Acalabrutinib to assail CLL in the frail Free

In this issue of Blood, Simon et al¹ report on the CLL-Frail study, which investigated acalabrutinib as initial therapy for patients with chronic lymphocytic leukemia (CLL), who were ≥80 years of age (67.4%) and/or frail (47.2%).

This investigator-initiated, phase 2 study conducted by the German CLL Study Group included a 52-patient safety population, of which 46 patients were included in the full analysis set (predefined as those patients who received ≥3 complete cycles of treatment). The study met its primary end point, with an overall response rate of 93% (43/46, all partial responses) in the full analysis set (see figure). Although the median follow-up of 19 months is short for a frontline CLL trial, the 1-year progression-free survival (PFS) and overall survival rates of 93% and 96%, respectively, are promising in an older population. All patients experienced at least 1 adverse event (AE), and severe AEs were reported in nearly two-thirds of patients (64%). Notably, just over half of patients (53%) in the full analysis set reported an improvement in their self-perceived frailty, as reflected by their FRAIL (Fatigue, Resistance, Ambulation, Illness, and Loss of weight) score after 6 cycles of treatment.

The results of the CLL-Frail study provide insight into a key knowledge gap in the field, highlight the challenges of treating this patient population, and provide the foundation for future investigation of optimal therapeutic strategies.

As the first prospective trial, to our knowledge, specifically designed to investigate continuous Bruton tyrosine kinase inhibitor (BTKi) treatment in older or frail patients with CLL—median age of 81—this study generated important data for a previously underrepresented patient population in frontline CLL trials. In the ELEVATE-TN and SEQUOIA trials, which established frontline acalabrutinib and zanubrutinib monotherapy as standard-of-care treatment approaches, respectively, the median age of patients was a decade younger, at 70 years.^2,3 Over one-third of patients with CLL are diagnosed at age 75 years or older,⁴ and most are initially observed, so these data on patients in their 80s, many of whom have complex medical comorbidities, are informative for patients commonly seen in academic and particularly also in community practice.

Prior studies with ibrutinib demonstrated that impaired functional status and presence of medical comorbidities negatively affect the outcomes of patients with CLL. For example, a pooled retrospective analysis of ∼700 patients treated outside of clinical trials at 15 centers in Italy demonstrated that those patients with an ECOG (Eastern Cooperative Oncology Group) performance status of >1 or a CIRS (Cumulative Illness Rating Scale) score of >6 had inferior PFS.⁵ Head-to-head comparisons of acalabrutinib and zanubrutinib vs ibrutinib have previously demonstrated more favorable toxicity profiles of the second-generation BTKi (ELEVATE-RR and ALPINE studies, respectively),^6,7 but until the results of the CLL-Frail trial, it was not known how well a more selective BTKi might perform in an older population with more comorbidities. The CLL-Frail study confirms that acalabrutinib is an effective and safe option for these patients, with similar results as the acalabrutinib monotherapy arm in the ELEVATE-TN study, which had a significantly younger median age.

The toxicities observed with acalabrutinib in this study highlight the challenges of treating an older population with multiple medical comorbidities. Infectious, cardiovascular, and bleeding AEs were relatively common (see figure), highlighting the particular importance of being vigilant for such toxicities in this population. Of the 5 patient-reported deaths, only 1 was due to disease progression. Three patients died of infection (2 cases of COVID-19 pneumonia, both in vaccinated individuals, and 1 case of bacterial pneumonia), and 1 patient suffered a sudden death at home (presumed to be cardiac arrest). COVID-19 infection was observed in 40% of patients, 12% of which were grade ≥3. One-quarter of patients experienced a cardiac AE, including 2 cases of atrial fibrillation and 3 cases of grade ≥3 cardiac failure (all 3 had some degree of heart failure at study entry and/or were taking heart failure medication). Hematoma occurred in 37% of patients (19/52), although none were grade ≥3, and bleeding events accounted for 11% of all AEs in the study. Taken together, these results demonstrate that acalabrutinib does come with some toxicity, although patients with CLL are at risk for many of these complications, particularly infections, irrespective of the treatment they are on, including those not on active treatment. Encouragingly, over half of patients reported an improved self-assessed frailty score after 6 cycles of treatment.

Since the time when this trial was designed and initiated, the CLL field has moved toward time-limited, venetoclax-based treatment options, which are now also standards of care. The median follow-up in the CLL-Frail study of only ∼1.5 years is limited, and due to the continuous treatment, with longer follow-up, additional toxicities will accumulate. Finite treatment provides the advantage of finite toxicity risk. An important gap in the field remains a robust understanding of the tolerability and feasibility of time-limited, venetoclax-based combinations in a frail patient population. Although the CLL14 trial investigating the time-limited combination of venetoclax plus obinutuzumab aimed to study an older patient population, the median age was 72 years, and only a third of patients were of age ≥75 years.⁸ Furthermore, the recently published AMPLIFY trial demonstrated a promising efficacy and safety profile of an all-oral, targeted-agent, fixed-duration treatment regimen of acalabrutinib plus venetoclax, but the median age of the patients was young at 61 years.⁹ 

Although the logistics of venetoclax ramp-up are more complex than initiation of single-agent BTKi, an all-oral, time-limited, doublet regimen may be appealing for older and frail patients, and it has the potential to limit the cumulative toxicities observed with continuous therapies. Thus, future trials of such time-limited regimens in the older and frailer population are needed, and in addition to early efficacy and safety assessments, would benefit from incorporating additional aspects such as the frailty score, patient-reported outcomes, and health care resource utilization data.

The CLL-Frail study, to our knowledge the first of its kind, has established an important foundation for further investigation of the exciting new treatment regimens being developed in CLL in the patients most likely to receive these regimens in practice.

Conflict-of-interest disclosure: C.E.R. has received institutional research funding from BeOne Medicines, Genentech, and Eli Lilly; and has received consulting fees from AstraZeneca, BeOne Medicines, Genentech, and Incyte. M.S.D. has received institutional research funding and consulting fees from AbbVie, Ascentage Pharma Group Inc, AstraZeneca, Genentech, MEI Pharma, and Novartis; and consulting fees from Adaptive Biotechnologies, BeiGene, Bristol Myers Squibb, Eli Lilly, Galapagos, Genmab, Janssen, Merck, Nuvalent, and Schrödinger.