Amsterdam institute for Immunology and Infectious diseases

Chemotherapy has until now been the most effective treatment for young and fit patients with chronic lymphatic leukemia (CLL). The disease is the most common form of leukemia in the Netherlands, with 1,000 new patients each year, and until now has been incurable. According to research led by researchers from the University of Cologne, Amsterdam UMC and the University of Copenhagen targeted combination therapy without chemo is more effective and also produces fewer side effects. The results of this largest-ever study of chronic lymphatic leukemia (CLL) were recently published in New England Journal of Medicine.

Formula 1

CLL originates in B cells, a type of white blood cell that produces antibodies against bacteria and viruses. One of the most common complications of CLL are (severe) infections. Research at Amsterdam UMC in recent years has contributed greatly to a better understanding about the biology of the disease. The old concept that these cancer cells are very difficult to kill turned out to be wrong. This insight led researchers to new treatment options. Arnon Kater, professor of hematology and chair of the HOVON CLL study group: "Just like a Formula 1 car on the track, we saw that the CLL cells in the blood are very vulnerable. The protein Bcl-2 protects the cells so they just do not die in the blood. Because of that protection, the cells have time, like a Formula 1 car, to go to the pit stop. The pit stop is the lymph node where the cancer cells can recharge and then divide." From previous studies, the researchers knew that the drug venetoclax effectively inhibits the Bcl-2 protein. Cells in the blood die as a result, but not in the pit stop, the lymph node. "Venetoclax therapy is effective but must be given for a very long time, which entails very high cost, long-term risk of side effects and resistance formation. By combining venetoclax with agents that can actually do their work in the pitstop, we figured out that combination treatments of limited duration were possible that would be more effective and longer lasting than chemotherapy," Prof. Kater explains.

About the study

The phase 3 study, also called the GAIA/CLL13 study, was conducted as a randomized trial in which a total of 920 fit patients with CLL participated in 159 hospitals in 9 European countries and Israel. About a quarter of the patients were from the Netherlands. The patients were divided into 4 groups and received treatment with either chemotherapy and a monoclonal antibody (standard treatment), or the drug venetoclax in combination with a monoclonal antibody (either rituximab or obinutuzumab). And the 4th group received ventoclax, obinutuzumab and the specific kinase inhibitor ibrutinib. In all 4 groups, the treatment was temporary.

It was found that the all groups with venetoclax had fewer side effects, and the combinations of venetoclax with obinutuzumab were more effective than the standard treatment with chemo. In particular, the treatment proved more effective in patients with an aggressive form of the disease (so-called IGHV unmutated variant, which occurs in 50 percent of patients). On average, after 3 years in the more aggressive disease group, 35 percent had the disease back after chemotherapy and less than 18 percent after the experimental treatments.

Benefits of combination therapy

Until now, chemoimmunotherapy has been the most effective treatment for patients. "This study shows that with smart temporary and safe combinations, you can make patients treatment-free for a long time, with a chance of resistance formation many times lower. And we also think it is even possible to stop combination therapy earlier than after a year. We now want to investigate this," says an enthusiastic Kater. This not only saves in side effects but also in healthcare costs.

This study has led to adjustments of the guidelines within Europe. This means that the new treatment is already available in the Netherlands for patients with CLL and is reimbursed by health insurance.

For more information contact Prof. Arnon Kater or read the scientific publication.