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ASH 2016: An Interview with Dr. George Follows on Late Resistance to Ibrutinib in CLL

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Brian Koffman, MD
George Follows, PhD, FRCP, FRCPath

 At ASH 2016 Dr. George Follows of Cambridge, England discusses our evolving understanding of life after ibrutinib for those of us with CLL.

Richter’s transformation tends to occur early on and may be a reflection of the heavy treatment many patients had received before starting ibrutinib in the early trials and is not part of this interview.

Rather, Dr. Follows focuses on later resistance and most of what he shares is good news from three trials presented in the important oral sessions at ASH 2016.

Key Take Aways:

  • Our CLL is evolving in a Darwinian “survival of the fittest’ manner, no matter what type of therapeutic pressures are applied. Subclones of cancer cells change and adapt to their environment, just as all living creatures do.
  • The subclones that are selected for survival and that eventually thrive and become predominant are those that are resistant to the chosen treatment, whether it be chemotherapy or one of the new targeted agents.
  • One example is a subclone with mutations in C481 found in some of those on ibrutinib that prevents its irreversible binding to the BTK receptor.
  • This renders the drug less effective at blocking BTK and controlling the cancer.
  • This subclone can grow to predominate in those resistant to ibrutinib, eventually leading to a clinical relapse.
  • Late relapses are often slow moving and can be seen long before the relapse is clinically important, giving us time to plan the next treatment.
  • Three important trial results were presented in the standing room only oral CLL session:
    1. Single agent venetoclax as the only therapy (monotherapy) is effective for the majority who relapse from ibrutinib or idelalisib.
    2. Some patients that need to come off ibrutinib due to side effects may better tolerate acalabrutinib. The data is very early and needs further review.
    3. Small numbers of patients given the triple therapy of obinutuzumab, ibrutinib and venetoclax have had very high responses rates with some reaching a level where no cancer can be detected (MRD – or minimal residual disease negative).

There has been an amazing progress since the last time the annual ASH Conference was held in San Diego December 10 – 13, 2011 (see my blog here for my personal story of meeting Dr. Byrd there in 2011).

At that time, ibrutinib (PCI-32765) and idelalisib (CAL-101) were exciting new molecules with promising tiny data sets from early phase 1 trials. Now only five years later, such targeted therapies have resulted in a sea change in how CLL is managed, improving outcomes for thousands of patients.

Our work is hardly done, but we should be thankful for a few moments in just how far we have come in such a short time.

Here are the three ASH 2016 oral abstracts, all out of Ohio State University (OSU), that Dr. Follows references that address remaining challenges:

  1. Venetoclax (VEN) Monotherapy for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapsed after or Were Refractory to Ibrutinib or Idelalisib
  2. Acalabrutinib Monotherapy in Patients with Ibrutinib Intolerance: Results from the Phase 1/2 ACE-CL-001 Clinical Study
  3. Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

You can read my interview with Dr. Follows here or view the video below. He is an excellent educator.

Dr. Brian KoffmanHi, Brian Koffman, a family doctor turned CLL patient, and founder and the medical director of the CLL Society, here on the third day of the American Society of Hematology meeting 2016 in beautiful and sunny San Diego.

Dr. George Follows – And George Follows, hematology consultant from cold and cloudy Cambridge over here enjoying the ASH conference in San Diego.

BKYes. Well, welcome to our beautiful southern California weather. We were talking in the last interview a little bit about that small group of patients that do progress on ibrutinib. Can you tell us more about what we know about that and how that relapse develops? I think it has to do with clones and sub-clones evolving. Can you kind of hold our hand through that?

GF – Yeah, so this is a fascinating area, Brian. When I think of patients coming off ibrutinib, you’ve got these early patients, sometimes they’re very heavily pre-treated, who come off because of infections, some toxicity issues, et cetera, early on. And then some of the patients who fail early with Richter’s transformation, so I think we’ll just leave that a little bit to one side. But those patients who’ve been on drug for a while, there’s fascinating data coming through now, presented here at the meeting, looking at serial deep sequencing and looking for these specific mutations, like the 4A1, PTK mutation, or gain of function mutations downstream. And why is this interesting? Well, it’s showing in that individual patient that you’ve got evolving mechanisms of how the leukemia is bypassing this block. So, you’ve got a really targeted therapy working well, but then the disease is escaping. And it’s Darwinian evolution. And taking that further, we can, well not we, but Dan Landau looking at these amazing clonal dynamics and see how things change with patients who are on ibrutinib. And enable to track particularly interesting things. How those 17 P-deleted clones are behaving differently from patients who have been treated with chemotherapy. So, if you’re into the science of it, wow, you can really lose yourself on that. It’s really exciting.

BKWhat’s interesting to me is that for these patients that do relapse, there was a lot of information suggesting that their outcomes were dismal. But there’s some new encouraging data that’s starting to gather. Can you comment on that?

GF – I think we’ve got to remember that the early use of ibrutinib were often with very challenging patients. They had so much treatment, and I think that influenced a lot of our thinking about ibrutinib. But what is becoming clear is these later-relapsing patients, a lot of them appear to be picking up these clones in the blood that can be there for quite a number of months going through a slow phase of relapse. And there’s data showing that these clones can be targeted perhaps better by going on for a completely different mechanism of treatment. So, moving away from B cell receptor pathway inhibition, and going straight for a drug like Venetoclax which drives apoptosis in a completely different way.

BKAnd there was some encouraging data this morning on that, I think there was, what, a 70% response rate that, it was Jeff Jones that presented from Ohio State.

GF – Yeah, wasn’t that great data! So, there was that trio of presentations from Ohio State which were really, um, pretty impressive. So, of course the first one, that can be implemented in practice if in your part of the world you can get access to Venetoclax, because that was really striking data. So, to recap the patients could go -032 trial, if they’d come off either ibrutinib or idelalisib.

BKAnd that was for relapsing off of those or being refractory to them.

GF – Relapsing or refractory or intolerant, but I think if we just concentrate on the ibrutinib arm, the vast majority, I think 91% actually, came off because of progressive disease. So, these are, historically these have been bad players. And yet the Kaplan-Meier curve. So, good response rates.

BKThe Kaplan-Meier curve is the curve that tells how many patients die over time.

GF – Absolutely right. So, when you look at those graphs, you say, well, look, how many of these patients are alive at one year, very impressive data.

BKSo there’s some options there for patients now.

GF – Yeah, and those options, so actually, to recap on those trio of presentations. So, the first one was Venetoclax as monotherapy, which is an option rolling out in the clinic that I think many of your viewers might be able to get access to at this stage if they’re relapsing on ibrutinib. And then the other couple of presentations, there’s one on Acalabrutinib, for patients who are intolerant of ibrutinib—

BKWhich is another BTK inhibitor that’s in the pipeline and is getting closer and closer to approval, at least in the US, we hope.

GF – Yes, and we’re taking part in a couple of Acalabrutinib trials back in the UK, and watching this space with interest. So obviously, we’re getting a very good early feel for the drug, which is encouraging. And so that data set was good. I’d like to digest it a little bit more. Perhaps a few more patients had come off study than as expecting, the numbers were small, and patients were intolerant of ibrutinib, I think had a median of nine months of ibrutinib prior to going on the Acalabrutinib. So just want to crawl over those numbers a little bit more. Then it was the third presentation.

BKSo, just before we leave that one, I think the efficacy was relatively similar.

GF – Good response rates.

BKAnd patients could have recurrence of the adverse events, but rarely were they worse than they were on the ibrutinib.

GF – Yeah, so that’s the take home message, that we were being given, that these chaps have come off ibrutinib because of quite a range of adverse events, really. I’m not sure some of them were particularly severe adverse events, in the overall grading of things. But they’d come off, gone on to other drug and were doing well. It just wasn’t clear to me, they said they had a response rate of 95%, but if the patients had had a median nine months on ibrutinib, were they already in a remission? Was that a fair way of assessing that trial? You know what I mean, I was trapped in the middle of a row, I was dancing to get to the microphone, but it wasn’t going to happen. So, I just want to crawl over that data a little bit more. But let me talk about the third one.

BKYes, what an exciting trial.

GF – That was exciting. So, Jeff Jones, he presents well, and the data’s exciting. So, if your viewers, just to put that in context, this is a trio approach of saying, well look, what are the most efficacious drugs we have for treating CLL at the moment. Well, the best antibody, Obinutuzumab, in terms of published data, there are competitors coming along, but Obinutuzumab is there as the best antibody for the cell surface. You’ve got ibrutinib, the most established way of targeting the B cell receptor pathway. And then you’ve got Venetoclax which comes in right at apoptosis driver by targeting BCL2.

BKProgrammed cell death, that’s cell suicide.

GF – Yep, sorry, you correct me if I use these terms too easily. So, they worked out their strategy of putting these three drugs together. And they said, well look, let’s put antibody in first, we’ll tolerate infusion reactions, because we don’t want to have the Tumor Lysis Syndrome, which is this feared thing that happened in the early cohorts of Venetoclax but has really disappeared, I think, and quite a lot in terms of—

BKThat’s why it was so effective, it killed the cancer so fast that the kidneys couldn’t handle it and led to that, horrible problems, and cardiac issues, deaths.

GF – Yeah, and all of those really serious things that actually, I must say, across the whole Venetoclax program, that has not been seen since. So, I think this very slow ramp up use of Venetoclax is very effective at least lessening, ameliorating that risk.

BKAnd taking the patients and saying, “Who needs to be in hospital? Who’s high risk?” That’s all part of the protocols now.

GF – Absolutely, anybody using Venetoclax knows that there are specific rules you have to follow. But back to the Ohio State trial design: So, then they brought in their drugs, Obinutuzumab and then ibrutinib and then ramped up the Venetoclax. And, small numbers, (So not allowed to get too excited!) but really quite impressive. These are difficult relapse-refractory patients but they were getting true MRD negative remissions in their first cohort. Correct me if I’m wrong here, but I think three of the four patients in the 400 milligram Venetoclax arm had gotten MRD negative remissions.

BKSo an MRD negative means down to one in 10,000 cells they can’t find in the peripheral blood.

GF – Yes, we throw this term around, MRD negative. It’s a cutoff level, that minimal residual disease point. And if our assays are not good enough to find it, well, at the moment, we call it MRD negative or 10 to the minus four.

BKOne of the things that I thought was interesting in that is that some of these patients, they couldn’t find the CLL in the blood. Even some, I think, they couldn’t find in their bone marrow. I think there was one. But they still had enlarged lymph nodes. Do you have a take on that, or what that means?

GF – Yeah, so there was a bit of discussion, wasn’t there, about how you define complete remission. A 1.5 centimeter node versus a 1.7. I think Jeff said, “Some dust on the camera lens.” But we all have our review panel meetings with radiologists, and we’re there saying, “Surely that’s a CR!” and “Where you put these lines to measure your lymph node size is a bit arbitrary.” But we don’t know, those lymph nodes. No one is going to go in and dissect them out. I think he commented quite a few of these nodes were in the abdomen. We haven’t seen PET data. We don’t know about activity. This could be residual tissue of very little clinical significance, or with longer follow-up, it could tell us something else, but at this stage we don’t know.

BKWell, I know that there’s few cases of this. But they have gone in sometimes where there’s been some residual nodes that were easily accessed, they biopsied and found just essentially some scarred down tissue and the nodes just stay enlarged.

GF – But that’s been a feature of treating lymphoma and lymphoproliferative disorders for years. That you can get left with residual tissue after treatment.

BKRight. Any final words that you want to share with the CLL patients on the basis of these papers that we’re discussing?

GF – Well, as we’ve said before, Brian, when we’ve talked, really exciting times for CLL. I think these truly efficacious drugs are coming through with pretty good toxicity. So, remember, these are chronic conditions, long-term medications. If we don’t get the toxicity right, we’re not going to get the quality of life right. And I think that’s the balance. But, I’m pretty encouraged. I think good things are coming.

BKDr. Follows, I always learn something talking to you. Great, thanks so much.

GF – Thanks, Brian. Thank you.

Enjoy the video.

What a long strange trip it’s been.

Stay strong.

We are all in this together

George Follows, PhD, FRCP, FRCPath, is a Consultant Hematologist at Cambridge University Hospitals and the Lymphoma / CLL Clinical Lead for Cambridge and the Anglia Cancer Network. He is also the UK CLL forum and Clinical Lead for Research for the West Anglia Cancer Research Network.

Dr. Brian Koffman, a well-known doctor, educator and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the medical director of the CLL Society Inc.

Originally published in The CLL Tribune Q2 2017.