Background. Clinical trials have documented the efficacy of ibrutinib in combination with venetoclax in CLL. Indeed, Ibrutinib plus venetoclax (I+V) is the first all oral fixed duration treatment approved for treatment naive patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) based on the results of the Captivate (phase II) and GLOW (phase III) trials. Discontinuation rates due to adverse events (AEs) were 5% in the Captivate trial, which enrolled patients with ≤70 yrs, and 10.4% in the GLOW trial, which included older and comorbid patients without del(17p). We hypothesized that, when appropriately selected, patients of all ages can tolerate and benefit from I+V.

Methods. This is the interim analysis of a retrospective multicenter study aiming at investigating the safety and efficacy of I+V in the real-world setting. Patients with previously untreated CLL/SLL, 18 years or older, who have completed 3 cycles of I and started V were eligible for the study. Patients treated with I+V in clinical trials were excluded. All patients were scheduled to receive fixed-duration I+V. After 3 lead-in cycles of I (420mg once daily), V was added for 12 cycles with the standard weekly ramp-up (20-50-100-200-400mg). The primary objective of this study was to determine the rate of discontinuation due to toxicity of I+V. Secondary objectives included overall response (ORR), safety, baseline characteristics associated with treatment discontinuation, and survival analysis.

Results. We gathered data from 220 patients (intention-to-treat population) from 45 institutions in 11 countries. At the time of data cut-off, 14 patients were still receiving I lead-in, and 4 discontinued I before initiating V [reasons for discontinuation: 2 atrial fibrillation (AF), 1 diarrhea, and 1 grade 5 infection]. Overall, 202 patients were included in the analysis (treated population). The median age at I+V initiation was 65 years [interquartile range (IQR) 56-70]. Most patients were males (121, 59.9%), and 24 (12.3%) had an ECOG performance status of 2 or higher. Regarding prognostic markers, 112/179 (62.6%) patients carried unmutated IGHV genes, and 29/148 (16.4%) and 7/192 (3.6%) had del(11q) and del(17p) (determined by fluorescence in situ hybridization), respectively. TP53 mutations were present in 7/171 (4.1%) cases.

At the data cut-off (30 June 2025), 201 (99.5%) patients were alive, and 151 (82.1%) were still on treatment. Among the 190 with at least 6 months of follow-up available for response assessment, the overall response rate was 95.6%.

AEs of any grade were present in 122 (61.6%) patients. Specifically, 86 (43.4%) experienced non-hematological AEs, of which 23 (11.3%) were grade 3 or higher (including, 9 infective events, including 2 febrile neutropenia; 4 arterial hypertension; 3 AF; 1 rash; 1 diarrhea; 1 ventricular arrhythmia). No fatal treatment-related AEs have been reported to date. Seven (3.6%) patients developed laboratory tumor lysis syndrome (TLS), but no clinical TLS occurred. One patient developed Richter transformation (large B-cell lymphoma variant). Regarding hematological AEs, grade 3 or higher neutropenia, anemia and thrombocytopenia occurred in 48 (64.8%), 9 (20.9%), and 6 (15%) of patients, respectively. One patient died after being diagnosed with lung cancer.

Seven (3.4%) patients discontinued I+V due to toxicity. Reasons for discontinuation included: acute generalized exanthematous pustulosis; AF; ventricular arrhythmia; heart failure (I was discontinued but V was completed as per treatment plan); neutropenia and heart failure; recurrent urinary tract infections and diarrhea; AF and stroke. The median age of patients who discontinued I+V treatment was 64.5 years (IQR 64-74). Five (71.4%) had at least one comorbidity: the most common was arterial hypertension (3/7, 43%).

The discontinuation rates for patients in a Captivate-like (aged ≤ 70 years) and Glow-like (≥ 65 years without del17p) subgroups were 3.2% (5/153) and 4.9% (5/102), respectively.

Conclusions. We herein confirm the efficacy and tolerability of I+V in the real-world setting. Notably, the discontinuation rate of I+V in our study compares favorably with the discontinuation rate in pivotal clinical trials, even in elderly patients, suggesting that I+V is an appropriate treatment option in a broad patient population. Longer follow-up will allow the assessment of real-world progression-free survival and time to next treatment after I+V.

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2025
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