A new real-world study using >2 years of electronic medical records shows that chronic lymphocytic leukaemia (CLL) patients 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 American Society of Hematology (ASH 2022) in New Orleans, LA, Dec 9-12, 2022, by Ryan Jacobs, MD (Dept. Hematology, Atrium Health Levine Cancer Institute, Charlotte, NC); below, Medicom interviewed Dr Jacobs, to find out more about the impact of this work.
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 electronic medical records from academic and non-teaching hospital systems to identify adults who were newly diagnosed with CLL between November 2018 through April 2022, and who initiated ibrutinib (n=710) or acalabrutinib (n=373) in the first-line setting. The primary outcome of this study was the time to next treatment (TTNT; the time from the index date to the initiation 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 2 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 was similar between the 2 groups (7.0% vs 9.9%, P=0.098).
After a mean follow-up of 17.1 [1.0-29.3] months for the ibrutinib cohort and 12.5 [1.0-29.1] months for the acalabrutinib cohort, the results showed overall benefit for ibrutinib: 5.9% of patients in the ibrutinib cohort started second-line or additional therapy as 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, the 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 in the USA 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.
Medicom spoke to Ryan Jacobs, M.D., Clinical Director, Division of Lymphoma Therapy & Research, Department of Hematologic Oncology, Atrium Health Levine Cancer Institute and principal study investigator about his results.
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. Here in the United States, there are 2 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 here treating 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 optimised 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. The results showed that 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 Bruton’s tyrosine kinase inhibitor, and thus has fewer off-target kinase effects. That study is currently all of the evidence that we have in terms of prospective data, which is of course the gold standard.
Next, it was really important that we look at the real world data for a couple of reasons. Firstly, we all know that 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 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 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 Bruton’s tyrosine kinase inhibitors. With real-world data we can ask: how do these agents compare in the first-line setting where they are actually being utilised more often? We are unlikely to ever get a prospective study comparing these 2 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 as well as the 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, which many people might call a “real world PFS” metric. PFS can be difficult to assess for low-grade lymphomas in structured chart extractions using electronic medical record analyses tools, because not all low-grade lymphoma patients immediately go from one treatment to another. I think a lot of CLL patients 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.
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 looking at the unstructured data to try to pull some of that data out. In addition, I would say another limitation to our study is 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, where we required a 1-year washout period. If patients had not received treatment for CLL at least one year prior to June 2019, and were then treated at any time after that with ibrutinib or acalabrutinib, then they were included and identified as first-line.
What should your colleague physicians take home and remember from the study?
Dr. Jacobs: One point to remember is that the endpoint was Time to Next Treatment (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 2 agents in the United States. Thus this important finding that favours 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.
Do you think that real-world compliance might explain your data?
Dr. Jacobs: Excellent point. I presented an abstract at SoHO, or the Society of Hematologic Oncology, where we looked at compliance, comparing a once-daily ibrutinib with twice-daily acalabrutinib [3]. And not surprisingly, I would even say it is intuitive, patients were more compliant with the once-daily medicine, ibrutinib. 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 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.
References
- Jacobs R. et al, Real-World Comparison of Time to Next Treatment for Patients with CLL Initiated on First-Line Treatment with Ibrutinib Versus Acalabrutinib. Presented at the American Society of Hematology (ASH 2022) on Monday, December 12, 2022, Abstract 797.
- Byrd JC, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. 2021 ASCO Annual Meeting. Abstract 7500. Presented June 5, 2021.
- Lu X, et al. Real-World Adherence to First-Line Ibrutinib and Acalabrutinib Single-Agent Among Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Clinical Lymphoma Myeloma and Leukemia, Volume 22, Supplement 2, 2022: S280-S281, abstract CLL-492
Photo taken from Levine Cancer Institute, https://atriumhealth.org/medical-services/specialty-care/cancer-care
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