Acalabrutinib in High-Risk Chronic Lymphocytic Leukemia Patients Naïve or Previous Treated. a Multicenter Retrospective Observational Real-Life Experience

In recent years, treatment of chronic lymphocytic leukemia(CLL) has changed considerably, in favor of a tailored and chemo-free approach, with the introduction of target drugs, such as BTK inhibitors (BTKi). Continuous BTKi, thanks to a prolonged disease control and low hematological toxicities, improved therapeutic results and responses close to eradicationeven in patients with an unfavorable risk profile [del(17p), TP53m, unmutated IGHV genes (uIGHV)]. Acalabrutinib, a covalent second-generation BTKi, demonstrated similar progression free survival (PFS) and overall survival (OS) of Ibrutinib, the first in class BTKi, in pts carrying del(17p) and/or del(11q), while showing a lower rate of treatment discontinuation for adverse events (AE) due to a more favorable toxicity profile. Despite these data, in clinical practice it's still unclear whether there's a difference of efficacy of Acalabrutinib in other high-risk (HR) subgroups (TP53m, uIGVH) and whether there might be a subgroup that could be a better candidate for treatment with Acalabrutinib.

The primary aim of the study was to evaluate the efficacy of Acalabrutinib in pts with HR CLL and to identify which subgroup may benefit the most from its use. The secondary aims were to describe clinical-biological features of pts with HR CLL candidates to Acalabrutinib in real life and to assess its tolerability profile.

A retrospective analysis was conducted on 129 pts with HR CLL [del(17p), TP53m and/or uIGHV], who started Acalabrutinib between June 2021 and June 2023, from 14 Italian centers. Pts were divided into two groups: the treatment-naïve (TN) group (n = 98) and the relapsed/refractory (RR) group (n = 31). Median ages were 70 and 75 years for TN and RR pts, respectively. For both, we analyzed survival data by stratifying pts into further subgroups according to HR biological features [10 TN and 2 RR pts with del(17p) and/or TP53m only, 68 TN and 18 RR with uIGHV only, 18 TN and 9 RR with uIGHV with del(17p) and/or TP53m). Four pts were not analysed due to unavailability of all biological data. Overall response rate (ORR), PFS, OS and AE according to CTCAE v.5.0 were evaluated.

Baseline characteristics were similar between the two groups. The uIGHV status was present in the majority of the pts (90% of TN and 93% of RR), whereas del(17p) was present to a lesser extent (24% and 29% of the two groups, as expected). TP53m was more frequent in RR than TN pts (29% vs 18%). A bulk disease (lymph nodes > 5 cm) was in 39% of TN and in 33% of RR pts, while splenomegaly in 71% and 58% of the two groups. Binet stage at the time of Acalabrutinib initiation was B/C in 95% of TN and 100% of RR pts and A in 5% of TN pts. After a median follow up of 16 and 14 months for the TN and the RR groups, respectively, 86% of TN and 84% of RR pts remained on treatment. Among TN, 29% of discontinuation was due to AEs, 14% due to progressive disease and 21% due to Richter syndrome transformation. Among RR, 20% of discontinuation was due to AEs and 20% due to progressive disease. Thirty-five% and 60% of discontinuations among TN and RR were for death or other causes. In the TN group, ORR at 12 months was 80%, 95% and 93% in del(17p) and/or TP53m only, uIGHV only, uIGHV with del(17p) and/or TP53m pts, respectively. In the RR group, ORR at 12 months was 100%, 93% and 75%, respectively for the three subgroups. The 12 months PFS was 92% in TN (P=0.45) and 94% in RR pts (P=0.71) and it was similar between the 3 subgroups of pts according to their biological risk. The 12 months OS was 94% in TN (P=0.12) and 94% in RR pts (P=0.71) with the worst OS for TN del(17p) and/or TP53m only (77%). AEs occurred in 57% of all pts: 53% of TN and 61% of RR pts had extra-hematological toxicities, whereas 17% of TN and 23% of RR pts had hematological toxicities. The most frequent extra hematological toxicity in TN pts was headache (15%) of which grade (G) 3 events were observed only in 6% of cases while no G4 headache reported. The most frequently reported extrahematological toxicity in RR pts was bleeding (23%) mostly G2/G3 (29% G1, 57% G2, 14% G3).

Acalabrutinib is widely used in pts with HR CLL. With a median follow up a little longer than a year, our study demonstrates good effectiveness, long term benefits and low rate of treatment discontinuation with Acalabrutinib as continuous drug in HR CLL population, both for TN and RR pts. No clear differences in efficacy have been observed between the 3 risk subgroups, but larger sample size and longer follow up are needed to strengthen our results.

Scarfo:Janssen: Honoraria; Lilly: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Octapharma: Honoraria. Visentin:Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; J&J: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Beigene: Consultancy, Research Funding, Speakers Bureau; AstraZenca SpA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Frustaci:AbbVie, BeiGene, AstraZeneca, Janssen: Consultancy; AbbVie, BeiGene: Other: Travel, accommodations, expenses. Morelli:BeiGene: Current Employment. Vitale:AstraZeneca: Honoraria, Other: support for attending meetings; Takeda: Other: support for attending meetings; AbbVie: Honoraria; Johnson & Johnson: Honoraria. Autore:BeiGene, AstraZeneca, AbbVie, Janssen: Honoraria. Sportoletti:Janssen; AstraZeneca, Abbvie; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tedeschi:AstraZeneca, AbbVie, BeiGene, Janssen, Lilly: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coscia:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support for attending meetings; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support for attending meetings; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support for attending meetings. Ghia:BeiGen: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Johnson&Johnson: Consultancy, Research Funding; Galapagos: Consultancy; Loxo@Lilly: Consultancy; MSD: Consultancy; Galapagos: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbvVie: Consultancy, Research Funding; Roche: Consultancy. Laurenti:AstraZeneca, AbbVie, Johnson and Johnson, BeiGene, Lilly: Membership on an entity's Board of Directors or advisory committees; AstraZeneca, AbbVie: Research Funding; AstraZeneva, AbbVie, Johnson and Johnson, BeiGene, Lilly: Honoraria.