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
Authors: Simon Florian , Ligtvoet Rudy , Bohn Jan-Paul , Noesslinger Thomas , Von Tresckow Julia , Liersch Ruediger , Gaska Tobias , Jentsch-Ullrich Kathleen , Gärtner Michael , Wolff Thomas , Schwaner Ingo , Wolf Dominik , Schneider Christof , Vehling-Kaiser Ursula , Ritgen Matthias , Spoer Christian , Eckart Michael J. , Decker Thomas , Chakupurakal Geothy , Schöttker Björn , Kisro Jens , Stumpf Janina , Tausch Eugen , Stilgenbauer Stephan , Kreuzer Karl-Anton , Robrecht Sandra , Fink Anna Maria , Fürstenau Moritz , Fischer Kirsten , Goede Valentin , Hallek Michael , Eichhorst Barbara F. 
Published: December 2024

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 &gt;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&lt;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.