CLL is a form of blood cancer that originates in the lymph nodes. It is the most common form of leukemia in the Western world, and no cure has been found for it yet. While treatments can keep the disease under control for many years, over time the drugs lose their effectiveness, because the cancer cells develop resistance. This is why it is important to have access to several drugs, so that the patient can switch when necessary but also it would be highly desired to be able to stop treatment for a prolonged period of time with the hope to reinitiate the same drugs when disease is progressing again.
Much more effective
The arsenal of drugs for treating CLL has increased in recent years with the advent of specific small molecule inhibitors such as ibrutinib and venetoclax, which are given in the form of tablets. The combination of these two drugs has now been directly compared to the treatment of standard chemotherapy plus antibody therapy for the first time. This trial was conducted on 211 CLL patients, mostly fragile older people who had never been treated before. The study, published in NEJM Evidence and led by Prof. Arnon Kater, reveals that a combination of the two inhibitors is much more effective than the standard approach.
Winning team
Years of fundamental research conducted at Amsterdam UMC helped set the stage for this clinical study. Molecular biologist Eric Eldering and hematologist Arnon Kater have been studying the behavior of CLL cancer cells in the lymph nodes and blood for more than fifteen years. Their research has produced valuable information about how cancer cells develop resistance to drugs.
Five years ago, Profs. Eldering and Kater found the first indications – initially in the laboratory, later in mice – that venetoclax and ibrutinib form an effective combination. Lab studies in cell cultures revealed what the ‘winning team’ of ibrutinib/venetoclax does: “Ibrutinib banishes malignant cells from the lymph nodes into the bloodstream, where they are at their most vulnerable,” explains Prof. Kater. “Venetoclax subsequently cleans them up.”
Stopping and restarting treatment
A next question the researchers wanted to answer was whether you can safely stop the combination treatment after 15 months. “Ibrutinib is now given continuously until it no longer works,” says Prof. Kater. “If you stop early, the disease quickly returns. But ideally, you want patients to be exposed to these drugs for as short a time as possible. There are several reasons for this. Ibrutinib has cumbersome side effects such as diarrhea and joint pain. The drug also makes patients more vulnerable to infections, such as coronavirus. Moreover, in a small group of patients, ibrutinib causes damage the heart. Besides, these drugs are highly expensive. But most importantly, the shorter you give the drug, the less chance the disease will have to build resistance. By stopping for certain periods and giving the medication only when needed, you can use the drugs for much longer.”
Prof. Arnon Kater, along with his Danish colleague Prof. Carsten Niemann, set up a study into whether patients could safely stop the combination of venetoclax and ibrutinib after one year. The study was performed under the umbrella of the Dutch/Belgian trial organization Hovon, of which Prof. Kater is chairman of the CLL working group and president-elect of the executive board, together with the Nordic CLL study group, led by Prof. Niemann. Using a highly sensitive test that can detect tiny amounts of cancer cells (MRD), they selected patients who had no detectable levels of CLL cells. These patients were randomized to continue or stop ibrutinib. As soon the test revealed cancer cells again, the treatment was restarted in patients that randomized for treatment cessation.
They found that a significant number of patients were able to stop for longer periods of time. Moreover, the medication still proved to work if the disease returned. This study has been published in Lancet Oncology.
CLL as a chronic disease
Is this good news for the patients? “We once proclaimed that CLL would one day change from a fatal disease to a chronic disease,” says Prof. Eldering. “Clinicians worldwide are on the right track to achieve this. Already patients can be treated much longer before resistance develops.”
“That’s because we have more drugs at our disposal,” adds Prof. Kater. “But so far, with every drug we’ve trialed, we’ve seen it losing its effectiveness eventually. This is probably also true of this combination. You can safely stop and start again, but the question is how long can you continue to do this? We don’t know that yet.”
Profs. Eldering and Kater are therefore investigating new ways to treat and hopefully cure this disease. Lines of research involving the metabolism of cancer cells and restoration of immune cell function appear promising. Last month the group published their findings in the scientific journals Blood and Blood advances, respectively.
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Prof. Arnon Kater
Prof. Eric Eldering
For more information contact Profs. Arnon Kater or Eric Eldering, or read the scientific publications:
Kater, A.P., et al. (2022) Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial. Lancet Oncol. 23, p818-828. DOI: https://doi.org/10.1016/S1470-2045(22)00220-0.
Kater, A.P., et al. (2022) Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evidence. DOI: https://doi.org/10.1056/EVIDoa2200006.
Chen, Z., et al (2022) Characterization of metabolic alterations of Chronic Lymphocytic Leukemia in the lymph node microenvironment. Blood 2021013990. DOI: https://doi.org/10.1182/blood.2021013990.
Van Bruggen, J.A.C., et al. (2022) Depletion of CLL cells by venetoclax treatment reverses oxidative stress and impaired glycolysis in CD4 T cells. Blood Advances. DOI: https://doi.org/10.1182/bloodadvances.2022007034.
Funding for this research was provided by AbbVie, Janssen, and Pharmacyclics, the Dutch Research Council (NWO), and the European ERC program.
People involved at Cancer Center Amsterdam:
Prof. Arnon Kater
Prof. Eric Eldering
Julie Dubois
Clemens Mellink
Anne-Marie Kersemaekers
Jos Dobber
Text: Irene van Elzakker
Photography: Adobestock and Marieke de Lorijn (portraits)