Fixed-Duration Venetoclax Plus Obinutuzumab Yields High CR Rates, Manageable Safety in CLL/SLL

The fixed-duration combination of obinutuzumab (Gazyva) and venetoclax (Venclexta) exhibited complete responses (CRs) and CRs with incomplete marrow recovery (CRi) in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL), according to data from a phase 2 trial (NCT05105841) conducted in Japan.¹

Results from the trial published in the International Journal of Hematology indicated that patients with CLL or SLL who received obinutuzumab and venetoclax (n = 10) achieved an overall response rate (ORR) of 100% (95% CI, 69.2%-100.0%). Among those patients, 80% achieved a CR, whereas 10% achieved either a CRi or nodular partial response (nPR); the CR/CRi rate was 90.0% (95% CI, 55.5%-99.7%).

All patients achieved undetectable measurable residual disease (uMRD) by the first day of their ninth cycle of treatment. Additionally, 3 months after treatment concluded, uMRD rates remained 100% among evaluable patients (n = 6). Trial investigators noted that 4 patients were not evaluable 3 months after the end of treatment because they had not reached the visit at the time of the data cutoff.

“[This] study provides evidence of the high efficacy and manageable safety profile of fixed-duration venetoclax plus obinutuzumab as a first-line treatment for Japanese patients with previously untreated CLL/SLL,” lead study author Koji Izutsu, MD, PhD, and colleagues wrote in the publication.

Izutsu is the chief of the Department of Hematology at the National Cancer Center Hospital in Tokyo, Japan.

What was the design of the trial evaluating obinutuzumab and venetoclax in CLL/SLL?

The trial investigators sought to identify fixed-duration therapies that were well tolerated by patients with CLL and SLL who were older and had high comorbidity burdens.

The study enrolled patients who were at least 65 years of age, or those at least 20 years with a creatinine clearance of 70 mL/min or higher, or a Cumulative Illness Rating Scale score above 6. A diagnosis of active CLL or SLL per 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with no prior treatment, was also required. Patients also needed to have an ECOG performance status of 2 or less and measurable disease with at least 1 lymph node larger than 1.5 cm.

If CLL had transformed into aggressive non-Hodgkin lymphoma, or if patients had prior treatment for CLL or SLL, they were not included in the trial.²

For the first 28-day cycle of treatment patients were administered intravenous obinutuzumab at 100 mg on day 1 followed by 900 mg on day 2, or 1000 mg on day 1; they were then given 1000 mg doses on days 8 and 15.¹ Patients received daily oral doses of venetoclax that ranged from 50 mg in week 1, 100 mg in week 2, 200 mg in week 3, to 400 mg in week 4 in their second cycle of treatment. For cycles 3 to 6, patients received a 1000-mg dose of obinutuzumab on day 1 of each cycle in addition to daily 400-mg doses of venetoclax. For cycles 7 to 12, patients received 400-mg doses of venetoclax monotherapy.

CR/CRi rate per independent review committee assessment was the primary end point for the trial; overall survival (OS), ORR, progression-free survival (PFS), duration of response (DOR), and time to progression (TTP) were secondary end points.

Baseline characteristics revealed that patients had a median age of 69.5 years (range, 52-76), and most were male (60%). Most patients had CLL (90%), with Binet stages A (33.3%), B (44.4%), or C (22.2%). Fewer patients had SLL (10%), all of whom had stage IV disease according to the Lugano classification. All patients had an ECOG performance status of 0, and 17p deletion was absent in all but 1 patient. Tumor lysis syndrome risk categories included high, medium, and low at rates of 20%, 50%, and 30%, respectively.

What were the additional data for the combination in CLL/SLL?

Median OS, PFS, DOR, and TTP data were not evaluated. However, no patients in the study experienced death or disease progression.

Regarding safety, all patients experienced adverse effects (AEs) of any grade, with 80% experiencing grade 3/4 AEs. Common any-grade AEs in patients included neutropenia or decreased neutrophil count (80%), anemia (30%), leukopenia (30%), nausea (40%), and infusion-related reactions (60%). Common grade 3 or 4 AEs were neutropenia or decreased neutrophil count (80%), leukopenia (30%), lymphopenia (30%), decreased platelet count (30%), and anemia (10%). Notably, no instances of grade 3 or 4 gastrointestinal disorders, pyrexia, or COVID-19 were reported.

“The nonrandomized, open-label design precludes direct statistical comparisons with standard regimens recommended in Japan. Additionally, the small sample size, which is primarily due to the low incidence of CLL/SLL in Japan, limits the generalizability of the findings. Furthermore, the absence of disease progression or deaths during the study may be attributable to the relatively short follow-up period,” Izutsu and colleagues added. “Further studies with larger patient populations and extended follow-up are warranted to confirm the long-term survival benefit and safety profile of venetoclax plus obinutuzumab.”

References

1. Izutsu K, Watanabe M, Toubai T, et al. Efficacy and safety of fixed-duration venetoclax plus obinutuzumab in untreated Japanese CLL and SLL: a phase 2 study. Int J Hematol. 2026;123(2):225-232. doi:10.1007/s12185-025-04095-w
2. Study to assess change in disease activity and adverse events of oral venetoclax in combination with intravenous (IV) obinutuzumab or oral ibrutinib in adult participants with untreated chronic lymphocytic leukemia (CLL)/​small lymphocytic lymphoma (SLL). ClinicalTrials.gov. Updated October 15, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT05105841