has comparable performance to FISH and thus could be utilized in the detection of cytogenetic abnormalities in CLL.
Access abstract here: https://library.ehaweb.org/eha/2025/eha2025-congress/4161390
Interplay of complex karyotype, IGHV mutational status, and TP53/ATM alterations and their impact on prognosis in patients with CLL. Researchers evaluated the relationship between complex karyotype (CK) and immunoglobulin heavy chain variable (IGHV), TP53, and ATM mutational status in CLL, as well as how the interactions affect CLL prognosis. Data from 1,605 patients diagnosed with CLL between 2005 to 2024 were analyzed. Seventeen percent of patients had CK with three or more cytogenetic aberrations, and six percent had five or more aberrations. CK was observed in 26 percent of patients with unmutated IGHV, compared to 11 percent of patients with mutated IGHV (p<0.001). Additionally, the prevalence of CK was higher in patients with TP53 (40%) or ATM (39%) aberrations, compared to those without those aberrations (8%). Compared to cases with mutated IGHV, cases with unmutated IGHV had a greater prevalence of TP53 aberrations (6% vs. 18%) and ATM aberrations (3% vs. 28%). There was a significant association between biallelic inactivation of TP53 and CK (p<0.001). In the overall cohort, unmutated IGHV, CK, and TP53 aberrations were associated with reduced overall survival (OS); however, when stratified by TP53 status, CK only had a negative impact on OS in TP53-aberrant cases, with a median OS of 3.7 years versus 10.7 years for cases without TP53 aberrations (p=0.005); this suggests that TP53 loss negatively impacts prognosis in the presence of CK. ATM aberrations were associated with reduced OS compared to absence of ATM aberrations in cases with mutated IGHV (median OS: 8.8 years vs. not reached, p=0.001), but not in cases with unmutated IGHV. CK did not negatively affect prognosis in patients with ATM aberrations. The authors propose that CLL with IGHV mutation and ATM aberration be considered high-risk disease.
Access abstract here: https://library.ehaweb.org/eha/2025/eha2025-congress/4159983
NGS-based molecular analysis of CLL: comparison of NGS at the moment of diagnosis vs. before treatment in a multicenter study. In this study, researchers compared mutation frequency and subclonal variants in patients with CLL who underwent NGS at diagnosis and before treatment and evaluated the impact of genetic alterations on time to first treatment (TTFT) and OS. A total of 115 patients underwent NGS at diagnosis and 67 underwent NGS before treatment. Subclonal variants were defined as variants with a variant allele frequency (VAF) between 1.0 and 9.9 percent. Unmutated IGHV and mutated TP53 were more frequent in the NGS before treatment group (68% and 19.4%, respectively) compared to the NGS at diagnosis group (31% and 7%, respectively). Among patients with TP53 mutations, about half of those who underwent NGS before treatment had del17p, compared to one patient who underwent NGS at diagnosis. The frequency of multiple gene mutations was higher in the NGS before treatment group versus the NGS at diagnosis group (46.2% vs. 19.9%). Patients with NGS before treatment had an average VAF of 32.5 percent, which was significantly higher than that of patients with NGS at diagnosis (20.4%, p=0.008). Additionally, occurrence of one or more mutations in the same gene was significantly increased in the NGS before treatment group compared to the NGS at diagnosis group (p=0.005). Though the distribution of clonal and subclonal mutations was similar between groups, average VAF of subclonal mutations was higher in the NGS before treatment group versus the NGS at diagnosis group (4.6% vs. 3.0%, p=0.0159). Researchers identified eight mutations in three patients that conferred BTK inhibitor resistance. Among 70 patients with TTFT and OS data, TTFT was significantly decreased in patients with high-risk mutations (ie, SF3B1, NOTCH1, TP53, ATM, BIRC3, EGR2, XPO1, NFKBIE) versus those without such mutations (129 vs. 176 months, p=0.003); similarly, patients with very high–risk mutations (ie, SF3B1, TP53, XP01) had significantly shorter TTFT compared to those without such mutations (100 vs. 175 months, p<0.001).
Access abstract here: https://library.ehaweb.org/eha/2025/eha2025-congress/4161692/
Use of acalabrutinib as first-line treatment for chronic lymphocytic leukemia in routine clinical practice in Spain: the PICAROS study. In this multicenter, observational study, researchers evaluated the real-world clinical use of acalabrutinib monotherapy as first-line therapy for patients with CLL. Adult patients who initiated acalabrutinib between July 2022 and July 2023 as first-line therapy (n=172, 89.6%) or after switching from a first-generation BTK inhibitor due to intolerance (n=20, 10.4%) were included for analysis. Median age at acalabrutinib initiation was 76.0 years, and 59.9 percent were male. Most patients (68.2%) had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1. In the overall cohort, median time to acalabrutinib initiation was 33.9 months; in the treatment-naïve group, median time to initiation was 25.4 months, and in the switching group, it was 71.1 months. The majority of patients (82.3%) had comorbidities at treatment start, most commonly hypertension (59.4%). Of 120 patients with CLL-International Prognostic Index (CLL-IPI) data, 64.2 percent were considered high risk and 15.8 percent were considered very high risk. Of those with available data, most patients had unmutated IGHV (100/142, 70.3%); TP53 mutation, del17p, and concurrent TP53 mutation/del17p were present in 19.0 (30/158), 19.1 (31/162), and 11.8 (18/152) percent of patients, respectively. At a median follow-up of 12 months, 84.9 percent of patients remained on treatment at data cutoff date (July 10, 2024). In total, 62.0 percent of patients experienced adverse events (AEs). The rate of treatment-related AEs (TRAEs) was 26.0 percent, and treatment-related cardiovascular AEs only occurred in 3.6 percent of patients. Among 161 patients with evaluable response data, objective response rate (ORR) was 88.8 percent, with 27.3 percent of patients (n=44) achieving complete response (CR) and 61.5 percent (n=99) achieving partial response (PR). Response rates were similar when stratifying patients into treatment-naïve and switching subgroups (ORR: 88.8% and 88.9%, CR: 27.3% and 27.8%, PR: 61.5% and 61.1%, respectively). These findings demonstrate the safety and efficacy of CLL in first-line treatment as well as the treatment of patients with intolerance to first-generation BTK inhibitors.
Access abstract here: https://library.ehaweb.org/eha/2025/eha2025-congress/4161733/
The demographics of patient population with CLL enrolled on clinical trials – the Stanford 10-year experience. In this study, researchers aimed to evaluate the demographic and geographic characteristics of clinical trial participants with CLL and compare them to a county-defined catchment area to identify disparities in representation. Data from patients enrolled in CLL clinical trials (including upfront and relapsed/refractory settings) at Stanford University from 2013 to 2024 were analyzed. The Cancer Institute’s catchment area included nine counties across the San Francisco Bay Area. A total of 201 patients had participated in CLL clinical trials, with 50 patients (20%) participating in more than one trial (up to a maximum of 4). Mean (standard deviation) age at first clinical trial was 61.7 (16.9) years, and 34 percent of participants were female. Most participants (85%) were White; nine percent of participants were Asian, seven percent were Hispanic, and two percent were Black/African American. Racial/ethnic information was unknown/not reported in three percent of participants. The majority of participants (98%) reported English as their primary language. Participants were most often insured with Medicare (49%), followed by managed care (26%) and private insurance (20%). Eighty-six participants (43%) resided outside of the catchment area, and their median travel distance was 72km. Ten percent of out-of-catchment participants came from out of state, with the remaining 90 percent residing in California. Race was significantly different when stratifying by catchment, with 81 percent of in-catchment participants being White compared to 91 percent of out-of-catchment participants (p=0.03). A similar proportion of in- and out-of-catchment participants were above the age of 65 years (51% and 53%, respectively; p=0.50), female (39% and 28%, respectively; p=0.10), and Medicare beneficiaries (45% and 52%, respectively. p=0.35). Researchers noted that there might be barriers to clinical trial participation for certain racial groups, as the observed racial differences did not reflect the overall demographics of California.
Access abstract here: https://library.ehaweb.org/eha/2025/eha2025-congress/4161727/
A clinical-molecular model for a personalized prediction of time to first treatment in patients with chronic lymphocytic leukemia. Researchers aimed to combine clinical and molecular prognostic factors to develop precise, personalized predictions to TTFT among patients with CLL. Data from 732 patients with CLL and 95 patients with monoclonal B-cell lymphocytosis (MBL), 373 of whom received treatment during follow-up, were included for analysis. Molecular analyses included NGS, FISH or arrays for CNVs, and polymerase chain reactions (PCRs) for IGLV3-21R110 and U1 g.3A>C mutations. A total of 1,774 potential driver mutations, 876 clonal and 898 subclonal (allele frequency <12.5%; detection limit: 0.4%), were identified. In patients with CLL, NOTCH1 was the most commonly mutated gene (18.9%), followed by SF3B1 (12.0%) and ATM (10.8%). The most frequently mutated genes in MBL were CHD2 (12.6%) and NOTCH1 (10.5%). Univariate analyses identified various alterations associated with shorter TTFT, including NOTCH1, SF3B1, ATM, TP53, XPO1, NFKBIE, EGR2, BIRC3, POT1, IGLV3-21R110, trisomy 12, del11q, and del17p, and their accumulation was gradually associated with decreased TTFT. Three models were developed to determine predictive genetic drivers. Model 1 included the following clinical parameters: MBL versus CLL, Binet Stage A versus Stage B/C, IGHV mutational status, and TP53/del17p alterations. Model 2 included clinical parameters plus the genetic drivers associated with TTFT on univariate analysis. Model 3 included clinical parameters plus all genes analyzed in this study. Model 2 had an expected logarithmic predictive density of –641.56, which was better than that of model 1 (–655.85) and similar to that of Model 3 (–641.23), indicating that Model 2 had better predictive value than Model 1 (p=0.017) and similar predictive value to Model 3 (p=0.845). The clinical-molecular predictive model was found to improve prediction of TTFT compared to clinical parameters alone, thereby improving risk stratification among patients with CLL.
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Gut microbiome imbalance drives immune exhaustion via short-chain fatty acids in CLL. In this study, researchers examined the association between gut microbiome activity and immune system alterations in CLL. Peripheral blood and fecal samples from 81 newly diagnosed and untreated patients with CLL and 21 healthy controls were analyzed. Three gut microbiome composition clusters were identified, with donor, Binet stage, IGHV mutation status, and CD38 expression level significantly contributing to differences in composition. Clusters 2 and 3 showed differential enrichment of pathways associated with synthesis of amino acids, fatty acids, and lipids, production of key cofactors and coenzymes, and substrates for core metabolic pathways, with higher enrichment scores of these pathways discriminating between controls and patients. Patients with Binet stage B/C, unmutated IGHV, and high CD38 expression had significantly decreased enrichment scores for short-chain fatty acid (SCFA) synthesis and/or fermentation–related pathways, compared to patients with Binet stage A, mutated IGHV, and low CD38 expression, respectively. Among 18 CLL samples with unmutated IGHV, TP53 wildtype, and no del17p, sodium butyrate (SB)–treated samples had significantly greater levels of CD8+ T cells and increased programmed cell death protein 1 (PD-1) expression on CD8+ T cells, whereas T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) expression was significantly decreased on T cell subsets and CD5+CD19+ B cells, compared to untreated controls. PD-1 and TIGIT co-expression was significantly decreased on CD3+ T cells, CD4+ T cells, and CD5+CD19+ B cells in SB-treated samples compared to controls.
Access abstract here: https://library.ehaweb.org/eha/2025/eha2025-congress/4160628/