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4618 Efficacy and Safety of Acalabrutinib Treatment in Very Old (≥80y) and/or Frail Patients with Chronic Lymphocytic Leukemia (CLL) – Primary Endpoint Analysis of the Phase II CLL-Frail Trial

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphoid Leukemias, CLL, Elderly, Clinical Research, Diseases, Lymphoid Malignancies, Adverse Events, Study Population, Human
Monday, December 9, 2024, 6:00 PM-8:00 PM

Florian Simon, MD1*, Rudy Ligtvoet, PhD1*, Jan-Paul Bohn2*, Thomas Noesslinger3*, Julia Von Tresckow, MD4*, Ruediger Liersch5*, Tobias Gaska, MD6, Kathleen Jentsch-Ullrich, MD7*, Michael Gärtner, MD8*, Thomas Wolff9*, Ingo Schwaner10*, Dominik Wolf, M.D.11*, Christof Schneider, MD12*, Ursula Vehling-Kaiser, MD13*, Matthias Ritgen14*, Christian Spoer15*, Michael J. Eckart, MD16*, Thomas Decker17*, Geothy Chakupurakal, MBBS18, Björn Schöttker19*, Jens Kisro, MD, PhD20, Janina Stumpf1*, Eugen Tausch, MD12*, Stephan Stilgenbauer, MD12, Karl-Anton Kreuzer21*, Sandra Robrecht, PhD22,23*, Anna Maria Fink, MD22*, Moritz Fürstenau, MD24*, Kirsten Fischer, MD22*, Valentin Goede, MD25*, Michael Hallek, MD26* and Barbara F. Eichhorst, MD27

1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf; German CLL Study Group, University of Cologne, Cologne, Germany
2Department of Internal Medicine V, Division of Hematology & Oncology, Medical University of Innsbruck, Innsbruck, AUT
3Medizinische Abteilung für Hämatologie und Onkologie; Hanusch Krankenhaus, Vienna, Austria
4Clinic for Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
5Gemeinschaftspraxis für Hämatologie und Onkologie, Clemenshospital Münster, Münster, Germany
6Brüderkrankenhaus St. Josef, Paderborn, DEU
7Gemeinschaftspraxis für Hämatologie und Onkologie, Magdeburg, DEU
8Onkologisches Ambulanzzentrum Hannover (OAZ), Hannover, Germany
9Oncoresearch Lerchenfeld UG, Hamburg, Germany
10Onkologische Schwerpunktpraxis Kurfürstendamm, Berlin, Germany
11Department of Medicine V, Medical University of Innsbruck, Innsbruck, Austria
12Department of Internal Medicine III, Division of CLL, University Hospital Ulm, Ulm, Germany
13Outpatient Clinic, Landshut, Germany
14Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
15MVZ Klinikum Deggendorf GmbH, Deggendorf, Germany
16Onkologische Schwerpunktpraxis Erlangen, Erlangen, Germany
17Onkologie Ravensburg, Ravensburg, DEU
18Praxis für Hämatologie und Onkologie Koblenz, Koblenz, DEU
19Hämatologisch-onkologische Schwerpunktpraxis Würzburg, Würzburg, Germany
20Lübecker Onkologische Schwerpunktpraxis, Lübeck, DEU
21Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf; German CLL Study Group, University of Cologne, Cologne, Cologne, DEU
22Department I of Internal Medicine, Faculty of Medicine and Cologne University Hospital, Cologne, Germany
23German CLL Study Group, University of Cologne, Cologne, Germany
24Department I of Internal Medicine, Faculty of Medicine and Cologne University Hospital, Koeln, Germany
25St. Marienhospital Cologne, Oncogeriatric Unit, Department of Geriatric Medicine, Cologne, Germany
26CECAD, Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Center for Molecular Medicine, Cologne, Germany
27Department I of Internal Medicine and Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, German CLL Study Group, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany

BACKGROUND: Very old and frail patients remain underrepresented in clinical trials, although accounting for roughly 20% of patients with CLL. A higher comorbidity burden and vulnerabilities in this cohort limit the use of results from younger and fit patients. The CLL-Frail trial aims to evaluate the efficacy and safety of acalabrutinib monotherapy in patients ≥80 years of age and/or a FRAIL scale score of ≥3. The FRAIL scale score is a 5-item self-assessment questionnaire for patients correlating with Fried‘s frailty phenotype (Abrahamian, 2017). We here present the primary endpoint analysis as pre-specified in the protocol. The analysis was performed after all patients had reached the initial response assessment (cycle 7, day 1 = approx. 6 months after initiation of therapy).

METHODS: Patients 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. Patients received acalabrutinib 100mg BID until progression or intolerance. The primary endpoint was overall response rate (ORR) at the initial response assessment for patients receiving at least 3 cycles of therapy (full analysis set, FAS) with the aim to test the null hypothesis of ORR ≤ 65%. Secondary endpoints included overall survival (OS), progression-free survival (PFS) as well as frequency and severity of adverse events.

RESULTS: 53 patients were included into the trial (ITT population), one patient withdrew consent before receiving study medication, and 46 patients completed at least 3 cycles of therapy (FAS).

In the ITT population median age was 81 years (range 54-91), 47% had a FRAIL scale score of ≥3. Median CIRS score was 9, with 68% of patients having a score >6. 79% of patients had an ECOG score ≥1. Unmutated IGHV and aberrant TP53 was present in 60% and 23%, respectively. 36 patients (68%) were treatment naïve. In the previously treated cohort, prior lines of treatment included chemoimmunotherapy in 13 patients (76%), while four patients (24%) were treated with targeted therapy.

At the data cut on the 15th of January 2024 the median observation time was 17.7 months, 34 patients (65%) remained on therapy. Six patients (12%) discontinued therapy before reaching cycle 4. Reasons for discontinuation in all patients were adverse events in ten (56%), death in five (28%) and withdrawn consent in three (17%) patients, respectively.

With 43 of 46 patients achieving a PR at cycle 7 day 1 the ORR in the FAS was 93.5% (95% confidence interval 82.1 - 98.6) meeting the primary endpoint of the trial (p<0.001). One patient had a stable disease and two patients had missing response assessments. There were no progressive diseases.

In the ITT population estimated 12-month PFS and OS rates were 87.5% and 91.9%, respectively. The estimated 12-month PFS and OS-rates in frail patients were 90.9% and 90.9%. 53% of FAS-patients had an improvement in their FRAIL scale scores, with 21% of patients considered frail at month 6, compared to 47% at screening, according to self-assessment.

All patients experienced at least one AE. Most common AEs were COVID-19 (40% of patients) and hematoma (37%). There were a total of 40 SAEs in 26 (50%) patients. There were no cases of severe (CTC° ≥3) bleeding. Since the interim safety analysis in 2023 there were no further cases of atrial fibrillation, the total remaining at two cases (CTC° 2 and 3).

Five patients (9%) died. Causes of death were infection in three cases (one bacterial and two COVID-19 pneumonia) and concomitant disease in one case. There was one deadly SAE termed suspicion of cardiac event, in a case of a 85-year old patient with sudden death at home and known cardiac comorbidities.

CONCLUSION: This is the first prospective trial aimed specifically at treatment evaluation in very old and/or frail patients with CLL. High response rates and the substantial improvement of frailty demonstrated a remarkable efficacy of the BTK-inhibitor acalabrutinib in this underrepresented age group.

Disclosures: Simon: Lilly: Other: Travel Support; AstraZeneca: Research Funding, Speakers Bureau. Bohn: Abbvie: Honoraria; Abbvie: Honoraria; BeiGene: Honoraria; Eli Lilly: Honoraria; Janssen: Honoraria. Noesslinger: Abbvie: Honoraria, Other: travel grant; Astra Zeneca: Honoraria, Other: travel grant; Beigene: Honoraria, Other: travel grants; Janssen: Honoraria, Other: travel grants; Lilly: Honoraria, Other: travel grants; Roche: Honoraria, Other: travel grants. Schwaner: AbbVie, Amgen, AstraZeneca, BeiGene, Janssen, Lilly, Roche: Consultancy. Schneider: Abbvie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag: Honoraria. Kisro: AbbVie, Astra, Beigene, BMS, Daichi, Incyte, Ipsen, Janssen, Lilly, MSD, Novartis, Oncopeptides, Phizer, Roche, Sanofi, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Tausch: Janssen: Consultancy, Other; AstraZeneca: Consultancy; BeiGene: Consultancy, Other; Roche: Consultancy, Research Funding; Abbvie: Consultancy, Other, Research Funding. Stilgenbauer: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Galapagos: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Lilly: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau. Robrecht: AstraZeneca: Honoraria. Fink: AstraZeneca: Honoraria, Research Funding. Fürstenau: Abbvie: Speakers Bureau. Fischer: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goede: AbbVie, Astra Zeneca, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hallek: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Eichhorst: AbbVie: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy, Speakers Bureau; Lilly: Consultancy; MSD: Consultancy, Speakers Bureau; Miltenyi: Consultancy; Roche: Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Hoffmann-La Roche: Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding, Speakers Bureau.

*signifies non-member of ASH