Safety of acalabrutinib treatment in very old (≥80 y) and/or frail patients with chronic lymphocytic leukemia ‐ interim safety analysis of the ongoing phase II CLL‐Frail trial

Abstract

Introduction: BTK-inhibitors have revolutionized treatment of CLL. However, although patients (pts) above 80 years of age represent roughly 20% of the general CLL-population they remain underrepresented in clinical trials. Comorbidities, frailty, and organ dysfunction have a high prevalence in older pts and significant impact on efficacy and tolerability of treatments as well as survival. The CLL-Frail trial aims to evaluate the efficacy and safety of acalabrutinib monotherapy in pts ≥80 years of age and/or a FRAIL scale score of ≥3. The FRAIL scale score is a 5-item questionnaire for pts correlating with Fried‘s frailty phenotype. Methods: Pts in need of treatment with previously treated and untreated CLL and ≥80 years of age and/or a FRAIL scale score ≥3 were eligible. A maximum of one previous therapy was allowed. At least 50% of pts needed to fulfil frailty criteria. Pts received acalabrutinib 100 mg BID until progression or intolerance. The primary endpoint was overall response rate at initial response assessment (cycle 7, day 1 = ∼6 months after initiation of therapy). A pre-planned interim safety analysis was conducted once 30 pts reached cycle 7, day 1. Results: 30 pts were enrolled in the first 12 months of recruitment. Median age was 82 years, 50% had a FRAIL scale score of ≥3. Median CIRS score was 10, with 73% of pts having a score >6. Median ECOG-Score was 1. Most pts had a Binet stage A (77%). Unmutated IGHV and TP53mut/del was present in 63% and 10%, respectively. 19 pts (63%) were treatment naïve. In the previously treated cohort, prior lines of treatment included chemoimmunotherapy in 73% and ibrutinib + obinutuzumab + venetoclax, bendamustine + ibrutinib + ofatumumab and obinutuzumab + venetoclax in 9% of pts each. At the data cut in November 2022 the median observation time was 8 months, 21 pts remained on therapy. Reasons for discontinuation were adverse events in five (56%) and death and withdrawn consent in two (22%) pts each, respectively. All pts experienced at least one AE, totalling in 200 AEs of which 35 (18%) were CTC grade >3 (patient level analysis is shown in Table 1). 15 severe adverse events were reported, of which eight (53%) were assessed as treatment-related by the investigator. There were no cases of severe (Grade ≥3) bleeding, two pts (6%) experienced atrial fibrillation with CTC grade two and three, respectively. Two cardiac SAEs termed cardiac failure were reported in pts who both had prior existing hypertension and atrial fibrillation. Four pts (13%) died, of which one death was deemed treatment related. Causes of death were infection in three cases (one bacterial and two COVID-19 pneumonia) and concomitant disease in one case. Conclusions: The first interim analysis of this international phase II study evaluating treatment with acalabrutinib in very old and/or frail pts with CLL did not show unexpected safety signals in comparison to prior published data. Encore Abstract - previously submitted to EHA 2023 The research was funded by: AstraZeneca Keywords: Cancer Health Disparities, Chronic Lymphocytic Leukemia (CLL), Ongoing Trials Conflicts of interests pertinent to the abstract. F. Simon Research funding: AstraZeneca T. Nösslinger Honoraria: Astra Zeneca, Abbvie, Beigene, Janssen, Roche, Gilead J. Bohn Other remuneration: Astra Zeneca, Abbvie, Janssen J. von Tresckow Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Beigene, Janssen, Lilly, Roche Honoraria: AbbVie, AstraZeneca, Beigene, Janssen, Lilly. Roche Educational grants: AbbVie, AstraZeneca, Beigene, Janssen, Lilly, Roche C. Schneider Honoraria: AbbVie, AstraZeneca S. Stilgenbauer Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Research funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis K. Kreuzer Consultant or advisory role: Roche, Janssen, Abbvie, Mundipharma Honoraria: Roche, Janssen, Abbvie, Mundipharma Research funding: Roche, Janssen, Abbvie, Mundipharma A. Fink Honoraria: AstraZeneca Research funding: AstraZeneca, Celgene Educational grants: AbbVie K. Fischer Consultant or advisory role: AstraZeneca Honoraria: AbbVie, Roche, Lilly Educational grants: Roche V. Goede Consultant or advisory role: Astra Zeneca, AbbVie, Janssen, Gilead, Merck, Berlin Chemie Honoraria: Astra Zeneca, AbbVie, Janssen, Gilead, Heel M. Hallek Consultant or advisory role: Roche, Janssen, Gilead, Bristol Myers Squibb, Abbvie Honoraria: Roche, Janssen, Gilead, Bristol Myers Squibb Research funding: Roche, Janssen, Gilead, Bristol Myers Squibb, Abbvie B. Eichhorst Consultant or advisory role: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, ArQule, Oxford Biomedica (UK), MSD, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen Honoraria: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, ArQule, Oxford Biomedica (UK), MSD, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen, Adapative Biotechnologies, Hexal Research funding: Abbvie, Beigene, AstraZeneca, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen Educational grants: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen