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Fixed-Duration, Triple-Combination Therapy Shows Efficacy for Patients With High-Risk CLL

August 30, 2023

September 2023

Anna Azvolinsky, PhD

Anna Azvolinsky, PhD, is a freelance medical and science journalist based in New York City.

The triple combination of obinutuzumab, ibrutinib, and venetoclax has shown a relatively high response rate among previously untreated patients with high-risk chronic lymphocytic leukemia (CLL), according to study results published in Blood. The limited-duration triple combination therapy achieved a complete response of 58.5% in the phase II CLL2-GIVe trial of 41 patients with high-risk CLL. Most adverse events (AEs) were grade 1 or 2 (75.2%); grade 3 or higher AEs included neutropenia, thrombocytonia, hypertension, and atrial fibrillation.

“This triple-combination regimen resulted in deep and durable responses with time-limited toxicity for patients with high-risk CLL,” said study author Stephan Stilgenbauer, MD, of Ulm University in Germany.

The frontline standard of care for patients with CLL is either continuous Bruton tyrosine kinase (BTK) inhibitor therapy or a fixed-duration combination of venetoclax and obinutuzumab. Yet, treatment with these agents is associated with shorter progression-free survival (PFS) in patients with high-risk CLL, Dr. Stilgenbauer stated.

Fixed-duration combinations are particularly attractive for patients with CLL because they reduce the prolonged challenges that are the result of the continuous occurrence of toxicities, he noted.

Second-generation BTK inhibitors have shown favorable outcomes among patients with high-risk CLL, but these patients appear to have a higher risk of acquiring resistance mutations with continuous BTK inhibitor exposure. Likewise, patients with high-risk CLL still have shorter PFS with the venetoclax and obinutuzumab combination.

All patients in the trial had high-risk disease, having either the 17p deletion (del17p; 4.9%), a mutation in TP53 (36.6%), or both (58.5%).

The German CLL study group treated patients with the combination of the BTK inhibitor ibrutinib, obinutuzumab, and venetoclax for six induction cycles followed by six consolidation cycles of ibrutinib plus venetoclax and then three cycles of ibrutinib monotherapy. Patients were then assessed for response, and those who were not in remission with undetectable measurable residual disease (MRD) after cycle 15 went on to receive ibrutinib maintenance up to cycle 36. After completion of cycle 36, patients could receive ibrutinib indefinitely at the investigator’s discretion. The primary endpoint of the trial was complete remission at cycle 15.

Forty of 41 patients completed the six induction cycles, and 34 of 40 patients completed at least to cycle 15 of the regimen. Six of the 40 patients discontinued early, including two patients who discontinued because of AEs. Six of the 34 patients who achieved a partial response and had no undetectable MRD continued ibrutinib maintenance through cycle 36.

The overall response rate was 100%, and 41.5% of patients (n=17) achieved a partial response. After a median of 38.4 months, the 36-month PFS was 79.9%, and the 36-month overall survival rate was 92.6%.

In an exploratory genetic analysis, the authors found that all 15 patients whose disease harbored a TP53 mutation achieved a complete response and did not have a PFS event on study. In contrast, patients whose disease harbored a del17p did progress and had a 36-month PFS rate of 67.6% (p=0.012). According to the authors, these data provide initial evidence that del17p may be a negative prognostic marker compared with the TP53 mutation. “The favorable outcome of patients with a sole TP53 mutation is hinting that certain subgroups of patients may particularly benefit from a fixed-duration treatment,” noted Dr. Stilgenbauer.

AEs were more frequent during the induction phase of therapy compared with consolidation or maintenance. The most common hematologic AEs were neutropenia and thrombocytopenia. Grade 3 or higher cardiovascular toxicity in the form of atrial fibrillation occurred in 2.4% of patients and in the form of hypertension in 4.9% of patients. Thirty-three serious AEs related to the drug regimen were reported.

“Additional larger trials in patients [with high-​risk CLL] are needed to establish the role of this triple-combination therapy in the frontline management of CLL,” said Dr. Stilgenbauer.

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


Huber H, Tausch E, Schneider C, et al. Final analysis of the CLL2-GIVe trial (obinutuzumab, ibrutinib, and venetoclax) in untreated CLL with del(17p)/TP53mut (published online ahead of print, 2023 Jun 26). Blood. doi: 10.1182/blood.2023020013.



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