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Ibrutinib, Venetoclax, and Obinutuzumab Triplet Shows Promise for Untreated, High-Risk CLL

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February 2022

A triple combination of ibrutinib, venetoclax, and obinutuzumab led to high rates of complete response (CR) and estimated 24-month survival in patients with untreated high-risk chronic lymphocytic leukemia (CLL), according to findings from the CLL2-GiVe trial published in Blood.

“In cross trial comparison, efficacy and tolerability looks promising as compared with standard treatment options available,” commented corresponding author Stephan Stilgenbauer, MD, of Ulm University Hospital in Germany.

In recent years, several significant advancements have been made in targeted treatment for patients with CLL who are considered high risk due to del(17p) or TP53 mutation. Dr. Stilgenbauer and colleagues noted that despite these advancements, outcomes such as remission and survival among this high-risk subset of patients with CLL continue to be worse than those in patients with standard-risk disease.

The study authors suggested that a combination of multiple agents with distinct mechanisms of action may ultimately improve prognosis in high-risk patients with CLL. In the ongoing, open-label CLL2-GiVe trial, Dr. Stilgenbauer and researchers investigated the efficacy and safety of a time-limited combination therapy comprising ibrutinib, venetoclax, and obinutuzumab in 41 previously untreated patients with CLL and del(17p) or TP53 mutation.

Treatment consisted of an induction phase that included the triple combination for cycles 1-6, a consolidation phase with ibrutinib and venetoclax for cycles 7-12, and a maintenance phase with only ibrutinib monotherapy for cycles 13-36 based on response and measurable residual disease (MRD) level. The investigators measured MRD in peripheral blood centrally during interim staging after cycles nine and 12 and at cycle 15 (final restaging).

The CR rate at cycle 15 was the primary endpoint. Researchers also examined the proportion of patients free from progressive disease following 12 treatment cycles, overall response rate (ORR), and time-to-event endpoints of progression-free survival (PFS) and overall survival (OS).

Eleven patients discontinued the study during cycle 14 as a result of MRD negativity, which included nine with CR. While 22 patients completed 15 or more cycles of treatment, 16 patients discontinued therapy after cycle 15 because of either MRD negativity and CR (n=12), an adverse event (AE; n=1), and MRD negativity and partial response (PR; n=3). Only five patients were still on treatment at the time of the study’s publication.

The median age of the study population was 62 years. More than half (58.5%) of patients had both del(17p) and TP53 mutation, while 36.6% had only TP53 mutation and 4.9% had only del(17p).

At cycle 15, the overall CR rate was 58.5% (95% CI 42.1-73.7; p<0.001), which included 41.5% of patients with CR and 17.1% of patients with CR or CR with incomplete hematologic recovery (CRi). Additionally, 34.1% of patients achieved a PR by the first day of cycle 15. The ORR at final restaging was 100%, which included 24 patients with CR/CRi and 17 PRs.

The majority of patients (78%) had undetectable MRD in peripheral blood at final restaging, and nearly 66% of patients had undetectable MRD in bone marrow. Approximately 96% and 88% of patients with CR at final restaging had undetectable MRD in peripheral blood and bone marrow, respectively.

The estimated PFS and OS rates at 24 months were both 95%. Median PFS and OS were 33.5 months and not reached, respectively. Patients with both del(17p) and TP53 mutation had a shorter estimated 24-month PFS rate (91.7%) compared with patients who had TP53 mutation only (100%).

All patients experienced at least one AE, but most were low grade in severity. Grade ≥3 AEs were reported in 24% of patients. The investigators reported a total of two deaths, including one from cardiac failure and one from ovarian carcinoma. Neither mortality event was related to the study treatment.

Any conflicts of interest declared by the authors can be found in the original article.


Huber H, Edenhofer S, von Tresckow J, et al. Phase 2 study of obinutuzumab (GA-101), ibrutinib and venetoclax (CLL2-GIVe) in patients with untreated high-risk chronic lymphocytic leukemia [published online ahead of print, 2021 Dec 17]. Blood. doi: 10.1182/blood.2021013208.


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