Translational research and the future of CLL treatment

Prof Steven Coutré – Stanford University School of Medicine, Stanford, USA

First of all could I get you to just talk about the background to your research and what you will be presenting today?

I’ve been involved in clinical trial research in CLL for a number of years, dating back to the very early trials with some of the new novel agents. Today I’ll be discussing data with one of those drugs, idelalisib.

What led you to do this research and why is there an interest in this topic?

CLL is the most common leukaemia in adults and there has certainly been a need for better therapies, better in terms of efficacy as well as safety, better tolerated therapies, especially given that this is a disease of the elderly where the average patient is over 70. So there has long been an interest in developing new therapies and fortunately we’ve had several come along about the same time. In the last five years we’ve really seen tremendous benefit for our patients and, at least in the US now, we have these drugs available for use.

Are these two drugs used in combination that you’ll be speaking about today?

No. So one of the drugs is ibrutinib and that’s approved as a monotherapy in patients with previously treated CLL. The other drug is idelalisib which is a PI3 kinase inhibitor and that’s also approved for previously treated CLL in combination with rituximab. So today I’ll be discussing the combination of idelalisib and rituximab for CLL patients.

What are the latest findings in that area?

We have increasing results from clinical trials now, beginning with the original trials and now to phase III randomised trials. In fact, that’s what led to the drug approval. So I’ll be discussing an update, a bit of an update, of those trials as we’ve followed patients for a longer period of time as well as the safety profile. This is in the context of a sort of mini-symposium where we’re discussing both ibrutinib, Dr Gribben, my colleague, will lead off and then I’ll review with idelalisib plus rituximab. Then actually there will be two other talks that is meant to be a debate about is there a future for standard chemotherapy or are we going to be using these novel drugs for all of our patients.

Can you tell me more about the safety profile of these drugs?

In general they’re quite well tolerated for most of our patients. There are unique issues between the drugs - with ibrutinib there is some bruising, for example, because of inhibition of platelet function. With idelalisib we’ve had an issue with diarrhoea as patients have stayed on the drug for a longer period of time. So we’re really trying to learn how best to use the drugs in specific patient populations. We need to learn more about long-term use of the drugs since, unlike our standard therapy, we’ve treated patients continuously. So we’ve learned a lot, we’ve seen how effective the drugs are and now the challenge is to find out who needs to stay on the drugs for longer periods of time.

And in terms of clinical trials, what new trials have you got planned and what have you got in the pipeline?

For CLL specifically there are a lot of ongoing trials with these drugs. Neither are approved for initial treatment of CLL with the exception of a small subgroup of patients with the 17p deletion. So I think everyone is eagerly awaiting results of trials, randomised trials, for initial treatment, we don’t have data. We have limited data from early trials but the larger randomised trials still have a little ways to go. We have large ongoing trials in our younger patients, for example, comparing with the standard regimen, the so-called FCR regimen. So what everyone is eagerly waiting for is those sorts of results – should we be using these drugs as part of initial therapy as well, so should everybody be on the novel drugs? There are also other exciting drugs coming along that target other pathways, for example a drug by the name of venetoclax which is also an oral drug that targets BCL2. So it gives us another way of approaching the disease. As we go forward of course we’ll be interested in combinations of these therapies.

This is a new kind of direction in treating CLL patients and the old line therapies hopefully will become less common.

That would be nice. I think that’s what our patients want; they tell us, ‘We don’t want chemotherapy,’ and so hopefully the promise of these drugs that we’ve seen so far will continue. As we gain more experience we’ll be more comfortable using them earlier in the stage of the disease for patients who need treatment and we’ll see if there’s a long-term answer. So even if they don’t eliminate the disease and they don’t cure, if we can manage it indefinitely that would be quite an accomplishment.

And are there any negatives to these new treatments?

Of course everyone always brings up cost. They are expensive, as are all of our new drugs, so that’s a big challenge. There will be a nice discussion of that at one of the sessions here at iwCLL also. There are side effects, there are certain issues, fortunately they haven’t been serious enough to really lead to great concern but they do require us to make choices about which patients are most appropriate for one therapy versus another.

Is there a take home message?

The take home message is that we’re really in a new era for CLL. I think the idea that this is a disease we can’t control indefinitely, that we should just give palliative therapy to our patients needs to be changed. I think these drugs have clearly demonstrated that we can change things and we have. So, as clinicians and in speaking with our patients and in treating them we have to make sure we’re educated about what these drugs can do and what the expectations are. I think if the community in general can embrace that attitude then everyone will benefit, mostly our patients.