P630: safety and treatment adherence with acalabrutinib in very old (≥80y) and/or frail patients with chronic lymphocytic leukemia (cll) - interim safety analysis of the ongoing phase-ii cll-frail trial

Background: BTK-inhibitors have revolutionized treatment of CLL. However, although patients 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 patients 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 patients ≥80 years of age and/or a FRAIL scale score of ≥3. The FRAIL scale score is a 5-item questionnaire for patients correlating with Fried‘s frailty phenotype (Abrahamian, 2017). Aims: The aim of this analysis was to show the safety of acalabrutinib as well as the feasibility of conducting a trial in this so far underrepresented patient group. 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. To adequately represent frail patients in this trial, at least 50% of patients needed to fulfill frailty criteria. Patients received acalabrutinib 100mg BID until progression or intolerance. The primary endpoint was overall response rate (ORR) at initial response assessment (cycle 7, day 1 = approx. 6 months after initiation of therapy). To account for age and frailty of this specific patient cohort a pre-planned interim safety analysis was conducted once 30 patients reached cycle 7, day 1. Results: 30 patients 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 patients having a score >6. Median ECOG-Score was 3. Most patients had a Binet stage A (77%). Unmutated IGHV and TP53mut/del was present in 63% and 10%, respectively. 19 patients (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 patients each. At the data cut on the 24th of November 2022 the median observation time was eight months, 21 patients remained on therapy. Reasons for discontinuation were adverse events in five (56%) and death and withdrawn consent in two (22%) patients each, respectively. All patients experienced at least one AE, totaling 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 patients (6%) experienced atrial fibrillation with CTC grade two and three, respectively. Two cardiac SAEs termed cardiac failure were reported in patients who both had prior existing hypertension and atrial fibrillation. Four patients (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. Summary/Conclusion: The first interim analysis of this international phase II study evaluating treatment with acalabrutinib in very old and/or frail patients with CLL did not show unexpected safety signals in comparison to prior published data.Keywords: Comorbidities, Chronic lymphocytic leukemia, Clinical trial, Elderly