Triplet therapy for all comers in the CLL-BAG trial

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Published: 24 Jun 2017
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Dr Paula Cramer – University of Cologne, Cologne, Germany

Dr Cramer speaks with ecancer at EHA 2017 about the results from CLL-BAG, a trial of bendamustine, obinotuzumab and venetoclax for CLL.

She describes the patient population in the trial as including relapsed and treatment naïve patients, and outlines the treatment dosage and schedule: debulking with bendamustine before staggered venetoclax and obiniotuzumab to prevent immune exhaustion.

Dr Cramer reports a 95% overall response rate, with 87% of patients reaching minimum residual disease, though notes a chance of secondary skin cancers among the adverse events following treatment.

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

This is a phase II trial, it’s called the CLL2-BAG trial. The name composes of the beginnings of the three different drugs we use. The first is the bendamustine which is only used as a debulking in the beginning for patients with a higher tumour load. Then it’s followed by an induction and maintenance phase where we combine two novel agents, one is the BCL2-anti venetoclax and the CD20 antibody obinutuzumab. It’s a phase II trial and because we wanted to evaluate this combination in real life we included an all comer population. So we have first line and relapsed refractory patients, we have fit and unfit patients and we have patients with high risk cytogenetics. So basically all patients that show up in your department were able to be included into that trial.

The idea of combining these three agents is based on the following. First we wanted to have a debulking for patients with a higher tumour load so these patients received two cycles of bendamustine which is a chemotherapeutic agent which has a good tolerability. Afterwards the two agents are combined in an induction and maintenance phase. First we started with the CD20 antibody in order to further reduce the tumour load, especially the lymphocytosis of the patients, and only from the second cycle onwards we started with the venetoclax with a slow dose ramp-up over five weeks as was already established in other trials. Combining these two agents the idea was just these two agents, I would say, are the most efficacious which are available for the treatment of CLL and combining the two the idea is just to achieve much deeper remissions in the patients because one of the goals of the trial was to stop treatment once patients had a very deep remission.

What kind of safety was associated with having all three?

For the 45 patients who started with the bendamustine debulking we only saw infections and cytopenias, as expected with the bendamustine debulking. For the 66 patients who then received induction treatment there also we didn’t see any cumulative or unexpected toxicities. Patients had cytopenias and infections, this was in line with what was previously published for the venetoclax so the obinutuzumab didn’t add any toxicity to that drug. Other more common adverse events were infusion related reactions in the beginning with the obinutuzumab administration. There were some secondary primary malignancies, mainly skin cancers. One very important finding is we didn’t see many tumour lysis syndromes which is a problem associated with venetoclax. There were only three cases, one occurred during the bendamustine debulking, one occurred with obinutuzumab in the beginning and only one occurred at the dose ramp up of venetoclax in a high risk patient. All of these tumour lysis syndromes were only laboratory TLS and they all were only grade 3 and resolved very quickly. So no problems with tumour lysis syndromes in this trial and this is based on this sequential start of the different drugs.

I was just about to ask on the importance of the timing of these three. If you were to change the scheduling one before the other or bring them closer together, further apart, do you think that would impact outcome significantly?

I wouldn’t start with venetoclax and obinutuzumab at the same time point because both of them are very potent drugs and what we see with the CD20 antibody is that the lymphocyte count goes down very rapidly and the same applies for the venetoclax. So if we do that together I think that’s not good to control. There is another trial where they did it the other way around and that worked as well.

The primary endpoint of the trial is the overall response rate at the end of induction treatment, so that’s after six cycles of combination of venetoclax plus obinutuzumab. The overall response rate we saw in this all comer population, let me remind you, half of the patients were treatment naïve but there were some very heavily pre-treated relapsed refractory patients, some had even undergone a low stem cell transplantation, one-third had high risk genetics, two-thirds were IgVH unmutated so it’s a difficult to treat patient population. The overall response rate was 95% which is very good. What’s exciting is the MRD negativity rate and this was 87% and even more exciting, I would say, is that we didn’t see any important differences between first line and relapsed refractory patients and also among the patients with a deletion 17p TP53 mutation we had an MRD negativity rate of 70% in the peripheral blood, I have to say, it’s not all bone marrow.

And how long will the follow-up for this trial be?

It’s an ongoing trial. So far we have documentation of most patients that they started with the maintenance phase and about half of the patients were already able to stop treatment. Most of them already stopped because of a deep remission with MRD negativity. Ongoing follow-up will, I hope, show that the rate of complete remissions will increase and also maybe the rate of MRD negativity, especially from the bone marrow, I hope that we will get more samples over time. Then the follow-up of this trial might help to answer the question if it’s really feasible to stop treatment if patients are in a very deep remission.

You did mention, and I would like to follow up, the secondary skin cancers there. How much of a risk is that? Is it something patients should be aware of?

It’s only four patients so it’s not that much. It’s something that we also see in a lot of other trials. These skin cancers, most of them occurred rather early, in the beginning of the trial, so I would say that they were pre-existing. It is something that is relevant for all lymphoma and especially for CLL patients because they have some disturbance of the immune system and they have a higher likelihood of developing any other cancer. So when I talk to my patients I always tell them to have their screening examinations done at the dermatologist.

You mentioned other trials where they changed the arrangement and follow-up, are there any plans to expand?

The combination of venetoclax and obinutuzumab is currently evaluated in phase III trials already. There is the CLL14 trial which already has completed recruitment. It’s a trial in first line setting of physically unfit patients so it’s the elderly comorbid patients. In that trial we compared venetoclax obinutuzumab as the experimental arm to the current standard, chlorambucil obinutuzumab. In addition, at the end of last year we started recruitment for another huge European phase III trial which is a four arm trial which also contains the current standard for physically fit first line patients, it’s FCR-OBR, and one of the experimental arms is the combination of venetoclax obinutuzumab.