First worldwide real-life data on fixed-duration ibrutinib+venetoclax treatment for previously untreated CLL/SLL patients: Updated interim analysis of Spain´s LI+VE observational study

Abstract Background Ibrutinib plus venetoclax (I+V) is the first once-daily, all-oral, fixed-duration regimen approved by EMA in front line (1L) for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). While pivotal trials demonstrated its efficacy and safety, real-world (RW) data remain scarce. The LI+VE study was designed to provide the first real-life data on I+V fixed-duration therapy (FDT) worldwide. Methods LI+VE is a multicenter, ambispective, observational study of patients (pts) treated with I+V as per routine clinical practice, conducted in Spain. Pts were included at Visit 1. At visit 1, retrospective data on disease characteristics and I+V FDT was collected on pts who had completed ≥1 cycle before inclusion (before signing informed consent), followed by a 2-year prospective follow-up. Here, we present an update of baseline characteristics, clinical management, tolerability and effectiveness in terms of response. Pts are shown as n/N, where n represents the number of pts with the event and N represents the number of patients with data available Results At cut-off date (04/21/2025), 93 pts were included (CLL, 87.8% and SLL, 12.2%). Median age was 63 (range: 41-84) years (29.3% aged ≥70 years). The majority were male (68.5%), with a Rai stage 0–II (71.1%). Among the pts with available ECOG assessments, 97.0% had an ECOG of 0–1. Cardiovascular (CV) risk factors were present in 69.7%, mainly hypertension (62.9%), with 60.2% at medium/high CV risk. Comorbidities were reported in 68.7%, with 49.1% having ≥2. Genomic risk status (available for 90/93 pts) showed unmutated IGHV in 54.4% and del(17p)/TP53 mutations in 4.5%. At the time of analysis 72/93 (77.4%) pts had completed visit 2, with a median of 11 completed cycles. In total, 23/93 had completed I+V FDT with a median time on treatment of 17.6 months. Of these,1 have started a 2L of treatment. 64/93 pts had completed V ramp-up (only 8 pts required hospitalization, all for tumor lysis syndrome (TLS) prophylaxis/premedication). Most pts (88/93, 94.6%) had completed the 3-cycle I lead-in. TLS risk was reduced from high to intermediate/low in 54.5% of pts after the 3-cycle I lead-in. No clinical or laboratory TLS occurred. After a median follow-up of 15.2 months (from I initiation), of 63 pts with available data, 39 (61.9%) showed complete response, 23 (36.5%) partial response, 1 (1.6%) stable disease, and 1 pt progressed. I was reduced to 280 mg in 2/93 pts (2%) due to thrombocytopenia and neutropenia and 12 V reductions (1 to 100 mg, 4 to 200 mg, and 7 to 300 mg, from cycles 4-16) occurred in 9 pts (9.7%) due to diarrhea (6), neutropenia (2), abdominal pain (1), thrombocytopenia (1), nephrotoxicity (1) and food poisoning (1). Adverse events (AEs) leading to I dose reduction were resolved or partially improved and 83.3% of those leading to V dose reduction were resolved in 66.7% of pts or partially improved in 33.3%. Treatment was temporarily interrupted in 33/93 (35.5%) (I in 26, V in 12 and both in 10 cases), mainly due to neutropenia (24.2%) and infections (12.1%). AEs leading to treatment interruptions were resolved in 60.6% of pts or partially resolved in 18.2%. Treatment was permanently discontinued in 2/93 pts. No CV toxicity leading to discontinuation was reported. The most common all grades AEs were diarrhea (30.1%), neutropenia (24.7%), upper respiratory tract infection (12.9%), arthralgia and bleeding (11.8% each). AEs were grade 1-2 in most pts (69.9%); the most common grade ≥3 AE was neutropenia (15.1%). Other AEs of clinical interest included cardiac events: hypertension (5.4%), atrial fibrillation (3.2%), arrhythmia (2.2%, 1/2 grade ≥3), and palpitations (1.1%), and other infections: urinary tract infection (5.4%, 1/5 grade ≥3), skin infection (3.2%), pneumonia (2.2%, 1/2 grade ≥3), gastrointestinal infection (1.1%), impetigo (1.1%), acute otitis media (1.1%), and intestinal sepsis (1.1%, 1/1 grade ≥3). The latter resulted in death. No new cases of severe cardiac disorders emerged in this follow-up. Conclusions This is the first RW study of I+V worldwide, providing early insights from a diverse CLL/SLL population in Spain. Rates of AEs, treatment discontinuation (not attributed to CV toxicity), and disease progression were low. These results support effectiveness and safety of I+V in clinical practice as a FDT option for pts with CLL/SLL. Further follow-up will help confirm this regimen's long-term effectiveness and safety profile in the RW setting.