Real-World Data Highlight Feasibility of Venetoclax Plus Obinutuzumab In First-Line CLL With Comorbidities

Findings from a retrospective, real-world analysis conducted through the Polish Adult Leukemia Group showed that first-line treatment with the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) was efficacious and generally well tolerated in patients with chronic lymphocytic leukemia (CLL) who had significant preexisting comorbidities.¹

Data showed that response-evaluable patients (n = 199) achieved an overall response rate (ORR) of 97.4%, including a complete remission (CR) rate of 32.7%. Three patients experienced stable disease as best response. In 2 patients who had progressive disease, 1 had Richter transformation to diffuse large B-cell lymphoma.

At a median follow-up of 25.9 months (95% CI, 24.5-27.9), the median progression-free survival (PFS) and overall survival (OS) were both not reached. The estimated 1- and 2-year PFS rates were 93.9% (95% CI, 90.7%-97.2%) and 88.4% (95% CI, 83.9%-93.2%), respectively. The respective 1- and 2-year OS rates were 94.3% (95% CI, 91.3%-97.5%) at and 92.7% (95% CI, 89.2%-96.4%).

Regarding safety (n = 220), 99.5% of patients had completed therapy, including 78.1% who received the full 12 cycles of protocol treatment. Grade 3 or 4 adverse effects (AEs) occurred in 68.6% of patients. Additionally, 82.7% of patients received a final dose of venetoclax at 400 mg and did not require any dose reductions. In 15.9% of patients who had venetoclax dose reductions, the primary reasons comprised hematologic toxicity (74.3%), infections (5.7%), liver toxicity (5.7%), patient decision (5.7%), diarrhea (2.9%), and fatigue (2.9%). Notably, venetoclax was not given to 2 patients due to infection or immune thrombocytopenia after receiving obinutuzumab.

“The combination of venetoclax [and] obinutuzumab in de novo CLL is an effective and generally well-tolerated first-line therapy in…patients with significant comorbidities under real-world conditions,” lead study author Klaudia Zielonka, MD, of the Department of Hematology, Transplantation and Internal Medicine, at the Medical University of Warsaw in Poland, and colleagues wrote in a publication of the data. “TP53 aberrations did not affect early treatment outcomes; however, longer follow-up is mandatory.”

Real-World Study Background and Breakdown

The combination of venetoclax (Venclyxto) and obinutuzumab is currently approved in the European Union for the treatment of patients with previously untreated CLL, based on data from the phase 3 CLL14 study (NCT02242942).² In the United States, the combination was approved by the FDA for patients with CLL or small lymphocytic lymphoma in May 2019.³

However, study authors noted that prospective clinical trial inclusion and exclusion criteria could create patient selection bias, and they explained that real-world data could help confirm the efficacy and safety of the combination in an older patient population often burdened by comorbidities.¹

The retrospective study included adult patients with previously untreated CLL who started treatment with venetoclax plus obinutuzumab in Poland between November 2021 and August 2024. Patients needed to have an ECOG performance status of 2 or less, along with comorbidities, defined as a CIRS total score of more than 6 and/or a creatinine clearance of more than 30 mL/min and less than 70 mL/min.

Patients received obinutuzumab at 100 mg on cycle 1, day 1, and 900 mg on cycle 1, day 2, followed by a 1000-mg dose on days 8 and 15 of cycle 1, then day 1 of cycles 2 to 6. Venetoclax was ramped up at daily doses of 20 mg daily during the first week and gradually increased to 400 mg after 5 weeks, starting at day 22 of cycle 1. Patients received venetoclax for up to 12 cycles or until disease progression and/or unacceptable toxicity.

ORR, CR rate, PFS, OS, and safety were the primary objectives of the study.

In the safety population, patients had a median age of 70 years (range, 45-86), and 25.5% were at least 75 years of age. Most patients were male (60.9%), had an ECOG performance status of 1 (56.0%), had Binet stage C disease (50%), had Rai high stage disease (51.4%), and were at intermediate risk for tumor lysis syndrome (51.6%).

Notably, 10% of evaluable patients (n = 190) harbored 17p deletions and/or TP53 mutations. IGHV mutational status was evaluated in 51 patients, and 72.5% of this group harbored IGHV mutations. The median time from CLL diagnosis to treatment was 1.6 years (range, 0-19).

Efficacy Outcomes After Early Discontinuation

In patients who discontinued therapy early (n = 36) for reasons other than disease progression or death, 63.9% had decreased renal function, and 83.3% had a CIRS index higher than 6.

The ORR in this subgroup was 85.7%; however, the estimated 24-month PFS rate was 49.4% (95% CI, 34.5%-70.6%) in this population (HR vs patients who completed protocol therapy, 12.024; 95% CI, 5.498-26.297; P < .001). The 24-month OS rate was 66.5% (95% CI, 52.8%-83.7% [HR: 12.502; 95% CI, 4.720-33.116; P < .001]).

Additional Safety Data

The most common any-grade AEs included neutropenia (83.2%), thrombocytopenia (57.3%), anemia (54.5%), febrile neutropenia (10%), upper respiratory tract infections (7.7%), pneumonia other than COVID-19 (8.6%), COVID-19 hospitalization (11.8%), COVID-19 pneumonia (6.4%), autoimmune hemolytic anemia (4.1%), immune thrombocytopenia (2.7%), diarrhea (6.8%), liver toxicity (1.8%), increased alanine aminotransferase levels (6.4%), increased aspartate aminotransferase levels (7.3%), increased alkaline phosphatase levels (4.1%), increased gamma-glutamyl transferase (2.3%), atrial fibrillation (1.4%), acute coronary syndrome (0.5%), increased bilirubin concentration (2.3%), cutaneous toxicity (2.7%), obinutuzumab infusion-related reactions (9.5%), secondary malignancies (2.3%), fever (2.3%), peripheral edema (1.4%), and central nervous system disorders (0.9%).

Any-grade biochemical TLS occurred at a rate of 19.5%, and the rate of clinical TLS was 3.6%.

References

1. Zielonka K, Izdebski B, Drozd-Sokołowska J, et al. Venetoclax and obinutuzumab in first-line treatment of unfit patients with CLL – real-life data analysis of the Polish Adult leukemia group. Leuk Lymphoma. Published online August 1, 2025. doi:10.1080/10428194.2025.2535693
2. Venclyxto. European Medicines Agency. Accessed August 21, 2025. https://www.ema.europa.eu/en/documents/product-information/venclyxto-epar-product-information_en.pdf
3. FDA approves venetoclax for CLL and SLL. FDA. May 15, 2019. Accessed August 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-and-sll