Real-World Outcomes of Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia

Abstract

Background: Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous disease characterized by variable clinical outcomes. The introduction of targeted therapies, particularly the BCL-2 inhibitor venetoclax, has significantly improved treatment outcomes in patients with relapsed/refractory (R/R) CLL. However, real-world data on the safety and effectiveness of venetoclax-based regimens remain limited. Methods: In this multicenter retrospective study, 147 adult patients with R/R CLL treated with venetoclax between April 2019 and August 2025 were analyzed. Venetoclax was administered as monotherapy or in combination with rituximab, obinutuzumab, or ibrutinib. Adverse events were graded according to CTCAE v4.0, and treatment responses were assessed based on IWCLL criteria. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were evaluated using Kaplan–Meier analysis. Results: The median age at venetoclax initiation was 64 years, and patients had received a median of two prior lines of therapy. Combination therapy was administered in 78.9% of patients. The overall response rate was 83.0%, including complete remission in 65.3% of patients. Grade ≥ 3 hematologic adverse events included neutropenia (18.4%), thrombocytopenia (14.3%), and anemia (7.5%). Tumor lysis syndrome (TLS) occurred in 28.6% of patients, predominantly during the dose ramp-up phase. At a median follow-up of 61 months, median OS and PFS were both 60 months. Bulky disease was associated with inferior survival outcomes. Conclusions: Venetoclax-based therapy is effective and well tolerated in patients with R/R CLL in a real-world setting. High response rates and durable survival outcomes were observed despite the inclusion of patients with high-risk clinical and biological features. These findings support the use of venetoclax as a key component of modern CLL treatment strategies and highlight the importance of real-world evidence in optimizing patient management.

1. Introduction

Chronic lymphocytic leukemia (CLL) is a mature B-cell neoplasm characterized by the clonal proliferation of CD5-positive lymphocytes involving the peripheral blood, bone marrow, lymph nodes, and spleen [1]. It is the most common leukemia in adults in Western countries, with a median age at diagnosis of approximately 65–70 years [1,2]. Although many patients have an indolent clinical course, a substantial proportion eventually develop progressive disease requiring treatment [1].

The clinical course of CLL is heterogeneous and is strongly influenced by cytogenetic and molecular abnormalities, including deletion 13q, deletion 11q, and trisomy 12 [2]. Among these, disruption of the TP53 pathway (del(17p) and TP53 mutations) is associated with resistance to chemoimmunotherapy and inferior survival outcomes [2,3]. Immunoglobulin heavy chain variable region (IGHV) mutation status is another key prognostic factor, with unmutated IGHV associated with more aggressive disease biology [2].

Over the past decade, the treatment landscape of relapsed/refractory (R/R) CLL has shifted from chemoimmunotherapy toward targeted therapies with improved efficacy and tolerability [3]. In particular, inhibitors of the B-cell receptor signaling pathway, including Bruton tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors, have transformed treatment paradigms [3]. BTK inhibitors can be classified as covalent (e.g., ibrutinib) and non-covalent agents, which are particularly relevant in patients with resistance or intolerance to first-generation inhibitors [4].

The BCL-2 family of proteins plays a central role in apoptosis regulation and tumor cell survival [5]. In CLL, BCL-2 overexpression leads to impaired apoptosis and prolonged survival of malignant B cells [5,6]. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that restores apoptosis by directly targeting this pathway [6,7]. Preclinical studies have shown that venetoclax induces apoptosis through a p53-independent mechanism [7].

Clinical studies have demonstrated that venetoclax is highly effective both as monotherapy and in combination regimens, achieving high response rates and deep remissions, including measurable residual disease negativity [8,9]. Despite these advances, CLL remains an incurable disease, and most patients eventually relapse [3]. Resistance mechanisms such as upregulation of alternative anti-apoptotic pathways, including MCL-1, may limit long-term efficacy [7].

Real-world data are essential, as patients treated in routine clinical practice often differ from those enrolled in clinical trials. Evaluating venetoclax-based therapies in real-world settings is critical for optimizing treatment strategies and improving outcomes [10].

2. Materials and Methods

2.1. Study Design

This multicenter, retrospective study included 147 adult patients diagnosed with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Clinical data were collected retrospectively from electronic medical records of participating centers between April 2019 and August 2025. Eligible patients were aged 18 years or older and had received venetoclax either as monotherapy or in combination with rituximab, obinutuzumab, or ibrutinib.

The multicenter design enabled the inclusion of a heterogeneous patient population representative of real-world clinical practice, including individuals with varying comorbidities, prior treatment exposures, and disease burdens. This approach enhances the external validity and generalizability of the study findings.

Patients were included if they had a confirmed diagnosis of CLL according to the IWCLL criteria and had received at least one dose of venetoclax for R/R disease. Patients with insufficient clinical data or follow-up duration of less than one month were excluded from the analysis.

Clinical data were collected from the time of initial diagnosis; however, survival analyses were performed based on venetoclax initiation, reflecting treatment exposure.

2.2. Assessments

Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [9]. Demographic characteristics, disease-related clinical features, venetoclax dosing, tumor lysis syndrome (TLS) risk stratification and prophylaxis, and treatment-related adverse events were recorded and analyzed.

Treatment responses were evaluated in accordance with the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria [1].

Clinical and laboratory data collected included baseline hematologic parameters, renal function, lactate dehydrogenase (LDH), and β₂-microglobulin levels, as well as cytogenetic and molecular characteristics when available.

Response evaluation was based on clinical examination, laboratory findings, and imaging studies when applicable. In routine clinical practice, radiologic and bone marrow assessments were not always performed simultaneously, reflecting real-world conditions.

Patients with clinical suspicion of Richter transformation or markedly elevated LDH levels were further evaluated, including PET/CT imaging when clinically indicated. Routine PET/CT screening was not performed.

This study was conducted in accordance with the Declaration of Helsinki. Approval was obtained from the local institutional ethics committees of the participating centers. Due to the retrospective nature of the study, informed consent was waived.

The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Local Ethics Committee of Ordu Training and Research Hospital (Decision No: 2026/50, 27 February 2026). All patient data were anonymized prior to analysis to ensure confidentiality and compliance with ethical standards.

2.3. Treatment Administration

Venetoclax was administered orally once daily following a weekly dose ramp-up schedule, starting at 20 mg for the first week and gradually increasing to a target dose of 400 mg daily.

In the venetoclax plus rituximab regimen, rituximab was administered intravenously at a dose of 375 mg/m² on day 1 of the first cycle, followed by 500 mg/m² on day 1 of each subsequent cycle for a total of six cycles.

For patients receiving venetoclax in combination with obinutuzumab, obinutuzumab was administered intravenously at 100 mg on day 1 and 900 mg on day 2, followed by 1000 mg on days 8 and 15 of the first cycle; thereafter, a dose of 1000 mg was administered on day 1 of each subsequent cycle.

Combination regimens were selected based on physician discretion, patient characteristics, and prior treatment history, reflecting real-world clinical decision-making.

Venetoclax-based combination regimens in the R/R setting were administered according to real-world clinical practice, including off-label use where applicable, based on physician discretion and national reimbursement policies.

Given the risk of tumor lysis syndrome associated with rapid tumor reduction during venetoclax initiation, TLS risk was managed through close clinical and laboratory monitoring, as well as appropriate prophylactic measures.

TLS risk stratification was performed based on tumor burden parameters, including lymph node size and absolute lymphocyte count, and patients were categorized as low-, intermediate-, or high-risk according to established guidelines [8].

Preventive strategies included oral or intravenous hydration, administration of uric acid-lowering agents such as allopurinol or rasburicase, and frequent laboratory monitoring during the dose escalation phase. High-risk patients were considered for inpatient monitoring during treatment initiation.

Dose interruptions or reductions were implemented as needed to manage treatment-related toxicities. Venetoclax therapy could be temporarily withheld and subsequently resumed at the target dose once adverse events had resolved.

For patients experiencing severe neutropenia, particularly grade 4 events, the use of granulocyte colony-stimulating factor (G-CSF) was recommended [10].

Supportive care measures, including antimicrobial prophylaxis and transfusion support when indicated, were applied according to institutional practices and physician judgment.

2.4. Statistical Analysis

Statistical analyses were performed using IBM SPSS Statistics software (version 26). Continuous variables were summarized as medians and ranges, while categorical variables were expressed as frequencies and percentages.

Overall survival (OS) was defined as the time from initiation of venetoclax therapy to death from any cause, and progression-free survival (PFS) was defined as the time from treatment initiation to disease progression or death.

Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Cox proportional hazards regression models were used to identify independent prognostic factors associated with survival outcomes.

Variables with a p-value < 0.20 in univariate analysis were included in multivariate models. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. A two-sided p-value < 0.05 was considered statistically significant. Missing data were handled using available-case analysis due to the retrospective nature of the study.

3. Results

3.1. Patient Characteristics

A total of 147 patients with CLL were included in the study. The median age at diagnosis was 60 years (range, 36–92), and the median age at venetoclax initiation was 64 years (range, 36–92).

The cohort consisted of 68% male and 32% female patients, with a median Eastern Cooperative Oncology Group (ECOG) performance status of 1 (range, 0–3).

The median follow-up duration from diagnosis was 61 months (range, 2–290), while the median follow-up after venetoclax initiation was 17 months (range, 1–73).

At the start of venetoclax therapy, the median Rai stage was 3 (range, 1–4). According to the Binet classification, 7.5% of patients were stage A, 35.4% stage B, and 49% stage C; staging data were unavailable for 8.2% of patients.

Bulky disease (lymph nodes > 7 cm) was present in 21.1% of patients.

Baseline laboratory parameters showed a median white blood cell count of 56.5 × 10⁹/L (range, 3–540), hemoglobin level of 10.7 g/dL (range, 4.5–15), and platelet count of 115 × 10⁹/L (range, 5–423). The median creatinine level was 0.98 mg/dL (range, 0.5–3.2), lactate dehydrogenase (LDH) was 298 U/L (range, 100–1920), and β₂-microglobulin was 2.97 mg/L (range, 1.6–12.9). Baseline laboratory findings are summarized in

Table 1. Baseline laboratory characteristics at venetoclax initiation.

Parameter	Median (Range)
White blood cell count (×109/L)	56.5 (3–540)
Hemoglobin (g/dL)	10.7 (4.5–15)
Platelet count (×109/L)	115 (5–423)
Creatinine (mg/dL)	0.98 (0.5–3.2)
Lactate dehydrogenase (U/L)	298 (100–1920)
β2-microglobulin (mg/L)	2.97 (1.6–12.9)

.

Cytogenetic and molecular analyses revealed del(17p) in 25.9% of patients, del(11q) in 3.4%, trisomy 12 in 6.1%, del(13q) in 15%, TP53 mutation in 7.5%, unmutated IGHV in 32%, and complex karyotype (≥3 abnormalities) in 0.7%. Genetic characteristics of the study cohort are presented in

Table 2. Cytogenetic and molecular characteristics of the study cohort.

Genetic Alteration	Patients, n (%)
del(17p)	38 (25.9%)
TP53 mutation	11 (7.5%)
del(13q)	22 (15.0%)
IGHV unmutated	47 (32.0%)
Trisomy 12	9 (6.1%)
del(11q)	5 (3.4%)
Complex karyotype	1 (0.7%)

IGHV, immunoglobulin heavy-chain variable region. Genetic data were not available for all patients; therefore, percentages are reported based on the total cohort and should be interpreted with caution.

. Genetic data were not available for all patients.

3.2. Prior Therapies and Venetoclax Regimens

Patients had received a median of 2 prior lines of therapy (range, 0–8).

Chemoimmunotherapy had been administered in 71.4% of patients, and 41.5% had previously received ibrutinib; none had undergone hematopoietic stem cell transplantation.

At venetoclax initiation, 21.1% of patients received venetoclax as monotherapy, while 78.9% received combination therapy. The most common combinations were venetoclax plus rituximab (44.9%), followed by venetoclax plus obinutuzumab (26.5%) and venetoclax plus ibrutinib (7.5%).

Venetoclax was discontinued due to disease progression in 8.8% of patients, treatment-related adverse events or intolerance in 11.6%, and planned completion of therapy in 31.3% of patients. At the time of data cutoff, a proportion of patients remained on active venetoclax treatment.

3.3. Treatment Response

Treatment responses were evaluated according to the 2008 IWCLL criteria and are summarized in

Table 3. Response to venetoclax-based therapy.

Response	n	%
Complete response (CR)	96	65.3
Partial response (PR)	26	17.7
Stable disease (SD)	8	5.4
Progressive disease (PD)	8	5.4
Not assessable	9	6.1

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

.

The overall response rate (ORR) was 83.0%, including complete remission (CR) in 65.3% and partial remission (PR) in 17.7% of patients. Stable disease (SD) was documented in 8 patients (5.4%), and progressive disease (PD) occurred in 8 patients (5.4%). Response assessment was not available for 9 patients (6.1%).

3.4. Adverse Events

Treatment-related adverse events are summarized in

Table 4. Summary of grade ≥ 3 adverse events.

Adverse Event	n	%
Neutropenia	27	18.4
Thrombocytopenia	21	14.3
Anemia	11	7.5
Pneumonia	14	9.5
Febrile neutropenia	13	8.8
Other infections	6	4.1
Nausea	5	3.4
Diarrhea	3	2.0
Headache	3	2.0
Tumor lysis syndrome (total)	42	28.6
Biochemical TLS	30	20.4
Clinical TLS	12	8.2

TLS, tumor lysis syndrome. Patients may have experienced more than one adverse event.

.

Tumor lysis syndrome (TLS) occurred in 28.6% of patients, including biochemical TLS in 20.4% and clinical TLS in 8.2%.

The most frequent grade ≥ 3 hematologic toxicities were neutropenia (18.4%), thrombocytopenia (14.3%), and anemia (7.5%).

The most common grade ≥ 3 non-hematologic adverse events were pneumonia (9.5%), febrile neutropenia (8.8%), and asthenia (4.1%). Other grade ≥ 3 adverse events included infections (4.1%), nausea (3.4%), diarrhea (2%), and headache (2%).

3.5. Survival Outcomes

At a median follow-up of 17 months after venetoclax initiation, the estimated 12- and 24-month progression-free survival (PFS) rates were 82.5% and 71.3%, respectively, while the corresponding overall survival (OS) rates were 86.6% and 75.3%.

Although the median PFS and OS were both estimated as 60 months (95% CI, 42.9–77.0 and 42.8–77.1, respectively), these estimates should be interpreted with caution because of the limited number of patients remaining at risk at later time points and the relatively short follow-up duration.

4. Discussion

Targeted therapies have significantly improved survival outcomes in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). In this multicenter real-world study, venetoclax demonstrated substantial clinical efficacy with an acceptable safety profile, consistent with previous reports in the R/R CLL setting [8,9].

Hematologic toxicity, particularly neutropenia, was the most prominent adverse event observed in our cohort. This finding is consistent with the known biological role of BCL-2 in the survival of hematopoietic precursor cells and its inhibition may result in myelosuppression [11]. In addition, patients with R/R CLL frequently present with bone marrow involvement and residual cytopenias related to prior therapies [10].

In previously published studies, grade 3–4 neutropenia has been reported in a substantial proportion of patients treated with venetoclax [5], whereas in our cohort, grade ≥ 3 neutropenia occurred in 18.4%.

Other hematologic toxicities, including thrombocytopenia and anemia, were also observed but were generally manageable and consistent with previously reported safety data [10].

Tumor lysis syndrome (TLS) remains a clinically important toxicity associated with venetoclax [11]. In our cohort, TLS occurred in 28.6% of patients, primarily during dose escalation. The observed incidence may reflect the inclusion of patients with higher tumor burden in real-world settings [12]. Consistent with previous studies, TLS was manageable with appropriate prophylaxis [12,13].

With regard to efficacy, venetoclax-based therapy achieved a high overall response rate of 83%, including complete remission in 65.3% of patients. These findings are consistent with pivotal studies demonstrating durable responses [13].

Combination therapy may contribute to deeper responses, as previously reported [14].

Bulky disease was associated with inferior outcomes in our study, consistent with previous reports [14].

Although the estimated median OS and PFS were both 60 months, these findings should be interpreted cautiously because of the relatively short follow-up duration after venetoclax initiation and the limited number of patients remaining at risk at later time points.

Several limitations should be acknowledged. The retrospective design introduces potential selection bias, and molecular data were not available for all patients. In addition, data on TLS stratification, dose modifications, cause-specific mortality, and subsequent therapies were not consistently available. Furthermore, the relatively short follow-up duration after venetoclax initiation limits the maturity of long-term survival analyses.

Recent studies have demonstrated that clonal hematopoiesis (CH) is highly prevalent in patients with CLL and may contribute to treatment-related cytopenias [15,16,17]. Emerging evidence suggests that CH may influence susceptibility to hematologic toxicity during targeted therapies, including venetoclax [15,16,17]. Although CH data were not available in our cohort, this mechanism may provide a biological explanation for the cytopenias observed in our study and represents an important area for future research.

In conclusion, venetoclax-based therapy is effective and well tolerated in patients with R/R CLL in routine clinical practice. Further prospective studies with longer follow-up are needed to validate these findings.