No lymphocytosis increase after cBTKi is a rare phenomenon except for CD49d-positive CLL mainly expressed in trisomy 12 Luca Laurenti, Feliciana Guglielmi, Antonio Mosca, Candida Vitale, Maria Chiara Montalbano, Gianmarco Favrin, Isacco Ferrarini, Andrea Galitzia, Raffaella Pasquale, Massimo Moratti, Gioacchino Catania, Roberta Murru, Diana Giannarelli, Enrica Antonia Martino, Riccardo Moia, Antonella Zucchetto, Erika Tissino, Francesco Autore, Annamaria Tomasso, Luca Stirparo, Tommaso Quaranta, Pier Luigi Abbate, Valter Gattei, Gianluca Gaidano, Massimo Gentile, Mauro Krampera, Giuliana Farina, Andrea Visentin, Vanessa Innao, Marzia Varettoni, Marta Coscia, Idanna Innocenti Blood Advances, 2026
Familial forms of chronic lymphocytic leukemia have a worse prognosis than sporadic forms: an Italian case-control study Alberto Fresa, Idanna Innocenti, Annamaria Tomasso, Candida Vitale, Alessandro Sanna, Anna Maria Frustaci, Andrea Visentin, Azzurra Romeo, Paolo Sportoletti, Annamaria Giordano, Francesca Perutelli, Roberta Murru, Francesca Romana Mauro, Antonio Mosca, Francesca Morelli, Roberta Laureana, Andrea Galitzia, Ilaria Angeletti, Esmeralda Conte, Riccardo Moia, Giovanni D’Arena, Raffaella Pasquale, Francesco Autore, Jacopo Olivieri, Luca Stirparo, Giulia Benintende, Francesco Angotzi, Florenzia Vuono, Andrea Corbingi, Maria Ilaria Del Principe, Diana Giannarelli, Alessandra Tedeschi, Marta Coscia, Eugenio Sangiorgi, Dimitar G. Efremov, Luca Laurenti Blood Advances, 2025 Familial chronic lymphocytic leukemia (CLL) constitutes 5% to 7% of CLL and has previously shown a more aggressive pattern of evolution than sporadic CLL, even if no difference in overall survival (OS) has been observed. This multicenter case-control study aimed to compare clinical features, molecular biomarkers, and patient outcomes of familial and sporadic CLL. Adult patients with CLL were enrolled from 18 Italian centers, with familial CLL defined as having at least 1 first-degree relative affected by CLL. Patients with sporadic CLL were matched for biological sex and age at diagnosis within 4 years (1:2 ratio). The Kaplan-Meier method was used to evaluate time-to-event outcomes. Of 480 enrolled patients, 160 had familial CLL and 320 sporadic CLL. Significant clinical and molecular differences between familial and sporadic CLL included the presence of lymphadenopathies at diagnosis >5 cm (7.2% vs 2.8%; P = .027) and unmutated immunoglobulin heavy chain variable gene (55.5% vs 36.2%; P < .001). First- and second-line treatments were required in 55.6% and 46.1% of familial CLL and 43.1% (P = .001) and 29.6% of sporadic CLL (P = .034), respectively. Both time to first treatment (TTFT) and time to next treatment (TTNT) were shorter for familial CLL than for sporadic CLL (median TTFT, 66 months vs 108 months; P = .005; median TTNT, 60 months vs 94 months; P = .030, respectively), although familiarity has not emerged as an independent prognostic factor. No difference in OS was observed. Considering the more aggressive course of familial CLL but similar OS, CLL screening in relatives is not recommended.
Rethinking the feasibility and safety of venetoclaxobinutuzumab in chronic lymphocytic leukemia: nontraditional factors may play a role in clinical practice Anna Maria Frustaci, Andrea Galitzia, Mariano Lucignano, Lorena Appio, Jacopo Olivieri, Alessandro Sanna, Claudia Baraté, Fabrizio Pane, Luana Schiattone, Beatrice Casadei, Isacco Ferrarini, Amalia Figuera, Paolo Sportoletti, Giacomo Loseto, Caterina Stelitano, Andrea Visentin, Melania Celli, Francesca Romana Mauro, Massimiliano Palombi, Marta Coscia, Vanessa Innao, Riccardo Moia, Marina Motta, Filomena Russo, Monica Tani, Annalisa Arcari, Elia Boccellato, Chiara Borella, Enrico Capochiani, Angela Ferrari, Massimo Gentile, Roberta Giachetti, Annamaria Giordano, Martina Bullo, Enrico Lista, Luigi Malandruccolo, Maurizio Musso, Marzia Varettoni, Federico Vozella, Francesca Cibien, Michele Merli, Laura Nocilli, Maria Cristina Pasquini, Azzurra Anna Romeo, Valentina Rossi, Gloria Turri, Anna Vanazzi, Marina Cavaliere, Alessandro Gozzetti, Lara Crucitti, Moira Lucesole, Marina Deodato, Annamaria Tomasso, Arianna Zappaterra, Roberta Murru, Caterina Patti, Luca Laurenti, Alessandra Tedeschi Haematologica, 2025 The concept of fitness for novel agents in chronic lymphocytic leukemia (CLL) remains debated. Comorbidities and treatment-related logistics are increasingly recognized as key factors in treatment feasibility. Venetoclax-obinutuzumab (VO) has demonstrated efficacy in both fit and unfit patients in clinical trials, yet real-world data remain limited. This retrospective, multicenter study analyzed disease- and patient-related factors affecting VO management and outcomes in 271 patients. Fitness was assessed using comorbidity indices (CLL-CI, CIRS, CCI), ECOG-PS, and caregiver need. Adverse events (AEs) and treatment modifications were evaluated across four treatment phases. Median age was 66 years (19% ≥75); 83% had comorbidities, 34% required polypharmacy, and 10% needed caregiver support. Overall, 96% completed debulking, 89% the full regimen, while 11% discontinued due to toxicity (Tox-DTD). Grade ≥3 AEs occurred in 55%, tumor lysis syndrome in 6%, severe infusion-related reactions in 5%. Overall, 3.3% died during treatment. Unfit patients did not show a significantly higher risk of treatment modifications due to AEs. Dose adjustments were more frequent during debulking. None of the validated fitness scores predicted treatment feasibility or Tox-DTD. Global feasibility was impacted by age (p .002), prior malignancies (p .003), prolonged steroid pre-treatment (p
Salvage treatment after covalent BTKi failure: An unmet need in clinical practice in Waldenstrom macroglobulinemia Anna Maria Frustaci, Arianna Zappaterra, Andrea Galitzia, Andrea Visentin, Michele Merli, Rita Rizzi, Isacco Ferrarini, Simone Ferrero, Vanessa Innao, Claudia Baratè, Pierluigi Zinzani, Benedetta Puccini, Francesco Autore, Monica Tani, Angela Ferrari, Gioacchino Catania, Maura Nicolosi, Raffaella Pasquale, Marina Motta, Roberta Murru, Silvia Gambara, Francesca Rezzonico, Marzia Varettoni, Emanuele Cencini, Enrico Lista, Nicolò Danesin, Bianca Maria Granelli, Marina Deodato, Francesco Piazza, Alessandra Tedeschi Hemasphere, 2025 Waldenstrom Macroglobulinemia (WM) therapeutic scenario has radically changed over the past 20 years with the development of effective therapies able to improve patients’ outcomes.1 The approval of covalent Bruton Tyrosine Kinase inhibitors (cBTKi), ibrutinib since 20 152 and zanubrutinib afterwards,3 replaced the role of chemoimmunotherapy (CIT) at least in the relapsed/refractory setting. However, despite the remarkable efficacy of cBTKi, the continuous treatment paradigm is associated with resistance development, clonal evolution and relapses, with about 13% of progressions with both zanubrutinib and ibrutinib at the ASPEN trial final analysis.4 Intolerance represents another main reason for discontinuation and this is more true with the first-in-class cBTKi (20% vs. 8.9% with zanubrutinib)4 and in clinical practice, where unselected patients are treated. While toxicity-related withdrawal allows a window of opportunity for administering alternative cBTKi,5 few therapeutic options have been evaluated for relapsed/refractory,6, 7 and none have received approval, rendering this scenario the most significant unmet clinical need in WM. We conducted this retrospective analysis to assess salvage therapy outcomes following cBTKi (cBTKi-S) in 22 Italian centers. This study was institutional review board approved by each participating institution in accordance with the Declaration of Helsinki. All patients receiving at least one dose of cBTKi-S were considered. Baseline clinical and disease characteristics at cBTKi-S initiation were reviewed. MYD88 and CXCR4 mutation tests were locally performed by Sanger sequencing. Duration of first cBTKi was calculated from therapy initiation to discontinuation. Reasons for cBTKi discontinuation, type of cBTKi-S, responses and progression assessment, according to modified IWWM-11 criteria8 and duration of response (DOR) were reviewed. DOR was calculated in responding patients from cBTKi-S initiation to progression. Progression-free survival (PFS) was defined as the time from cBTKi-S to progression or death due to any cause, OS as the time from cBTKi-S to death due to any cause. Kaplan-Meier analysis was used to estimate cBTKi-S survival outcomes and the log-rank test was applied to compare time to event outcomes between groups. From December 2015 to November 2023, 233 consecutive WM patients treated with cBTKi were included. Of these, 78 (33.5%) discontinued cBTKi (74 ibrutinib, 4 zanubrutinib) and received subsequent salvage therapies, representing our study population. Median age of the 78 patients was 75.5 years (range, 46.8–92.8). All but two received cBTKi for relapsed/refractory disease after a median of two prior lines (range, 1–6), including CIT in 92.3%. Primary reasons for cBTKi discontinuation were progression (69.2%), intolerance (29.5%) and secondary malignancy (1.3%). All the 24 intolerant patients had been treated with ibrutinib. Among them: 7 (29.2%) had permanently reduced dosage and 8 (33.3%) discontinued therapy for more than 7 days, then unsuccessfully rechallenged before shifting to a next generation inhibitor. Median time of cBTKi exposure was 16.0 months (range, 1.2–98.4), being 24.3 months in the group of progressive patients versus 10.8 months in intolerants. Patients’ characteristics and reasons to receive cBTKi-S in progressive and intolerant population are reported in Table 1. cBTKi-S treatment included: CIT (31 patients, 39.7%), proteasome inhibitors in combination with rituximab (PI 16, 20.5%), venetoclax (9, 11.5%), non-covalent BTKi (ncBTKi 8, 10.3%), alternative cBTKi (10, 12.8%), and clinical trials (4, 5.1%). To avoid IgM rebound, the cBTKi was discontinued only after cBTK-S start in all cases except those enrolled in clinical trials as per protocol compliance. Table 1 reports treatment type stratified according to salvage reason. Median follow-up of cBTKi-S treatment was 10.5 months. Overall response (ORR) to cBTKi-S was achieved in 39 patients (50%), including six complete/very good partial remissions (7.7%). ORR according to different cBTKi-S were: 38.7%, 37.5%, 66.7%, 37.5%, 90.0% and 75.0% for CIT, PI, venetoclax, ncBTKi, alternative cBTKi and clinical trials, respectively. Disease remained stable in 14 patients (17.9%), while 25 (32.1%) progressed. Overall, 7/39 (17.9%) responders further progressed while on cBTKi-S and 2 underwent further lines of therapy. None of the baseline clinical and disease characteristics, including MYD88 and CXCR4 mutational status, influenced response to cBTKi-S. BTK mutational status at progression was not assessed. Median PFS, DOR and overall survival (OS) for the entire cohort were 8.1, 18.0 and 21.0 months, respectively. MYD88L265P mutated patients showed a significantly better PFS and OS compared to wild type patients (p = 0.048 and p = 0.001, respectively). A clinically meaningful difference with fewer PFS (HR 0.62, 95% CI 0.33–1.15) and OS events (HR 0.7, 95% CI 0.32–1.53) was observed in the intolerant population (median PFS: 16.0 months; OS: not reached) compared to the cBTKi progressive group (median PFS: 6.2 months; OS: 17.3 months). In fact, the 1-year PFS (65% versus 35%, respectively) resulted statistically significant (p = 0.016), while no difference was observed in terms of OS (78.3% versus 66.6%, respectively, p = 0.26). When considering cBTKi-progressive patients only, PFS and OS were not affected by the regimen administered. PFS was 5.8, 5.0, 6.9, 3.9 months for CIT, PI, venetoclax and ncBTKi, respectively while it was not reached for clinical trials. Patients pretreated with 1-2 versus ≥3 lines at cBTKi-S had a significantly better PFS, with each additional line of therapy affecting both PFS (HR 1.84, 95% CI 1.41–2.39, p < 0.001) and OS (HR 1.9, 95% CI 1.39–2.6, p < 0.001). Time on previous cBTKi instead, did not affect PFS or OS and did not differ between patients receiving cBTKi for ≥12 months versus <12 months. Although cBTKi changed the WM treatment paradigm, representing the best salvage treatment after CIT failure, therapeutic challenges persist in case of progression or intolerance. There is a general consensus on the possibility to shift to a next generation cBTKi in case of toxicity-driven discontinuation.9 In our series, despite the limitation of small sample number, we confirm cBTKi shift as a valid option in this setting, with only 2/10 patients (20%) showing disease progression and 18 months DOR in responders. Differently from other lymphoproliferative disorders, in WM there is a lack of approved novel agents beyond ibrutinib and zanubrutinib. In this setting early phase clinical trials with new targeted agents showed promising results. Venetoclax allowed to achieve 75% ORR in cBTKi exposed patients with 30 months median PFS.6 Similarly, in cBTKi-pretreated patients pirtobrutinib led to an ORR of 79%, 22.1 months being the median PFS observed in the whole population.7 In our series, despite a high ORR achieved with venetoclax (67%), PFS was significantly shorter (6.9 months). In addition, we could not confirm the favorable outcomes with pirtobrutinib as only 37.5% showed a response. Bortezomib and CIT may still be considered an option even more in those cases in which the accessibility to compassionate use programs is not readily available. Recently, in a small series of 16 patients relapsing after cBTKi, bortezomib showed an ORR of 88% with a median PFS and OS of 18 and 32 months, respectively.10 In our retrospective series with the same sample size, only 37.5% of patients responded to bortezomib-based treatments with a PFS not reaching 6 months. Similar dismal results were also achieved with CIT (38.7% ORR and 5.8 months PFS). Interestingly, the number of lines received before cBTKi-S significantly impacted both PFS and OS, with the risk of progression or death increasing by approximately 84% to 90% for each additional line received. Our series mirrors an everyday clinical practice population. These suboptimal results may reflect the selection of a distinctive category of patients with a more aggressive disease considering that median cBTKi exposure was 16 months. In particular, our cohort was characterized by a higher rate of MYD88 wild type compared to literature. Of note, it is challenging to accurately determine the true biological risk characteristics of this population, considering that the evaluation of prognostic factors was conducted exclusively using Sanger sequencing and not in all patients, potentially underestimating the actual cohort of patients with high biological risk. The lack of approved salvage treatment after cBTKi failure remains a critical need and raises issues regarding the immediate supply of effective drugs, thus translating in inadequate disease control and treatment initiation under deteriorated clinical conditions. The evidence of better outcomes of cBTKi in second line, underlines the potential importance of initiating BTKi therapy earlier in the disease course, to maximize the benefit. In conclusion, while acknowledging the limitations of this study primarily due to its retrospective nature, our findings provide a snapshot of the current therapeutic landscape in WM after cBTKi failure. Importantly, although none of the baseline disease characteristics influenced response to cBTK-S, the sample size is too small to make any powered evaluation. On this basis, there is an urgent need for approval in this setting. Prospective clinical trials with other targeted agents, immunotherapies, and cellular therapies are currently ongoing in cBTKi-exposed patients to address this therapeutic gap (Figure 1). Anna Maria Frustaci and Alessandra Tedeschi conceived the work. Andrea Visentin, Michele Merli, Rita Rizzi, Isacco Ferrarini, Simone Ferrero, Vanessa Innao, Claudia Baratè, Pierluigi Zinzani, Benedetta Puccini, Francesco Autore, Monica Tani, Angela Ferrari, Gioacchino Catania, Maura Nicolosi, Raffaella Pasquale, Marina Motta, Roberta Murru, Silvia Gambara, Francesca Rezzonico, Marzia Varettoni, Emanuele Cencini, Enrico Lista, Nicolò Danesin, Bianca Maria Granelli, Marina Deodato, Francesco Piazza provided patients data. Anna Maria Frustaci and Arianna Zappaterra collected and assembled the data. Andrea Galitzia performed the statistical analysis. Anna Maria Frustaci, Alessandra Tedeschi, Andrea Galitzia, and Arianna Zappaterra analyzed the data and prepared the manuscript. All authors participated in the critical review and revision of this manuscript and provided approval of the manuscript for submission. Anna Maria Frustaci received honoraria from Janssen, Beigene, Abbvie, AstraZeneca. Andrea Visentin participated scientific advisory boards organized by Johnson & Johnson, Abbvie, AstraZeneca, BeiGene, Takeda. Michele Merli participated scientific advisory boards organized by Eli Lilly. Alessandra Tedeschi received consulting fees and travel support for scientific events from Janssen, Beigene, Abbvie, Lilly, AstraZeneca. Andrea Visentin received advisory board participation fees from Janssen, Abbvie, Beigene, CSL Behring, Astrazeneca, Beigene, and Takeda. Isacco Ferrarini reports research fundings from Abbvie, BeiGene, and Eli-Lilly. Simone Ferrero is a consultant for Janssen, EUSA Pharma, Recordati, Abbvie, and Sandoz; is on the advisory board of Janssen, EUSA Pharma, Recordati, Incyte, Roche, Astra Zeneca, and Italfarmaco; received speaker's honoraria from Janssen, EUSA Pharma, Recordati, Lilly, Beigene, Gilead, Novartis, Sandoz, and Gentili; and received research funding from Gilead, Incyte and Morphosys. Roberta Murru received scientific advisory board participation fees and travel support from Abbvie, AstraZeneca, Beigene, Johnson & Johnson. Marzia Varettoni participated scientific advisory boards and received speaker honoraria from Abbvie, AstraZeneca, Beigene and received advisory board participation fees from Johnson & Johnson. Francesco Piazza participated to advisory board and received speaker honoraria from Kite Gilead, Roche, and BeiGene and participated to advisory board from Abbvie and Johnson & Johnson. Open access publishing facilitated by Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, as part of the Wiley – SBBL agreement. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Acalabrutinib in High-Risk Chronic Lymphocytic Leukaemia Naïve Patients: An Italian Multicenter Retrospective Observational Real-Life Experience Idanna Innocenti, Annamaria Tomasso, Diana Giannarelli, Lydia Scarfò, Roberta Murru, Andrea Visentin, Anna Maria Frustaci, Francesca Morelli, Candida Vitale, Antonio Mosca, Alessandro Sanna, Giuliana Farina, Roberta Laureana, Massimo Gentile, Andrea Galitzia, Raffaella Pasquale, Francesco Autore, Jacopo Olivieri, Azzurra Romeo, Marina Deodato, Luca Stirparo, Andrea Corbingi, Vanessa Innao, Francesca Perutelli, Francesca Martini, Paolo Sportoletti, Alberto Fresa, Maria Ilaria Del Principe, Alessandra Tedeschi, Marta Coscia, Paolo Ghia, Luca Laurenti Hematological Oncology, 2025 grant by AstraZeneca Italia. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Kinetics of lymphocytosis in naïve chronic lymphocytic leukemia patients treated with covalent Bruton's tyrosine kinase inhibitors: An Italian multicenter real-life experience Idanna Innocenti, Antonio Mosca, Annamaria Tomasso, Andrea Galitzia, Lydia Scarfò, Francesca Morelli, Eugenio Galli, Francesca Martini, Eugenio Sangiorgi, Roberta Laureana, Giulia Benintende, Veronica Mattiello, Sabrina Chiriu, Maria I. Del Principe, Giulia Zamprogna, Massimo Gentile, Enrica A. Martino, Emilia Cappello, Maria C. Montalbano, Giuliana Farina, Vanessa Innao, Luca Stirparo, Caterina Patti, Paolo Sportoletti, Alberto Fresa, Gioacchino Catania, Marta Coscia, Silvia Bellesi, Alessandra Tedeschi, Alessandro Sanna, Andrea Visentin, Francesco Autore, Raffaella Pasquale, Livio Trentin, Marzia Varettoni, Paolo Ghia, Roberta Murru, Luca Laurenti Hemasphere, 2024 Chronic lymphocytic leukemia (CLL) therapy has recently undergone a revolution with the introduction of a new class of drugs: covalent Bruton's tyrosine kinase inhibitors (cBTKi), paving the way for a chemotherapy-free approach.1-4 Presently, cBTKi can be utilized in the first line of CLL management, thanks to the results of phase III clinical trials such as RESONATE-2 and ELEVATE-TN, which demonstrated the superiority of Ibrutinib over chemotherapy with chlorambucil5 and acalabrutinib over chemoimmunotherapy with chlorambucil + obinutuzumab,6 in terms of progression-free survival (PFS) in both cases. Ibrutinib exhibited better PFS, overall survival (OS), and overall response rate than the monoclonal anti-CD20 antibody ofatumumab in previously treated patients with CLL.7 Additionally, the ASCEND study, another phase III randomized clinical trial, demonstrated that acalabrutinib significantly improved PFS compared to a physician's choice of Idelalisib + rituximab or bendamustine + rituximab, in patients with relapsed/refractory CLL.8 BTK plays a pivotal role in B-cell receptor (BCR) signal transduction,9 stimulating important pathways such as NFKB10, 11 and CXCR4.12 Consequently, BTK is involved in B-cell survival, proliferation, and adhesion, while its activation promotes B-cell proliferation.13 Paradoxically, ibrutinib has shown to increase absolute lymphocyte count (ALC) in the initial phase of treatment, regardless of previous lines of therapy. Ibrutinib-induced lymphocytosis may be explained by the redistribution of lymphocytes from neoplastic nodal compartments into the peripheral blood.14 Furthermore, it was noted that Ibrutinib-induced lymphocytosis is transient in most patients, resolving within 8 months, but may rarely persist for over 12 months without impacting survival.14 This evidence led to the introduction of a new criterion in the assessment of CLL therapy response: partial response with lymphocytosis (PR-L).15 Subsequently, the kinetics of lymphocytosis in CLL treated with ibrutinib monotherapy showed that lymphocytosis occurred in the majority of patients treated in first line was higher in immunoglobulin variable heavy chain (IGHV) mutated settings and resolved in 95% of patients after a median of 18.4 months.16 Little is known about frequency and duration of lymphocytosis in patients treated with the second-generation cBTKi acalabrutinib. Therefore, the aim of this study is to outline the kinetics of lymphocytosis in CLL patients treated with acalabrutinib compared to ibrutinib. We conducted a multicenter retrospective real-life study involving 17 Italian centers. The study was carried out according to the Helsinki Declaration, Good Clinical Practice, and the applicable national regulations and approved by the local ethical committee. All patients provided written informed consent. The primary endpoint was to define the kinetics of lymphocytosis in naïve patients treated with acalabrutinib monotherapy compared to those treated with ibrutinib, over a 12-month observational period. We included patients receiving therapy with ibrutinib or acalabrutinib, in the first line at the target dose of 420 mg/day for ibrutinib and 200 mg/day for acalabrutinib. We enrolled 204 patients divided into two arms: the ibrutinib arm (n = 136) and the acalabrutinib arm (n = 68). The median age was 73 years for the ibrutinib arm and 71 for the acalabrutinib arm. For each patient, we defined the clinical and biological features of disease at baseline, including IGHV mutational status, chromosomal abnormalities by FISH, and molecular biology mutations. At baseline, we considered stage, lymph node involvement, and the presence of splenomegaly. Clinical characteristics and molecular features are reported in Table 1. Subsequently, we assessed the ALC through serial blood count tests at baseline and at different time points: 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, and 12 months after the start of treatment. We calculated the median ALC, expressed both in terms of cells/mm3 and as a percentage compared to the baseline, at each time point. For statistical analysis, we used the Mann–Whitney test to compare median ALC values, considering only those with a p-value < 0.05 as statistically significant. We observed that in the ibrutinib group (IBR), the median ALC at baseline was 63,270/mm3, while in the acalabrutinib group (ACALA), it was 82,905/mm3. Median ALC peaked at two weeks in both arms and then immediately began to decline, reaching the baseline level at 1 month. From Month 1 to Month 12 ALC steadily declined, reaching a normal lymphocyte count (<4000/mm3, according to iwCLL guidelines) at Month 12 for ACALA. ACALA exhibited lower ALC from Month 6 to Month 12 compared to IBR. At Month 12, IBR did not reach the median normal lymphocyte count. For each data point, we calculated the percentage compared to the baseline, which provides a more representative view of lymphocyte count changes at each time point of the study (Supporting Information S1: Table S1). Subsequently, we examined the decline in lymphocytosis to understand if well-defined clinical or biological features could independently impact the kinetics of lymphocyte count in both arms. ACALA had less patients with a molecularly unfavorable prognostic profile; despite this, it seems to have no impact on the kinetics of lymphocytosis in both arms according to our subanalysis (data not shown). IGHV mutational status did not differ between the two arms, but IGHV mutational status had an impact on the lymphocytosis decline. We considered separately cases with unmutated and mutated IGHV genes for IBR and ACALA. They exhibited a similar increment at Day 14 followed by a steady decline. Unmutated IGHV curves of IBR and ACALA overlapped until Month 12. Mutated IGHV for IBR and ACALA followed a similar pattern until Month 6, after which ACALA exhibited a stronger reduction, albeit only as a percentage of baseline, due to ACALA starting from a higher baseline level (Figure 1, Supporting Information S1: Tables S2 and S3). Because there were more cases with TP53 mutations (del17p or TP53 mutated), we evaluated whether the TP53 mutational status had an impact on ALC kinetics within the subgroups. As shown in Supporting Information S1: Table S4, there was no difference in ALC kinetics according to TP53 mutational status among the IGHV mutated and unmutated cases in the IBR arm. Regarding clinical features and the burden of disease at baseline, the two arms were homogeneous with only one exception: more patients treated with acalabrutinib (53%) had Binet staging C before therapy, while only (39%) of patients treated with ibrutinib had stage C. Despite this difference being statistically significant (p = 0.04), our analysis demonstrated that the stage had no impact on the kinetics of lymphocytosis (data not shown). Even with different grades of lymphadenopathy and splenomegaly, including the presence of bulky masses, the trend of lymphocytosis during treatment with both cBTKi remained unaltered (data not shown). We have provided the first description of the kinetics of lymphocytosis in patients treated with acalabrutinib and conducted the first comparative study of lymphocyte counts during 12 months of treatment with two cBTK inhibitors. We observed that, similar to Ibrutinib, acalabrutinib leads to an increase in lymphocyte count immediately after starting therapy. This observation confirms previous works identifying lymphocytosis as a “class effect” of cBTKi.14 We observed that while there is an appreciable reduction in lymphocyte count starting from the second month of treatment in both groups, the decrease in lymphocytosis appears to be faster and more profound in patients treated with acalabrutinib from the 6th month onward. We also investigated whether certain disease's features could explain the differences in the kinetics of lymphocytosis. There was a significant difference in the distribution of patients with a poor molecular prognosis (del17p/TP53) between the two groups, with a marked prevalence in the IBR arm. This difference can be attributed to the evolution of cBTKi use in clinical practice: when ibrutinib was introduced, it was only allowed for patients with a poor prognosis. Conversely, acalabrutinib was used in clinical practice when the administration of cBTKi was already well established in all untreated patients. However, according to our data, having a del17p/TP53 mutation or NOTCH1 mutation does not interfere with the kinetics of lymphocytosis during treatment with the two different cBTKi. NOTCH1 mutations and higher CD49D expression have been associated with reduced ibrutinib-induced lymphocytosis,17, 18 but in this cohort, we did not observe any effect. The IGHV mutational status did not differ between the two groups; however, when examining lymphocyte count curves in mutated IGHV, starting from the 6th month to the end of the study period, the median percentage of baseline declined more in the ACALA arm reaching a statistical difference. Overall, IGHV mutated/unmutated patients treated with acalabrutinib had a similar increase in lymphocyte count after 14 days, followed by a sharper decline, achieving median normal lymphocyte count earlier than the IBR arm. These data suggest that the main differences of lymphocytes count between the two cBTKi is due to IGHV mutated status. The clinical burden of disease at baseline had no impact on the kinetics of lymphocytosis between the two arms. Currently, there is lack of data in the literature comparing the differences between ACALA and IBR concerning lymphocytosis, IGHV mutational status, and the extent of lymphocyte mobilization in peripheral blood. Particularly, there is scarcity of mechanistic explanations for the divergent behavior of the two cBTK inhibitors. In order to verify this hypothesis, our group is conducting research into chemokine receptors and adhesion molecules. In conclusion, we describe the kinetics of peripheral blood lymphocytosis after ibrutinib or acalabrutinib in patients with CLL treated in front line. Both treatments exhibited a similar peak at 2 weeks after initiation, followed by a more pronounced and rapid decrease in the acalabrutinib treatment group, particularly in IGHV mutated cases. MoH ricerca corrente 2024. Antonio Mosca, Annamaria Tomasso, Andrea Galitzia, Luca Stirparo, Francesca Martini, Francesca Morelli, Roberta Laureana, Giulia Benintende, Veronica Mattiello, Sabrina Chiriu, Maria I. Del Principe, Giulia Zamprogna, Massimo Gentile, Enrica A. Martino, Emilia Cappello, Maria C. Montalbano, Giuliana Farina, Vanessa Innao, Lydia Scarfò, Caterina Patti, Paolo Sportoletti, Alberto Fresa, Gioacchino Catania, Marta Coscia, Silvia Bellesi, Alessandra Tedeschi, Alessandro Sanna, Andrea Visentin, Francesco Autore, Raffaella Pasquale, Livio Trentin, Marzia Varettoni, Paolo Ghia, and Roberta Murru collected the data. Eugenio Galli performed the statistical analysis. Idanna Innocenti and Antonio Mosca wrote the manuscript and Eugenio Sangiorgi and Luca Laurenti supervised the project. Paolo Ghia received honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Janssen, Lilly/LoxoOncology, MSD, and Roche, and research funding from AbbVie, AstraZeneca, BMS, and Janssen, and is an Editor of HemaSphere. Marzia Varettoni received honoraria from AbbVie, AstraZeneca, BeiGene, and Janssen. The remaining authors declare no conflict of interest. This research received no external funding. This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Prot. ID 5765 13/10/2023). Written informed consent was obtained from the patients to publish this study. The data that support the findings of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Therapeutic strategies and treatment sequencing in patients with chronic lymphocytic leukemia: An international study of ERIC, the European Research Initiative on CLL Thomas Chatzikonstantinou, Lydia Scarfò, Eva Minga, Georgios Karakatsoulis, Dimitra Chamou, Jana Kotaskova, Gloria Iacoboni, Christos Demosthenous, Elisa Albi, Miguel Alcoceba, Salem Al‐Shemari, Thérèse Aurran‐Schleinitz, Francesca Bacchiarri, Sofia Chatzileontiadou, Rosa Collado, Zadie Davis, Marcos Daniel de Deus Santos, Maria Dimou, Elena Dmitrieva, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El‐Ashwah, Alicia Enrico, Andrzej Frygier, Sara Galimberti, Andrea Galitzia, Eva Gimeno, Valerio Guarente, Romain Guieze, Sean Harrop, Eleftheria Hatzimichael, Yair Herishanu, José‐Ángel Hernández‐Rivas, Ozren Jaksic, Elżbieta Kalicińska, Kamel Laribi, Volkan Karakus, Arnon P. Kater, Bonnie Kho, Maria Kislova, Εliana Konstantinou, Maya Koren‐Michowitz, Ioannis Kotsianidis, Zuzana Kubova, Jorge Labrador, Deepesh Lad, Luca Laurenti, Thomas Longval, Alberto Lopez‐Garcia, Juan Marquet, Stanislava Maslejova, Carlota Mayor‐Bastida, Biljana Mihaljevic, Ivana Milosevic, Fatima Miras, Riccardo Moia, Marta Morawska, Uttam K. Nath, Almudena Navarro‐Bailón, Jacopo Olivieri, Irina Panovska‐Stavridis, Maria Papaioannou, Cheyenne Pierie, Anna Puiggros, Gianluigi Reda, Gian M. Rigolin, Rosa Ruchlemer, Mattia Schipani, Annett Schiwitza, Yandong Shen, Tereza Shokralla, Martin Simkovic, Svetlana Smirnova, Dina S. A. Soliman, Stephan Stilgenbauer, Tamar Tadmor, Kristina Tomic, Eric Tse, Theodoros Vassilakopoulos, Andrea Visentin, Candida Vitale, George Vrachiolias, Vojin Vukovic, Renata Walewska, Zhenshu Xu, Munci Yagci, Lucrecia Yañez, Mohamed Yassin, Jana Zuchnicka, David Oscier, Alessandro Gozzetti, Panagiotis Panagiotidis, Francesc Bosch, Paolo Sportoletti, Blanca Espinet, Gerassimos A. Pangalis, Viola M. Popov, Stephen Mulligan, Maria Angelopoulou, Fatih Demirkan, Tomas Papajík, Bella Biderman, Roberta Murru, Marta Coscia, Constantine Tam, Antonio Cuneo, Gianluca Gaidano, Rainer Claus, Niki Stavroyianni, Livio Trentin, Darko Antic, Lukas Smolej, Olga B. Kalashnikova, Mark Catherwood, Martin Spacek, Sarka Pospisilova, Michael Doubek, Eugene Nikitin, Anastasia Chatzidimitriou, Paolo Ghia, Kostas Stamatopoulos Hemasphere, 2024 Novel small molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Indeed, BTK (BTKi) and BCL2 inhibitors (BCL2i) alone or in combination with each other or other compounds have proven superior to chemoimmunotherapy (CIT) in both the frontline and the relapsed/refractory (R/R) setting.1 ERIC, the European Research Initiative on CLL, conducted this international multicenter retrospective study focused on the era of CIT, aiming to (i) reveal the treatment patterns in the “real world” and (ii) assess the outcomes of patients who received frontline treatment between 2000 and 2016. Overall, 7382 patients with CLL (7134, 96.6%) or SLL (248, 3.4%) from 76 centers in 25 countries in five continents were included. The median age at diagnosis was 64 (interquartile range [IQR]: 56–71) years and the median age at first treatment was 66 (IQR: 58–74) years. The median follow-up was 7.33 (IQR: 4.56–10.81) years from diagnosis and 5.27 (IQR: 3.04–7.99) from first treatment. The vast majority of patients (6873/7134, 93.2%) received at least one line of chemotherapy or CIT; only 197/7134 (2.7%) received exclusively novel agents. Baseline characteristics and disease-specific biomarkers are listed in Supporting Information Material. The most common first-line regimen was FCR (2609, 35.3%), mostly in young patients (median age at first treatment: 60 years, IQR: 54–66), followed by chlorambucil monotherapy (1293, 17.5%), mostly in older patients (median age at first treatment: 74 years, IQR: 65–80). BTKis as first-line treatment were used in 149/7134 (2%) patients who either participated in clinical trials and/or had TP53 aberrations; 20/7134 (0.3%) received frontline venetoclax-based regimens, all in the context of clinical trials (Figure 1). Detailed outcomes for the most common frontline regimens are provided in Supporting Information Material. BTKis were the most common type of R/R treatment (1581/8145, 19.4%). Reflecting the approval of novel agents for patients with R/R CLL, the use of all types of chemotherapy and CIT decreased after 2014, except bendamustine plus rituximab (Figure 2). There were 387 patients with an early (<24 months) need for second-line treatment after 2016: 203/387 (52.4%) received chemotherapy and CIT, 147/387 (38%) novel agents (108/387 [27.9%] BTKi, 24/387 [6.2%] PI3Ki, and 15/387 [3.9%] venetoclax-based treatments), and 37/387 (9.6%) other treatments (Figure 2 & File S1). ORR and discontinuation rates due to progression of patients treated with novel agents are given in the File S1. Among patients treated with BTKi with or without anti-CD20 monoclonal antibodies (Mab), 55/567 (9.7%) discontinued treatment due to toxicity in second and 120/1014 (11.8%) in later lines. The median time to discontinuation was 5 months (95% confidence interval [CI]: 3.7–12.5) for patients treated in second line and 14 months (95% CI: 8–20.9) for patients treated in later line. Patients treated with BTKi in second line discontinued treatment due to toxicity earlier compared to those treated at later lines. Considering that administration of BTKi in second versus later lines happened more recently, this may simply reflect the fact that physicians had more choices and discontinued faster in second line. Taken together, our findings mirror the long-term results of the RESONATE trial yet are strikingly lower compared to the “real world” study by Mato et al.,2, 3 despite the longer median follow-up on ibrutinib in our study (>27 vs. 17 months). We attribute this difference to a number of reasons. First, the aforementioned study included patients treated soon after ibrutinib approval when physicians may have been less experienced on how to manage new adverse events. Second, most patients in our study derived from large academic centers with expertise in managing patients with CLL, including ibrutinib-related toxicities. Third, differences in patients' fitness status and comorbidity burden could have influenced physician decisions. Finally, cultural and healthcare system differences between the United States and the rest of the world may have also played a role. Patients treated with PI3Ki with or without an anti-CD20 Mab had the numerically highest toxicity-related discontinuation rates (24/76 [31.6%] and 84/285 [29.5%] in second or later line, respectively) (median time to discontinuation: 8.1 months [95% CI: 5–14.2] in second line and 10.8 [8–12] in later line), confirming the safety issues of previous studies.4-6 Continuous venetoclax therapy was discontinued due to toxicity in 3/60 (5%) and 20/179 (7%) patients in second or later line, respectively (median time to discontinuation: 38.6 months [95% CI: 37.6–not estimable] in second line and 4.5 months [2.5–25] in later line). None of the 29 patients treated with BTKi plus venetoclax with or without an anti-CD20 Mab discontinued treatment due to toxicity, while only 1/56 (1.8%) (at 5.1 months after treatment initiation) and 4/112 (3.6%) discontinued venetoclax plus rituximab in second or later line, respectively (in later line, the median time to discontinuation was 4.6 months [1.6–not estimable]). Infection was a common reason for discontinuation of all novel agent-based therapies (18/64 (28.1%), 16/60 (26.7%), and 8/15 (53.3%) for BTKi, PI3Ki, and venetoclax-based treatments, respectively). Most patients discontinued BTKi and PI3Ki-based treatments due to unspecified nonhematological toxicity (28/64 [43.8%] and 23/60 [38.3%], respectively). Atrial fibrillation/flutter (6/64, 9.4%) and autoimmune phenomena (15/60, 25%) were among the prevailing reasons for discontinuation in BTKi and PI3Ki-treated patients, respectively. Cytopenias (5/15, 33.3%) were the second most common reason (after infection) for discontinuing venetoclax-based treatments. Information on tumor lysis syndrome (TLS) was available on 148 patients with R/R CLL treated with venetoclax-based regimens. Only 2/148 (1.4%) patients, both high-risk for TLS, developed clinical TLS; laboratory TLS was present in 8/148 (5.4%) patients. Information on the timing of TLS and the ramp-up scheme/TLS prophylaxis in each case were not captured. All patients who developed TLS recovered and continued treatment. Our results are in line with RCTs and previous large “real world” studies,7-13 highlighting the ability of hematologists to prevent this adverse event in the “real-world” setting. Seventy-one patients were double refractory to both BTKi and venetoclax (File S1). Most patients with available biomarkers had unmutated IGHV genes (34/43, 79.1%) and 64.5% (20/31) had TP53 aberrations before first-line treatment. After the second novel agent failure, 62% (44/71) received an additional line of therapy. The median time-to-next treatment (TTNT) from the second novel agent treatment was 11.4 months (95% CI: 7.95–14.65) and the median overall survival (OS) from the second novel agent treatment was 19.88 months (95% CI: 14.72–30.32). Overall, 43 patients received a subsequent line of therapy for CLL after failing the second targeted agent. The median OS and TTNT from the start of the subsequent line of treatment were 12 and 9 months, respectively. Hence, we confirm the poor prognosis of these patients reported in previous “real world” studies, especially when noncovalent BTKis and other novel approaches (e.g., CAR-T cells) are unavailable.14, 15 In a multivariable analysis in patients receiving frontline therapy, increased age, male sex, unmutated IGHV genes, and TP53 aberrations predicted a shorter TTNT, while unmutated IGHV gene status was the only statistically significant predictor for the need for the next treatment (File S1), perhaps reflecting missing information on TP53 mutation status in 71.3% (5266/7382) of patients. FCR conferred a longer TTNT (p = 0.002, 95% CI: 0.64–0.91) versus other types of frontline treatment. Similarly, in patients with R/R CLL, increased age at second-line treatment, unmutated IGHV genes, and TP53 aberrations were statistically significant predictors for a shorter OS. The only protective factor from death in patients with R/R CLL was treatment with novel agents in the first or second line (File S1), highlighting the importance of incorporating novel agents early in the CLL treatment algorithm. We chart a major shift in treatment patterns before and after the introduction of novel targeted agents in 2014. Against that, many patients with R/R CLL in our cohort were still treated with CIT even after 2014. This may be explained, at least in part, by the fact that CIT was considered a valid retreatment option for patients with long first remissions for quite some time after 2014. Notably, even after 2016, novel agents were used in only 38% of patients with an early (<24 months) need for second-line treatment. Possible reasons include access to medication, physicians' reluctance, and the evidence–practice gap. This highlights the need for more timely and effective knowledge dissemination, but even more importantly, reduction of drug costs and adoption of less strict rules for drug reimbursement. We acknowledge certain limitations to our study. First, the median age at diagnosis and first treatment is lower than traditionally expected, perhaps due to the fact that many patients were included from referral centers for CLL. Second, the assessment of response was performed by treating physicians based mainly on complete blood counts and physical examination, likely overestimating the response in some cases. Finally, missing information, sampling, and attrition bias also apply. Recognizing these limitations, we mitigated them by collecting data on consecutively treated patients in each participating center and focusing on robust metrics (i.e., TTNT and OS). Altogether, we document the effectiveness and safety of novel agents in patients with R/R CLL previously treated with CIT or chemotherapy regimens. We also witness a great delay in the timely implementation of the existing evidence in the real world with a slow uptake of drugs proven to be highly efficacious. Thus, dedicated efforts to improve it should be considered for the future generation of treatments. Thomas Chatzikonstantinou and Lydia Scarfò collected data, coordinated the study, wrote the paper, assessed and verified the data, and performed the analysis. Georgios Karakatsoulis wrote the paper and performed the analysis. Gloria Iacoboni, Jana Kotaskova, and CD collected data, coordinated the study, and contributed to interpretation and manuscript editing. Eva Minga and Dimitra Chamou coordinated the data collection, curate the data, and contributed to interpretation and manuscript editing. Elisa Albi, Miguel Alcoceba, Salem Al-Shemari, Thérèse Aurran-Schleinitz, Francesca Bacchiarri, Sofia Chatzileontiadou, Rosa Collado, Zadie Davis, Marcos Daniel de Deus Santos, Maria Dimou, Elena Dmitrieva, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El-Ashwah, Alicia Enrico, Andrzej Frygier, Sara Galimberti, Andrea Galitzia, Eva Gimeno, Valerio Guarente, Romain Guieze, Sean Harrop, Eleftheria Hatzimichael, Yair Herishanu, José-Ángel Hernández-Rivas, Ozren Jaksic, Elżbieta Kalicińska, Kamel Laribi, Volkan Karakus, Arnon P. Kater, Bonnie Kho, Maria Kislova, Εliana Konstantinou, Maya Koren-Michowitz, Ioannis Kotsianidis, Zuzana Kubova, Jorge Labrador, Deepesh Lad, Luca Laurenti, Thomas Longval, Alberto Lopez-Garcia, Juan Marquet, Stanislava Maslejova, Carlota Mayor-Bastida, Biljana Mihaljevic, Ivana Milosevic, Fatima Miras, Riccardo Moia, Marta Morawska, Uttam K. Nath, Almudena Navarro-Bailón, Jacopo Olivieri, Irina Panovska-Stavridis, Maria Papaioannou, Cheyenne Pierie, Anna Puiggros, Gianluigi Reda, Gian Matteo Rigolin, Rosa Ruchlemer, Mattia Schipani, Annett Schiwitza, Yandong Shen, Tereza Shokralla, Martin Simkovic, Svetlana Smirnova, Dina S. A. Soliman, Stephan Stilgenbauer, Tamar Tadmor, Kristina Tomic, Eric Tse, Theodoros Vassilakopoulos, Andrea Visentin, Candida Vitale, George Vrachiolias, Vojin Vukovic, Renata Walewska, Zhenshu Xu, Munci Yagci, Lucrecia Yañez, Mohamed Yassin, Jana Zuchnicka, David Oscier, Alessandro Gozzetti, Panagiotis Panagiotidis, Francesc Bosch, Blanca Espinet, Paolo Sportoletti, Gerassimos A. Pangalis, Viola M. Popov, Stephen Mulligan, Maria Angelopoulou, Fatih Demirkan, Tomas Papajík, Bella Biderman, Roberta Murru, Marta Coscia, Constantine Tam, Antonio Cuneo, Gianluca Gaidano, Rainer Claus, Niki Stavroyianni, Livio Trentin, Darko Antic, Lukas Smolej, Olga B. Kalashnikova, Mark Catherwood, Martin Spacek, Sarka Pospisilova, Michael Doubek, Eugene Nikitin, and Anastasia Chatzidimitriou collected data and contributed to interpretation and manuscript editing. Paolo Ghia and Kostas Stamatopoulos designed and coordinated the study and wrote the paper. Thomas Chatzikonstantinou received honoraria from AbbVie. Lydia Scarfò received honoraria from AbbVie, AstraZeneca, BeiGene, Lilly, Janssen, Octapharma. Gloria Iacoboni received honoraria and travel support from Novartis, Kite/Gilead, Bristol-Myers Squibb, Abbvie, Autolus, Miltenyi, and AstraZeneca. Rosa Collado received support for attending meetings from Janssen-Cilag and S.A. Sara Galimberti received honoraria support for attending meetings from AbbVie, AstraZeneca, Jazz, Novartis, and Incyte, honoraria from Roche, Celgene, Pfizer, and Janssen, and support for attending meetings from Jazz, AstraZeneca, and Roche. Romain Guieze received honoraria, consulting fees, and support for attending meetings from AbbVie, Beigene, Roche, Janssen, and AstraZeneca. Eleftheria Hatzimichael received honoraria from AbbVie, Janssen-Cilag, AstraZeneca, and Roche. Yair Herishanu received honoraria from Janssen, AbbVie, Roche, AstraZeneca, Medion, and Lilly. José-Ángel Hernández-Rivas received honoraria as a consultant from Janssen, AbbVie, AstraZeneca, Lilly, and BeiGene and support for attending meetings from Janssen, AbbVie, AstraZeneca, and BeiGene. Ozren Jaksic received honoraria from Johnson and Johnson, AstraZeneca, and Lilly, honoraria from Johnson and Johnson, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Johnson and Johnson, and AbbVie. Kamel Laribi received consulting fees from AbbVie, AstraZeneca, Janssen, Beigene, Takeda, and Novartis. Maya Koren-Michowitz received honoraria from Novartis, Pfizer, and Gad Medical LTD. and support for attending meetings from Novartis. Arnon P. Kater received advisory board fees and research money from Janssen, AbbVie, BMS, AstraZeneca, and Roche/Genentech, and support for attending meetings from Janssen and AbbVie. Ioannis Kotsianidis received honoraria and consulting fees from AbbVie and Janssen. Ivana Milosevic received honoraria from AbbVie, Roche, Sandoz, AstraZeneca, and Janssen, and support for attending meetings from AbbVie, Roche, and Takeda. Almudena Navarro-Bailón received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, Takeda, Janssen, and Beigene. Jacopo Olivieri received honoraria from AbbVie, AstraZeneca, and Janssen. Gianluigi Reda received consulting fees from AbbVie, AstraZeneca, Janssen, and Beigene, and is currently employed by AstraZeneca. Gian M. Rigolin received honoraria for participation in speaker's bureau from AbbVie, Astra Zeneca, Beigene, and Janssen, and support for attending meetings from Janssen. Mattia Schipani received honoraria and support for attending meetings from AstraZeneca, AbbVie, and Janssen-Cilag and owns shares of stock in AbbVie, AstraZeneca, Merck, Eli Lilly, Sanofi, Johnson and Johnson, Pfizer, Gilead, and GSK. Tereza Shokralla and Stephan Stilgenbauer reports research funding from, consultancy or advisory role for, honoraria from, speakers' bureau participation for, and travel support from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, Gilead, GlaxoSmithKline, Hoffmann-La Roche, Incyte, Infinity, Janssen, Novartis, and Sunesis. Eric Tse received support for attending meetings from Takeda. Theodoros Vassilakopoulos received honoraria from Takeda, Roche, Genesis Pharma, Merck, Novartis, Gilead, Sandoz, AstraZeneca, Integris, and Servier, and support for attending meetings from Takeda, Roche, Genesis Pharma, Merck, Pfizer, and Winmedica. Candida Vitale received honoraria from AbbVie, consulting fees from AstraZeneca, and support for attending meetings from AstraZeneca, Takeda, and Janssen. Renata Walewska received honoraria from AbbVie, AstraZeneca, and Beigene, support for attending meetings from Janssen, AbbVie, and AstraZeneca, and advisory board fees from AbbVie, AstraZeneca, Janssen, Beigene, and SecuraBio. Lucrecia Yañez received honoraria from AbbVie, AstraZeneca, Novartis, Gilead, Janssen, Jazz, MSD, and Pfizer, support for attending meetings from AbbVie, AstraZeneca, Gilead, Janssen, and Pfizer, and advisory board fees from AbbVie, AstraZeneca, Jazz, Janssen, Beigene, and Celgene. Francesc Bosch received consulting fees, honoraria, and payment for expert testimony from AbbVie, Genentech, Novartis, Takeda, Janssen, Roche, Mundipharma, Celgene/BMS, AstraZeneca, Lilly, Beigene, Gilead and TG Therapeutics, Advantage Allogene, Lava Therapeutics, and Enterome. Stephen Mulligan received advisory board fees from AbbVie, AstraZeneca, Janssen, Roche, and BeiGene. Maria Angelopoulou received consulting fees from AbbVie, Takeda, Janssen, Roche, Genesis, Gilead, and Amgen and honoraria from AbbVie, Takeda, Roche, Genesis, Gilead, and Novartis. Fatih Demirkan received support for attending meetings from Janssen and AbbVie. Tomas Papajík received honoraria and advisory board fees from AbbVie, Janssen-Cilag, and AstraZeneca, and support for attending meetings from AstraZeneca. Marta Coscia received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, and Janssen. Constantine Tam received honoraria from AbbVie, Beigene, Janssen, and LOXO. Antonio Cuneo received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, Beigene, Janssen, and Lilly. Gianluca Gaidano received honoraria from Abbvie, AstraZeneca, BeiGene, Hikma, Incyte, Janssen, and Lilly. Niki Stavroyianni received honoraria from Janssen, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Janssen and AstraZeneca. Lukas Smolej received consulting fees, honoraria, and support for attending meetings from AbbVie, AstraZeneca, and Janssen and advisory board fees from AbbVie and AstraZeneca. Martin Spacek received honoraria and consulting and advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, and Janssen. Michael Doubek received research support and honoraria from AbbVie, AstraZeneca, and Janssen. Eugene Nikitin received honoraria from AbbVie. Kostas Stamatopoulos received research support from AbbVie, AstraZeneca, Janssen, Novartis, and Roche; honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Lilly, and Janssen. Paolo Ghia received research support from AbbVie, AstraZeneca, BMS, Janssen and honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Genmab, Janssen, Loxo Oncology @Lilly, MSD, Roche, and is an Editor of HemaSphere. Georgios Karakatsoulis, Eva Minga, Dimitra Chamou, Jana Kotaskova, Christos Demosthenous, Elisa Albi, Miguel Alcoceba, Salem Al-Shemari, Thérèse Aurran-Schleinitz, Francesca Bacchiarri, Sofia Chatzileontiadou, Zadie Davis, Marcos Daniel de Deus Santos, Maria Dimou, Elena Dmitrieva, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El-Ashwah, Alicia Enrico, Andrzej Frygier, Andrea Galitzia, Eva Gimeno, Valerio Guarente, Sean Harrop, Elżbieta Kalicińska, Volkan Karakus, Bonnie Kho, Maria Kislova, Εliana Konstantinou, Zuzana Kubova, Jorge Labrador, Deepesh Lad, Luca Laurenti, Thomas Longval, Alberto Lopez-Garcia, Juan Marquet, Stanislava Maslejova, Carlota Mayor-Bastida, Biljana Mihaljevic, Fatima Miras, Riccardo Moia, Marta Morawska, Uttam K. Nath, Irina Panovska-Stavridis, Maria Papaioannou, Cheyenne Pierie, Anna Puiggros, Rosa Ruchlemer, Annett Schiwitza, Yandong Shen, Tereza Shokralla, Martin Simkovic, Svetlana Smirnova, Dina S. A. Soliman, Tamar Tadmor, Kristina Tomic, Andrea Visentin, George Vrachiolias, Vojin Vukovic, Zhenshu Xu, Munci Yagci, Mohamed Yassin, Jana Zuchnicka, David Oscier, Alessandro Gozzetti, Panagiotis Panagiotidis, Blanca Espinet, Paolo Sportoletti, Gerassimos A. Pangalis, Viola M. Popov, Bella Biderman, Roberta Murru, Rainer Claus, Livio Trentin, Darko Antic, Olga B. Kalashnikova, Mark Catherwood, Sarka Pospisilova, and Anastasia Chatzidimitriou have no conflict of interest to disclose. This project was supported in part by AbbVie; AIRC under 5 per Mille 2018-ID. 21198 program (to PG and GG); PNRR-MAD-2022-12375673 (Next Generation EU, M6/C2_CALL 2022), Italian Ministry of Health, Rome, Italy, Conceptual development of research organization (FNBr 65269705) provided by the Ministry of Health of the Czech Republic, and National Institute for Cancer Research (Programme EXCELLES, ID Project No. LX22NPO5102) funded by the European Union—Next Generation EU. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Chronic Lymphocytic Leukemia: Management of Adverse Events in the Era of Targeted Agents Andrea Galitzia, Monica Maccaferri, Francesca Romana Mauro, Roberta Murru, Roberto Marasca Cancers, 2024 The treatment landscape for CLL has undergone a profound transformation with the advent of targeted agents (TAs) like Bruton’s Tyrosine Kinase inhibitors (BTKis) and BCL-2 inhibitors (BCL-2is). These agents target crucial cellular pathways in CLL, offering superior efficacy over traditional chemo-immunotherapy, which has led to improved progression-free and overall survival rates. This advancement promises enhanced disease control and potentially normal life expectancy for many patients. However, the journey is not without challenges, as these TAs are associated with a range of adverse events (AEs) that can impact treatment efficacy and patient quality of life. This review focuses on detailing the various AEs related to TA management in CLL, evaluating their frequency and clinical impact. The aim is to present a comprehensive guide to the effective management of these AEs, ensuring optimal tolerability and efficacy of TAs. By reviewing the existing literature and consolidating findings, we provide insights into AE management, which is crucial for maximizing patient outcomes in CLL therapy.
Prediction of severe infections in chronic lymphocytic leukemia: a simple risk score to stratify patients at diagnosis Roberta Murru, Andrea Galitzia, Luca Barabino, Roberta Presicci, Giorgio La Nasa, Giovanni Caocci Annals of Hematology, 2024 Chronic Lymphocytic Leukemia (CLL) is well-known for increasing susceptibility to infections. Factors such as immune dysregulation, IGHV status, hypogammaglobulinemia, and patient comorbidity and treatment, contribute to higher infection rates and mortality. However, the impact of hypogammaglobulinemia on infection rates is controversial. We aimed to identify clinical and biological parameters linked to the risk of severe infectious events. Additionally, we set up a straightforward risk infection score to stratify CLL patients at diagnosis, thereby enabling the development of suitable infection prevention strategies. We retrospectively evaluated 210 unselected CLL patients diagnosed between 1988 and 2018. This evaluation encompassed demographics, Binet stage, immunoglobulin (Ig) levels, treatment history, comorbidities, and IGHV mutational status at diagnosis. The frequency and severity of infectious events were recorded. Analysis revealed that age, IGHV mutational status, Binet stage, and hypogammaglobulinemia were statistically associated with the Time to First Infection (TTFI) in univariate and multivariate analyses. Using hazard ratios from the multivariate analysis, we finally devised a risk scoring system that integrated age, IGHV mutational status, immunoglobulin levels, and Binet stage to stratify patients at diagnosis based on their specific infection risk. In our cohort, disease progression and infections were the leading cause of death. These findings pointed out the clinical need for a screening process strategic for defining infectious risk at the time of CLL diagnosis, with a significant enhancement in the clinical management of these patients.
Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY Thomas Chatzikonstantinou, Lydia Scarfò, Georgios Karakatsoulis, Eva Minga, Dimitra Chamou, Gloria Iacoboni, Jana Kotaskova, Christos Demosthenous, Lukas Smolej, Stephen Mulligan, Miguel Alcoceba, Salem Al-Shemari, Thérèse Aurran-Schleinitz, Francesca Bacchiarri, Mar Bellido, Fontanet Bijou, Anne Calleja, Angeles Medina, Mehreen Ali Khan, Ramona Cassin, Sofia Chatzileontiadou, Rosa Collado, Amy Christian, Zadie Davis, Maria Dimou, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El-Ashwah, Alicia Enrico, Alberto Fresa, Sara Galimberti, Andrea Galitzia, Rocío García-Serra, Eva Gimeno, Isabel González-Gascón-y-Marín, Alessandro Gozzetti, Valerio Guarente, Romain Guieze, Ajay Gogia, Ritu Gupta, Sean Harrop, Eleftheria Hatzimichael, Yair Herishanu, José-Ángel Hernández-Rivas, Luca Inchiappa, Ozren Jaksic, Susanne Janssen, Elżbieta Kalicińska, Laribi Kamel, Volkan Karakus, Arnon P. Kater, Bonnie Kho, Maria Kislova, Eliana Konstantinou, Maya Koren-Michowitz, Ioannis Kotsianidis, Robert J. Kreitman, Jorge Labrador, Deepesh Lad, Mark-David Levin, Ilana Levy, Thomas Longval, Alberto Lopez-Garcia, Juan Marquet, Lucia Martin-Rodríguez, Marc Maynadié, Stanislava Maslejova, Carlota Mayor-Bastida, Biljana Mihaljevic, Ivana Milosevic, Fatima Miras, Riccardo Moia, Marta Morawska, Roberta Murru, Uttam Kumar Nath, Almudena Navarro-Bailón, Ana C. Oliveira, Jacopo Olivieri, David Oscier, Irina Panovska-Stavridis, Maria Papaioannou, Tomas Papajík, Zuzana Kubova, Punyarat Phumphukhieo, Cheyenne Pierie, Anna Puiggros, Lata Rani, Gianluigi Reda, Gian Matteo Rigolin, Rosa Ruchlemer, Marcos Daniel de Deus Santos, Mattia Schipani, Annett Schiwitza, Yandong Shen, Martin Simkovic, Svetlana Smirnova, Dina Sameh Abdelrahman Soliman, Martin Spacek, Tamar Tadmor, Kristina Tomic, Eric Tse, Theodoros Vassilakopoulos, Andrea Visentin, Candida Vitale, Julia von Tresckow, George Vrachiolias, Vojin Vukovic, Renata Walewska, Ewa Wasik-Szczepanek, Zhenshu Xu, Munci Yagci, Lucrecia Yañez, Mohamed Yassin, Jana Zuchnicka, Maria Angelopoulou, Darko Antic, Bella Biderman, Mark Catherwood, Rainer Claus, Marta Coscia, Antonio Cuneo, Fatih Demirkan, Blanca Espinet, Gianluca Gaidano, Olga B. Kalashnikova, Luca Laurenti, Eugene Nikitin, Gerassimos A. Pangalis, Panagiotis Panagiotidis, Viola Maria Popov, Sarka Pospisilova, Paolo Sportoletti, Niki Stavroyianni, Constantine Tam, Livio Trentin, Anastasia Chatzidimitriou, Francesc Bosch, Michael Doubek, Paolo Ghia, Kostas Stamatopoulos Eclinicalmedicine, 2023 Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.
Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia Anna Maria Frustaci, Giovanni Del Poeta, Andrea Visentin, Paolo Sportoletti, Alberto Fresa, Candida Vitale, Roberta Murru, Annalisa Chiarenza, Alessandro Sanna, Francesca Romana Mauro, Gianluigi Reda, Massimo Gentile, Marzia Varettoni, Claudia Baratè, Chiara Borella, Antonino Greco, Marina Deodato, Giulia Zamprogna, Roberta Laureana, Alessandra Cipiciani, Andrea Galitzia, Angelo Curto Pelle, Francesca Morelli, Lucio Malvisi, Marta Coscia, Luca Laurenti, Livio Trentin, Marco Montillo, Roberto Cairoli, Alessandra Tedeschi Therapeutic Advances in Hematology, 2022
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Correction to “Salvage treatment after covalent BTKi failure: An unmet need in clinical practice in Waldenstrom macroglobulinemia” AM Frustaci, A Zappaterra, A Galitzia 2025
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MOST CITED SCHOLAR PUBLICATIONS
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Kinetics of lymphocytosis in naïve chronic lymphocytic leukemia patients treated with covalent Bruton's tyrosine kinase inhibitors: An Italian multicenter real‐life experience I Innocenti, A Mosca, A Tomasso, A Galitzia, L Scarfò, F Morelli, E Galli, ... HemaSphere 8 (12), e144 , 2024 2024 Citations: 4
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Acalabrutinib in High‐Risk Chronic Lymphocytic Leukaemia Naïve Patients: An Italian Multicenter Retrospective Observational Real‐Life Experience I Innocenti, A Tomasso, D Giannarelli, L Scarfò, R Murru, A Visentin, ... Hematological Oncology 43 (1), e70033 , 2025 2025 Citations: 2
Therapeutic strategies and treatment sequencing in patients with chronic lymphocytic leukemia: An international study of ERIC, the European Research Initiative on CLL T Chatzikonstantinou, L Scarfò, E Minga, G Karakatsoulis, D Chamou, ... HemaSphere 8 (9), e70004 , 2024 2024 Citations: 2
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Familial forms of chronic lymphocytic leukemia have a worse prognosis than sporadic forms: an Italian case-control study A Fresa, I Innocenti, A Tomasso, C Vitale, A Sanna, AM Frustaci, ... Blood Advances 9 (21), 5399-5408 , 2025 2025 Citations: 1
Treatability with ibrutinib plus venetoclax in patients with CLL in the real-world. the eric international thrive study A Visentin, T Chatzikonstantinou, L Scarfo, P Talimtzi, M Angelopoulou, ... Blood 146 (Supplement 1), 6287-6287 , 2025 2025 Citations: 1
Acalabrutinib in High-Risk Chronic Lymphocytic Leukemia Patients Naïve or Previous Treated. a Multicenter Retrospective Observational Real-Life Experience I Innocenti, A Tomasso, D Giannarelli, L Scarfo, R Murru, A Visentin, ... Blood 144 (Supplement 1), 6798-6798 , 2024 2024 Citations: 1
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No lymphocytosis increase after cBTKi is a rare phenomenon except for CD49d positive CLL mainly expressed in trisomy 12 L Laurenti, F Guglielmi, A Mosca, C Vitale, MC Montalbano, G Favrin, ... Blood Advances, bloodadvances. 2025018640 , 2026 2026
Treatment with acalabrutinib in IGHV mutated setting and presence of splenomegaly are the main predictors of faster lymphocyte count decrease in CLL during monotherapy with cbtki L Laurenti, A Mosca, F Guglielmi, A Tomasso, A Visentin, L Scarfo, ... Blood 146 (Supplement 1), 7427-7427 , 2025 2025
