Real-world evidence of obinutuzumab and venetoclax in previously treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma

Abstract

Venetoclax-obinutuzumab (Ven-O) is frequently administered off-label in relapsed/refractory (r/r) CLL/SLL where venetoclax-rituximab is the approved regimen. We conducted this retrospective, real-world study to evaluate Ven-O in r/r CLL/SLL. Between 7/2019 and 6/2022, 40 patients with r/r CLL/SLL on Ven-O were included. The median age was 72, 28.2% had TP53 mutation and/or 17p deletion, median number of prior therapies was 1 (range, 1–6), and 55% had prior BTK inhibitor exposure. The overall response rate was 90% (complete response [CR] or CR with incomplete marrow recovery in 27.5% and partial response in 62.5%) of patients, and the 2-year progression-free survival was 81.2% (95% CI, 69.5–94.8). Therapy was well tolerated. No laboratory or clinical TLS occurred with venetoclax (Howard criteria). One (3%) patient experienced laboratory TLS with obinutuzumab initiation. In summary, this retrospective cohort study demonstrated that Ven-O achieves frequent, durable responses and can be safely administered in r/r CLL/SLL.

Introduction

Combinations of venetoclax (BCL2 inhibitor) plus an CD20 antibody (obinutuzumab [Ven-O] or rituximab [Ven-R] are approved in chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) in the frontline and relapsed/refractory (r/r) settings, respectively.^1,2 Obinutuzumab is a glycoengineered type-II anti-CD20 monoclonal antibody which produces enhanced antibody-dependent cell-mediated cytotoxicity and phagocytosis compared to rituximab.³

Obinutuzumab is more effective than rituximab (R) in treatment naïve CLL/SLL. In the CLL11 trial, obinutuzumab-chlorambucil (O-Chl) improved overall survival (OS) compared with R-Chl in previously untreated patients with CLL and coexisting conditions. In the CLL13 trial, Ven-O was associated with improved undetectable minimal residual disease (uMRD) rates compared with chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in previously untreated patients with CLL/SLL who were fit and did not have TP53 aberrations, but Ven-R was not superior to chemoimmunotherapy.

Whether obinutuzumab is superior to rituximab in previously treated patients with CLL/SLL is unknown, with only limited safety and preliminary efficacy from the initial phase I trial and scant real-world evidence to support its use.⁴ Despite this, Ven-O is increasingly administered in the r/r setting based on extrapolations from the aforementioned comparative data in the frontline setting as well as practical considerations (e.g., obinutuzumab is started prior to venetoclax and can reduce tumor lysis syndrome [TLS] risk prior to venetoclax, whereas rituximab is started only after the venetoclax ramp-up).

There is a need for real-world evidence to determine whether Ven-O can be safely administered with low rates of TLS in the r/r setting. Laboratory TLS has been reported in 5.7%−13% of CLL patients treated with venetoclax in real-world cohorts, which is higher than reported in clinical trials.^5,6 Additionally, differences in patients (e.g., age and comorbidities) and CLL characteristics (e.g., higher rates of unfavorable biologic and clinical risk factors) in the r/r setting might affect TLS risk. Herein, we aimed to generate real-world evidence on the safety and efficacy of Ven-O and rates of TLS in previously treated patients with CLL/SLL.

Methods

This retrospective, observational study was approved by the Dana-Farber Harvard Cancer Center Institutional Review Board (DFHCC #22–161) and included patients at the Massachusetts General Hospital Cancer Center and MGH-affiliated community practices.

Eligible patients for this analysis had CLL or SLL, previously received systemic therapy, and were initiated on commercially sourced Ven-O between July 1, 2019, and June 30, 2022. Patients who received Ven-O as part of a clinical trial were excluded. Data was collected through March 21, 2023. Response was assessed per iwCLL 2018. Complete response (CR) did not require bone marrow confirmation if all other iwCLL CR criteria were achieved, while CR with incomplete bone marrow recovery (CRi) required bone marrow confirmation. Adverse events (AEs) were assessed per National Cancer Institute Common Terminology Criteria for AEs (CTCAE) version 5.0 and the maximum grade per patient was reported irrespective of causality. Pretreatment risk of TLS was defined per the venetoclax package insert. Clinical and laboratory TLS were classified using the Howard criteria.⁷

The primary safety objective was to determine the proportion of patients who develop laboratory or clinical TLS (Howard criteria), and the primary efficacy objectives was to determine the proportion of patients who achieve CR/CRi and PR. The secondary objectives were to estimate the frequency and severity of laboratory or clinical TLS with obinutuzumab and the venetoclax ramp-up, obinutuzumab infusion related reactions (IRRs), and hematologic AEs, as well as progression free survival (PFS).

Patient and disease characteristics are summarized using descriptive statistics (numbers and percentages for categorical variables; median and range or interquartile range for continuous variables as appropriate). Responses were tabulated and summarized descriptively, and frequencies/proportions were calculated. PFS and OS calculated using the Kaplan Meier method. PFS was calculated from the start of treatment until progression or death due to any cause.

Study data were collected and managed using REDCap electronic data capture tools. Analyses were performed using SPSS version 29.0.1.

Results

Between July 1, 2019, and June 30, 2022, 40 patients with relapsed or refractory CLL were initiated on Ven-O (Table 1). The median age was 72 years (range, 51–94), 28.2% (n=11/39) had a TP53 mutation or 17p deletion, and 65.6% (n=21/32) of patients had an unmutated IGHV, 28.2% (n=11/39) had 3 or more karyotypic abnormalities. The median pretreatment absolute lymphocyte count (ALC) was 25,500/𝜇L (range, 400–456,000/𝜇L), and median pre-venetoclax ALC was 850/𝜇L (IQR 630–1,440/𝜇L). The median number of prior therapies was 1 (range, 1–6), 55% (n=22) had a prior covalent BTK inhibitor (cBTKi) (37.5% [n=15/40] with progression on cBTKi and 17.5% [n=7/40] with intolerance of cBTKi) . The median creatinine clearance (CrCl) was 57 mL/min (range, 22–134) and 82.5% had CrCl <80 mL/min. The proportions of patients with high and medium TLS risk were 10% (n=4) and 42.5% (n=17), respectively.

Table 1:

Baseline characteristics

	All Patients N=40
Age, median (range)	72 (51–94)
Age ≥65 years, n (%)	31 (77.5)
Female sex, n (%)	9 (22.5)
White race, n (%)	37 (92.5)
ECOG PS ≥2, n (%)	4 (10)
Del(17p) or TP53 mutated, n (%)	11/39 (28.2)
TP53 mutated*	7/28 (25)
Del(17p)**	7/39 (17.9)
Unmutated IGHV, n (%)***	21/32 (65.6)
Complex karyotype, n (%)**	11/39 (28.2)
Number of prior lines, median (range)	1 (1–6)
≥2 prior therapies, n (%)	15 (37.5)
Previous cytotoxic chemotherapy, n (%)	28 (70)
Previous chemoimmunotherapy (no BTK/BCL2 inhibitor)	18 (45)
Previous bendamustine	18 (45)
Previous fludarabine	13 (32.5)
Previous chlorambucil	4 (10)
Previous anti-CD20 monoclonal antibody, n (%)	31 (77.5)
Previous covalent BTK inhibitor therapy, n (%)	22 (55)
Previous cBTKi discontinued for progression	15 (37.5)
Previous cBTKi discontinued for intolerance	7 (17.5)
Previous venetoclax therapy, n (%)	1 (2.5)
CrCl (min/mL), median (range)	57 (22–134)
CrCl ≥80 mL/min, n (%)	7 (17.5)
CrCl ≥60 and <80 mL/min, n (%)	12 (30)
CrCl ≥30 and <60 mL/min, n (%)	19 (47.5)
CrCl <30 mL/min, n (%)	2 (5)
TLS risk assessment, n (%)
Low	19 (47.5)
Medium	17 (42.5)
High	4 (10)
Pre-obinutuzumab ALC, median (range)	25,500/𝜇L (400–456,000)
Pre-obinutuzumab ALC ≥25,000/𝜇L, n (%)	20 (50)
Baseline maximal tumor dimension (cm), median (range)	2.1 (0.6–22)

Abbreviations: ALC, absolute lymphocyte count; BTK, Bruton’s tyrosine kinase; cBTKi, covalent BTK inhibitor; CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; IGHV, immunoglobulin heavy chain variable region gene; TLS, tumor lysis syndrome.

^*12 patients did not have mutational status available

^**1 patient did not have cytogenetics available

^***8 patients did not have IGHV status available

With a median follow-up of 32.0+ months (range, 1.41–51.4), the median time on treatment was 15.6 months (range, 1.18–51.4) including a median of 15.5 months of venetoclax (range, 0.1–50.7). All patients received their initial obinutuzumab dose with split dosing over days 1 (100 mg) and 2 (900 mg), 72.5% (n=29) initiated venetoclax per the CLL14 schedule on day 22 of cycle 1, 7.5% (n=3) received venetoclax accelerated dose ramp-up, and 20% (n=8) delayed venetoclax initiation until cycle 3 day 1. At data cutoff, 9 (22.5%) remained on active venetoclax and 31 (77.5%) patients have completed venetoclax, including 10/31 (33.2%) patients who received 24 cycles of venetoclax, 13/31 (41.9%) patients who received less than 24 cycles due to patient/provider decision during the COVID-19 pandemic, 5/31 (16.1%) patients for toxicity, and 3/31 (9.7%) patients due to disease progression (2 CLL and 1 Richter’s transformation to diffuse large B-cell lymphoma [DLBCL]). For patients who discontinued venetoclax electively prior to 24 cycles, the median time on venetoclax was 12.4 months (range, 0.03–17.5).

Prophylactic rasburicase was administered to three patients prior to their cycle 1 day 1 obinutuzumab dose. All patients received uric acid lowering agents and standard hydration, oral and/or intravenous, during the venetoclax ramp-up per the package insert. Venetoclax was initiated inpatient in 15% (n=6) patients, due to high TLS risk (n=4) or other reasons (painful adenopathy, n=1; hypercalcemia, n=1). Herpes simplex virus/varicella zoster virus and pneumocystis prophylaxis were employed in 47.5% (n=19) and 20% (n=8) of patients, respectively.

The overall response rate (ORR) was 90% (n=36) including CR/CRi in 27.5% (n=11) and PR in 62.5% (n=25; Table 2). Among patients with previous cBTKi exposure, the ORR was 86.4% (n=19/22) with CR/CRi in 13.6% (n=3/22). Among 11 patients with TP53 mutation and/or 17p deletion, the ORR was 100% (n=11/11) with CR/CRi in 27.3% (n=3/11). MRD was assessed in the peripheral blood by flow cytometry (n=16) in 16/31 (52%) patients who have completed therapy; 56.3% (n=9/16) achieved undetectable MRD (<10⁻⁴; uMRD4), 31.2% (n=5/16) with detectable MRD4, and 12.5% (n=2/16) not evaluable (inadequate assay sensitivity); 100% (n=4/4) assessed for MRD in the BM achieved undetectable MRD4.

Table 2:

iwCLL response outcomes

	ORR	CR/CRi	PR
All patients (n=40), % (n)	90 (36)	27.5 (11)	62.5 (25)
TP53 mutation and/or 17p deletion (n=11), % (n)	100 (11)	27.3 (3)	72.7 (8)
Prior covalent BTK inhibitor exposure (n=22), % (n)	86.4 (19)	13.6 (3)	76.2 (16)

Abbreviations: BTK, Bruton’s tyrosine kinase; CR, compete response; CRi, complete response with incomplete count recovery; PR, partial response.

The 2-year PFS was 81.2% (95% CI, 69.5–94.8) and appeared similar for patients with or without a TP53 mutation and/or 17p deletion (81.8% [95% CI, 61.9–100] and 80.9% [95% CI, 67.1–97.5], respectively; Figure 1). Of the 9 PFS events, 5 had progression with CLL, including 2 occurring on venetoclax and 3 occurring only after completing treatment (after treatment-free intervals of 122, 174, and 181 days); 2 had progression with Richter’s transformation (one DLBCL occurring on venetoclax, and one classic Hodgkin lymphoma occurring after completing treatment). Two died without evidence of progression, including one who died at age 83 years during sleep (unknown cause) and one heavily pre-treated patient (prior fludarabine, bendamustine, rituximab, and ibrutinib) who died of progressive multifocal leukoencephalopathy (PML). Of 11 patients with a TP53 mutation and/or deletion, 7 stopped venetoclax after a median of 23.8 months (range, 15.2–29.4) and 5/7 remain alive and progression/treatment-free following a median post-treatment surveillance of 16 months (range, 0.4–23.8) (Figure 2). Of patients who were previously treated with a covalent BTK inhibitor, the 2-year PFS was 70.3% (95% CI, 52.8–93.6).

Figure 1.

Progression-free survival for all patients median progression-free survival has not been reached after a median follow-up duration of 32+ months (range, 1.4–51.4). The 2-year progression-free survival was 81.2% (95% confidence interval, 69.5–94.8).

Figure 2.

Posttreatment outcomes for patients with TP53 mutation or 17p deletion. *one patient with 6 prior lines of CLL therapy including allogenic stem cell transplant electively stopped venetoclax after 1.8 years in anticipation of kidney transplant (later canceled for newly diagnosed renal urothelial carcinoma) and this patient had progression of CLL/SLL after 0.3 years. **one patient with a history of hypertension and cerebral vascular accident discontinued venetoclax at 1.3 years (patient decision due to COVID19 pandemic) and passed away at home in the context of uncontrolled hypertension. PB-uMRD4, undetectable MRD in peripheral blood at <10–4; MRD-NA, MRD not available.

One patient (3%) experienced laboratory TLS per Howard criteria on cycle 1 day 1 obinutuzumab, with hyperphosphatemia and hypocalcemia, which resolved with intravenous hydration and administration of a phosphate binder (sevelamer; Table 3), and no cases of clinical TLS occurred. No laboratory or clinical TLS occurred during the venetoclax ramp-up.

Table 3:

Adverse events

TLS (Howard Criteria)	Laboratory TLS		Clinical TLS
Obinutuzumab lead-in, n (%)	1/40 (2.5)*		-
Venetoclax ramp-up, n (%)	-		-
Myelosuppression	Grade 1–2	Grade 3	Grade 4	Grade 5
Neutrophil count decrease, n (%)	10 (25)	9 (22.5)	11 (27.5)	-
Growth factor administration	14 (35)
Febrile neutropenia	2 (5)
Platelet count decrease, n (%)	21 (52.5)	9 (22.5)	4 (10)	-
Platelet transfusion	4 (10)
Anemia, n (%)	21 (52.5)	10 (25)	-	-
Red blood cell transfusion	9 (22.5)
Infections requiring antimicrobials	Oral antimicrobials		Intravenous antimicrobials
Bacterial infections, n (%)	20 (50)		12 (30)
Viral infections, n (%)	2 (5)		1 (2.5)
Fungal infections, n (%)	3 (7.5)		-
Infusion-related reactions	Grade 1–2	Grade 3	Grade 4	Grade 5
Infusion-related reaction, n (%)	11 (27.5)	1 (2.5)	-	-

Abbreviations: TLS, tumor lysis syndrome.

^*One patient experienced laboratory TLS with cycle 1 day 1 of split dose obinutuzumab meeting criteria with associated hypocalcemia and hyperphosphatemia.

IRRs occurred in 30% (n=12) of patients including grades 1–2 in 27.5% (n=11) and grade 3 in 2.5% (n=1), with no grade ≥4 IRRs (Table 3). IRR incidence appeared higher in patients with ALC ≥25,000/𝜇L (40% [n=8/20] vs 20% [n=4/20]), although this was not statistically significant (p=0.301). Maximal lymph node diameter did not appear higher among patients who experienced an IRR (2.35 cm [IQR, 1.70–3.70] vs 2.05 cm [IQR, 1.40–3.55], p=0.715). Of 11 patients who experienced grade 1–2 IRRs, 4 were already admitted for the initial infusion and thus received a slowed infusion as a secondary IRR mitigation strategy and might account for the low incidence of grade ≥3 IRR.

The incidence of grade ≥3 hematologic toxicity irrespective of causality was 60% (n=24), including grade 3–4 neutropenia in 50% (n=20), grade 3–4 anemia in 25% (n=10) and grade 3–4 thrombocytopenia in 45% (n=18; Table 3). Two patients (5%) experienced febrile neutropenia. Growth factor support was administered in 35% (n=14) patients, and platelet and red blood cell transfusions were administered to 10% (n=4) and 22.5% (n=9) of patients, respectively.

Infections requiring antimicrobials occurred in 65% (n=26) patients (Table 3). Bacterial infections requiring intravenous (IV) and oral (PO) antibiotics occurred in 30% (n=12) and 50% (n=20) patients. Viral infections requiring IV and PO antivirals occurred in 2.5% (n=1) and 5% (n=2). Fungal infections requiring PO antifungals occurred in 7.5% (n=3) patients: 2 oral candida (each resolved with nystatin suspension administration) and 1 fungal pneumonia occurring in a patient with a previous history of central nervous system aspergillus despite concomitant posaconazole suppression. COVID-19 infection occurred in 12.5% (n=5) patients. All were mild and managed outpatient, including 40% (n=2/5) treated with a therapeutic monoclonal antibody and 60% (n=3/5) recovered fully without SARS-CoV-2 therapy.

Hypogammaglobulinemia (immunoglobulin G <500mg/dL) requiring initiation of immunoglobulin replacement therapy occurred in 20% (n=8) during the treatment period and appeared numerically more common among patients who previously received fludarabine/bendamustine (26.9% [n=7/26] vs 7.1% [n=1/14]; p=0.222) and anti-CD20 monoclonal antibody therapy (22.6% [n=7/31] vs. 11.1% [n=1/9]; p=0.655), although neither association was statistically significant.

Seven (17.5%) patients required venetoclax dose reduction due to myelosuppression (n=3), fatigue (n=2), myalgias (n=1), and gastrointestinal side effects (n=1), and 5 (12.5%) discontinued venetoclax due to toxicity including myelosuppression (n=3) and gastrointestinal side effects (n=2). Patients with a venetoclax dose reduction continued therapy at the following dose levels: 300 mg (n=3); 200 mg (n=2); 100 mg (n=1); and 20 mg (n=1, receiving concomitant posaconazole). Although no treatment-related deaths occurred, one patient with three prior therapies, including fludarabine, bendamustine, rituximab and ibrutinib, died 34 days after completing venetoclax of PML.

Discussion

In this retrospective cohort study, which included patients treated at an academic center and affiliated community practices, we found that venetoclax-obinutuzumab achieves frequent, durable responses and can be safely administered to previously treated patients with CLL or SLL. Despite very limited published experience confirming its safety in r/r CLL or SLL, Ven-O is increasingly used in this setting. Therefore, this real-world evidence helps to address this evidence gap, confirming that Ven-O has an acceptable safety profile including a low incidence of TLS in relapsed/refractory CLL/SLL.

That obinutuzumab is superior to rituximab in previously untreated patients with CLL or SLL is well established, with higher rates of uMRD with Ven-O compared with Ven-R, and superior OS with O-Chl compared with R-Chl. Whether obinutuzumab is similarly more effective than rituximab in the r/r setting is unknown, these frontline data have led many hematologists to recommend Ven-O for r/r CLL or SLL. In this real-world study in r/r CLL/SLL, Ven-O achieved high rates of OR (90%) and CR/CRi (27.5%) and responses were durable (2-year PFS of 81.2%). Additionally, rapid reduction in circulating disease during the obinutuzumab lead-in further underscored its activity in the r/r setting. Cross-study comparisons between these real-world evidence with the MURANO data should be avoided. Beyond the inherent limitations with comparing real-world and prospective clinical trials data, key differences exist between the treated populations. Our cohort included a higher proportion of patients previously treated with a covalent BTK inhibitor (55%; n=22/40) and 37.5% (n=15/40) had stopped their covalent BTK inhibitor due to progression. Additionally, 32.5% (n=13/40) patients stopped venetoclax due to patient and/or provider decision, which was driven by the COVID-19 pandemic.

No cases of laboratory or clinical TLS occurred during the venetoclax ramp-up, and just one (3%) patient developed laboratory TLS during their initial obinutuzumab infusion. This is consistent with expected TLS rates with frontline Ven-O and numerically lower than previously real-world evidence of venetoclax in CLL/SLL (5.7–13%).^8,9 Importantly, some patients received prophylactic rasburicase prophylaxis with obinutuzumab initiation or were admitted for intravenous hydration and TLS monitoring. Hematologists focus on TLS risk with venetoclax, but these data suggest that obinutuzumab contributes to TLS risk in the r/r setting. TLS laboratories should be obtained pretreatment on days 1 and 2 of cycle 1, and additional TLS monitoring should be considered for patients with increased TLS risk (e.g., high tumor burden, renal insufficiency, or inability to tolerate fluids).

That TLS did not occur with the venetoclax ramp-up is likely attributable in large part to the reduction in circulating disease with lead-in obinutuzumab. While these data suggest that among patients debulked with obinutuzumab, there is an opportunity to develop less burdensome TLS mitigation strategies, which in their current form drive the underutilization of venetoclax in CLL/SLL, we do not advocate for relaxing TLS monitoring requirements and recommend that hematologists follow the guidance in the venetoclax package insert.

The incidence of IRRs was lower than expected with Ven-O in r/r CLL or SLL, occurring in 30% of patients (grade 1–2 in 27.5% and grade 3 in 2.5%), compared with grade 1–2 in 44.8% and grade 3–4 in 9% in the frontline setting.¹ Whether IRR risk with Ven-O is actually lower in the r/r setting is unknown, with conclusions from our experience limited as this is a small retrospective cohort study. Notably, several patients were admitted for their first dose of obinutuzumab, and for admitted patients who developed grade 1–2 IRR as an inpatient, the obinutuzumab rate was typically slowed for the remaining infusion, which might have prevented grade 3–4 IRRs.

Grade 3–4 neutropenia occurred in 50% of patients and 35% of patients received growth factor support, and 5% developed febrile neutropenia. This is comparable to Ven-R where grade 3–4 neutropenia, growth factor administration, and febrile neutropenia occurred in 57.7%, 47.9%, and 3.6% of patients, respectively.¹⁰ Grade 3–4 anemia and thrombocytopenia occurred in 25% and 45% of patients, with RBC and platelet transfusions in 10% and 22.5% of patients, respectively. Rates of severe anemia and thrombocytopenia appeared numerically higher than with Ven-R, although it is difficult to draw conclusions from cross study comparisons, especially between this real-world analysis and a clinical trial dataset. Importantly, most patients had improvement with continued Ven-O, suggesting that these events were principally driven by CLL.

Despite that most patients in this analysis had a CrCl <80 mL/min and >50% had a CrCl <60 mL/min, none developed laboratory or clinical TLS with venetoclax. The venetoclax package insert recommends that patients with CrCl <80 mL/min be considered at increased risk for TLS and suggests that they be more closely monitored for TLS, e.g., by managing a patient with medium TLS risk and renal insufficiency as if they had high TLS risk. Based on our real-world analysis, mild renal insufficiency may weigh less as a factor in decisions related to TLS risk and mitigation strategy.

The optimal duration of venetoclax therapy in r/r CLL or SLL is unknown, especially in patients with a TP53 mutation and/or 17p deletion. In the MURANO trial, which led to the approval of Ven-R in r/r CLL or SLL, venetoclax was discontinued after 24 cycles irrespective of risk factors or MRD response status.¹⁰ For most patients with r/r CLL or SLL receiving Ven-O, we stop venetoclax after 24 cycles irrespective of MRD response status, although some exceptions exist. Although we frequently continue venetoclax for patients who are heavily pretreated with poor remaining treatment options, we typically recommend that venetoclax be administered for 24 cycles when combined with obinutuzumab or rituximab in the relapsed/refractory setting.

For patients with CLL/SLL and a TP53 mutation or deletion, some continue venetoclax until progression or intolerance. In our study, 63.6% (n=7/11) patients with a TP53 mutation or deletion stopped therapy after a median of treatment duration of 23.8 months (range, 15.2–29.4). With a median post-treatment surveillance of 16 months (range, 0.4–23.8), 71.4% (n=5/7) remain progression and treatment-free. In the 6-year follow-up of the CLL14 study, patients with CLL harboring a TP53 mutation or deletion receiving Ven-O had a median PFS of 52 months.¹¹ While these data are limited by small number of patients with a TP53 mutation or deletion enrolled on CLL14, time-limited treatment with Ven-O is a reasonable consideration in these high-risk patients. Prospective data in a larger cohort of patients with CLL/SLL associated with a TP53 mutation or deletion receiving time-limited therapy with Ven-O is ultimately necessary to determine the optimal treatment strategy for these patients.

This study is limited by its retrospective design and small sample size. However, these real-world data provide reassurance that Ven-O is feasible and can be safely administered in previously treated patients with CLL or SLL, including a cohort of patients who are ineligible for clinical trials, e.g., those with renal insufficiency or poor performance status. Another limitation is that several patients received less than 24 cycles of venetoclax due to patient or physician discretion, driven by the COVID-19 pandemic, and that this might impact response duration. These data are also limited by lack of MRD outcomes data, as this was not available for patients treated at affiliated community sites.