Autore, Francesco

Fresa, Alberto

Giannarelli, Diana

Innocenti, Idanna

Laurenti, Luca

Mosca, Antonio

Stirparo, Luca

Tedeschi, Alessandra

Tomasso, Annamaria

English

PubliCatt

Hematological Oncology- LETTER TO THE EDITOR OPEN ACCESSAcalabrutinib in High‐Risk Chronic LymphocyticLeukaemia Naïve Patients: An Italian MulticenterRetrospective Observational Real‐Life ExperienceIdanna Innocenti1 | Annamaria Tomasso2 | Diana Giannarelli3 | Lydia Scarfò4,5 | Roberta Murru6 |Andrea Visentin7 | Anna Maria Frustaci8 | Francesca Morelli9 | Candida Vitale10 | Antonio Mosca2 |Alessandro Sanna11 | Giuliana Farina12 | Roberta Laureana13 | Massimo Gentile14,15 | Andrea Galitzia16 |Raffaella Pasquale17 | Francesco Autore1 | Jacopo Olivieri17 | Azzurra Romeo18 | Marina Deodato8 | Luca Stirparo2 |Andrea Corbingi18 | Vanessa Innao19 | Francesca Perutelli10 | Francesca Martini4 | Paolo Sportoletti20 |Alberto Fresa2,21 | Maria Ilaria Del Principe13 | Alessandra Tedeschi8 | Marta Coscia22 | Paolo Ghia4,5 |Luca Laurenti1,21Department of Laboratory and Haematological Sciences, Haematology Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolicadel Sacro Cuore, Roma, Italy | 2Hematology Section, Department of Radiological and Hematological Sciences, Università Cattolica del Sacro Cuore, Roma,Italy | 3Facility of Epidemiology and Biostatistics, GSTeP, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy | 4Strategic ResearchProgram on CLL, IRCSS San Raffaele, Milano, Italy | 5Medical School, Università Vita Salute San Raffaele, Milano, Italy | 6Hematology and Stem CellTransplantation Unit, Ospedale Oncologico A. Businco, ARNAS G. Brotzu, Cagliari, Italy | 7Hematology Unit, Department of Medicine—DIMED, Universityof Padua, Padova, Italy | 8Department of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano,Italy | 9Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy | 10Department of Molecular Biotechnology and HealthSciences, University of Torino and Division of Hematology, University Hospital (A.O.U.) Città della Salute e della Scienza di Torino, Torino,Italy | 11Hematology, Department of Oncology, AOU Careggi, Firenze, Italy | 12Hematology and Medical Oncology, AORN Sant’Anna e San Sebastiano,Caserta, Italy | 13Hematology, Department of Biomedicine and Prevention Tor Vergata, University of Rome, Roma, Italy | 14Hematology Unit AO ofCosenza, Cosenza, Italy | 15Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy | 16Department of MedicalSciences and Public Health, University of Cagliari, Cagliari, Italy | 17SOC Clinica Ematologia, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC),Udine, Italy | 18Hematology and Stem Cell Transplantation Unit, S.M. Goretti Hospital, Polo Universitario Pontino, Latina, Italy | 19UOC di Ematologia,Azienda Ospedaliera di rilievo nazionale di alta specializzazione, ARNAS—Garibaldi di Catania, Catania, Italy | 20Department of Medicine and Surgery,Institute of Hematology, Centro di Ricerca Emato Oncologica (CREO), University of Perugia, Perugia, Italy | 21Hematology‐Oncology and Stem‐CellTransplantation Unit, Department of Onco‐Hematology and Innovative Diagnostics, Istituto Nazionale Tumori‐IRCCS‐Fondazione G. Pascale, Napoli,Italy | 22Department of Medicine and Surgery, University of Insubria, and Hematology Division, ASST Sette Laghi, Ospedale di Circolo, Varese, ItalyCorrespondence: Annamaria Tomasso (annamariatomasso2@gmail.com)Received: 15 November 2024 | Revised: 23 December 2024 | Accepted: 28 December 2024Funding: This study was supported with an unconditional grant by AstraZeneca Italia. The funder had no role in study design, data collection and analysis,decision to publish or preparation of the manuscript.Keywords: acalabrutinib | cBTKi | CLL | high riskTo the Editor,In recent years, the treatment of chronic lymphocytic leukaemia(CLL) has changed considerably, in favour of a chmo‐freeapproach with covalent BTK inhibitors (cBTKis), such as ibru-tinib, acalabrutinib and zanubrutinib, that have improved ther-apeutic results even in patients with an unfavourable risk profile[del(17p), TP53m, unmutated IGHV genes (uIGHV)] [1–4]. The‘continuous therapy’ with cBTKis achieves a high response rate,predominantly partial, with an excellent progression free sur-vival (PFS) and overall survival (OS) even in the setting of high‐risk (HR) patients [5, 6]. ESMO Guideline update on new tar-geted therapies recommends the use of BTKi as first line forIdanna Innocenti and Annamaria Tomasso contributed equally as co‐first authors.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properlycited.© 2025 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.Hematological Oncology, 2025; 43:e70033 1 of 5https://doi.org/10.1002/hon.70033patients with a TP53m and/or del(17p) [7], because reported PFSrates suggest longer duration of disease control, and for patientswith an uIGHV without a TP53m or del(17p), especially if unfitor elderly. Despite these data, in clinical practice it's still unclearwhether there's a difference of efficacy of cBTKis in HR sub-groups [del(17p), TP53m, uIGHV]. Therefore, this nationwidemulticentre retrospective study aims to describe efficacy andsafety of acalabrutinib in TN patients with HR CLL and toidentify which subgroup of HR may benefit most from thistreatment. This study was conducted according to the HelsinkiDeclaration, Good Clinical Practice and the applicable nationalregulations, and approved by the local Ethical Committee (studyTABLE 1 | Patients clinical and biological characteristics at baseline, overall response rate and causes of discontinuation.Clinical and biological characteristics at baseline TN CLL (n = 98) p valueAge, years (median, IQR) 70 (65–77) 0.14Gender, n (%)M 62 (63) 0.65F 36 (37)uIGHV, n (%) 87 (90) 0.67Del(17p), n (%) 23 (24) 0.53TP53m, n (%) 17 (18)Groupdel(17p) and/or TP53m only 10 (10) 0.35uIGHV only 68 (71)uIGHV with del(17p) and/or TP53m 18 (19)Rai stage, n (%)Low (I‐II) 44 (45) 0.36High (III‐IV) 54 (55)Binet stage, n (%)A 5 (5) 0.43B 46 (47)C 47 (48)Lymph nodes burden, n (%)No nodes 7 (7) 0.90< 5 cm 52 (54)5–10 cm 27 (27)> 10 cm 12 (12)Splenomegaly, n (%)No 28 (29) 0.16Yes 70 (71)Overall response rate and discontinuationORR 12 months, %del(17p) and/or TP53m only 4 (80) 0.49uIGHV only 54 (95) 0.78uIGHV with del(17p) and/or TP53m 14 (93) 0.21Patients remaining on treatment, n (%) 84 (86) 0.80Temporary suspension, n (%) 24 (29) 0.92Definitive treatment discontinuation, n (%) 14 (14) 0.81Reason for treatment discontinuationProgressive disease, n (%) 2 (14)Richter transformation, n (%) 3 (21)Adverse event, n (%) 4 (30)Death, n (%) 3 (21)2 of 5 Hematological Oncology, 2025number 6390). Its primary endpoint was to evaluate the efficacyof acalabrutinib as first‐line treatment in patients with CLL withan unfavourable biological profile [del(17p) and/or TP53m and/or uIGHV] in terms of overall response rate (ORR). The sec-ondary endpoints were to compare PFS and OS across subgroupsof HR CLL treated with frontline acalabrutinib and to assess itstolerability profile. We enrolled 98 TN patients with HR CLL,who started acalabrutinib between June 2021 and June 2023.Response evaluation was done at 12 months since the start oftreatment [8]. Data regarding definitive treatment discontinua-tion and safety were also collected. We analysed the survival databy stratifying patients into further subgroups according to theHRbiological characteristics [del(17p) and/or TP53m only, withuIGHV only, uIGHV with del(17p) and/or TP53m]. Two patientswere not analyzed due to unavailability of all biological data.Clinical characteristics and biological features at baseline arereported in Table 1. The 10% of patients had del(17p) and/orTP53m only (group A), 71% uIGHV only (group B) and 19% haduIGHV with del(17p) and/or TP53m (group C). After a medianfollow up of treatment of 16 months, the 86% of patientsremained on treatment. ORR among all patients at 12 monthswas 94% as follows: complete remission (CR) and partialremission (PR) rate were 17% and 77%, respectively. ORR at12months were 80%, 95% and 93% in group A, group B and groupC, respectively (Table 1). The 12 months PFS and the 24‐monthsestimated PFS were 92% and 81%, and they were similar betweenthe three subgroups of patients according to their biological risk.At 12months, PFSwere 80% in groupA, 91% in group B and 100%in group C (P = 0.45) (Figure 1). The 12‐months OS and the 24‐months estimated OS was 94% and 88% for the whole cohort. The12‐months OS were 77%, 94% and 100% in group A, B and C,respectively (P = 0.12) (Figure 1). After a median follow up of16months, discontinuation occurred in 14 patients (14%) and themain cause of discontinuation was for adverse events (AEs)(30%), in 4% of the cohort. AE were identified 57% of the patients.Fifty‐two patients (53%) had extraematological toxicities and 17patients (17%) had haematological toxicities. The most experi-enced extraematological toxicity was headache (15%) of whichgrade (G) 3 was observed in only 6% of cases while no G4headache reported. Arthralgias (3%), hypertension (3%) andatrial fibrillation (1%) were found with very low incidences andalways of mild grade (G1 and G2). Furthermore, we found adiscrete rate of infections and skin, gastrointestinal and livertoxicities from acalabrutinib (29%). With regard toFIGURE 1 | (A): Kaplan–Meier curves of PFS in TN patients with high‐risk features. (B): Kaplan–Meier curves of OS in TN patients with high‐riskfeatures.3 of 5haematological toxicity, the most represented was anaemia, witha rate of 10% (Supplementary material). Our analysis confirmsgood efficacy of acalabrutinib in patients with HR CLL in termsof ORR, slightly higher than the ELEVATE TN trial that had alonger follow‐up of 28 months [9]. Results from this analysis ofpatients treated with acalabrutinib confirm durable responses,PFS and OS rates similar to patients without HR features [5, 6].Acalabrutinib caused both haematological and extra haemato-logical toxicities and we observed lower discontinuation ratesdue to AEs than those reported in randomised trials [9]. Thereason for this difference could be the shorter follow‐up of ourstudy or alternatively it could be an indication that over time wehave learned to better manage toxicities and avoid suspension.Here we confirm however, as also described in the pooled anal-ysis of HR patients treated in clinical trials with acalabrutinib,that in the first line the major cause of discontinuation of aca-labrutinib is due to adverse events; However, this finding haslittle statistical significance given the small sample size and shortfollow‐up [10]. Our results also suggest that the major toxicity ofacalabrutinib is the extra haematological one, as headache,compared with a mild haematological toxicity of less than 25% ofcases (supplementary material). Our analysis showed good re-sults even in terms of survival variables such as PFS and OSconsistent with previous trials [9]. Furthermore, no clear efficacyor survival advantages of acalabrutinib according to a particularHR biological set‐up [del(17p) and/or TP53m only, uIGHV only,uIGHV with del(17p) and/or TP53m patients] emerged, butlarger sample size and longer follow up are needed to strengthenour results. Possible limitations of this study are its retrospectivenature and the relatively short median observation time of thecohort; the main strength of the study is the number of patientswith HR CLL treated with acalabrutinib in real world clinicalpractice. In conclusion, acalabrutinib is a good option in real lifein patients with HR CLL. Our study demonstrates effectiveness,long term benefits and low rate of treatment discontinuationwithacalabrutinib as continuous drug in TN HR CLL population.AcknowledgmentsThe authors have nothing to report.Ethics StatementThis study was conducted in accordance with the Declaration of Hel-sinki and approved by the Institutional Review Board of FondazionePoliclinico Universitario Agostino Gemelli IRCCS.ConsentWritten informed consent was obtained from the patients to publish thispaper.Conflicts of InterestThe authors declare no conflicts of interest.Data Availability StatementData available on request.Peer ReviewThe peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/hon.70033.Idanna InnocentiAnnamaria TomassoDiana GiannarelliLydia ScarfòRoberta MurruAndrea VisentinAnna Maria FrustaciFrancesca MorelliCandida VitaleAntonio MoscaAlessandro SannaGiuliana FarinaRoberta LaureanaMassimo GentileAndrea GalitziaRaffaella PasqualeFrancesco AutoreJacopo OlivieriAzzurra RomeoMarina DeodatoLuca StirparoAndrea CorbingiVanessa InnaoFrancesca PerutelliFrancesca MartiniPaolo SportolettiAlberto FresaMaria IlariaDelPrincipeAlessandra TedeschiMarta CosciaPaolo GhiaLuca LaurentiReferences1. J. C. Barrientos, J. A. Burger, J. C. Byrd, et al., “Characterizing theKinetics of Lymphocytosis in Patients With Chronic LymphocyticLeukemia Treated With Single‐Agent Ibrutinib,” Leukemia and Lym-phoma 60, no. 4 (2019): 1000–1005, https://doi.org/10.1080/10428194.2018.1512710.2. D. A. Bond and J. A. Woyach, “Targeting BTK in CLL: BeyondIbrutinib,” Current Hematology Maligning Report 14, no. 3 (2019): 197–205, https://doi.org/10.1007/s11899‐019‐00512‐0.3. T. A. Eyre and J. C. Riches, “The Evolution of Therapies TargetingBruton Tyrosine Kinase for the Treatment of Chronic LymphocyticLeukaemia: Future Perspectives,” Cancers 15, no. 9 (2023): 2596, https://doi.org/10.3390/cancers15092596.4. G. F. Perini, C. C. P. Feres, L. L. C. Teixeira, and N. Hamerschlak,“BCL‐2 Inhibition as Treatment for Chronic Lymphocytic Leukemia,”Current Treatment Options in Oncology 22, no. 8 (2021): 66, https://doi.org/10.1007/s11864‐021‐00862‐z.5. C. Chung, G. Umoru, K. Abboud, and E. 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Acalabrutinib in High-Risk Chronic Lymphocytic Leukaemia Naïve Patients: An Italian Multicenter Retrospective Observational Real-Life Experience

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Acalabrutinib in High-Risk Chronic Lymphocytic Leukaemia Naïve Patients: An Italian Multicenter Retrospective Observational Real-Life Experience

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