The background of the GAIA or CLL13 study is that venetoclax, a BCL-2 inhibitor, in combination with
obinutuzumab given for twelve months of treatment as a targeted time-limited treatment regimen is
approved in all CLL patients but, in fact, the approval study, the CLL14 trial, was done only in unfit
CLL patients. Therefore the question was still open – what about the comparison of venetoclax
obinutuzumab versus these more intensive chemoimmunotherapy regimens we use, or used so far, in
CLL – fludarabine cyclophosphamide rituximab or bendamustine rituximab. That was one question,
but because the study has two co-primary endpoints the second question is what about intensification
of this combination when we add the BTK inhibitor ibrutinib. Therefore we also wanted to evaluate a
triple combination in comparison to chemoimmunotherapy with respect to efficacy but also with
respect to safety.

What was the design of this study?

This was a phase III study with four different treatment arms. We did a central screening in the study
in order to exclude patients with TP53 mutation or deletion 17p because we had a
chemoimmunotherapy arm and we did that by central screening. Patients were stratified due to age
because in the chemoimmunotherapy arm the patients up to the age of 65 years received FCR and
elderly patients received bendamustine rituximab. Then there was a 1:1:1 randomisation between all
four different treatment arms which contained, as mentioned, venetoclax plus obinutuzumab,
venetoclax plus obinutuzumab plus ibrutinib. There was another arm containing venetoclax plus
rituximab because we also wanted to address the question of what is the influence of the CD20
antibody.

What did you find?

We had two co-primary endpoints, one of them was the rate of undetectable MRD and we analysed
that already last year and data were presented at ASH 2022. We found higher rates of undetectable
MRD rate of venetoclax obinutuzumab but also with the addition of ibrutinib in comparison to
chemotherapy. What I presented here at the late breaking abstracts session is that also the interim
progression free survival analysis after more than three years shows superiority. Now with respect to
hierarchical testing and for statistics we tested for the triple combination, venetoclax obinutuzumab
ibrutinib – clearly superior risk reduction for relapse by 65% and also the venetoclax obinutuzumab
combination is doing a risk reduction by more than 60%.

How could this affect future treatments with CLL?

It gives, on the one hand, confidence that this is an excellent treatment option in patients in front line
when they are younger, so confirming the approval status. It also helps balancing the decision,
particularly in patients with less favourable genetic profiles. These are, for example, patients with an
unmutated IGHV status where the alternative treatment would be continuous treatment with a BTK
inhibitor. Therefore these data are very helpful in the daily practice to inform your patient what is the
expected PFS with venetoclax obinutuzumab and ibrutinib which is quite similar but you have time off
with the venetoclax obinutuzumab regimen.

I would not yet use the triple regimen, it’s not approved this triple combination. I think we also need
here further follow-up in order to see what is really the benefit of this regimen because we have seen
some more toxicity, particularly more infections, in comparison to the double combination with
venetoclax plus obinutuzumab.