A new, real-world study using more than 2 years of EMRs shows that patients with chronic lymphocytic leukemia (CLL) treated with first-line acalabrutinib were 89% more likely to initiate a next-line treatment when compared with patients treated with first-line ibrutinib.1 The study results were presented at the 2022 annual meeting of the American Society of Hematology (ASH 2022) by Ryan Jacobs, MD.

Evidence-based treatment guidelines recommend Bruton’s tyrosine kinase inhibitors (BTKi) ibrutinib (once-daily) or acalabrutinib (twice-daily) as preferred regimens for chronic lymphocytic leukemia (CLL); however, direct comparisons of the effectiveness of ibrutinib versus acalabrutinib as first-line therapy in CLL have not been performed. The objective of the study presented by Dr. Jacobs was to use de-identified pharmacy EMRs from academic and non-teaching hospital systems to identify adults who were newly diagnosed with CLL between November 2018 and April 2022, and who initiated ibrutinib (N=710) or acalabrutinib (N=373) in the first-line setting. The primary outcome was the time to next treatment (TTNT; the time from the index date to initiation of a next or additional treatment), which acted as a clinically meaningful surrogate measure for disease progression for patients with CLL.

Although most baseline characteristics were similar between the two cohorts, the authors noted that corticosteroid use was lower in the cohort starting ibrutinib (14.5% vs 20.1%; P=0.018), while antiplatelet use was higher (7.0% vs 3.5%; P=0.017). Furthermore, more patients in the ibrutinib cohort entered the study with existing chronic pulmonary disease (13.6% vs 8.8%; P=0.024), peripheral vascular disease (7.8% vs 4.1%; P=0.022), or hypertension (41.4% vs 32.2%; P=0.003), although other important cardiovascular determinants, such as atrial fibrillation, were similar between the groups (7.0% vs 9.9%, P=0.098).

After a mean of 17.1 [1.0-29.3] months for the ibrutinib cohort and 12.5 [1.0-29.1] months for the acalabrutinib cohort, an overall benefit was seen for ibrutinib: 5.9% of patients in the ibrutinib cohort started second-line or additional therapy, compared with 7.5% of patients in the acalabrutinib cohort. After adjusting for baseline characteristics, patients treated with acalabrutinib were 89% more likely to start a next or additional treatment than those treated with ibrutinib (HR, 1.89; 95% CI, 1.12-3.13; P=0.016). When the researchers censored added anti-CD20 therapy at any time, results remained similar (HR, 1.82; 95% CI, 1.08-3.03; P=0.025). At 12 months, 95.3% of patients treated with ibrutinib had not initiated a next treatment, versus 91.2% of patients treated with acalabrutinib. At 15 months, 94.6% of patients treated with ibrutinib had not initiated next therapy, versus 88.3% of patients treated with acalabrutinib. These findings from real-world clinical practice suggest that first-line treatment for CLL with once-daily, all-oral ibrutinib in routine practice may provide patients the opportunity to maintain monotherapy treatment for a longer period without the need to start a next line of therapy.

Physician’s Weekly spoke to Dr. Jacobs, principal study investigator, about his results.

PW: Why is real-world data here so important?

Dr. Jacobs: Insights from real-world data are becoming more important to help physicians understand optimal treatments and sequencing, especially for patients living with chronic diseases like CLL. There are two FDA-approved BTK inhibitor treatment options: ibrutinib and acalabrutinib. Ibrutinib was the first-in-class covalent BTK inhibitor that we have been able to use in the clinic to treat CLL since 2014, and acalabrutinib was sort of a second-generation BTKi that was approved in 2019. There are currently no comparative clinical trials in first-line CLL among the BTKi class, highlighting the critical need to leverage real-world experience to support optimized treatment selection. These results demonstrate the possible impact of using ibrutinib versus acalabrutinib in the front-line setting and provide healthcare professionals with additional data showing differences in time to next treatment.

For context, we did perform a prospective, open-label study—the non-inferiority ELEVATE-RR study.2 It was in a select group of high-risk patients with a poor prognosis who had relapsed or refractory disease. With a median follow-up of 40.9 months, acalabrutinib and ibrutinib were equally effective in terms of preventing disease progression. However, the incidence of cardiac events, such as atrial fibrillation and hypertension, was lower with acalabrutinib, but having said that, we were anticipating the toxicity profile to be different. Acalabrutinib is a more selective BTK inhibitor and thus has fewer off-target kinase effects. That study is currently all of the evidence we have in terms of prospective data, which is of course the gold standard.

It was really important that we look at the real-world data for a couple reasons. We see differences in real-world data outcomes relative to prospective trials. Typically, the real-world setting brings in a different and more diverse patient population. In addition, the manner in which we screen treatment for off-trial treatment is much different than on-trial. This study can be seen as a real-world supplement to ELEVATE-RR, providing additional information that may be important in making therapeutic decisions.

But in addition to those points about real-world differences, the majority of patients are actually being treated in the current CLL era in the first-line setting with BTK inhibitors. With real-world data, we can ask “How do these agents compare in the first-line setting where they are actually being utilized more often?” We are unlikely to ever get a prospective study comparing these two agents, almost as a product of their mutual success. They both already have FDA approval in this space.

We were able to look at both the real-world differences and frontline efficacy with our study. As our primary endpoint, we chose to use an under-reported endpoint on prospective trials called Time to Next Treatment (TTNT), which many people might call a “real-world progression-free survival (PFS)” metric. PFS can be difficult to assess for low-grade lymphomas in structured chart extractions using EMR analyses tools, because not all patients with low-grade lymphoma immediately go from one treatment to another. I think a lot of patients with CLL, as well as their clinicians, would argue that TTNT is perhaps a more valid endpoint clinically, because we want to see the total maximum time of benefit from a treatment and not just necessarily the time on treatment or before discontinuation or the time until disease progression. TTNT tells us the time until clinically significant progression requires additional treatment.

PW: What were the limitations of your study? 

Dr. Jacobs: The primary limitation was that in this structured chart extraction, we cannot extract the reasons for discontinuation. Now that we are putting a manuscript together, we are going to go back and look at the unstructured data to try to pull some of that data out. Another limitation to our study is that there’s not a totally clean way within a structured extraction to identify first-line patients.

To tackle that second limitation, we used a precedent that had been used in the CLL real-world data analyses in the past, in which we required a 1-year washout period. If patients had not received treatment for CLL at least 1 year prior to June 2019 and were then treated at any time after that with ibrutinib or acalabrutinib, they were included and identified as first-line.

PW: What are the take-home messages from the study?

Dr. Jacobs: One point to remember is that the endpoint was TTNT. Overall, both treatment groups were doing very well. At 15 months, the overwhelming majority of patients were still free of needing to go to the next treatment. There did seem to be a higher proportion of patients on the ibrutinib arm that had not moved on to next line of therapy, at 94.6%, and that was compared with 88.3% on the acalabrutinib arm. That represented an 89% reduction in the risk to needing to move on to next line of therapy. That is an interesting finding, maybe even a little controversial. My personal experience is that acalabrutinib is, among specialists, the preferred option between the two agents. Thus, this important finding that favors ibrutinib probably leads to more questions than answers. However, it is always good for us to evaluate these questions to evaluate what role ibrutinib has now that we have these more selective BTK inhibitors. I think it is always important to look at the real-world data to see if we can answer questions.

PW: Do you think that real-world compliance might explain your data?

Dr. Jacobs: I presented an abstract at the Society of Hematologic Oncology annual meeting for a study in which we looked at compliance, comparing once-daily ibrutinib with twice-daily acalabrutinib.3 Not surprisingly—I would even say it is intuitive—patients were more compliant with the once-daily medicine, ibritinib. It, therefore, follows that if your patient is missing doses here and there, perhaps they are not really maintaining as significant of a BTK occupancy as you would like for optimal disease control. As far as what was underpinning the TTNT difference in our real-world data, I think compliance is as good of a guess as any. In our daily practices, that is something to really keep an eye on.