Chronic lymphocytic leukaemia update from EHA 2013

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Published: 28 Jun 2013
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Prof John Gribben - Barts & The London Trust Cancer Centre, UK and Dr Jacqueline Barrientos - North Shore-LIJ School of Medicine, USA

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Europe. It is most frequently diagnosed in elderly patients and many patients present with comorbidities, both of which impact on the use of aggressive standard treatments. Targeted therapies can be utilised effectively in patients with CLL and could be used to minimise the side effects of chemotherapy. In a cohort of 250 CLL patients treated with ibrutinib, 150 received therapy for over 1 year. Within this group of patients only 20 patients stopped responding to therapy, including 5 patients who developed mutations that led to resistance. Ibrutinib has also been investigated in combination with bendamustine and rituximab in relapsed or refractory patients. In the CLL11 trial, GA101 plus chlorambucil, rituximab plus chlorambucil and chlorambucil alone were compared in elderly patients with comorbidities. Addition of GA101 or rituximab to chlorambucil both significantly increased PFS versus chlorambucil alone. However, large number of patients with GA101 had Grade 3 and 4 infusion toxicities, mostly in the first couple of infusions. Data on another experimental treatment, CC-292, was presented. It has been found to be generally well tolerated and was associated with significant nodal reduction and partial responses in heavily pre-treated CLL patients.
Understanding the clonal heterogeneity of CLL will likely impact on the management of this disease in the future.


This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

18th Congress of EHA

Chronic lymphocytic leukaemia (CLL) update from EHA 2013

Dr Jacqueline Barrientos - North Shore-LIJ School of Medicine, USA interviewed by Prof John Gribben - Barts & The London Trust Cancer Centre, UK

Welcome to ecancer. I’m John Gribben from Barts Cancer Centre in London and we’re here in Stockholm at the 18th annual meeting of the European Haematology Association. I’m joined by Dr Barrientos from the Hofstra Medical School in New York and we’re here to discuss not only the updates in CLL at EHA here this week but also hot on the heels of ASCO meeting in Chicago last week. So what would you say was your take home message from what you heard about CLL at ASCO last week?

I think the take home message in my mind is that we are now entering an era in the CLL therapy where you can use targeted agents so that you can minimise the side effects from the chemotherapy, particularly in patients with multiple comorbidities, as we saw from the data presented by Susan O’Brien in treatment naïve, older than 65, where she presented idelalisib with rituximab and another who presented the data on GA101 or obinutuzumab with chlorambucil and also chlorambucil with Rituxan. So it’s very interesting.

So what you’re describing, of course, is that there’s a lot of new agents appearing in CLL and one of the challenges we face is how we’re going to get all these agents tested in the way that we want to.


So why don’t we take them through one by one? I think one of the things that’s very interesting as we’ve gone from meeting to meeting is how we see the further follow-up on these studies, how many patients are remaining on. But there was some interesting data that has been appearing about mechanisms of ibrutinib resistance. So what’s your take on that?

That one was very interesting because it took us about three years to get to these patients that we presented at ASCO. So just to put things into perspective, there have been about 250 patients treated with ibrutinib in CLL and out of them there have been 150 patients that have been taking ibrutinib for over a year. Out of that 150 patients there have only been 20 patients that stopped responding, 13 of them still had CLL, the other 7 were not studied. Out of the 13 patients they only had tissue samples from 10 of them and 5 of the patients actually had a mutation in the BTK and that was the first time that we have seen that a mutation in the BTK will render you not responsive to the drug any more.

So very similar to imatinib that we’re used to. And in the same way do the mutations predicted to be at the binding site, so…?

Yes, four of them were in… it was a cysteine to serine substitution at 481. And another patient had a mutation in the substrate of the BTK which was a PLC gamma.

So do you think that what we should be doing, then, is we see patients become resistant, do a mutational analysis, the way we do for our CML patients?

I think why not. It may help us in defining what would be the next therapy.

Now we’re going to spend a lot of time focussing on the newer agents but there was a study from the UK on looking at a slightly older combination. So the UK ADMIRE study was presented. So what was your take home message there?

From what I understand, the addition of Mitosan didn’t increase the outcome that we had seen with FCR alone. So moving forward we may consider doing chemo-immunotherapy with a new targeted agent so that you don’t have as much toxicity but again we all need the data and clinical trials to come to a…

I agree, we already see that the majority of our patients with CLL can’t tolerate FCR so adding more standard agents seems less exciting than looking at the addition of some of those new agents. So you’ve talked a little bit about idelalisib, so we are seeing further follow-up in these refractory patients presented. Are you still impressed with the data?

I am, particularly when Susan O’Brien presented her data she reported even though the patients were on idelalisib not for a longer period of time, the PFS at 24 months was 96%. So people were still in remission even though many of them had to stop due to the undue side effects from the toxicities, most commonly the diarrhoea which was reported in the 20% range for grade 3 diarrhoea.

Yes, there have been different studies. We all know that GI toxicity is probably the major toxicity that you see with that whole class of drugs but we are seeing different toxicities as you add idelalisib in with other agents. Do you think that’s going to turn out to be the dose limiting tolerability? And do you think that as you have these patients on these drugs sometimes for years that’s going to be a problem for the patients?

From our clinical perspective, many of the patients are able to get back on the drug later on. I don’t know if you remember when she presented the data she said a lot of the time for most of us we didn’t know when and how to stop it. Now that we are seeing it more and more we are learning how to treat it and how to manage it. For my part I have learned that the moment that they tell me that they have diarrhoea I immediately stop the drug and I cannot do an intervention, an aggressive work up, rather than the usual posture that you do with typical diarrhoea.

That you just have to keep going because the disease is more important.


Does it worry you that if people start taking more drug holidays that you may be seeing emergence of resistant clones?

That’s something that we are all concerned about.

But haven’t seen it yet?

No. It’s something that we will learn in the future.

So when you’re talking to your patients about it who are on these clinical trials, how long do you tell them that you’re comfortable for them to stay off the drug, for so-called drug holidays?

About two to three weeks is fine, I have no issues because I know that the moment that I start the drug the lymph nodes go away immediately again, similar to when they started the therapy. Now more than a month, it’s kind of hard for many reasons, particularly because general protocol if you are off the drug for more than a month then you have to discuss with a medical monitor to see if it’s reasonable to resume the drug. Because if you have to stop it for more than a month something must have happened for you to do so because most patients don’t want to stop in these new drug clinical trials.

Absolutely. The other data that we saw at ASCO and at EHA was the CLL11 data, so taking an old drug but adding a new antibody to it. So how do you feel about the CLL11 study data that has been presented to date?

I am very happy that that study was done because it shows that GA101, which we had heard had worked in the phase I, now it’s an improvement in the CR rates and in the overall response rates as compared to chlorambucil alone. From the initial study that, even though it’s not mature enough, the Rituxan versus GA101 combination, it looks like the GA101 is also a superior drug which we had the idea, hoped for, but it doesn’t always work that way.

It’s nice to see it substantiated in a phase III clinical trial. I think one of the exciting things for me, two things, one, doing trials in these less fit elderly patients so specifically only accruing those patients…

With multiple comorbidities.

Exactly. I think they’ve been largely under-explored in clinical trials in the past. The other issue I found very exciting was finding patients becoming minimal residual disease negative with GA101, something we haven’t ever looked for in this patient population. Obviously they haven’t yet presented the data in a way that tells us that those patients are going to do better but extrapolating from other studies we would expect that we really are seeing better and better responses. Anything about the infusion related toxicities that concern you about GA101?

Yes, there was a large number of patients that had a grade 3 and grade 4 infusion toxicities and, from talking to the principal investigator actually in EHA, he said that this is actually more impressive and more severe than the Rituxan infusion reactions that we’re all used to.

It’s quite strange, of course, because we were told it was glycoengineered to try to decrease some of the toxicities.

But you know that the same happened with ofatumumab. We thought that when you had fully humanised it it was going to be…

So probably the mechanism of action whereby these drug reactions occur. But again with the GA101 it looked as if it really was just the first couple of infusions so it looked as if after we got the patients past that the drug was very well tolerated. I think the spectrum of toxicity was very similar to what we see with rituximab.

Yes, and I understand that the protocol was amended also to separate. Instead of giving you 1000mg up front they did 100 and then 900 the next time.

Well we talked already about these new agents and how they’re being used in combination and of course that’s exactly what we’re seeing with ibrutinib now. So obviously a lot of people were attracted by the idea that we’re going to be moving into targeted therapies without chemotherapy but now, of course, we’re seeing the combinations of ibrutinib with rituximab and now also ibrutinib with bendamustine and rituximab. What’s your feeling of how those compare and whether we’re going to be moving towards new agents plus old agents together?

I think there’s still a role for chemotherapy in certain patient populations, particularly because when you see the single agent relapsed refractory disease data, the people that do worse are the patients with 11q or 17p deletion so they tend to relapse sooner. So maybe for those patients it might be better to do some form of combination regimens so that they stay in remission longer. But the data that we have from the combination of bendamustine and rituximab and ibrutinib is not mature enough to tell us how long you’re going to be in remission. The data was presented by Jennifer Brown at last year’s EHA and previously by Susan O’Brien at ASCO and it was only thirty patients so it was hypothesis generating and also to see if it was safe. We proved that it was safe but it’s just we don’t know for how long you’re going to go into remission. It would be great to see if these people with poor prognostic markers can get into remission for a longer period of time.

The issue, of course, is that the addition of these other agents gets rid of the lymphocytosis faster but it’s not my impression that having persistent lymphocytosis is a major problem to patients whose nodes have shrunk. Many of those patients go on just slower to get into remission. So I’m wondering myself whether or not in the longer run patients would prefer to just get there more slowly without the chemotherapy. Because at the moment we’re not seeing any evidence that adding in the chemotherapy makes us stop the drug, you’re still continuing with ibrutinib long-term.

Yes and from a clinical perspective the patients also request no chemotherapy. When they come to our centres they are always asking for combinations that don’t have any chemotherapy or that the chemotherapy is minimal.

You talked already about some of the biomarkers, things like looking for mutations in binding to ibrutinib. But of course there’s a lot of work being presented now at these meetings on the whole exome, whole genome sequencing and the clonal heterogeneity of CLL. So we’ve gone from thinking that every cell is the same to knowing that our patients have a very heterogeneous disease. Do you think that kind of stuff is going to make it into the mainstream? Do you think it’s relevant?

I think so, I think so. Now that we’re learning that it’s the cell of origin, the one that is more important in cancer, it will be a different world in the future. We’re seeing it in other cancers still, in CLL.

I guess the studies being done so far are usually with chemotherapy, we’re only beginning to see these sorts of studies being done in the patients with the new therapies to see whether they also only target some sub-clones preferentially or whether they actually do eradicate what we hope is going to be the cancer stem cells.

So, for example, think of the patients, the five patients, that stopped responding to ibrutinib that had the mutated BTK. They all had complex cytogenetics or 11q or 17p. So what would have happened if we had started these patients before they developed those clones? Would they be still in remission and responding? Would that put you at a…?

Well you get into a very interesting question there about should we be offering some of these agents in a period where normally we would watch and wait. But I guess then that enters into a whole issue of the economics of these drugs as well as their efficacy and I guess we’ll have to await the results of clinical trials for those.

Yes, unfortunately we’ve learned from other targeted agents, like in the CML world, that it’s very expensive.

Yes. So any other issues that we haven’t covered here that you thought that were take home from these meetings?

I think these two drugs that target the B-cell signalling receptor are the drugs that are opening up our eyes to targeted therapies in the future for patients with CLL. So I think that our patients can have a lot of hope that in the future there will be many more options of care which we will need many years to learn about the data, wait for it to mature to know how to work and use these drugs with these patients. But it’s very encouraging, it’s a revolution in the last couple of years.

Now the one thing that was new today was Jennifer Brown presented data on the other BTK inhibitor.

Yes, the Celgene compound, 292.

CC-292. Now that’s twice a day dosing versus once a day dosing. What’s your take on the data presented so far?

I think we could consider that maybe some of the off-target effects from ibrutinib are allowing you to have less dosing as compared to 292 which is a very pure BTK inhibitor. Maybe you need some of that extra off-target signalling to achieve the results that you were looking for.

So a targeted therapy works by a little bit of serendipity or happening to have a little bit of off-target effect that turns out to be hugely beneficial. Yes, I think exciting times, lots of compounds, probably more compounds than we have patients to study at the moment.

Yes, and at ASCO they also presented the updated data on the Infinity compound, IPI-145.

The gamma delta PI3 kinase inhibitor. That was also looking very interesting. Again seeing patients clearing the peripheral blood faster than we saw with the pure delta inhibitors so looking like…

Maybe the gamma compound helps you clear…

Maybe the gamma compounds help you clear some things. So another compound to watch.

And the other one is the ABT-199 compound.

Yes, John Seymour presented that data. That’s also looking very exciting. What do you think about those couple of adverse events that occurred on that study related to tumour lysis?

When you have tumour lysis it shows you that the drug works. Now, we just need to tweak it a little bit to figure out how to deliver the drug without causing fatalities. So, moving forward, there will be more observation with more laboratories to see if you tolerate the drug without having hyperkalemia or hyperphosphatemia that may lead to bad outcomes. So we are all looking forward to resuming the study and work with that compound because it is working and it’s showing activity in our patients with CLL that have been refractory to many prior therapies.

So, in conclusion, what we’re hearing from these meetings is, again, lots of new clinical data on new compounds in CLL. It seems that a disease that has been largely ignored for such long period of time with no new agents suddenly has very many exciting agents that are being explored both alone, showing very high efficacy, long durations of response, and now also being used in combinations. We’ve seen the results of randomised clinical trials looking at new antibodies as well as combinations of old agents plus antibodies like rituximab that had already been around. We’re also seeing joining together a better understanding of the science of the disease as well as it being put into the clinical practice. So I think, in conclusion, it’s a very exciting time in CLL and each time we’re coming to the meetings we’re very excited to see a longer follow-up on the patients on these very exciting new compounds.