CLL14: A chemotherapy-free regimen of venetoclax plus obinutuzumab for CLL

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Published: 20 Jun 2019
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Dr Othman Al-Sawaf - Univesity of Cologne, Cologne, Germany

Dr Othman Al-Sawaf speaks to ecancer at the 2019 European Hematology Association (EHA) Annual Meeting about the CLL14 trial.

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.


CLL14 is a randomised phase III trial that we conducted. In this trial the aim was to check in patients with previously untreated CLL and co-existing conditions whether standard chemoimmunotherapy with chlorambucil obinutuzumab can be challenged by a new chemotherapy free regimen of venetoclax and obinutuzumab. The primary endpoint in this analysis was progression free survival and the primary endpoint was met last year. Here the primary analysis was presented in which the primary analysis was presented.
The major finding here was that in 432 patients who were randomised to either receive the chlorambucil obinutuzumab over twelve cycles or venetoclax obinutuzumab also over twelve cycles with combination therapy given each for six cycles and six cycles of either chlorambucil monotherapy or six cycles of venetoclax monotherapy and all patients discontinued treatment afterwards. The major finding here was that patients treated with venetoclax obinutuzumab had a significantly longer progression free survival than patients treated with chlorambucil obinutuzumab. Also in the subsequent analysis of secondary endpoints we saw that patients treated with venetoclax obinutuzumab had higher response rates and, interestingly, also much deeper remissions meaning that the rate of MRD negativity in patients treated with venetoclax obinutuzumab was significantly higher than in patients with chlorambucil obinutuzumab. This indicates that we can achieve much deeper responses with a chemotherapy free fixed duration treatment.

What are the clinical implications?

For the clinic this means that we now have for patients who are a little bit challenging to treat because in this trial all patients were treatment naïve so they didn’t have any previous treatment and they had to have a relevant burden of coexisting conditions. This was assessed by the cumulative illness rating scale, so all patients had to have at least six points on that scale, meaning that they had relevant coexisting conditions which would make intensive chemoimmunotherapy, for instance with FCR, not feasible in these patients.
With the result of this study we can now offer our patients a new treatment that is, on the one hand, tolerable and, on the other hand, highly efficacious. So the existence of coexisting conditions does not exclude them now from having an effective treatment.

Can you tell us about toxicities?

Major toxicities were as expected – haematological toxicities like neutropenia. We did see some infections although there was no excess in any of the toxicities and overall all were manageable with standard clinical approaches.

Can you tell us about the subgroup analysis?

In the subgroup analysis that was presented here for the first time we had a look on patients with complex karyotype. Complex karyotype is known to be a challenge in all haematological malignancies because it represents genomic instability of the condition itself and we know from other conditions like AML and MDS, and also from CLL for that matter, that it is associated with less response to treatment, shorter response to treatment and, in some cases, also shorter overall survival.

So we wanted to see now as the data, particularly in CLL, are mostly based on retrospective analysis whether we can prospectively evaluate whether chemoimmunotherapy or targeted therapy with venetoclax obinutuzumab in any way does make a difference in this challenging group of patients. We were able to show that with chlorambucil obinutuzumab, so with the chemoimmunotherapy, patients had a shorter PFS as well as shorter overall survival in patients with complex karyotype. In strong contrast to that we saw that patients in the venetoclax group, irrespective of complex or non-complex karyotype, had similar rates of deep responses, similar rates of clinical responses and at the end also similar rates of progression free survival and overall survival which makes this a viable option for our patients in the clinic because before we didn’t have enough data to suggest any particular treatment for these patients. Now this suggests that, first of all, we should check for complex karyotypes because 15% of patients in our analysis had complex karyotype, so one should check for that before starting first line therapy. When we have it one should consider venetoclax obinutuzumab as an option in these patients as it shows good efficacy in those.