Venetoclax Combo Shows High Efficacy, Manageable Safety in First-Line CLL and SLL

The fixed-duration combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) demonstrated high efficacy and manageable safety in a phase 2 study (NCT05105841) of Japanese patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).¹

Among the 10 patients treated with the regimen (9 with CLL, 1 with SLL), the rate of complete remission (CR) or CR with incomplete marrow recovery (CRi) based on the best overall response was 90.0% (95% CI, 55.5%–99.7%), with 80.0% achieving CR and 10.0% achieving CRi. The overall response rate (ORR) was 100.0% (95% CI, 69.2%–100.0%). Both end points were assessed by independent central review.

The doublet also showed success in its exploratory end point of undetectable minimal residual disease (uMRD), with a uMRD rate of 100.0% at 3 months following the end of treatment. A high uMRD rate with this combination was also observed in the phase 3 CRISTALLO trial (NCT04285567), where the same combination demonstrated an 81.3% uMRD rate in treatment-naive patients with CLL.

Furthermore, the regimen also displayed a manageable safety profile, with the most common treatment-emergent adverse events (TEAEs) being infusion-related reactions (60.0%), decreased neutrophil count (50.0%), and nausea (40.0%). Approximately one-third (30.0%) of patients experienced at least 1 serious TEAE. All 10 patients had TEAEs related to obinutuzumab, while 9 had TEAEs related to venetoclax.

Taken together, the efficacy and safety results hold therapeutic promise in this treatment-naive Japanese patient population, a group for whom approved treatment options are limited.

“The present 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,” wrote authors Izutsu et al in the study published in the International Journal of Hematology.¹

This phase 2 trial was an open-label, multicenter, nonrandomized 2-cohort study evaluating the safety and efficacy of venetoclax plus obinutuzumab in previously untreated patients with CLL or SLL.² The study enrolled patients at least 65 years of age across 20 sites in Japan to receive either oral venetoclax plus intravenous obinutuzumab in 28-day cycles for a total of 12 cycles, or oral venetoclax plus oral ibrutinib (Imbruvica) in 28-day cycles for a total of 15 cycles.

Eye on Japan: Relevance to Clinical Practice

Of note in this study was the specific geographic focus on Japan. While CLL is the most common leukemia in Western countries, its prevalence is relatively low in Asian countries such as Japan.¹

Venetoclax has been approved in Japan for CLL and SLL treatment since 2019.³ Importantly, the approval in Japan only indicates venetoclax for the relapsed or refractory setting, prompting the present investigation in the untreated Japanese population.

Combining venetoclax with the anti-CD20 monoclonal antibody obinutuzumab is a recommended treatment for first-line CLL in the United States under the National Comprehensive Cancer Network guidelines, supported by studies such as the phase 3 CLL14 study (NCT02242942) where the combination demonstrated superior efficacy to chlorambucil plus obinutuzumab. Meanwhile, in Japan, treatment guidelines by the Japanese Society of Hematology primarily recommend Bruton tyrosine kinase-based therapies as first-line treatment.

Although the study’s nonrandomized design and small sample size, likely reflective of the low incidence of CLL/SLL in Japan, limit generalizability of the findings, the results observed support further investigation of this combination regimen in larger trials to confirm its clinical benefits in the first line.

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. Published online November 10, 2025. 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 November 24, 2025. https://www.clinicaltrials.gov/study/NCT05105841

3. Ito T, Kamimura T, Kiguchi T, et al. Venetoclax treatment for chronic lymphocytic leukemia/small lymphocytic leukemia in Japan: post-marketing surveillance. Int J Hematol. 2024;120(5):613-620. doi:10.1007/s12185-024-03832-x