Researchers from Cologne University, Amsterdam UMC, and Copenhagen University have found that a chemo-free targeted drug-combination therapy is more effective and produces fewer side effects for patients with chronic lymphocytic leukemia (CLL).

Chemotherapy has been the most effective front-line treatment to date for relatively young patients with chronic lymphocytic leukemia (CLL). The disease is the most common form of blood cancer in the Western world, causing a substantial health burden on patients and society.

Researchers from Cologne University, Amsterdam UMC and Copenhagen University now show that a chemo free targeted drug-combination therapy is more effective and produces fewer side effects for patients with CLL. The results of this study were published in the New England Journal of Medicine.

Laying the groundwork

Together with colleagues and collaborators, Arnon Kater, professor of hematology at Amsterdam UMC and chair of the HOVON CLL study group, has been studying the behavior of CLL cancer cells in the lymph nodes and blood for more than fifteen years, uncovering valuable information about how cancer cells develop resistance to drugs and evade the immune system.

“CLL cells circulate in the blood and accumulate in the lymph node, where they can manipulate various cells within that microenvironment to promote their growth and survival,” explains Prof. Kater. “About five years ago, we saw evidence from pre-clinical studies that venetoclax and ibrutinib formed a particularly effective combination. What happens is that ibrutinib banishes malignant cells from the lymph nodes into the bloodstream, where they are at their most vulnerable. Venetoclax subsequently cleans them up.”

Targeted therapies

Traditional chemotherapy drugs work by killing rapidly dividing cells, including cancer cells, but also normal healthy cells. Venetoclax, ibrutinib, and antibodies used in this study, however, are targeted therapies that specifically target the proteins and pathways that are overexpressed or dysregulated in CLL cells, which can lead to selective killing of cancer cells while sparing normal healthy cells.

The GAIA–CLL13 trial

The phase 3 randomized trial, also known as the GAIA/CLL13 trial, was conducted with a total of 926 patients with CLL and a low burden of coexisting conditions (‘fit’) in 159 hospitals in 9 European countries and Israel. About a quarter of the patients came from the Netherlands. The patients were placed in four groups and received either chemotherapy and an anti-CD20 antibody (standard treatment), or the drug venetoclax in combination with an anti-CD20 antibody (either rituximab or obinutuzumab). The fourth group received a triple combination of ventoclax, obinutuzumab and the BTK inhibitor ibrutinib.

Phase 3 results – detectable disease

At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax–obinutuzumab group (86.5%) and the venetoclax–obinutuzumab–ibrutinib group (92.2%) than in the chemoimmunotherapy group (52.0%), but it was not significantly higher in the venetoclax–rituximab group (57.0%).

Progression-free survival & side effects

Three-year progression-free survival was 90.5% in the venetoclax–obinutuzumab–ibrutinib group and 87.7% in the venetoclax–obinutuzumab group, versus 75.5% in the chemoimmunotherapy group. Like detectable disease rates, progression-free survival also was not significantly higher in the venetoclax–rituximab group (80.8%).

More beneficial

“Data from this trial confirm that the combination of venetoclax–obinutuzumab is more beneficial than the standard chemoimmunotherapy regimens,” says Prof. Kater. “In fact, the percentages of patients in the venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib groups with undetectable minimal residual disease in peripheral blood are among the highest reported in first-line therapy for CLL at 86.5% and 92.2%, respectively.”

Arnon: “As far as the data from the venetoclax–obinutuzumab–ibrutinib group in the current trial, we confirmed phase 2 trial results that showed promising progression-free survival. But whether the triple combination is even more beneficial than other targeted regimens needs more study.”

Mutational status of IGHV

The researchers also evaluated efficacy of the treatment regimens in regard to the mutational status of IGHV, the immunoglobulin heavy chain variable region gene, which plays an important role in the immune system's ability to recognize and respond to foreign substances. In CLL, the IGHV gene can be either mutated or unmutated.

Unmutated IGHV in CLL means that the DNA sequence of the gene is similar to the germline (inherited) version of the gene, with few or no changes. This is often associated with more aggressive disease, as the cancer cells are more similar to immature B cells and have a stronger ability to survive and proliferate. About 50% of CLL patients have unmutated IGHV.

The researchers found the percentages of patients with unmutated IGHV who had progression-free survival at 3 years were 65.5% (chemoimmunotherapy), 76.4% (venetoclax–rituximab), 82.9% (venetoclax–obinutuzumab), and 86.6% (venetoclax–obinutuzumab–ibrutinib), but the percentages of patients with mutated IGHV who had progression-free survival at 3 years were not significantly different, at 89.9%, 87.0%, 93.6%, and 96.0%, respectively.

“In our trial, venetoclax–obinutuzumab or venetoclax–obinutuzumab–ibrutinib therapy produced a significant progression-free survival benefit among patients with unmutated IGHV,” says Prof. Kater. “However, chemoimmunotherapy may still be better for patients with mutated IGHV at this point.”

Benefits of diverse combination therapy

“With more drugs at our disposal, we can devise combinations that achieves better disease-free progressions, while reducing the risk of developing resistance to therapies due to shorter treatment times,” says Prof. Kater. “By stopping for certain periods and giving the medication only when needed, you can reduce side-effects, use the drugs for much longer, and reduce healthcare costs.”

For more information, contact Prof. Arnon Kater, check out the NEJM editorial, or read the scientific publication:

Barbara Eichhorst, M.D., Carsten U. Niemann, M.D., Arnon P. Kater, M.D., et al. (2023) First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med 388:1739-1754. DOI: 10.1056/NEJMoa2213093.

People involved at Amsterdam UMC - Cancer Center Amsterdam:

Prof. Arnon P. Kater

Prof. Marinus van Oers


This clinical research was supported by grants from AbbVie, Janssen, and Roche.

Adaptation by Laura Roy.

This article was created for Cancer Center Amsterdam.