22 May 2023

A chemo-free drug combination therapy is a more effective treatment for chronic lymphocytic leukaemia (CLL) than chemoimmunotherapy, according to a major European study.

Writing in New England Journal of Medicine, the researchers describe how venetoclax with obinutuzumab, with or without ibrutinib, was shown to be the most effective combination.

A team led by scientists from Cologne University, Germany, Amsterdam UMC, The Netherlands, and Copenhagen University, Denmark, showed how the combination therapy also produces fewer side effects.

The phase 3 GAIA/CLL13 randomised trial was conducted with 920 fit patients with CLL, in 159 hospitals in nine European countries and Israel, making it the largest ever study conducted in CLL.

The patients were placed in four groups and received either standard treatment of chemoimmunotherapy, or venetoclax combined with an anti-CD20 antibody (either rituximab or obinutuzumab). A fourth group received ventoclax, obinutuzumab and ibrutinib, a kinase inhibitor.

Compared to the standard chemoimmunotherapy, all groups with venetoclax had fewer side effects. The research team found combining venetoclax with obinutuzumab was the most beneficial compared to standard chemoimmunotherapy.

After 15 months of treatment, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%) and venetoclax-obinutuzumab-ibrutinib group (92.2%), compared to the chemoimmunotherapy group (52.0%).

The scientists looked at the effects of the combination treatments in patients whose disease does not carry a mutation in the IGHV gene – a group which has less favourable prognosis compared to IGHV-mutated disease.  

On average, after three years in the IGHV­-unmutated group, 34.5% of those who received chemoimmunotherapy relapsed, compared to 17.1% of those who received the venetoclax-obinutuzumab combination therapy.

Professor Arnon Kater, professor of haematology at Amsterdam UMC and chair of the HOVON CLL study group, said: “This study shows that with clever temporary and safe combinations, you can allow patients to be treatment free in the long-term, with a much lower chance of developing resistance.

“And we also think that it is even possible to stop the combination therapy earlier than after a year. We now want to investigate this. This not only reduces side effects, but also healthcare costs.”



Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; on behalf of GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. (2023) “First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia”, New England Journal of Medicine, doi: 10.1056/NEJMoa2213093

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2213093

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