Fixed-duration ibrutinib-venetoclax for first-line treatment of patients with chronic lymphocytic leukemia: the REALITY-WW prospective real-world study cohort

Abstract

The fixed-duration combination of ibrutinib and venetoclax has shown significant benefits in the first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) through clinical studies with follow-up extending up to 5.5 years. However, there remains an important gap in real-world data regarding efficacy and tolerability outcomes of this regimen outside of clinical trial settings. The REALITY-Worldwide study has been initiated as a prospective observational study aimed at understanding the usage, factors for therapy decision, and clinical response of first-line fixed-duration ibrutinib-venetoclax in routine clinical practice. The primary endpoint is physician-assessed overall response rate according to 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Secondary endpoints and outcomes of interest include duration of response, progression-free survival, overall survival, time to next treatment, tumor lysis syndrome risk, adverse events, patient-reported outcomes, factors associated with physician decision to initiate fixed-duration ibrutinib-venetoclax in clinical practice, medical resource utilization, and patient-reported outcomes. The study aims to enroll approximately 200 patients across Europe, the Middle East, and Latin America. A pooled analysis will include subsets of data collected from REALITY-WW and the ongoing multicenter REALITY-2 study in Germany.

Keywords: CLL/SLL; REALITY-WW; ibrutinib-venetoclax; mechanism of action; prospective; real-world.

Figure 1.

Synergistic mechanism of action of ibrutinib and venetoclax in CLL/SLL. The figure illustrates the complementary actions of ibrutinib and venetoclax in CLL/SLL treatment. CLL and SLL are the same disease, but CLL cells are found mostly in the blood and bone marrow while SLL cells are found mostly in the lymph nodes [24]. Protective lymphoid niches for CLL/SLL cells are complex microenvironments composed of diverse cell types and signaling pathways that play a crucial role in the survival and proliferation of CLL/SLL cells [21]. These niches are primarily located in the bone marrow and lymph nodes, where CLL/SLL cells interact with various stromal cells. Ibrutinib decreases CLL/SLL cell proliferation and mobilizes CLL/SLL cells from protective lymphoid niches into peripheral blood, increasing their dependence on BCL-2. The CLL/SLL cells then become more sensitive to venetoclax-induced apoptosis [17]. Ibrutinib primarily targets dividing CLL/SLL cells, while venetoclax is more effective against resting CLL/SLL cells [22]. The combination therapy with FD ibrutinib-venetoclax results in synergistic cytotoxicity, leading to faster and more extensive CLL/SLL cell apoptosis compared with either drug alone [18,22,23,29].

Figure 2.

REALITY-WW study design. Data collection will start at baseline, after the informed consent form is signed and within 30 days before initiation of FD ibrutinib-venetoclax treatment for the first participating patient. Data will be collected at patient visits conducted within local routine clinical practice every 3 cycles (approximately every 12 weeks [±4 weeks] or as per routine clinical practice). The treatment begins with a 3-cycle lead-in of ibrutinib 420 mg/day. Each cycle is 28 days. The venetoclax dose will be escalated weekly from 20 to 400 mg/day over 5 weeks from cycle 4. Patients will receive all-oral FD ibrutinib 420 mg/day plus venetoclax 400 mg/day for 12 cycles (cycle 4 through cycle 15). The treatment phase will continue until discontinuation of ibrutinib or venetoclax or the end of FD ibrutinib-venetoclax treatment. The primary endpoint is overall response rate by the end of 15 treatment cycles (approximately week 60). Adverse event collection starts with the first use of ibrutinib within the study. Tumor lysis syndrome risk categories will be collected at baseline and after the ibrutinib lead-in period. Follow-up starts as soon as the patient permanently discontinues FD ibrutinib-venetoclax treatment at the physician’s discretion. In the follow-up phase, data collection will continue at patient visits conducted within local routine clinical practice (approximately every 12 weeks [±4 weeks]) or until documentation of the subsequent CLL/SLL treatment or the end of the study, whichever comes first. The end of the study will be the last documented data collection point within the study for the last participating patient.