CLL14: Venetoclax plus obinutuzumab in untreated CLL

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Published: 11 Jun 2021
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Dr Othman Al-Sawaf - University Hospital of Cologne, Cologne, Germany

Dr Othman Al-Sawaf speaks to ecancer about the four-year follow-up of the CLL14 trial looking at venetoclax and obinutuzumab in untreated chronic lymphocyte leukaemia.

Dr Al Sawaf explains that venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. In the CLL14 trial, the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab was compared in patients with previously untreated chronic lymphocytic leukaemia. He then discusses the methodology and key findings of the study. In the end, he talks about the future impact of the results from this study.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

Our study is called CLL14, it’s a study that has been running since late 2015. It’s a randomised phase III study aimed at patients with previously untreated CLL, so previously untreated chronic lymphocytic leukaemia with co-existing conditions. All patients had to have a cumulative illness rating scale above six points and/or a creatinine clearance below 70ml/min as a surrogate for an impaired fitness status. The aim was to see whether a combination of venetoclax plus obinutuzumab given over twelve cycles is superior regarding progression free survival compared to patients who received chlorambucil obinutuzumab as a conventional chemo monotherapy also given over twelve cycles.

The study tried to investigate how patients tolerate and how effective the treatment without chemotherapy based on the BCL-2 inhibitor venetoclax is compared to the oral chemotherapy of chlorambucil in combination with a CD20 antibody obinutuzumab. The treatment schedule was based on six initial cycles of combination therapy. So all patients in both arms started off with three administrations of obinutuzumab as an infusion of the CD20 antibody and followed by the addition of the oral compound, either venetoclax or chlorambucil. The combination was given until the end of six cycles and afterwards in both arms patients continued on a, so to speak, consolidating additional six cycles of either venetoclax monotherapy or chlorambucil monotherapy. All patients discontinued treatment after those twelve cycles, regardless of their minimal residual disease status. After that they entered a follow-up which continues until today, so we will continue follow-up for up to nine years after the last enrolment in order to see how the long-term efficacy and tolerability of this approach is.

The primary key finding of CLL14 was that the progression free survival is significantly longer after venetoclax obinutuzumab than after chlorambucil obinutuzumab and this was first observed in 2019 when we had the primary readout. Now all patients are off treatment for at least three years and we see that the majority of patients after venetoclax obinutuzumab still remain without progression free survival events. So the four year progression free survival rate is currently at 72% after venetoclax obinutuzumab compared to just 35% with chlorambucil obinutuzumab which suggests that we can with this fixed duration approach achieve long-lasting remission in the majority of patients with previously untreated CLL.

The results from this ongoing follow-up analysis inform practice because we already have in most countries venetoclax obinutuzumab is already available or approved. In many countries also it is reimbursed so it is a treatment regimen that is available for us in our day-to-day clinical care.  The rationale of these follow-up analyses is that we try to understand how the long-term efficacy is and what we can expect in terms of efficacy and safety in the long term.
What we can see now with this follow-up analysis is that, particularly when we look at the minimal residual disease rates which we are still constantly monitoring in our patients, we are seeing that a considerable fraction of patients actually maintain their MRD negative status after venetoclax obinutuzumab, even three years after the last drug intake. But we also see that there is a considerable subgroup of patients who lose their MRD response, so they become MRD positive again but without actual disease progression.

This is important for us in our day-to-day clinical care that we know that the disease might eventually come up again and these kinds of treatments don’t cure the patients but that they substantially delay the time until disease relapse occurs. Therefore we now are able to better understand the disease dynamics in low and high risk patients and therefore are able to really understand how the disease might develop in our patients. We can see now, for instance, that if we do see a disease relapse after venetoclax obinutuzumab in most cases these are very benign relapses that don’t warrant immediate retreatment or initiation of a second line treatment.

We also see that those few patients who actually require next line of treatment, until today only 17 patients have actually started the next line of therapy after venetoclax obinutuzumab in CLL14, but we do see that the majority of those respond without any issues to a second line BTK inhibitor, for instance, which suggests that we are able, at least for the first one or two or even three treatments lines of CLL, can be managed in a quite straightforward fashion.