Early Phase Clinical Trials for Lymphomas

May 04, 2020

Information

May 3, 2020

Yale Cancer Center

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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.