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What Is the CLL Microenvironment?

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Published on July 2, 2015

Dr. Michael Hallek joined Andrew Schorr at the 2015 CLL Live conference in Niagara Falls, as he explains the “CLL microenvironment” and discusses advances in approaches to treatment. Dr. Hallek explores the role of genetics and shares his optimism about—and commitment to—CLL research.

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Transcript | What Is the CLL Microenvironment?

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

Andrew Schorr:

Andrew Schorr on location in Niagara Falls, Ontario, Canada, with Dr. Michael Hallek, who is not from here.  Here from Cologne, Germany, and helps lead the CLL German group, right, and has many researchers and has really been devoting his life to helping ultimately cure CLL. 

Dr. Hallek, let's talk a little bit about what you're learning now about what you call the microenvironment.  It seems like your understanding now with your research and your partners that cells are sort of supporting one another, healthy cells, even, are supporting leukemic cells.  So will that be the next wave of treatment, do you think? 

Dr. Hallek:

Well, we've learned over the past few years that the CLL cell is totally dependent, it's addicted to the microenvironment, to the host.  It needs the environmental macrophages, T cells, fibroblasts and many other cells, the stroma cells to survive.  And actually that's not going to be exploited only in the future.  It's already in the existing treatments. 

We believe that most of the effects of ibrutinib (IMBRUVICA®), of idelalisib (ZYDELIG®), so of the novel agents, can only be understood if we look at their mechanism of action on the micro environment.  So they act not only on the CLL cell but even more strongly so we think on the microenvironment, and therefore you can see in the initial phase of the treatment that these cells are migrating out of the compartments. That's the lymph nodes, the spleen, and streaming into the blood and have this initial phase of lymphocytosis.  So I would call these kinase inhibitors the first micro environmental acting or modulating drugs that we already have, and in the future we will probably have more of those. 

Andrew Schorr:

Okay.  Now, there's still efficacy for some patients of what's been a stand by, FCR…

Dr. Hallek:

Yeah. 

Andrew Schorr:

…and you've proven that it still works well for many patients, but then there are other doctors saying, well, really, now it's time for a nonchemo, totally nonchemo approach.  So people are hearing both, and they're not sure, and depending upon what their country, their province can afford is what's offered to them. 

Dr. Hallek:

I would say there [are] always many opinions of doctors in almost every different situation.  What is based on the evidence that we currently have, on the published evidence, is that patients that do not have a very dismal prognostic marker, such as deletion 17p or p53 mutation, those two, can usually benefit well from chemoimmunotherapy, which is a combination of either FC or bendamustine (TREANDA®) or in the less?fit patients, chlorambucil (LEUKERAN®) plus an anti?CD20 antibody.  That is currently presenting the standard of care in first?line for CLL. 

And then the choice of chemotherapy, of the chemotherapy backbone, if you wish, depends on how fit you are and how much you can tolerate.  That's a clear published standard.  Whether there's any different opinion or deviation from that may be explained by personal choices, by an aversion against chemotherapy—we have to acknowledge that some patients don't like it—or some biased opinion of any physician because they basically have good experience with single agent. 

But I think it's a good rule at least in medicine to not always jump on the newest horse immediately but to carefully test its value before you change things. 

Andrew Schorr:

Now, about transplant.  Transplant has been around for a while, often for people 17p sometimes it's recommended, they're not responding to other therapies.  But now you have these novel agents that are sort of taking all comers.  They're helping people with 17p.  Will transplant fall by the wayside? 

Dr. Hallek:

I could only hope that we do not need transplant anymore, because it's, as we do it right now, a fairly toxic treatment. So you can't recommend it in the first?line setting for most of our patients anyway, because they are too old with CLL. 

However, our use and recommendation for allogeneic transplantation over the last five years has dramatically decreased in all transplant centers.  So if you talk to every expert, and here's a consensus forming, you can see that the numbers have dropped.  Why?  Because the novel agents are highly effective in this deletion 17p, p53 population, and here is—in contrast to what I said before to the last question—here is a population that seems to benefit strongly, even in first line, in first?line treatment of these novel inhibitors. 

So we treat our patients with deletion 17p or with p53 mutations immediately with a kinase inhibitor and then wait, and don't do a transplant, don't recommend a transplant anymore.  The patient should be advised, however, that there can be a relapse, and then in the second option allogeneic transplant is a potentially curative method. 

I think it's also important to discuss the options with the patients immediately.  So to tell them if you have such a high risk, genetic aberration, that you should be aware that the disease can come back, and you should prepare for a transplant.  And finally, the options between a potentially curative but dangerous treatment like allogeneic transplantations versus delaying the treatment or the—trying to do something should be understood by the patient in the very beginning because it's very important that we don't only—we do not only decide by ourselves but share this information with the patient to make a shared decision. 

Andrew Schorr:

Okay.  So now you're looking at the genetics, genomics of CLL, but at many centers they don't do that yet.  Is that something a patient should advocate for, get a clear biologic picture of my CLL? 

Dr. Hallek:

It's a good question.  If there is an early-stage treatment, no symptoms, nothing to do, it's an option.  It's actually a quite funny phenomenon that in the Americas patients tend to need more knowledge than in Europe, and this is again a balanced decision for the following reason.  So if you have a disease that is early stage and you need no treatment whatsoever and then all of a sudden you discover that you have an unfavorable genetic feature, call is unmutated IgVH or ZAP-70 positive or even worse, p53 mutation, well, then the watch and wait turns into watch and worry.  And if you hadn't done the test, you would have enjoyed a quite good life without knowing that you were at risk. 

So this actually change of the attitude is something—it's easy for us to make the test.  It's difficult for the patient to carry the consequences, and therefore usually I actually talk to the patients.  So some patients want to create an enterprise.  They want to create their own new company or so, and of course for doing that they need to know will they actually survive long enough to do that. And for those patients, it may be actually justified.  For the majority of patients in Germany, they say, well, if I don't know I'm fine because the disease will tell anyway, and sometimes over time things will turn up. 

This changes when it comes to decisions of treatment.  As soon as you need treatment, you need to know the genetic features in every single patient. And therefore a patient in need of a treatment needs to be tested genetically by FISH, I think for p53 mutations as well, and the mutational status becomes increasingly important.  So that's the test we are doing, and I would recommend to at least do the FISH analysis in the p53 mutations in every patient, because it changes the management from this time on. 

Andrew Schorr:

I always close with one other question, Dr. Hallek, and that is you're at sort of ground zero of CLL research.  People are hoping to live longer, and you've seen that change during your career.  Looking out, what you know in research and starting to be in the clinic, are you hopeful for people living with CLL today in variety of types of CLL? 

Dr. Hallek:

I'm very, very hopeful, and the only hesitation to say this is my concern to promise too much.  But right now I think we are really making huge steps towards treatment modulation and treatments that will allow most CLL patients to live a normal life with a very good quality of life.  I'm very optimistic, and I actually do everything I can to achieve this because it would be not only for my patients but also for me personally a great professional satisfaction. 

Andrew Schorr:

Okay.  So, Dr. Michael Hallek, thank you.  I want to thank you on behalf of thousands of patients worldwide in the leadership you've had in Germany and worldwide for all you do. 

Dr. Hallek:

You're very welcome. 

Andrew Schorr:

Thank you. 

Dr. Hallek:

My pleasure. 

Andrew Schorr:

Andrew Schorr on location, Niagara Falls, Dr. Michael Hallek traveling the world to help CLL patients.  Remember, knowledge can be the best medicine of all. 

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

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