EHA 2015

Ibrutinib combined with bendamustine plus rituximab in previously treated CLL and SLL

Dr Paula Cramer - University of Cologne, Köln, Germany

Let me begin with the relapsed setting in CLL and SLL. This was difficult to treat until we had all these novel drugs that became available. Before we had them on hand we treated most patients with chemo-immunotherapy, also in relapse, and we often used BR instead of FCR, so we changed the chemotherapy backbone.

So that’s bendamustine rituximab?

Yes, that was the most commonly used combination, at least in Europe.

Now you’re using ibrutinib, tell me what is ibrutinib doing, theoretically, and then I’d like to know how you’ve used it.

Ibrutinib is the first in class kinase inhibitor, inhibiting the signal transduction of the B-cell receptor pathway. It was developed as a single agent first and tested mainly in the relapsed patients, so the idea was now to combine the chemo-immunotherapy with BR with this novel agent, ibrutinib.

What did you do in the study?

The HELIOS study was a phase III trial which was an international trial in 21 countries and we included almost 600 patients. These patients were randomised double blind to receive either ibrutinib or placebo combined with bendamustine rituximab.

I gather that you had quite a good response to adding ibrutinib.

Yes, the primary endpoint, the progression free survival, was significantly improved. We just recently had the interim analysis which proved that the addition of ibrutinib significantly improved the progression free survival time. After a median observation time of 17 months the median progression free survival for the bendamustine rituximab arm was only 13.3 months and with the addition of ibrutinib the median was not yet reached. This was highly statistically significant and we could see that the risk of progression or death was reduced by 80%.

In what way does your study enlighten the further clinical use of this drug?

It shows that it’s very efficacious and also safe to use it in the relapsed setting. Also that it is safe to use it in combination with bendamustine rituximab chemo-immunotherapy. So now we have a trial that shows not only that ibrutinib can and should be used as a single agent but also in combination with chemotherapy and an antibody treatment. So we have three principles of treatment taken together.

You say the drug was safe but were there any new toxicities?

Actually no. What we saw in this trial was exactly what we expected. Regarding the addition of ibrutinib we didn’t see any cumulative toxicity, no rise in haematological adverse events or infections. What we saw more commonly in the BR ibrutinib arm was atrial fibrillation and bleeding events which were very rare and also what we knew before was rash and diarrhoea which were all low grade.

What about minimum residual disease?

This is certainly a difference between the two trials. We saw both a higher complete remission rate in patients with ibrutinib added to bendamustine rituximab and also there was a difference in the MRD rate.