CLL2-GIVe Trial: Regimen of Obinutuzumab, Ibrutinib, and Venetoclax Effective in High-Risk CLL

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The first-line combination of obinutuzumab, ibrutinib, and venetoclax appears to be effective in treating high-risk chronic lymphocytic leukemia (CLL), according to data presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.1

Results of the CLL2-GIVe trial, which tested the time-limited, response-adaptive treatment of obinutuzumab, ibrutinib, and venetoclax in high-risk patients with CLL, showed a complete response rate of 58.5%, with 78% of patients achieving undetectable measurable residual disease (MRD). The 36-month overall survival rate for the “GIVe” regimen was 92.6%, and the progression-free survival rate was 79.9%. The triplet combination was also found to be well tolerated, with a small number of patients experiencing serious adverse events, study authors reported.

Henriette Huber, MD

Henriette Huber, MD

“The CLL2-GIVe regimen is a potent and promising fixed-duration, first-line treatment for patients with high-risk CLL, with a manageable safety profile worthy of further exploration in phase III studies,” said lead study author Henriette Huber, MD, of Städtisches Klinikum Karlsruhe and University Hospital Ulm, Germany.

As Dr. Huber reported, novel agents have helped to increase survival in all cytogenetic subgroups of CLL, particularly those with high-risk disease. However, there is still a need for improvement among patients with 17p deletion del(17p) and/or TP53 mutation.

In a single-arm, phase II trial of untreated patients with high-risk CLL, continuous ibrutinib monotherapy demonstrated a 4-year progression-free survival of 79%.2 In the Alliance A041202 trial, patients with high-risk CLL receiving ibrutinib in combination with rituximab had a 4-year progression-free survival rate of 72.8% compared with 52.6% with chemoimmunotherapy alone.3 And, in the CLL14 trial, 1 year of treatment with venetoclax or obinutuzumab yielded a 4-year progression-free survival rate of 54.2% in patients with high-risk CLL.4

Study Methods and Major Findings

The phase II CLL2-GIVe trial tested the triplet combination of obinutuzumab, ibrutinib, and venetoclax as a time-limited, first-line regimen in patients with high-risk CLL. Dr. Huber and colleagues recruited 41 untreated patients with 17 del(p) and/or TP53 mutation to 8 German centers.

The treatment regimen consisted of three parts: six cycles of induction with the triplet combination of obinutuzumab, ibrutinib, and venetoclax; six cycles of consolidation with ibrutinib and venetoclax; and three cycles of ibrutinib monotherapy until cycle 15.

Measurable residual disease was assessed by flow cytometry in peripheral blood at cycles 9, 12, 15, and 36, and the final restaging in bone marrow occurred at cycle 15. For patients who achieved complete remission at cycle 15 and undetectable MRD at cycles 9 and 12, ibrutinib treatment ended at cycle 15. Otherwise, ibrutinib was continued until cycle 36.

The primary endpoint of the study was complete remission rate at cycle 15. As Dr. Huber reported, 58.5% of patients met the study’s primary endpoint of complete remission at cycle 15, and 41.5% of patients achieved a partial response, for an overall response rate of 100%.


  • The triplet regimen of obinutuzumab, ibrutinib, and venetoclax demonstrated a complete response rate of 58.5%, with a high rate of undetectable measurable residual disease, in the first-line setting of high-risk chronic lymphocytic leukemia.
  • The 3-year progression-free survival and overall survival rates were 79.9% and 92.6%, respectively.

“In this investigator-initiated trial, 87.8% of patients reached undetectable MRD at cycles 9 and 12 in peripheral blood, and at cycle 15, 78% of patients had undetectable MRD in peripheral blood,” said Dr. Huber, who noted that 65.9% of patients had undetectable MRD in the bone marrow.

After a median observation time of 38.4 months, the progression-free survival rate was 79.9%, and the overall survival rate was 92.6%. Median overall survival and progression-free survival were not reached. “Correlative analyses between progression-free survival and cytogenetics showed that the presence of 17p deletion has an impact on progression-free survival,” said Dr. Huber. “However, there was no significant correlation between the presence or absence of complex karyotype and survival.”

Safety Profile

Adverse events were reported in all 41 patients. The most frequent grade ≥ 3 hematologic adverse events were blood and lymphatic disorders. Neutropenia and cytopenia were reported in 48.8% and 17.1% of patients, respectively. The most frequent nonhematologic adverse events of any grade were gastrointestinal disorders, which occurred in 85.4% of patients—mostly low-grade diarrhea, said Dr. Huber. Infections occurred in more than 80%, including 19.5% being grade ≥ 3.

“The safety profile was manageable, but patients should be monitored concerning infections,” said Dr. Huber. “Supportive measures are relevant.” 

DISCLOSURE: Dr. Huber reported financial relationships with AbbVie, Janssen, and Novartis.


1. Huber H, Tausch E, Schneider C, et al: Final analysis of the prospective multicenter CLL2-GIVe trial of obinutuzumab, ibrutinib, and venetoclax in untreated patients with CLL with 17p deletion/TP53 mutation. 2022 ASH Annual Meeting and Exposition. Abstract 343. Presented December 10, 2022.

2. Allan JN, Shanafelt T, Wiestner A, et al: Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations. Br J Haematol 196:947-953, 2022.

3. Ruppert AS, Booth AM, Ding W, et al: Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202. Leukemia 35:2854-2861, 2021.

4. Al-Sawaf O, Zhang C, Tandon M, et al: Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14). Lancet Oncol 21:1188-1200, 2020.

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