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Lisa Garvin: Welcome to Cancer Newsline a podcast series from the University of Texas MD Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment and prevention providing the latest information on reducing your family's cancer risk. I'm your host Lisa Garvin and today we'll be talking about a fairly rare type of lymphoma, mantle cell lymphoma. We have 2 guests to address the topic today Dr. Jorge Romaguera and Dr. Michael Wong who are both professors in the lymphoma and myeloma department here at MD Anderson. And Dr. Romaguera we'll start with you, let's talk about mantle cell lymphoma, it's a B cell lymphoma, it's a fairly rare lymphoma that mostly affects men, correct?Dr. Jorge Romaguera : Yes, it's about 6 % of the non-Hodgkin's lymphomas and it affects men's 3 times more than women and the median age is about 63, 65 years of age.Lisa Garvin: Why is it called mantle cell, it has to do with part of the lymph node it affects?Dr. Jorge Romaguera : Yes there is a--if you look at the structure in a microscope of a lymph node you'll see that it has follicles and the outer portion of the follicle is the mantle zone and this is where the cells we believe are derived from and that's why they call it mantle cell lymphoma.Lisa Garvin: It seems like over the years you had said earlier when we were talking before the podcast, you said there really is no cure but there are ways to make inroads for patients with this disease.Dr. Jorge Romaguera : Correct we have been able to not only improve survival but find out many pathways through which we can try to inhibit the cell proliferation or even kill it and this has been a big area of research and we hope that this will improve survival and who knows maybe even cure patients.Lisa Garvin: Now typically and either one of you can answer this, typically your mantle cell lymphoma patients come to you at a fairly advanced stage, is that correct Dr. Wong?Dr. Michael Wong: Yes mantle cell lymphoma, we actually did a--published a paper on the behavior mantle cell lymphoma, actually was the largest U.S. study ever. So in 2008 we publish the paper with the SEER data, SEER means, S-E-E-R is the national institute of big database so among several thousand patients with mantle cell lymphoma over a 30 year period of time. The majority of all the patients present with late stage which is stage III or stage IV disease that speaks the nature of the disease, it is very, it is almost like a silent killer. In the early stages you don't feel anything by the time you found it is already late so that's one of the behaviors and nature of mantle cell lymphoma.Lisa Garvin: And plus the fact that it's not really a solid tumor makes diagnosing and detection fairly difficult I would think.Dr. Michael Wong: Yes, well that's a very interesting point you know we have lung cancer, colon cancer, breast cancer, prostate cancer being called a solid tumor. We have leukemia call it liquid tumor, but lymphoma is kind of a semi liquid tumor or semi solid tumor because it is in the bone marrow, in the blood but it also forms solid masses, so lymphoma is a semi solid or semi liquid tumor.Lisa Garvin: Now this disease has kind of, it's kind of schizophrenic in a way because it can be both aggressive and slow growing, can you explain that?Dr. Michael Wong: This schizophrenic is a very good term with it and because we never can predict how the mantle cell lymphoma it will behave, some patients present with an [inaudible] disease given therapy some clones grow very fast, become a very aggressive disease. Some patients present with a very progressive disease, we treat them and they are in remission for many years so we, our technology is almost there we can tell which one from which one by but we're not quite there we will be there in a few years, we can tell which one and how to treat them.Lisa Garvin: And I know of course staging a disease is very important for deciding the treatment regimen and up until recently there really wasn't any standardized staging was there Dr. Romaguera?Dr. Jorge Romaguera : The staging for mantle cell lymphoma is pretty much similar as for other lymphomas, we pay special interest in the blood which frequently is involved, it's about up to 50 % of the time and the colon which is up to 90 % involved in 90 % of the cases is involved. In few patients it only present as a stage I you want to make very sure that indeed it's only localize so you want to do the studies and that might change therapy. Otherwise, like Dr. Wong was saying most of these patients present with stage IV and the treatment it's not necessarily geared by the stage, we have a model called the MIPI, M-I-P-I, mantle cell lymphoma international prognostic index, and we have some other biologic markers that are probably more important than whether the disease is only on one side or whether it's a stage IV. One of them is the proliferation index it's called a KI67.Lisa Garvin: And these are the kind of diseases that are really diagnosed under the microscope.Dr. Jorge Romaguera : Yes, it is diagnosed--you have to have preferably a biopsy of the lymph node as with any lymphoma to be able to give the diagnosis of the mantle cell lymphoma. There are 15 % of the patients or so who might not present with lymph nodes, the so-called indolent leukemic behavior and those we do have tools to diagnose mantle cell even if we just have some loose cells in the bone marrow and blood and not a lymph node.Lisa Garvin: With MIPI and trying to figure out a prognosis for people this is a fairly recent development, is it not, and of course does MIPI help you select the right patients for the right treatment?Dr. Michael Wong: MIPI is a gathered wisdom of many clinical doctors who treat mantle cell lymphoma but the MIPI formulation is innovated or made by our German friends, German doctors a German mantle cell lymphoma group and they did a very good job. But in our day-to-day practice we don't always, we don't always use that, it's very complex and we don't always use that as everyday practice. MIPI is good to calculate the risk when the patient are newly diagnosed but when the patient's relapse which is the majority of our practice and we do not practice according to MIPI, we have our own insights and clinical experience.Lisa Garvin: So MD Anderson is basically tailoring its treatments to the patients.Dr. Jorge Romaguera and Dr. Michael Wong: Yes.Lisa Garvin: And of course this kind of leads neatly into something that MD Anderson is focusing on through moon shots and other things is the use of targeted therapies or immunotherapies and it sounds like mantle cell lymphoma is perfectly set up for these kinds of discoveries.Dr. Michael Wong: Mantle cell lymphoma is a perfect set up, I remember my former mentor Dr. Fenato Cabineas [phonetic] before he retired he told me that, I was a fellow, that was 14 years ago, Dr. Cabineas told me that MCL, mantle cell lymphoma is the best B cell lymphoma model, you could use it for your research because if you find something that works on mantle cell lymphoma it is likely works on [inaudible] lymphoma and large B cell lymphoma, that is so true. And his vision it just [inaudible] out with the reality and data many years later and that mantle cell lymphoma is the best disease model to study lymphoma.Lisa Garvin: Now so have we found any like biomarkers or tumor cell receptors that we can exploit to treat this disease?Dr. Jorge Romaguera: The main ones that has a lot of applications in terms of deciding treatment and that has even recently been confirmed in a retrospective analysis of the European mantle cell lymphoma network, that is the proliferation index, in other words how fast the cells are growing. And there are numbers of which you get worried, in other words if I had a patient that is a stage I but has a proliferation index which is elevated, well the proliferation index trumps over the stage and we'll make the decide to treat. I can have a patient that is a stage IV but has a proliferation index of 5 which is very low, I might just observe it. So that's come to be the most important mark, there are others that are being studied and seem to be important but have not yet been correlated in big trials like mutations in some genes like the ATM gene, the P53 seems to be important prognostically, they seem to be associated with the more aggressive blastoid looking cell when you look at under the microscope. So these are things that are probably going to be in the use, in the future used to decide perhaps prognosis but perhaps more importantly the therapeutic approach. If they have an overexpression of this or the other marker we can tailor therapy according to what marker is overexpressed.Lisa Garvin: And it sounds like, so go ahead Dr. Wong.Dr. Michael Wong: To echo Dr. Romaguera's point, is KI67 is perhaps the most important of this disease marker that is so far suitable for [inaudible] our clinical practice, in the first week of December 2014 American Society were annual meeting what is called the ASH meeting I presented our single center study with 50 patients with relapse mantle cell lymphoma and in that 50 patients that were treated with rituximab and ibrutinib and we will talk about the ibrutinib later, so if we treat the patient with rituximab/ibrutinib combination and if the KI67 is less than 50 the response rate was 100 %.Lisa Garvin: Wow.Dr. Michael Wong: And 34 of the patients with KI67 less than 50, they all responded to therapy. The rate of complete response is very high, was 56 %, it was a very good regarded data set, it was related to me the highlights of that conference, which is international conference. But if the KI67 is over 50 the response rate is only 50 %, the complete response rate is 8 % so KI67 is very, very important, if the KI67 is high, the tumor is aggressive and we sometimes have to do an intrathecal therapy to prevent the relapse with this kind of mantle cell lymphoma into the brain years from now. There's lot of insights there's a lot of gathered expertise experience that has cumulated at MD Anderson through years of generations but efforts so we actually know a few things on mantle cell lymphoma, how to treat them.Lisa Garvin: So it sounds like the future of managing this disease and perhaps moving the survivorship needle is really on these targeted therapies and/or immunotherapies. Ibrutinib is kind of the golden child these days it's gotten a lot of attention for treatment of melanoma and other diseases but it sounds like you have a trial for Ibrutinib for mantle cell lymphoma?D. Michael Wong: rSo at the MD Anderson site led the 18 center international phase 2 clinical trial with a single agent of Ibrutinib in relapsed mantle cell lymphoma. The try was finished in 2013 and in November, October 2013 was published in the New England Journal of Medicine, his trial was the basis, the FDA approved this drug through the breakthrough mechanism. So [inaudible] to all the patient's, the response rate was a single oral agent was unprecedented and was around 68 % but that was you know only about a year ago, the 68 % is very good and the world is using that drug to treat mantle cell lymphoma but we think it's already low so we added the rituximab to it and we presented that at the last conference and the response rate overall is 88 % and the complete response rate has doubled them 20 % to 40 % and as I mentioned before the KI67 is less than 50 is 100 % response. So we think the single agent response is no longer as good as the combined therapy so we are using the combined therapy now a days in our practice and we have better results without any of the toxicities.Lisa Garvin: And Dr. Romaguera you said there are several drugs kind of being tested in early phase clinical trials, let's talk about some of those.Dr. Jorge Romaguera: Well, there are several--mantle cell lymphoma is the perfect model as Dr. Wong says to evaluate drugs that might be useful because by the nature of how it evolves you know it creates a lot of abnormal pathways it omits them so you have--you can target each of those pathways. So ibrutinib as an example it targets B cell receptor pathways in one of the points so that's the latest model but the earliest, the first drug to be ever approved for relapse mantle cell is Velcade which targets proteasome which is an important pathway for practically all cells in your body. There are inhibitors of other pathways such as the small molecule BCL2 inhibitors, those are going to be I think very important in the future. There are inhibitors of pathways which we called [inaudible] pathways, all these probably are confusing terms but the important thing is that through the new technology and biotechnology we've been able to pinpoint all of the different steps in each pathway and pharmaceuticals mostly are developing specific inhibitors for each of those molecules along the pathways, along all those pathways and these that I've mentioned briefly are just a few of the pathways that we have been successful in, you know, interfering with in the most recently being the Ibrutinib with the BCL2 pathway.Lisa Garvin: Well, it sounds like you have a lot more tools in your toolbox now particularly for relapsed cases.Dr. Jorge Romaguera: Yes.Dr. Michael Wong: Because the good advocacy and clinical results when we treat a newly diagnosed patient for mantle cell lymphoma the new agents whether it's [inaudible] immunotherapy are always tested in the relapse setting before they are tested in the front line setting, therefore we have numerous drugs and technologies against relapse to mantle cell lymphoma. Relapse from mantle cell lymphoma is not curable, it's deadly and that's why there's a clinical urgency for us to develop a number of therapies. Yes, we do have successful stories such as Ibrutinib, [inaudible], Velcade or rituximab, however those agents does not last forever. It only last for a certain period of time for example the [inaudible] the original response for Ibrutinib was only 17 months so after 17 months we anticipated the resistant, actually it's already reality resistance already emerged and many, many patients already come to MD Anderson, we are already progressed on Ibrutinib so we, it is our obligation as a leader in the field to lead [inaudible] to overcome the resistance.Lisa Garvin: It sounds like you've got a lot of options in a lot of different areas.Dr. Michael Wong: That is correct it is a very, very exciting time for mantle cell lymphoma patients.Lisa Garvin: And you said here at MD Anderson we're actually kind of bringing those efforts together into a program of excellence can you address that?Dr. Michael Wong: That's very correct we actually in 2011 our institution and the 2 departments, the Department of lymphoma myeloma and the Department of stem cell transplant and cellular therapy combines our collective effort of clinicians, transplanters, basic researcher, immune you knowledge us, translation research, radiologists, radiation oncologists, we all come together and form a mantle cell lymphoma program of excellence. Mantle cell lymphoma is very rare in the community each doctor in their lifetime career they see a lot of patients with lung cancer, colon cancer, breast cancer [inaudible] but the probably only will see one or two mantle cell lymphoma patients. It's very hard for them to accumulate a lot of experience but at MD Anderson mantle cell lymphoma it is a very common disease in the mantle cell lymphoma program of excellence. We treat, Dr. Romaguera and I treat mantle cell lymphoma every day. In fact our life, our careers is dedicated just for mantle cell lymphoma so when you're driving down your, down the road doing something in your daily life or your kids go to school or when there's movies playing on the night, all those moments I probably are thinking about what to do in mantle cell lymphoma is the next step. So that's my career, that's our career, our dedication to mantle cell lymphoma, we want to eradicate this disease within our career time.Lisa Garvin: I know you guys have your work cut out for you and we'll need to come and talk to you again and see how these trials are doing. Dr. Romaguera, Dr. Wong any final thoughts?Dr. Jorge Romaguera: Just to remind patients that you know when you have a recurrence or when you have a disease that you're starting with, you always have the choices that have already been tried and might be available but you have these other choices that are part of a clinical trial and in my experience, I always tell my patients you will always have the non-trial options any time you want but you should try to do the clinical trials first because often times you try the conventional and when you need the clinical trials you either don't qualify for they are not there, so you have to plan for the years that you will have the disease.Dr. Michael Wong: I have something to say to our patients is that mantle cell lymphoma is a deadly disease so if there's a newly diagnosed, if you are newly diagnosed with mantle cell lymphoma and your doctor may offer you a therapy and again we would like to emphasize that your doctor and us we are on one team, we would like to join you as a team so that we can care for you to help you get rid of the lymphoma. It is, mantle cell lymphoma is fatal but also complicated disease, the therapy is very complex so typically when a patient comes to us with a newly diagnosed patient we have a strategic plan for the whole life process. That's considered maybe [inaudible] were some steps so even your doctor offer you some therapy I think it never hurts actually most of the times is going to help you to have a second opinion. We would like to work together if your doctor offers you the best therapy we would like to continue to work with you and send you back for therapy we will help you monitor but your life is valuable you deserve a second opinion.Lisa Garvin: And that's a perfect way to end this, thank you so much, very exciting stuff.Dr. Michael Wong & Dr. Jorge Romaguera: Thank you for inviting us.Lisa Garvin: If you have questions about anything you've heard today on Cancer Newsline contact ask MD Anderson at 1 877 MDA-6789, or online at MD ask. Thank you for listening to this episode of Cancer Newsline, tune in for the next podcast in our series. ................
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