TP53 disruption represents a central event driving clonal evolution, therapeutic resistance, and adverse outcome in several B-cell neoplasms, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These diseases represent paradigmatic models to show how TP53-mutant subclones emerge, expand under treatment pressure, and differentially respond to novel therapeutic strategies. In normal cells, TP53 regulates DNA damage responses, cell-cycle arrest, and apoptosis, acting as tumor suppressor gene. In CLL, MCL, and DLBCL, TP53 disruption may occur through point mutations, deletions of chromosome 17p, or loss of heterozygosity, often resulting in dominant-negative or gain-of-function effects. Importantly, TP53 alterations are frequently subclonal at diagnosis but confer a strong selective advantage during therapy, leading to clonal expansion and disease progression. In CLL, TP53 abnormalities are detected in approximately 5–10% of patients at diagnosis and increase to over 30% at relapse. TP53 disruption is the strongest prognostic and predictive biomarker, anticipating failure of chemo-immunotherapy and guiding the upfront use of targeted agents. BTK inhibitors and the BCL2 inhibitor venetoclax partially overcome TP53-mediated resistance by inducing p53-independent cell death, resulting in effective clonal containment rather than eradication. In MCL, TP53 alterations are present in 20–30% of cases and are enriched in blastoid and pleomorphic variants. TP53-mutated MCL is characterized by primary chemoresistance and adverse outcome, even with intensive regimens. BTK inhibitor–based approaches and venetoclax combinations achieve partial suppression of TP53-mutant clones but rarely induce durable disease control, supporting early consideration of cellular therapies. In DLBCL, TP53 disruption occurs in 15–25% of cases and is strongly associated with genomic complexity, MYC cooperation, and primary refractoriness to conventional treatments. In this context, TP53 serves as a marker of chemoresistant biology and identifies patients who may benefit from early intensification strategies, including T-cell directed therapies. Overall, TP53 alterations define an evolutionary high-risk state across B-cell neoplasms. Understanding how novel therapies differentially modulate TP53-mutant clonal dynamics is essential for biology-driven risk stratification and for the development of new therapeutic strategies. References Tamellini E et al. — Cell Death Dis. 2025;16(1):819. https://doi.org/10.1038/s41419-025-08127-5 Malcikova J et al. — Leukemia. 2024;38(7):1455-1468. https://doi.org/10.1038/s41375-024-02267-x Wierda WG et al. — Blood. 2025;146(7):779-788. https://doi.org/10.1182/blood.2024027025 Brown JR et al. — Blood. 2026;147(1):24-34. https://doi.org/10.1182/blood.2025029208 Jain P, Wang M. — Blood. 2025;145(7):683-695. https://doi.org/10.1182/blood.2023023412 Dreyling M et al. — Lancet. 2024;403(10441):2293-2306. https://doi.org/10.1016/S0140-6736(24)00184-3 Jerkeman M et al. — Hemasphere. 2025;9(10):e70233. https://doi.org/10.1002/hem3.70233 Dabrowska-Iwanicka A, Nowakowski GS. — Blood. 2024;144(25):2573-2582. https://doi.org/10.1182/blood.2023023561 Walker JS et al. — Blood Cancer J. 2025;15(1):120. https://doi.org/10.1038/s41408-025-01253-5 Rutherford SC. — Hematology ASH Educ Program. 2025(1):489-495. https://doi.org/10.1182/hematology.2025000106

BACKGROUND:The addition of a FLT3 inhibitor (FLT3i) to standard chemotherapy to treat fit newly diagnosed (ND) patients with FLT3-mutated acute myeloid leukemia (AML) represents the standard of care resulting from clinical trial results. However, evidence regarding FLT3i adoption in routine clinical practice is still scarce. METHODS:Clinical data are reported from 394 ND patients with FLT3-mutated AML enrolled in the retrospective observational Italian Cohort Study on FLT3-mutated patients with AML and treated with an upfront intensive regimen with (FLT3i group, n = 92) or without (CT group, n = 302) the addition of a FLT3i. RESULTS:With a median follow-up time of 34.5 months, an effectiveness benefit obtained by FLT3i incorporation both in terms of overall survival (median, 34.9 in the FLT3i vs 12.7 months in the CT group, p < .01) and relapse-free survival (median, 18.9 in the FLT3i vs 7.6 months in the CT group, p = .01) was documented, with a higher composite complete remission rate (75.4% in the FLT3i vs 62.4% in the CT group, p = .052). FLT3i benefit seemed to be independent from the transplant rate. CONCLUSIONS:In conclusion, the benefit of FLT3i addition to upfront intensive treatment in newly diagnosed FLT3-mutated AML patients was confirmed in a large, real-life cohort study.

Introduction: Several randomized controlled trials have demonstrated superiority of BTK inhibitors (BTKis) over chemoimmunotherapy (CIT) in patients with treatment naïve (TN) CLL. In some of these trials, BTKis have also led to a statistically significant improvement in overall survival (OS). However, it is largely unknown if the adoption of BTKis in TN CLL has improved OS of patients with CLL in the real world (RW). Methods: This is a retrospective, observational study that aimed to explore differences in the OS of patients with TN CLL treated a) in different eras [CIT-era group vs BTKi-era] and b) with BTKis vs fludarabine-cyclophosphamide-rituximab (FCR) in a RW setting. In the latter comparison, we excluded patients >70 years at first-line (1L) treatment and patients with TP53 aberrations. Patients who received 1L treatment for CLL between 2010 and 2020 in 14 countries were included in the study. Patients were allocated to two different groups (CIT-era and BTKi-era groups) according to the actual use of BTKis in each country. The year when the use of BTKis surpassed 25% was defined as the cutoff year for each country. Cases treated before the cutoff year were allocated to the CIT-era group, and cases treated after the cutoff year were allocated to the BTKi-era group. OS was defined as the time from CLL-directed treatment to death (event) or last follow-up date (censoring). For the propensity score matching (PSM), we matched patients based on age at 1L initiation, biological sex, and TP53 aberrations for the group comparison and on age at 1L initiation and biological sex for the BTKis vs FCR comparison. Results: A total of 5642 patients (CIT-era group: 4321 and BTKi-era group: 1321) from 37 centers were eligible for the study. The cutoff year was 2020 for the Czech Republic and Russia, 2019 for Brazil, Croatia, Germany, Greece, 2018 for Israel and Turkey, 2017 for Italy and Spain, and 2016 for Switzerland and the United Kingdom. Cases treated in India and Serbia did not reach the 25% cut-off and were allocated to the CIT-era group. BTKis represented the most common treatment in 1L for the BTKi-era group [484 (37%), ibrutinib-based: 443 (91.5%), acalabrutinib-based: 34 (7%), and zanubrutinib-based: 7 (1.5%)], while only 67 (5.1%) cases were treated with venetoclax-based regimens, reflecting the later approval of these regimens in 1L. In the CIT-era group, FCR (1478, 34.1%) chlorambucil-based (1131, 26.2%) and bendamustine plus anti-CD20 antibody (549, 12.7%) were the most common treatments. The use of BTKis in 1L in the CIT-era group was minimal (141, 3.3%). In both groups, most patients were males [2755 (64%) in the CIT-era group and 836 (63%) in the BTKi-era group, p=0.8]. Patients in the CIT group were younger at the start of 1L treatment [67 years (IQR=59-74) vs 69 (IQR=62, 76) p=0.001 for the CIT and BTKi-era groups, respectively]. TP53 mutations and del(17p) were similarly distributed among the two groups [del(17q): 304 (11%) vs. 130 (13%), p=0.09 | TP53 mutations: 202 (15%) vs. 100 (12%), p=0.09]. Unmutated immunoglobulin heavy variable (IGHV) gene status and del(11q) were more frequent in the CIT-era group [449 (19%) vs 126 (15%), p= 0.02 | 1.209 (65%) vs 532 (59%), p= 0.003, respectively]. The follow-up time from 1L treatment was longer for the CIT group [64 months (IQR: 31-98) vs 48 (IQR: 22- 63)] for CIT and BTKi groups, respectively. OS was similar between the two groups [HR: 0.98 (95%CI: 0.88-1.10), p=0.8), median OS: CIT-era group: 7.8 years (95% CI: 7.5, 8) vs BTKi-era group: not reached (7.5, not estimable (NE)]. However, the OS difference was statistically significantly better for the BTKi-era group when we compared OS with PSM for age at 1L initiation and biological sex (HR=0.88 (95%CI: 0.79-0.99), p= 0.04) and for age at 1L initiation, biological sex, and TP53 aberrations [HR:0.73 (95%CI: 0.61-0.88), p< 0.001]. Finally, in the PMS analysis, the OS of patients treated with BTKis was not statistically significantly different compared to cases treated with FCR in 1L (HR: 0.80 (95%CI: 0.56, 1.15), p= 0.2). The median OS for patients treated with BTKis (n=211) and FCR (n=1259) was 10 years (95% CI: 10, NE) and 10.8 years (95% CI: 9.8-11.9), respectively. Conclusion: Our findings show that the availability of BTKis has improved the OS of patients with TN CLL. Patients treated with BTKis had a similar OS with cases treated with FCR in the RW setting.

Introduction Management of chronic lymphocytic leukemia (CLL) has advanced significantly over the past decade with the introduction of targeted therapies (TT). Despite that, important challenges persist in optimizing treatment, especially for patients (pts) with concurrent cardiovascular comorbidities (CVC). We examined real-world treatment patterns and outcomes among pts with CLL and CVC, aiming to better understand therapeutic approaches and effectiveness in this complex population. Methods This retrospective multicenter longitudinal study included pts diagnosed with CLL between 2010 and 2020 (index period), who had at least one CVC at diagnosis or prior to first-line treatment (1L) initiation. Demographic and clinical variables were collected from physician-reported records. Pts were followed from the index date until the last follow-up (f/u), end of study (September 2024), or death, whichever came first. Clinical outcomes were assessed following 1L initiation and were described for both the overall study population and pts who received only TT. Results A total of 1393 pts from 20 centers in 7 countries were included. Most pts were male (898/1393, 64.5%) and had received at least 1 line of CLL-directed treatment (857/1393, 61.6%). The median f/u from diagnosis and 1L initiation were 8.4 years (yrs) [IQR=8-9] and 4 yrs [IQR=1.9-6.9], respectively. The median age (mAge) at diagnosis and 1L was 69 (IQR=62-76) and 71 (IQR=64-78) yrs, respectively. Most pts were diagnosed with arterial hypertension (1112/1393, 79.8%), followed by atrial fibrillation/flutter (AF) (180, 12.9%). Ischemic heart disease [excluding myocardial infarction (MI)], stroke, cardiomyopathy, MI, heart failure, other cardiac arrythmias (excluding AF), and cardiac valve disease were present in 139 (10%), 85 (6.1%), 61 (4.4%), 59 (4.2%), 52 (3.7%), 41 (2.9 %), 31 (2.2%), respectively. At the time of 1L initiation, most pts had unmutated IGHV genes (316/547, 57.8%), while 94/641 (14.7%) had TP53 aberrations. The most common 1L treatments were chlorambucil-based (CHL) regimens [295/857 (34.4%), CHL monotherapy: 117 (13.7%) and CHL plus anti-CD20 monoclonal antibody: 178 (20.1%)] and BTK inhibitors (BTKis) [141/857 (16.5%), ibrutinib (I): 92 (10.7%), acalabrutinib (A): 45 (5.3%), zanubrutinib (Z): 4 (0.5%)]. Fludarabine-cyclophosphamide-rituximab (FCR) and bendamustine-rituximab (BR) were used in 133 (15.6%) and 53 (6.2%), respectively. Venetoclax-based (ven) regimens were used in 55 [6.4%, 50 (5.8%) received ven-obinutuzumab] pts. I plus ven was used in 7 (0.8%) pts. After 2020, the use of BTKis [86/234 (36.7%), A: 43 (18.8%), I: 39 (16.7%), Z: 4 (1.7%)] and ven regimens (48, 20.5%) increased markedly, while chemoimmunotherapy use declined [CHL regimens: 43 (18.4%), BR: 12 (5.1%) and FCR: 5 (2.1%)]. The overall survival (mOS) and time to next treatment or death (mTTNTD) from 1L initiation were 8.4 yrs (95%CI=7.7-9.4) and 3.6 yrs (95%CI=3.2-4), respectively. Of the pts who received TT only, the mOS was not reached [95%CI=5.6 yrs, not estimable (NE)], and mTTNTD was 5.6 yrs (95%CI=4.5-NE). The 3-year-TTNTD for BTKis [mAge: 73yrs], ven regimens (mAge: 69yrs), FCR (mAge: 61), and CHL regimens (mAge: 75yrs) was 71% (95%CI=62-80), 87.1% (95%CI=74-100), 67.5% (95%CI=60-76) and 44.2% (95%CI=39-51), respectively. Overall, 54/141 (38.3%) pts discontinued BTKis in 1L. The reasons were toxicity (tox) (20, 14.2%, CV tox: 9/20 and non-CV tox: 11/20), disease progression (PD) (15, 10.6%), CLL-unrelated (CLL-u) deaths (13, 9.2%) and other reasons (6, 4.2%). Of the 55 pts who received ven regimens, 6 (10.9%) discontinued treatment earlier than scheduled [non-CV tox: 3 (5.5%), other reasons: 2 (3.6%), and CLL-u death: 1 (1.8%)]. FCR (n=133) was discontinued earlier than scheduled in 15 (11.3%) pts [non-CV tox: 12 (9%), PD: 1 (0.8%), other reasons: 2 (1.5%)]. Finally, CHL regimens (n=295) were discontinued in 36 (12.2%) pts [non-CV tox: 14 (4.7%), PD: 12 (4.1%), other reasons: 9 (0.8%), CLL-u death: 1 (0.3%)]. Conclusion We highlight a shift toward the use of TT in pts with CLL and CVC and illustrate differential patterns in TTNTD and discontinuation according to regimen. Differences in pts age and treatment duration across regimens may have contributed to the varying incidence of CV tox leading to discontinuation, especially in pts receiving BTKi. The study's retrospective nature, age and f/u differences preclude any comparison of TTNTD between treatments.

Acute myeloid leukemia (AML) is mainly a disease of the elderly: however, knowledge about the outcomes of treatment of core-binding factor (CBF) AML in an older population is limited. We retrospectively collected data on 229 patients with CBF-AML followed long-term in the last two decades. The 5-year overall survival was 44.2% (95% confidence interval [95% CI]: 39.9-47.5) and the 5-year event-free survival was 32.9% (95% CI: 25.5-40.1). In a subgroup of patients ≥70 years old who completed intensive therapy (induction + ≥3 courses of consolidation including autologous stem cell transplantation: 10 patients) the median event-free survival was 11.8 months (95% CI: 9.4-15.2) and overall survival was 40.0% (95% CI: 36.4- 44.1) at 5 years. In univariate analysis, age ≥70 years (hazard ratio [HR]=1.78, 95% CI: 1.15-2.54, P=0.008), failure to achieve remission following induction (HR=8.96, 95% CI: 5.5-13.8; P<0.0001), no consolidation therapy (HR=0.75, 95% CI: 0.47-1.84, P=0.04) and fewer than three cycles of consolidation (HR=1.48, 95% CI: 0.75-3.2; P=0.0004) predicted poorer event-free survival. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a complete remission seems to be the most important first step and at least three cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.

This study aimed to define the incidence and risk factors for diffuse large B cell lymphoma variant of RT (DLBCL-RT) in 976 patients with CLL who received ibrutinib therapy. DLBCL-RT was recorded in 83 (8.5%) patients, with a 7-year 15.6% rate. Most patients exhibited clinical signs of aggressive lymphoma, enlarged lymph nodes in 83%, cytopenia in 60%, and Suvmax values ≥ 5 at CT/PET in 98%. Among patients for whom the data was available, 83% had unmutated IGHV, 60% TP53 disruption, 26% mutated NOTCH1, 10% were categorized in subset #8 and 82% had a clonally-related lymphoma. Response to chemoimmunotherapy was achieved by 32% of patients. Median OS was 4.7 months, with cytopenia at DLBCL-RT diagnosis being the only significant factor for inferior survival (HR, 1.68). In multivariable analysis, factors predictive for increased risk of DLBCL-RT were age <70 years (HR: 1.98, p = 0.019), TP53 disruption (HR: 1.72, p = 0.044), with a trend to significance for prior treatment (HR: 1.91, p = 0.065). According to the number of these risk factors, DLBCL-RT rate varied from 4% to 22.6% (p < 0.0001). In conclusion, patients with CLL receiving ibrutinib with age <70 years, TP53 disruption and previously treated are at increased risk for developing DLBCL-RT and deserve close monitoring.

Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.

In chronic lymphocytic leukemia (CLL), the role of complex karyotype (CK) for prognostic stratification remains a topic of debate, and the impact of specific cytogenetic abnormalities is still unclear. This study aims to investigate the clinical and biological features of CLL with t(14;19)(q32;q13) (tCLL) involving the BCL3 gene. Patients with tCLL were younger and more commonly presented unmutated IGHV gene, subset #8 stereotypy, trisomy of chromosome 12, and complex karyotype than other patients without t(14;19) (oCLL). The presence of t(14;19) was associated with a shorter time to treatment and overall survival compared to oCLL. Gene expression analysis revealed a unique transcriptome profile in tCLL, characterized by the upregulation of BCL3 and the activation of B-cell receptor, PI3K-Akt. Conversely, apoptosis-related pathways were suppressed in tCLL. While the BTK gene was upregulated, the BCL2L11 gene, coding for the pro-apoptotic protein BIM, was downregulated. Notably, patients with tCLL were characterized by a trend (p = 0.058) for a longer time to the next treatment with BTK inhibitors (BTKi) compared to those treated with a venetoclax-based (Ven-based) regimen. We underscore the adverse outcomes of tCLL, its distinct molecular features and gene expression patterns. Therefore, our data suggest that identifying tCLL could help tailor therapeutic approaches.

Introduction: Patients with CLL and mutated immunoglobulin heavy variable (IGHV) genes (M-CLL) are clinically heterogeneous. While genomic aberrations contribute to adverse outcomes in certain M-CLL subgroups, they do not fully account for M-CLL heterogeneity, suggesting the need for further research. Methods: This is a retrospective, observational study aiming to identify factors associated with shorter overall survival (OS) after first-line (1L) treatment in M-CLL. The study included patients diagnosed with M-CLL between 2000-2022 in 26 centers with a follow-up >6 months after 1L treatment. Special attention was given to immunogenetic features, including BcR stereotypy. Besides, we developed a novel immunogenetic metric that considers the amino acid composition of the germline IGHV genes, following the IMGT physicochemical classification table. Each aligned position across the IGHV gene sequences was assigned different scores based on the relation between the assessed amino acids: 0 if identical, 1 if in the same physicochemical group, and 2 if in different groups. This scoring system enabled the generation of a distance matrix for all IGHV genes, which was then used as input for hierarchical clustering, leading to the creation of 15 clusters. Univariable (UVA) and multivariable (MVA) analyses were performed to identify risk factors associated with shorter OS. The variables assessed in the UVA were age at 1L initiation, biological sex, type of 1L treatment, TP53 mutations, FISH aberrations, and karyotype. Results: 1933 patients from 26 centers in 12 countries were evaluated. The median age at 1L treatment was 69 years (IQR: 62-76). Most patients were males (1184, 61.3%) and 1249 (64.7%) were alive at last follow up. The median follow-up from 1L treatment was 4.6 years (IQR: 1.8-8.1). Before 1L treatment, 623/1090 (57.2%), 195/1077 (18.1%), 107/1342 (8%) and 103/1240 (8.3%) carried del(13q), trisomy 12, del(17p) and del(11q) detected by FISH, respectively. TP53 mutations were detected in 118/1012 (11.7%) cases and karyotype with ≥3 and ≥5 (CK5) aberrations in 82/610 (13.4%) and 17/610 (2.8%) cases, respectively. The most common stereotyped subsets were #2 (59/1112, 5.3%) and #4 (11/1112, 1%). Most patients (1346, 69.8%) received 1 line of treatment, while 344 (17.8%), 138 (7.2%) and 101 (5.2%) received 2, 3, and ≥4 lines, respectively. FCR was the most common 1L treatment (395, 20.8%) followed by chlorambucil (Chl) monotherapy (320, 16.9%). BTK inhibitors (BTKis) were used in 241 cases [12.5%; ibrutinib: 162 (8.3%), acalabrutinib 65 (3.4%), zanubrutinib: 10 (0.5%), pirtobrutinib 4 (0.2%)]. BR, Chl-rituximab and Chl-obinutuzumab were used in 185 (9.8%), 126 (6.6%) and 98 (5.2%) cases, respectively. Finally, 70 (3.6%) received venetoclax-obinutuzumab 1L treatment and 33 (1.7%) received ibrutinib-venetoclax. The median OS was 11 years (95% CI: 10.4-11.8). In UVA, older age at 1L, male sex, TP53 aberrations (TP53-abs), del(11q) and CK5 were associated with shorter OS (p<0.001, p=0.03, p<0.001, p<0.001, p=0.001, respectively). Compared to FCR/BR, targeted treatments led to a similar OS (p=0.3), while other non-targeted treatments resulted in shorter OS (p<0.001). Regarding the new immunogenetic metric, clusters 13 (IGHV1-24 and IGHV1-69-2 genes), 4 (IGHV2 genes) and 8 (IGHV3-13) associated with shorter OS (p=0.07, p=0.02, and p=0.002, respectively). To assess the relevance of this finding, we scanned our immunogenetic database consisting of 42,154 M-CLL IG rearrangements. While the IGHV1-24, IGHV1-69-2 and IGHV3-13 genes were very rare (0.6%), IGHV2 gene rearrangements represented a sizeable M-CLL subgroup (1969 cases, 4.7%). In MVA, only age at 1L and CK5 retained statistical significance for OS (HR: 1.08, 95% CI: 1.04-1.3, p<0.001, HR: 2.5, 95% CI: 1.04-6.2, p=0.04, respectively). In patients <70 years, older age at 1L, TP53-abs, del(11q), and clusters 4 and 8 were associated with shorter OS (p<0.001, p=0.01, p=0.007, p=0.01, and p=0.01, respectively). The type of treatment effect was similar to the whole cohort. In MVA, age at 1L andTP53-absretained statistical significance (HR:1.07, 95% CI:1.02-1.11, p=0.003, HR:1.9, 95% CI:1.02-3.5, p=0.04, respectively). Conclusion: Older age, CK5 and TP53 aberrations are independent high-risk factors for shorter OS in M-CLL. Utilization of IGHV2 subgroup genes emerged as adverse-prognostic for OS and merits further evaluation.

Background. Clinical trials have documented the efficacy of ibrutinib in combination with venetoclax in CLL. Indeed, Ibrutinib plus venetoclax (I+V) is the first all oral fixed duration treatment approved for treatment naive patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) based on the results of the Captivate (phase II) and GLOW (phase III) trials. Discontinuation rates due to adverse events (AEs) were 5% in the Captivate trial, which enrolled patients with ≤70 yrs, and 10.4% in the GLOW trial, which included older and comorbid patients without del(17p). We hypothesized that, when appropriately selected, patients of all ages can tolerate and benefit from I+V. Methods. This is the interim analysis of a retrospective multicenter study aiming at investigating the safety and efficacy of I+V in the real-world setting. Patients with previously untreated CLL/SLL, 18 years or older, who have completed 3 cycles of I and started V were eligible for the study. Patients treated with I+V in clinical trials were excluded. All patients were scheduled to receive fixed-duration I+V. After 3 lead-in cycles of I (420mg once daily), V was added for 12 cycles with the standard weekly ramp-up (20-50-100-200-400mg). The primary objective of this study was to determine the rate of discontinuation due to toxicity of I+V. Secondary objectives included overall response (ORR), safety, baseline characteristics associated with treatment discontinuation, and survival analysis. Results. We gathered data from 220 patients (intention-to-treat population) from 45 institutions in 11 countries. At the time of data cut-off, 14 patients were still receiving I lead-in, and 4 discontinued I before initiating V [reasons for discontinuation: 2 atrial fibrillation (AF), 1 diarrhea, and 1 grade 5 infection]. Overall, 202 patients were included in the analysis (treated population). The median age at I+V initiation was 65 years [interquartile range (IQR) 56-70]. Most patients were males (121, 59.9%), and 24 (12.3%) had an ECOG performance status of 2 or higher. Regarding prognostic markers, 112/179 (62.6%) patients carried unmutated IGHV genes, and 29/148 (16.4%) and 7/192 (3.6%) had del(11q) and del(17p) (determined by fluorescence in situ hybridization), respectively. TP53 mutations were present in 7/171 (4.1%) cases. At the data cut-off (30 June 2025), 201 (99.5%) patients were alive, and 151 (82.1%) were still on treatment. Among the 190 with at least 6 months of follow-up available for response assessment, the overall response rate was 95.6%. AEs of any grade were present in 122 (61.6%) patients. Specifically, 86 (43.4%) experienced non-hematological AEs, of which 23 (11.3%) were grade 3 or higher (including, 9 infective events, including 2 febrile neutropenia; 4 arterial hypertension; 3 AF; 1 rash; 1 diarrhea; 1 ventricular arrhythmia). No fatal treatment-related AEs have been reported to date. Seven (3.6%) patients developed laboratory tumor lysis syndrome (TLS), but no clinical TLS occurred. One patient developed Richter transformation (large B-cell lymphoma variant). Regarding hematological AEs, grade 3 or higher neutropenia, anemia and thrombocytopenia occurred in 48 (64.8%), 9 (20.9%), and 6 (15%) of patients, respectively. One patient died after being diagnosed with lung cancer. Seven (3.4%) patients discontinued I+V due to toxicity. Reasons for discontinuation included: acute generalized exanthematous pustulosis; AF; ventricular arrhythmia; heart failure (I was discontinued but V was completed as per treatment plan); neutropenia and heart failure; recurrent urinary tract infections and diarrhea; AF and stroke. The median age of patients who discontinued I+V treatment was 64.5 years (IQR 64-74). Five (71.4%) had at least one comorbidity: the most common was arterial hypertension (3/7, 43%). The discontinuation rates for patients in a Captivate-like (aged ≤ 70 years) and Glow-like (≥ 65 years without del17p) subgroups were 3.2% (5/153) and 4.9% (5/102), respectively. Conclusions. We herein confirm the efficacy and tolerability of I+V in the real-world setting. Notably, the discontinuation rate of I+V in our study compares favorably with the discontinuation rate in pivotal clinical trials, even in elderly patients, suggesting that I+V is an appropriate treatment option in a broad patient population. Longer follow-up will allow the assessment of real-world progression-free survival and time to next treatment after I+V.

In Chronic Lymphocytic Leukemia (CLL), t(14;19)(q32;q13), leading to the overexpression of BCL3, is found in ∼1

Castleman disease (CD) is a group of lymphoproliferative disorders that share common histopathological features yet have widely different aetiologies, clinical features and grades of severity as well as treatments and outcomes. Siltuximab is currently the only therapy approved by the FDA and EMA for idiopathic multicentric CD and is recommended as first-line therapy in treatment guidelines. Despite the extensive characterization of siltuximab treatment in clinical trials, available evidence from real-world practice is still scant. This collection of clinical experiences focuses on patients treated with siltuximab therapy, particularly regarding the idiopathic multicentric CD diagnostic work-up, and on treatment administration in patients with complex disease entering differential diagnosis with CD or concomitant diseases. Thus, these data help further characterize and improve the use of siltuximab in real practice in terms of effectiveness and safety of long-term administration as well as consequences of treatment interruption.

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

Novel drugs have profoundly changed the outcomes in chronic lymphocytic leukemia (CLL) patients, and the traditional prognostic factors that were identified in the era of chemoimmunotherapy need to be validated in the context of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are the immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)/TP53 abnormalities, and the complex karyotype. In this review, we discuss the prognostic role of these genomic markers in relation to novel treatments. Moreover, we present and discuss new scoring systems that were elaborated and validated in the era of new drugs. In routine clinical practice, the application of an extensive genomic work-up with validated prognostic markers could improve the identification of “very high-risk” CLL patients who could benefit from novel, more effective targeted treatments.

AbstractWe performed a cohort study that included all patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who received ibrutinib in the Italian National Health Service. With a median follow‐up of 42.2 months (IQR 30.8–54.6 months), the study involved 3306 patients with a median age of 72.1 years, of whom 42.6% had received ≥2 previous lines of treatment. The estimated 24‐month probabilities of being on treatment and alive were 57.9% (95% confidence interval [CI]: 59.6–56.2) and 76.6% (95% CI: 75.2–78.1), respectively. The median time to treatment discontinuation (TTD) was 31.3 months (95% CI: 29.5–33.5). Out of 3306 patients, 2015 (60.9%) discontinued treatment, with 993 cases attributed to death or disease progression (30.0% of all cases). Among the 1022 patients who discontinued treatment for reasons other than progression or death, 564 (17.1%) patients did so due to toxicity or medical decision, while 458 patients (13.8%) were lost to follow‐up. Multivariable analysis revealed that age, Eastern Cooperative Oncology Group Performance Status, the number of previous lines of therapy, refractoriness to the last treatment, and reduced renal function were associated with shorter TTD and overall survival (OS). The coexistence of 17p− and TP53 mutations had an independent unfavorable impact on TTD and OS. Nonstandard doses were associated with shorter TTD and advanced stage with shorter OS. The median OS postprogression and postdiscontinuation for other reasons were estimated at 12.9 (95% CI: 11.3–16.2) and 22.7 months (95% CI: 20.2–28.3), respectively. This large real‐world study shows that ibrutinib is an effective treatment for R/R CLL. Baseline patient characteristics and double‐hit TP53 aberrations were associated with inferior prognosis, and discontinuation due to CLL progression portended a poor outcome.