Early Phase Clinical Trials for Lymphomas
May 04, 2020Information
May 3, 2020
Yale Cancer Center
visit: http://www.yalecancercenter.org
email: canceranswers@yale.edu
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- 00:00Support for Yale Cancer Answers comes from AstraZeneca, proud partner in personalized medicine and developing tailored treatments for cancer patients.
- 00:11Learn more at astrazeneca-us.com. Welcome to Yale Cancer Answers with doctor Anees Chagpar.
- 00:18Yale Cancer Answers features the latest information on cancer care by welcoming oncologists and specialists who are on the forefront of the battle to fight cancer.
- 00:29This week, it's a conversation about lymphoma with Dr. Shalin Kothari.
- 00:33Doctor Kothari is an Assistant Professor of Medicine and Hematology at the Yale School of Medicine
- 00:38where Doctor Chagpar is a Professor of Surgery.
- 00:42Start by
- 00:43telling us a little bit about yourself
- 00:46and about what you do as a hematologist and oncologist.
- 00:51I joined Yale Cancer Center three months ago and my specialty and my focus is lymphoma, lymphoma patients, treating them and researching newer
- 01:04therapies for lymphoma.
- 01:07Tell us a little bit more about lymphoma.
- 01:09I mean, it seems like a broad term
- 01:13that encompasses many different things.
- 01:15Yeah, you're
- 01:16right. There are approximately 65 different types of lymphomas,
- 01:20so when we talk about lymphoma we really have to get granular because every different type of lymphoma has a different treatment,
- 01:30and many times we can even wait and watch.
- 01:34So it is very important to figure out what the sub type of lymphoma is before jumping to any therapies.
- 01:43And one of the things that is very important to keep in mind is that lymphomas usually require a big chunk of tissue for a good diagnosis.
- 01:53So one of the things that typically can go wrong and does go wrong frequently at centers is that we don't have enough tissue,
- 02:02and that's why we are left in the dark
- 02:06as to what the exact diagnosis is.
- 02:08But to tell you what lymphoma is in general,
- 02:13lymphoma is essentially a cancer of immune cells and immune cells live in different areas of the body,
- 02:22such as lymph nodes. And one of the biggest lymph nodes that we have in our body is the spleen,
- 02:31and in the belly and sometimes even in the liver.
- 02:35So these are the most common sites where lymph nodes can get enlarged and that can lead
- 02:43to lymphoma.
- 02:47How do people present with lymphoma? I mean do
- 02:49they present with big lymph nodes?
- 03:02That is one of the possible signs or symptoms rather but it can also present as just a very subtle blood abnormality. Which is detected by a blood test.
- 03:05So the symptoms range from fevers,
- 03:07night sweats, weight-loss along with a swollen lymph node.
- 03:11Either it could be in the neck.
- 03:14It could be in the chest,
- 03:16in the belly, or it could just be as indolent as just a small abnormality in the blood that can only be detected by a blood test.
- 03:27Many of those, the latter types of lymphomas,
- 03:30are detected by a routine blood test that was done.
- 03:34It is more often an incidental finding.
- 03:37In either case, how do you make that diagnosis?
- 03:40You mentioned that you would need a sufficient amount of tissue if you just had a routine blood test,
- 03:47you've been feeling a little under the weather,
- 03:49you thought, maybe it's just a cold and feeling a little rundown,
- 03:55a little tired.
- 03:57I've got a bit of night sweats and fevers,
- 04:00but I thought it was a cold.
- 04:02So I went to the doctor,
- 04:04he drew some routine blood tests
- 04:07and now you're telling me that he suspicious of lymphoma.
- 04:10How do we get from that to actually making a diagnosis?
- 04:14That's a great question. Typically
- 04:16we start with a blood test,
- 04:18but before that the doctor that you are going to see would do a full physical exam.
- 04:24So one of the things that if the patient is not complaining him or herself,
- 04:29then they would do a full physical exam to make sure that there are no swollen lymph nodes.
- 04:35Typical areas that we look at our the
- 04:38neck, under the armpits or at the groin crease so there are these typical areas that we look for lymph nodes and then we do a
- 04:51comprehensive lung and abdominal exam,
- 04:53so that is just to look at whether there is anything swollen.
- 04:59We can feel just by hand.
- 05:01But then the next steps are to look at different sub types of white blood cells
- 05:08in in the blood, and look at whether they are increased in number or do they show any signs of markers on the surface of the cells which shouldn't
- 05:20be there.
- 05:24And that's another blood test, correct? And so you do that,
- 05:26and then what happens?
- 05:28Well then we figure out what type of lymphoma it is.
- 05:33As I said before there are 65 different types of lymphomas
- 05:40as given by WHO classification,
- 05:42so it is absolutely crucial to figure out what the type of lymphoma is and that happens by putting together the entire spectrum of data.
- 05:56So that includes the way the patient presented,
- 06:00what are the symptoms?
- 06:03What did those tests in the blood show and also the biopsy specimen?
- 06:10We put all three pieces of information together,
- 06:15figure out the subtype, figure out the stage of lymphoma,
- 06:18and decide whether we need to treat the patient or not.
- 06:22So what do
- 06:24you biopsy in that situation?
- 06:25You're feeling a little under the weather,
- 06:29they did a routine blood test,
- 06:32they said, your white count is out of wack,
- 06:36you go to the oncologist,
- 06:39or the hematologist who does this full physical exam,
- 06:43And if you did not have Lymphadenopathy
- 06:47your lymph nodes were not swollen up,
- 06:49they're going to run this special blood test to look at the different types of white blood cells and so on so forth,
- 06:58but then what do
- 06:59you biopsy in that particular case that you're describing?
- 07:03There is nothing to biopsy and the most common type of lymphoma that presents the way you described is CLL.
- 07:11Or chronic lymphocytic leukemia, where the lymphoma cells are there circulating in the blood so there is nothing really to biopsy.
- 07:19We just acquire a few tubes of blood and do all the tests that we would have done on a biopsy specimen but on a blood specimen instead.
- 07:30Sometimes we also have to do a bone marrow biopsy which is
- 07:35a test looking at the hollow part of the bone that's the factory of all the cells that I just described that can become
- 07:45cancerous but you know the field is trying to move away from doing bone marrow biopsies because our tests in the peripheral blood and tissue are getting more and more
- 07:56sensitive. We can get most of the information that we need but that being said,
- 08:01there are still many situations where we have to do a bone marrow biopsy.
- 08:06And so if somebody presents on the other side of the spectrum,
- 08:11feeling terrible, fevers,
- 08:14chills, night sweats, losing weight for no reason,
- 08:18notices a lump in the neck,
- 08:20then feeling more,
- 08:23lumps in the groin,
- 08:26you go to the doctor,
- 08:29and the doctor gets worried.
- 08:31What then? Do they do
- 08:34a biopsy of the lymph nodes?
- 08:36Is that how that works in that scenario that you're describing?
- 08:41Biopsy becomes very, very important and we work very closely with our interventional radiologists or even surgeons
- 08:48sometimes, depending on the location of the swollen lymph node.
- 08:52So either surgeons or an Interventional
- 08:54Radiologist would biopsy the specimen,
- 08:57and then that specimen would go to the pathologist who would
- 09:01look at that tissue under the microscope,
- 09:05stain it with different markers that we already know may be positive in these different types of lymphomas,
- 09:12and then we figure out the subtype of the lymphoma and within usually within a week or two we are ready to start the therapy.
- 09:22If the patient is really sick at that time,
- 09:26then sometimes we even have to admit the patient while all these results are back and just give some
- 09:33medications to temporize rather than starting
- 09:35full blown therapy that we would have given that we would give in the future.
- 09:41So what's the
- 09:42most common kind of lymphoma?
- 09:44I mean, you say there's 65 different types,
- 09:47your head could spin,
- 09:49especially with all of the different therapies.
- 09:52If each one of these is treated differently,
- 09:55what's
- 09:55most common?
- 09:59That's also a tricky question to answer, and the reason is that we branch the way we classify lymphomas.
- 10:03The broad categories are Hodgkin lymphoma and non Hodgkin's lymphoma,
- 10:08but then it gets complicated very quickly so that classification,
- 10:13Non Hodgkin Lymphoma, is the most common,
- 10:16so how do you know
- 10:18what's a Hodgkin's lymphoma? What's a non Hodgkin's lymphoma?
- 10:22Hodgkin's lymphoma has a very classic appearance on the tissue biopsy specimen,
- 10:27so that's something that the pathologist would tell us that it is either Hodgkin or non Hodgkin lymphoma.
- 10:36And you were saying Non Hodgkin's is the most common
- 10:39right? So pretty much everything else falls under Hodgkin's.
- 10:43The way I like to think about it is what is the origin of the cancer cells?
- 10:53There are different types of lymphocytes.
- 10:55The immune cells that we talked about before, so it could be B cell or a T cell.
- 11:01There are Non Hodgkin's lymphoma's that originate from a B cell,
- 11:06so they're called B cell lymphoma's.
- 11:08Those that are Non Hodgkin Lymphoma that originate from T cells and they're called T cell lymphomas.
- 11:15Then the way I think about it next is under B cell lymphoma,
- 11:21which is the most common out of B and T cell lymphomas,
- 11:24is looking at whether they're
- 11:27aggressive in presentation or indolent in presentation,
- 11:31so that's how I like to
- 11:33broadly classify them
- 11:35And when we had talked about that first case,
- 11:40which was really indolent cancer where somebody was picked up on a routine blood test,
- 11:47you called it CLL you called it a leukemia.
- 11:52What's the difference between a leukemia,
- 11:54and a lymphoma or are they the
- 11:57same?
- 12:00They are not the same, but this leukemia in general,
- 12:02means that there are cancer cells circulating in the blood and most of the time when we talk about the routine leukemias,
- 12:14I don't treat leukemia patients,
- 12:17But CLL is an exception because
- 12:20that particular type of cell circulating in the blood is a lymphocyte,
- 12:25but it has not honed into a lymph node or something that is tangible or can be seen on a physical exam.
- 12:33So that's why it's sort of not really a misnomer,
- 12:38but it can get people confused.
- 12:41You had mentioned earlier that 65 different types of lymphomas are all treated differently,
- 12:49and for some of them you can actually just watch them.
- 12:54That is correct,
- 12:54and that's exactly why the classification and working very closely with the pathologist is absolutely crucial.
- 13:03The subtype that we talked about, CLL, many times
- 13:08we can just wait and watch.
- 13:10And one of the things we want to look at is whether the cell burden,
- 13:17the cancer cell burden in the body is large enough to either compress on our normal organs or prevent production of other cell lines such as platelets or red blood
- 13:30cells. So if we see those signs,
- 13:33then that's when we pull the trigger to start the treatment,
- 13:38but many of the times, particularly for CLL,
- 13:42we can wait and watch,
- 13:44but that being said, there are many other indolent lymphomas such as follicular lymphoma and even very minor subsets of mantle cell lymphoma.
- 13:54Lots of great information, but we're going to have to take a short break for a medical minute.
- 14:01Please stay tuned to learn more about lymphoma and early
- 14:06phase clinical trials with my guest
- 14:08Doctor Shalin Kothari. Support for Yale Cancer Answers comes from AstraZeneca dedicated to providing innovative treatment options for people living with cancer. Learn more at astrazeneca-us.com.
- 14:19This is a medical minute about melanoma.
- 14:22While Melanoma accounts for only about 4%
- 14:24of skin cancer cases, it causes the most skin cancer deaths. When detected early,
- 14:30however, melanoma is easily treated and highly curable. Clinical
- 14:33trials are currently underway to test innovative new treatments for melanoma.
- 14:38The goal of the specialized programs of research excellence in skin cancer, or SPORE grant, is to better understand the biology of skin cancer with a focus on discovering targets
- 14:50that will lead to improved diagnosis and treatment.
- 14:53More information is available at yalecancercenter.org.
- 14:57You're listening to Connecticut Public Radio.
- 15:01Welcome
- 15:01back to Yale Cancer Answers.
- 15:03This is doctor Anees Chagpar and I'm joined tonight by my guest doctor Shalin Kothari.
- 15:11We're talking about lymphoma and early phase clinical trials.
- 15:15Now, right before the break,
- 15:17Shalin was telling us about lymphoma being this really large basket of 64 different types of cancers,
- 15:25essentially all of which are bound together by this term lymphoma.
- 15:30Because they are cancers of lymphocytes,
- 15:33those immune cells that all of us
- 15:36need to help fight infections.
- 15:38Some of these present in a really indolent fashion,
- 15:42some of them present with symptoms of fevers and night sweats and weight loss and enlarged lymph nodes,
- 15:50and even getting your spleen enlarged.
- 15:52And we talked a little bit about how the diagnosis can sometimes be made on something as simple as a routine blood test,
- 16:02but other times really requires a tissue biopsy.
- 16:06Right before the break you were saying that some cancers don't require any treatment and that you can simply wait and watch.
- 16:17But other cancers do require treatment.
- 16:20Can you tell us a little bit more about how lymphoma is classically treated and a bit about some of the research that's going on in terms of treatment
- 16:32of lymphomas?
- 16:36Classically lymphoma is treated, and
- 16:38it becomes a bit challenging because every subtype is again treated very different,
- 16:43but let's say we talk about B cell lymphoma's,
- 16:47then most of the regimens that we use for the first year as a frontline therapy for the patient,
- 16:55we would use a antibody drug called Rituximab or a CD20 antibody,
- 17:00which is one of the very common markers on B cells.
- 17:05So
- 17:05are these like chemotherapies? Is that what it is?
- 17:09I would say they are more of a protein infusion.
- 17:13It's more of an antibody infusion.
- 17:15That particular drug that I talked about is not a chemotherapy,
- 17:19but it is typically combined with two or three or even four different types of chemotherapy drugs in combination.
- 17:27So usually we have to find different ways to trick the cancer cell into dying,
- 17:33and that requires different tools,
- 17:35so that the cancer cell is attacked from different angles.
- 17:40That's why we combine these therapies together as a cocktail which has been studied for many years,
- 17:46and we have a good idea of what goes with what and what regimen,
- 17:50what cycle, how many cycles,
- 17:52how many weeks of a break,
- 17:54all of that has been figured out over a period of time and that is a good segue to what you were asking me about the research.
- 18:04All of these questions as to what drug to use,
- 18:08how do cancer cells figure it out?
- 18:11A way to survive with these therapies and what is the dose of the drug to use?
- 18:18What is a dose of a drug that doesn't cost too much toxicity through the patient?
- 18:25What is the schedule of that combination of drugs?
- 18:29All of that is studied in clinical trials,
- 18:32so, for example at Yale for lymphomas,
- 18:35we have around 60 to 70 different types of clinical trials ongoing.
- 18:41And they can range from early phase clinical trials,
- 18:44to late phase clinical trials.
- 18:46And my team,
- 18:49we are actively involved in enrolling patients into these clinical trials so that they can benefit and they can help other patients benefit in the future because any therapy that
- 19:01we use today at some point in the past was studied as a clinical trial which is now benefiting everyone who has lymphoma.
- 19:12But a lot of patients may think,
- 19:15I just want what is standard.
- 19:17I don't want to be a human Guinea pig.
- 19:20Somebody else can be a human Guinea pig.
- 19:23How do I know that what you're giving me is going to work?
- 19:28Or is going to work better than
- 19:31standard? What do you say to patients who say that?
- 19:42That's an excellent question and a lot goes into research before we decide to introduce the drug as a clinical trial. Typically a drug is studied for years and when I say years, it could be even a decade or at least four to five years before we
- 19:55even think of
- 19:57designing a clinical trial for use in patients and the way we do that is,
- 20:03we start with testing lymphoma cells with that drug in a Petri Dish in a Translational Research Laboratory.
- 20:12And then we move on to
- 20:15lymphomas in mammals. So we use either mice or other mammals just to see what the drug does in those animals through those phases, and
- 20:27we figure out the dose,
- 20:29or at least the range that we should study in humans because we have a lot of
- 20:39formulas and calculations that we can do to figure out
- 20:45where to start as a starting dose for the drug in a particular patient.
- 20:51So with all of these
- 20:52different types of lymphoma and all of these different therapies,
- 20:58what do you think is the most exciting in terms of where research is going?
- 21:05The research is definitely moving towards using less and less of what you described as chemotherapy,
- 21:13and for good reasons. Chemotherapy can cause a lot of toxicity.
- 21:18which of course is very effective in killing cancer cells,
- 21:24but it can also cause other unwanted toxicities and the research is moving very very fast towards using novel therapeutic agents
- 21:35which really look at genetic and even cellular level to figure out what exactly is driving the cancer cell.
- 21:44What is that genetic change that is leading that cancer cell to go from 2 cells to four cells,
- 21:524 to 8 and so on and so forth.
- 21:55And once we figure that out,
- 21:58we can use a drug that directly targets that particular mutation,
- 22:02or a pathway that we think is crucial for that cancer cell to survive.
- 22:08So as you can imagine,
- 22:10if are that selective then we can reduce the toxicities that drug would cause otherwise.
- 22:16Yeah, that makes
- 22:17sense. That's like all of this personalized medicine that people are talking.
- 22:22Yes in some ways, yeah.
- 22:24So tell us about your research.
- 22:26Do
- 22:27you work in that field?
- 22:29Yeah, I dedicate 50%
- 22:32of my time into a translational research laboratory where I study mantle cell lymphoma.
- 22:37We're trying to figure out
- 22:40newer therapies for mantle cell lymphoma,
- 22:43which is a subtype of aggressive B cell lymphoma's for the most part.
- 22:50And currently there are a couple of drugs that are already known,
- 22:56these novel therapies that are already known to be active in mantle cell lymphoma,
- 23:02but many or most versions will eventually develop resistance to those drugs,
- 23:07so we have to find newer therapies that will work after those two drugs or three drugs stop working.
- 23:15So that's what my focus is in the research laboratory to figure out.
- 23:20And how do you do that?
- 23:26As I discussed before,
- 23:29we take lymphoma cells in a Petri dish,
- 23:32one of the first steps that we start with and
- 23:36we first figure out
- 23:39what is driving the cancer cell to divide.
- 23:42So then we get, let's say a list of
- 23:4610 different genes and five different pathways to target.
- 23:49Then we look at previous research that has already been done and see what can we target in that pathway and then try to design either a designer drug or collaborate
- 24:01with other laboratories around the world that have already designed a drug for that particular pathway and see if that works against the lymphoma cells.
- 24:12When you say that you're trying to find therapies that will help in the cases of resistant lymphoma
- 24:19when you're looking at pathways that cause cancer cells to divide,
- 24:24I would think that those would help even up front as frontline therapies do.
- 24:30Do you try to figure out why they were resistant to the first line chemotherapy or the first line drug?
- 24:39Because presumably those already were targeting certain pathways that made cancer cells divide to begin with.
- 24:45That is true, and that really,
- 24:47again depends on the type of lymphoma.
- 24:50For example, mantle cell lymphoma is the frontline therapy that we use even to this date with Rituximab that I talked about in combination
- 25:02with other chemotherapy agents and to be honest,
- 25:05most of the lymphoma frontline therapy is still that cocktail of chemotherapy with Rituximab,
- 25:11and for good reason the bar is so high for these novel therapies to be used in front line.
- 25:20We don't want to harm patients.
- 25:23We have to find those novel drugs that will either improve, further the response to the frontline therapy and
- 25:31if not, then most most of the time they end up being used in second or third line.
- 25:39If the patients develop resistance to the frontline
- 25:42therapy.
- 25:48How often do patients with mantle cell lymphoma actually become resistant?
- 25:50Mantle cell lymphoma is one of the areas where there's a lot of research that needs to be done.
- 25:55In mantle cell,
- 25:59for example,
- 26:02I would say almost 70 to 80%
- 26:05of patients develop resistance to the frontline therapy.
- 26:08And as you can imagine,
- 26:11we already know that's what to use in second line third line.
- 26:16But then eventually most patients develop resistance to all these lines of therapy.
- 26:22And why is that? That's the $1,000,000 question.
- 26:25It's not easy to figure that out,
- 26:28but we do know that there are
- 26:32different mutations that the cancer cell can
- 26:36keep evolving. That's probably the best way to think about it.
- 26:41So if you introduce frontline therapy to a cancer cell,
- 26:45and let's say there are 10 cells to kill,
- 26:48maybe 8 of them get killed but the other two they find a way to change their path of dividing and circumvent the way the frontline
- 27:00therapies worked. So now they have become smarter.
- 27:03They have acquired new mutations,
- 27:05new genetic changes that
- 27:07weren't there the first time and then you introduce second line therapy and again,
- 27:12the same thing happens where you kill most of the cells but not all,
- 27:17and then those few cells that are left behind,
- 27:20they eventually start dividing again because they have acquired newer mutations.
- 27:25It sounds a lot like what our audience might be familiar with in terms of antibiotic resistance that you see one antibiotic and the idea is that
- 27:34you don't want to keep taking different antibiotics,
- 27:37especially when you don't need them.
- 27:39Because then you have the generation of super bugs that are resistant to all antibiotics.
- 27:46Is
- 27:46that a similar kind of concept?
- 27:49Similar concept, but we are not worried about a generation of superbugs in this case because most lymphomas if not treated can be deadly.
- 27:59If they need treatment, if they're aggressive kinds of lymphomas,
- 28:02and if they are not treated,
- 28:04they can be deadly, so we don't typically worry about what will happen to that cancer cell, and
- 28:10what different types of mutations they're going to acquire.
- 28:13Because we really don't have the time in that particular patient,
- 28:17so in other words,
- 28:19we typically switch from one line of therapy to the next line of therapy very quickly.
- 28:26The moment we know that this particular patients lymphoma stopped responding,
- 28:31then we quickly move to the next line because it's crucial to try to keep it at a very low level of burden or even completely cure it.
- 28:43Doctor Shalin Kothari is an Assistant Professor of Medicine and Hematology at the Yale School of Medicine.
- 28:49If you have questions, the address is canceranswers@yale.edu and past editions of the program are available in audio and written form at Yalecancercenter.org.
- 28:58We hope you'll join us next week to learn more about the fight against cancer here on Connecticut Public Radio.