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Two Real-World Studies Analyze Clinical Outcomes for Patients With CLL After Treatment With cBTKi and BCL2i
Two recent retrospective studies by Toby Eyre, MD, Oxford Cancer and Hematology Centre, Oxford University NHS Foundation Trust, Oxford, UK, and colleagues, and Anthony Mato, MD, MSCE, Director of the CLL Program, University of Pennsylvania, and colleagues investigated clinical outcomes of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who had received both a covalent Bruton’s tyrosine kinase inhibitor (cBTKi) and B-cell lymphoma 2 inhibitor (BCL2i) in a real-world setting. Although the research teams used two different databases to retrieve the data for each study, the outcomes showed to be similar: Both studies found low response rates and time to progression for patients with CLL after receiving cBTKi and BCL2i therapy and discontinuing their use, highlighting the need for more effective therapies after this stage of treatment (Leukemia & Lymphoma. 2023 Mar 29:1-12. doi: 10.1080/10428194.2023.2190436; Clin Lymphoma Myeloma Leuk. 2022 Oct 7; 23[1]:57-67. doi: 10.1016/j.clml.2022.09.007).
For their study, Dr Eyre and colleagues pulled deidentified patient data from the Flatiron Health electronic health record (EHR)-derived database, which consisted of data from approximately 280 cancer clinics in the US (approximately 800 sites of care). The patients included in the study met the following criteria: They had been diagnosed with CLL (ICD-9-CM: 204.1x, ICD-10-CM: C91.1x, C83.0x); had at least two clinic visits for systemic therapy on or after January 1, 2011; and had been treated for CLL with at least one cBTKi and at least one BCL2i and discontinued both agents.
Rather than using the Flatiron Health database for their study, Dr Mato and colleagues pulled patients’ CLL data from the deidentified oncology electronic medical record (EMR) ConcertAI RWD360 database. The patients in this study needed to meet similar criteria to the first study: They had been diagnosed with CLL (ICD-9-CM: 204.1x, ICD-10-CM: C91.1x) and they were required to have received at least one systemic anti-cancer therapy agent—including cBTKi, BCL2i, rituximab, or a chemotherapy agent—between December 1, 2011 and October 31, 2020.
Both studies found that the outcomes for these patients became progressively worse as the treatment options for CLL were exhausted. In the study by Dr Mato and colleagues, 9,578 patients were included and of these 52.0% received at least one cBTKi, 6.1% received both a cBTKi and BCL2i, and 2.3% received all four therapies (cBTKi, BCL2i, rituximab, and chemotherapy). Of those who discontinued these treatments, only 39.5% (post-cBTKi), 59.7% (post-cBTKi and BCL2i), and 55.0% (post-all four therapies) received subsequent therapy. For those who discontinued the cBTKi treatment, the median time from treatment discontinuation to the discontinuation of subsequent therapy or death was 9.5 months. For those who discontinued both cBTKi and BCL2i it was 5.6 months, and for those who discontinued all four therapies it was 3.9 months.
In the study by Dr Eyre and colleagues, 548 patients were included and of these 95.1% received the initial cBTKi therapy prior to the initial BCL2i, 4.4% received the BCL2i prior to cBTKi therapy, and 0.5% received both agents in the same line of therapy. In total, 317 (57.8%) of the patients that received both cBTKi and BCL2i also received subsequent therapy. Outcomes for the subsequent therapy following the cBTKi or BCL2i treatment included: a real-world response rate of 34.4%; a median duration of real-world response of 13.3 months; and a median real-world progression-free survival of 9.2 months. The median overall survival was 25.5 months from the start of the immediate next line of therapy.
“While decreasing outcomes over time is in part to be expected, the issue appears particularly pronounced among patients with CLL due to the limited treatment options for such a long survival period,” said Dr Mato and colleagues.
The main limitation in both studies was that the real-world data are not directly comparable to clinical trial outcomes in hematology. For instance, in the study by Dr Mato and colleagues the information was collected for routine clinical practice, not for research purposes, which may have resulted in data errors or missing data.
Overall, the researchers found that once patients with CLL have been treated with cBTKi and BCL2i, and even when rituximab and chemotherapy have also been used, few options are left to continue their CLL therapy. Therefore, “outcomes decline rapidly, as evidenced . . . by the shortening durations of subsequent therapy and the low number of patients receiving any subsequent treatment.” Both research teams emphasize the need for more effective therapies that will have longer lasting impacts for the chronic disease.
