nhl: keys to an accurate diagnosisthis slide is just to illustrate the lymphatic circulatory system....

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NHL: Keys to an Accurate DiagnosisDecember 12, 2014

Speaker: Stephen J. Schuster, MD

Slide 1: Welcome & Introductions

OPERATOR:Hello, everyone, and welcome to NHL: Keys to an Accurate Diagnosis, a free telephone/web educationprogram. It is my pleasure to introduce your moderator Lauren Berger of The Leukemia & LymphomaSociety.

LAUREN BERGER:Thank you and hello, everyone. On behalf of The Leukemia & Lymphoma Society, a warm welcome toall of you.

Our special thanks to Dr. Stephen Schuster for sharing his time and expertise with us today.

For more than 60 years The Leukemia & Lymphoma Society has helped to pioneer innovations such astargeted therapies and immunotherapies that have improved survival rates and quality of life for so manyblood cancer patients. To date we have invested over $1 billion in research to advance therapies andsave lives. Until there is a cure, LLS will continue to fund promising research.

We would like to acknowledge and thank Genentech and Biogen Idec, and Pharmacyclics, Inc. andJanssen Biotech, Inc. for their grants to support this patient program.

Slide 2: NHL: Keys to an Accurate Diagnosis

I am now pleased to introduce Dr. Stephen Schuster, Director of the Lymphoma Program and LymphomaTranslational Research, Robert and Margarita Louis-Dreyfus Associate Professor of Chronic LymphocyticLeukemia and Lymphoma, at the Abramson Cancer Center at the University of Pennsylvania PerelmanCenter for Advanced Medicine in Philadelphia.

Dr. Schuster, I am now privileged to turn the program over to you.

DR. STEPHEN SCHUSTER:Thank you for the introduction, Lauren. It’s a pleasure to be here today and I’d like to welcome theparticipants.

What I’d like to do is just give an overview of non-Hodgkin’s lymphomas and then after this we’ll have aperiod of questions.

Some of the slides will be busy and the idea is that they’ll be available for a resource that the participantscan go back to afterwards if they want more detailed information. But I’m going to try to stick with broadconcepts that hopefully the data and information on the slides will illustrate.

So the title of this is Keys to an Accurate Diagnosis. So what I’d like to do is talk about how a diagnosis ismade and some background regarding the non-Hodgkin’s lymphomas.

Slide 3: Facts and Figures: Non-Hodgkin Lymphomas

So these lymphomas are the most common blood cancer and I’ll talk about the relationship of lymphomasto blood cancer and why we consider them a blood cancer in a bit. But they are indeed more commonthan the acute leukemias and multiple myeloma, which are related blood cancers.

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DR. STEPHEN SCHUSTER:Among all cancers, lymphomas are considered the seventh most common in females and the sixth mostcommon in men. We expect this year to have over 70,000 new diagnoses of non-Hodgkin’s lymphomasmade, and about 18,000 deaths related to non-Hodgkin’s lymphoma, which actually, if you look at thedifference between the diagnosis rate and the death rate, you can see that there’s a lot of people thatare living with this diagnosis or successfully treated for this diagnosis.

Slide 4: The Immune System

Most of these are B-cell disorders and we’re going to talk about B-cell and T-cell lymphoma and some ofthe differences as we go through the background.

So it’s helpful to understand what this tumor is when we talk about a lymphoma. People can understandlung cancer because they know what a lung is and they can understand colon cancer because theyknow where their colon is, and these are pretty discrete organs. The immune system is not a discreteorgan in that sense. It’s a liquid organ that occupies essentially the entire body. The cells of the immunesystem are T-cells and B-cells and malignancies can arise from any normal cell in the body and that goesfor T-cells and B-cells, so people can develop cancers of B-cells and these are called B-cell lymphomas,or cancers of T-cells, and these are called T-cell lymphomas.

In general, the normal function of T-cells is for our immunity. Basically these cells can help us fight viralinfections. They help protect our body from foreignness, so they were an obstacle that had to besurmounted for organ transplantation. But they recognize self and non-self. And what’s really exciting isthese cells, we’ve known for about 50 years in mouse models, that they’re capable of killing cancersincluding lymphomas, and within the last few years the technology has become available to actually usethese T-cells to treat lymphomas as well as other cancers.

The B-cells are the cells that ultimately give rise to antibodies, which are proteins that circulate in theblood and act as an immunologic memory. For example, if you’re vaccinated for tetanus, you’ll makeantibodies that neutralize tetanus toxin, that float around in the fluid portion of your blood and protectyou against tetanus. So there’s two arms to the immune system and under normal circumstances that’swhat these cells do.

Slide 5: Lymphatic System

Now where is this system, where are these cells? And this slide shows the lymphatic system. They’reeverywhere essentially. You see a whole body there. There’s this yellow circulatory system that you’ll seewith little nodes sort of strung along it like pearls on a chain. But you’ll also see bone marrow and gutand spleen and tonsils. Essentially these lymphocytes of the immune system are throughout the entirebody, but they tend to circulate from tissues like bone marrow, skin, gut, spleen, thymus, tonsils. Theytend to move through the tissues into these yellow vessels and then circulate through this yellow vascularsystem called the lymphatic system. And then actually connect with the circulatory system. Little bit moreabout this later.

But these cells, because they – these cells in fluids, antibodies, because they have to deal with theenvironment, they need essentially to be everywhere in the body. And of course, because these cells areanywhere, lymphoma can arise anywhere. If it arises in the lymph node, we call it a nodal lymphoma. If itarises outside of a lymph node in a tissue, we call it an extranodal lymphoma.

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DR. STEPHEN SCHUSTER:

Slide 6: Lymphatic Circulation

This slide is just to illustrate the lymphatic circulatory system. Everybody knows about the arterial andvenous systems because for some reason in high school we all learn about that and we learn aboutcapillaries, but they never tell us about this second circulatory system, the lymphatic system, which isactually quite important.

Most of the fluid, when the artery pumps blood into capillaries, most of the fluid portion and some of thecells egress from the capillaries into the tissues. And then the remainder will go on into the veins. Thisfluid and these cells that come from the capillaries throughout – and percolate into the tissues of thebody – are basically then picked up, once they’ve been through the tissues, by these lymphatics, whichare shown in yellow on this slide. These lymphatics have little windows throughout, so any cells in fluidsfrom any of the surrounding tissue can get in. And then they pass through these circular structures callednodes and I’ll show you them in a bit. And then actually go back into the blood, into the venous blood,back to the heart, get pumped out through the arteries. So there’s cells of the immune system circulatingthroughout the blood, but also throughout the tissues and the lymphatic system of the body.

Slide 7: Lymph Node Anatomy

On this slide, shows those circular or spherical structures, that were linked together by the lymphaticvessels, they’re called nodes, lymph nodes. And this sort of shows the afferent or inflow at the top,portion of a lymphatic channel. Then the structure of a lymph node. And then the efferent or exit flow ofthe channel. And you can see there’s this complex network that comprises the lymph node that thelymphatic fluid in cells, that have come in through the tissues, percolate through before they leave. Andthere’s these structures called follicles, and I’ll show you what they look like, throughout. And there’s alot of action going on in these. So the cells that come in for the afferent lymphatics will sometimes go tothese follicles, and also called germinal centers, and they will, you know, undergo lots of genetic eventsand maturational changes to become antibody-producing cells. And then exit through the lymphatics tothe rest of the body where they can do their thing.

T-cells, in this gray – or in this brown area – can undergo a variety of events that relate to immunization.And T-cells can move into these germinal centers to help B-cells in their development. So it’s a complexactivity level going on in a lymph node. But that’s where a lot of the immune processing happens.

Slide 8: Lymph Node: Microscopic View

This is a lymph – what a pathologist sees if he cuts a lymph node in a thin section and stains it with ablue dye and for DNA and looks under the microscope. You can see these follicles or germinal centersare highlighted. You could see how in the central portion it kind of opens up. You see these clear zones,so the channels kind of coalescing the lymph node sinuses, kind of coalescing to form the efferentvessels. And the T-cells are around here in the center and the B-cells are in these germinal centers withsome T-cells mixed with them. This is what we see. This is a normal lymph node.

If you develop a lymphoma in a lymph node, it’s a nodal lymphoma.

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Slide 9: Lymphocyte: Microscopic View

By the way, just in case you were wondering what a lymphocyte looked like, B and T, you really can’t tellthe difference with the blue and pink stain that’s used routinely, but this is it. It’s a small nondescript-looking cell, but very powerful in terms of its ability to protect us from the world.

Slide 10: Causes of Non-Hodgkin Lymphomas

What causes lymphomas, what makes these lymphocytes become malignant? Somehow theselymphocytes undergo a maturation arrest and then expansion at some level of development and that iswhat we call lymphoma. What makes that happen? Well, there’s some data to suggest that the risk ofdeveloping lymphoma is related to chemical exposures like pesticides, fertilizers, fumigants, solvents,things like that. Again, when I say cause, causality means an increase in risk, not a cause-effect thateveryone who sees a particular pesticide is going to get lymphoma, but it might increase the risk.Individuals with compromised immune systems like those that have HIV, AIDS or that are onimmunosuppressive drugs to prevent organ rejection that are prescribed by doctors, can have anincreased incidence of lymphomas and that’s because the immune system, the cells of the immunesystem regulate each other and actually can police each other and can keep cells that have undergonetransformation in check.

There is some hereditary predisposition to develop lymphoma, but it’s not the simple Mendelian geneticsthat you all know, like a dominant and recessive gene, like Mendel’s peas that you learned about in highschool. It’s a relative risk within certain families, in certain types of lymphomas.

Chronic infections, like hepatitis-C virus infection, can relate to chronic stimulation of the immune systemand result in the development of marginal zone lymphomas. We’ll talk about that. Or Helicobacter pyloriinfections, bacterial infection of the stomach with that organism that causes ulcers, can lead tolymphomas as well.

But most of the time you can’t identify a risk factor in an individual patient and we don’t really know thecause.

Slide 11: Cellular Origins of Lymphomas & Leukemias

This slide just shows the relationship between the cells that give rise to lymphomas and those otherblood cancers. You can see that all blood cells come from stem cells in the bone marrow and if thesestem cells become malignant you’re dealing with an acute leukemia. And there are less mature cellintermediates that can become malignant, that is a single cell can undergo a maturation arrest and thenan expansion of that clone to lead to an acute leukemia or a lymphoblastic leukemia or lymphoma. Butmost lymphomas come from these mature T-cells and mature B-cells that are circulating throughout thelymphatic system, found in lymph nodes and extranodal tissues, and if any one of these cells undergoesa maturation arrest, that is it stops developing or doesn’t die as it should and begins to expand innumber, that’s what we call lymphoma, a non-Hodgkin’s lymphoma. Tumor of these mature B or T-cells.So it’s a blood cancer in the sense that it’s derived from a stem cell, as shown on the slide.



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Slide 12: Normal B Cell Life Cycle and Related Lymphoid Malignancy

And this slide shows the normal B-cell life cycle and at the bottom the corresponding malignancies thatarise if there’s a maturation arrest and clonal expansion at any level of cellular development. So theblood cells, stem cells in the bone marrow, evolve into a – or develop into a lymphoid stem cell. Andthen there’s pre-B-cells and then B-cells. Okay, so it’s at this level of maturation that if a cell undergoesmalignant transformation, one gets a B-cell lymphoma or a Hodgkin lymphoma or CLL and this canhappen in lymph nodes or outside of lymph nodes. And this particular slide shows a lymph nodetransferring the germinal center. If it happens there, you get a follicular lymphoma and we’ll talk a bitmore about that. If it happens after that and at the level of a plasma cell, you get multiple myeloma.Okay, so any of these steps in B-cell development can – any one of these steps, which will havepopulations of cells passing through them, can have a single cell that undergoes malignanttransformation and expansion. These CDs, by the way, are proteins on the – they’re the names forproteins on the surface, that we can use to map the differentiation stage or age and development stageof the individual cells. And the malignant counterparts of these cells often contain these same antigensand we use these not only for diagnosis, but for a therapeutic target.

Slide 13: Normal T-Cell Life Cycle and Related Lymphoid Malignancy

I don’t want to use a lot of time, so I’ll just say that T-cells similarly can go from the bone marrow throughthe thymus, develop into help or CD4 cells, cytotoxic or CD8 cells. These CDs again are proteins on thesurface. We can map the stages and you can see the corresponding malignancies at the bottom.

Slide 14: Classification of Lymphomas: The First 50 Years

Pathologists have used a series of classifications over the years that have become increasingly frequentand dramatically improved with each successive classification system. Current system that’s used is theWHO or World Health Organization classification system. And there’ll be a new version of that comingout shortly.

Slide 15: Diagnosis and Classification of Lymphomas

Now that system and our pathologists use three ways to diagnose a lymphoma. And this requires abiopsy. Biopsy means surgical or mechanical removal of a piece of tissue for analysis. Histology meanslooking at the biopsy under the microscope and some people just call that a biopsy. And so the way thepneumonic, you know, to remember, is BIG. Biopsy, immunophenotype and genotype. BIG. You need B,you need I and you need G to make a specific diagnosis. And I’m going to run through some lymphomasquickly and show you how we use that approach.

The histology refers to what it looks like under the microscope. The tumor size and pattern of cells.Immunophenotype are the CDS, or tumor-specific proteins, that can be stained for. And the genotype arespecific genetic changes that identify certain types of lymphoma. Let me show you some examples.



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Slide 16: Biopsy

So under the microscope, histology or biopsy under the microscope. Just a plain ordinary tissue stain.You can look at the difference in cell size. On the left you have large cells. On the right you have smallcells. And so you have a large cell lymphoma on the left and on the right a small lymphocytic lymphoma.So size, you only need a microscope to see size.

Slide 17: Follicular Lymphoma Biopsy

What else can you see on a microscope – under a microscope? You could see under low power theorganization of populations of cells. So on the left side panel you’ll see this – these almost look likefollicles. They’re not normal follicles because they’re back to back. Recall that those germinal centers Ishowed you before were spread out. But these back to back follicles are these malignant cellsattempting to recapitulate their normal counterpart. So this is a follicular lymphoma, which derives fromthe germinal center or the follicles of lymph nodes. And under low power we see it trying to be a follicle.On the right, under high power, we see it’s a small cell type of lymphoma. So without doing any fancystains, doing stuff that was done in the nineteenth century, we can tell a lot.

Slide 18: Immunophenotyping: Follicular Lymphoma

Now comes the fancy stains. And these are – you see the surface of the malignant cell on the left isdecorated with a variety of CD proteins. CD is just the identification number for a protein, nothing to dowith a compact disk or certificate of deposit, it’s just a cluster differentiation antigen term. And you couldsee on CD20, has been stained in the tissue section on the right, and the brown pigment is anywhereCD20 is. And so this is a CD20-positive lymphoma. If you recall from a slide I showed earlier on B-celldevelopment, CD20 is essentially found on all B-cell lymphomas. On follicular lymphoma shown on theslide, you can see at the bottom, there is a specific immunophenotype or staining pattern that includesCD20.

Slide 19: Genotyping: Follicular Lymphoma t(14;18)

And then there’s genotype. Remember BIG. Biopsy, immunophenotype and genotype. This is the G inBIG. And this can be done either by metaphase cytogenetics, letting the cells divide, looking at thechromosomes for abnormalities, or molecular biology, that is using PCR techniques or fluorescent in situhybridization techniques, a variety of modern scientific – or even deep sequencing now – a variety ofmodern scientific techniques to look for genetic changes. And there are certain ones that are diagnosticof certain lymphomas.

A translocation between chromosome 14 and 18, as shown on this slide, is seen in follicular lymphoma,and helps makes that diagnosis.

Slide 20: Non-Hodgkin Lymphomas (NHL): Clinical Groups

Now from a clinical perspective, I told you how we make a pathologic diagnosis, from a clinicalperspective we call these lymphomas indolent – we group them as indolent, aggressive or highlyaggressive, depending on the survival of patients with a specific diagnosis, when untreated.



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DR. STEPHEN SCHUSTER:So indolent lymphomas have an untreated survival measured in years. That’s our metric or yardstick.Aggressive lymphomas, depending on stage, in months. And highly aggressive lymphomas, in days toweeks. So once we have a diagnosis, the question we’ll ask ourselves next is, is that specific type oflymphoma indolent, aggressive or highly aggressive.

Slide 21: Relative Incidence of NHL Clinical Groups

And by the way, the distribution as shown here on this slide, about a third of lymphomas are indolent andabout half are aggressive and highly aggressive lymphomas are pretty uncommon, about 5%. MCL ormantle cell lymphoma can be either indolent or aggressive. It’s heterogenous.

Slide 22: Clinical Classification of Lymphomas

This slide just shows some of the common – in yellow – some of the common types of indolentlymphomas, follicular lymphoma being the most common, small lymphocytic lymphoma/CLL probablybeing the second most common of the low grade or – I say low grade, but I mean indolent lymphomas.The aggressive lymphomas by and large, diffuse large B-cell lymphoma is the most common. And for thehighly aggressive lymphomas there’s two, Burkitt’s lymphoma and lymphoblastic lymphoma.

Slide 23 “Indolent” Lymphomas: WHO Classification

This is the World Health Organization classification of lymphomas. It’s a list and you can go back to theseslides later and refer to the specific diagnoses and I’ve grouped them for you into B-cell neoplasms andT-cell neoplasms or B-cell lymphomas and T-cell lymphomas, because that’s the way the World HealthOrganization divides the lymphomas.

Slide 24: Characteristics of “Indolent” Lymphomas

So these are the indolent lymphomas. Again, and these are generally malignancies of small cells, whenwe look at the biopsy under the microscope. Most of the time they’re B-cell tumors. Most of the cells arenot dividing. Follicular lymphoma is the most common. It frequently involves the blood or bone marrow.Patients live many years with this diagnosis in general. It’s very sensitive to a variety of our therapies and85 to 90% of patients have advanced stage at diagnosis and I’ll talk about the significance of that in a bit.

Slide 25: “Aggressive / Highly Aggressive” Lymphomas: WHO Classification

This is your list of aggressive lymphomas. It includes only one type of follicular, Grade III-B lymphoma.These are considered the aggressive lymphomas or highly aggressive lymphomas, and I’ve groupedthem by B and T-cell diagnoses for your reference. Again, you can go back to these.

Slide 26: Characteristics of “Aggressive” Lymphomas

These are usually large cells under the microscope or on the biopsy. Still most of the time they’re B-cells,diffuse large B-cell lymphomas, the most common. Most of the times these cells are dividing. They canoccur in lymph nodes or outside of lymph nodes. They’re potentially curable in more than half the cases.And these are much more often early stage at diagnosis, meaning localized within the body. And most of



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DR. STEPHEN SCHUSTER:the time people feel sick when they have these, as opposed to the low grade lymphomas where patientsdon’t feel sick. Feeling sick are the so-called B symptoms.

Slide 27: Staging of Lymphomas

I mentioned staging in passing and that means – staging is assessing where in the body the lymphomais. And we do this at the time of diagnosis and we repeat it after treatment to restage patients. It’s theassessment of where the lymphoma is and how much is in the body. And we use physical exam, bloodcounts, chemistries, X-rays, CAT scans, PET scans, sometimes bone marrows, and in the end we comeup with the bottom line here, which is the stage.

Slide 28: Staging of Lymphomas

This slide, for your reference, shows the Ann Arbor Staging System, I, II, III and IV, with Stage IV beingthroughout the body and Stage I being a single lymph node region. Stage II, two lymph node regions onthe same side of the diaphragm or membrane that divides the thorax from the abdomen. Stage III, lymphnode regions on both sides of the diaphragm.

You should know, though, stage doesn’t always correlate – I said 85% of patients with low gradelymphomas or indolent lymphomas are Stage IV and that’s because these are circulating cells. It doesn’treally affect much the prognosis. So Stage IV doesn’t necessarily mean worse in that case. And it hasmore of an impact with aggressive lymphomas in terms of prognosis than low grade lymphomas. Sostage has to be taken in consideration with the type of lymphoma that you have.

Slide 29: Prognosis of non-Hodgkin Lymphomas

What’s the prognosis? Advanced stage for indolent lymphomas, most of them are advanced. They saythey’re incurable, but with the treatments we’re using these days, I don’t really know whether they’reincurable, we won’t know for another five years how many patients we’re actually curing. But patients, Ido know, generally live a long time.

We cure more than half of the patients with aggressive lymphomas using modern immuno-chemotherapyand even more frequently we cure the highly aggressive lymphomas. The paradox here is that you cancure the diseases the more aggressive they are, it’s more – they’re more easily cured.

Slide 30: Follicular Lymphoma: Biopsy

Now the next series of slides are just to illustrate some of the common diagnoses and some features.Follicular lymphoma, it’s graded by the number of large cells. Grade I and Grade II are consideredindolent. Grade III is considered an aggressive lymphoma. You can see under low power it tends to formthese follicles. That’s the biopsy. Then we have next immunophenotype, BIG. It’s got a particular stainingpattern. And its specific cytogenetic pattern that I mentioned before, the translocation 14;18. That’s the Gin BIG.



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Slide 31: Follicular Lymphoma Cell

And then I have a summary slide here which shows the histology or biopsy, small cleaved cells formingaggregates. It’s got an immunophenotypic fingerprint. These are CD10-positive, CD20-positive B-cells.

Slide 32: Follicular Lymphoma t(14;18)

Okay, CD5-negative. It’s got the translocation 14;18. And then some clinical features are listed below.And again you can go back to these slides.

Slide 33: Follicular Lymphoma

I just want you to get the idea of how we make a diagnosis. We look under the microscope at thehistology, that’s the biopsy. Then we look at the immunophenotype and the cytogenetics. Then you goto the book and find out if it’s indolent, aggressive or highly aggressive. And how to treat it.

Slide 34: Lymphoplasmacytic Lymphoma (Waldenström’s)

Look under the microscope at lymphoplasmacytic lymphoma or Waldenström’s, there’s no follicles andyet the cells are small like the follicular lymphoma cells.


It doesn’t have as distinctive a fingerprint, but it is CD20-positive B-cell. It does not have CD10 likefollicular, so the immunophenotype helps. And occasionally there is this 9;14 translocation. Not all thetime, but sometimes. It helps in the diagnosis.


So this summary slide tells you the diagnostic features and some of the standard treatments.

Slide 37: Extranodal Marginal Zone Lymphoma (MALT)

Extranodal marginal zone lymphomas, these are small B-cell lymphomas that can involve stomach orother extranodal sites like lung. It has a vaguely nodular pattern, but that’s because the marginal zone,the cells around the germinal center are crushing down the germinal center. And again these are smallB-cells.

Slide 38: Marginal Zone Lymphoma (MALT)

That’s the biopsy. You can’t tell the difference between marginal zone and lymphoplasmacytic from thestaining pattern. They are CD20-positive B-cells.

Slide 39: Extranodal Marginal Zone Lymphoma (MALT)

And this slide lists the features. What’s interesting here is that gastric or stomach extranodal marginalzone lymphoma is often associated with this bacterial infection, Helicobacter pylori. And if you catch this



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DR. STEPHEN SCHUSTER:early enough and the cells – lymphoma cells have not become invasive, you can actually treat patientswith antibiotics and they get better. Also if it’s localized to the stomach, other options like radiotherapyare appropriate.

Slide 40: Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

This slide shows CLL or chronic lymphocytic leukemia. No follicles here. Small B-cells. Again, these slidesare more for your reference.


It’s got a unique fingerprint. Does not have CD10 like the follicular, but it’s got CD5 and some CD20.


And its features are shown here, summarized on this slide. And like all low grade lymphomas, noadvantage to early treatment.

Slide 43: Diffuse Large B-Cell Lymphoma (DLBCL)

Diffuse large B-cell lymphoma, this is the most common aggressive lymphoma. It spans all ages, buttends to be a little more common in elderly men. Men just slightly more common than women. Nodal,extranodal, it’s a B-cell lymphoma, so it’s CD20-positive, CD20 being a great target for the antibodyRituxan®.

Slide 44: Mediastinal Large B-Cell Lymphoma

In young women there’s a type of large B-cell lymphoma that’s commonly seen. It involves the middlechest or mediastinum. It’s called mediastinal large B-cell lymphoma. It has a rather favorable prognosis.

Slide 45: Peripheral T-Cell Lymphoma (PTCL)

Peripheral T-cell lymphomas in general tend to be aggressive. And they’re uncommon, less than 10% oflymphomas. There are variants. Peripheral T-cell lymphoma not otherwise specified. AILT orangioimmunoblastic T-cell lymphoma. Adult T-cell leukemia/lymphoma, that’s ATLL. And anaplastic largecell lymphoma. These are all variants of peripheral T-cell lymphoma. Each variant has its own prognosisand treatment. The diagnosis, however, are the CD4 stain being positive or CD3 stain being positive andCD20 being negative, because they’re T-cell markers.

Slide 46: Anaplastic Large T-Cell Lymphoma (ALCL)

This shows anaplastic large cell lymphoma, which is in young people frequently ALK-positive oranaplastic lymphoma kinase positive. In elderly people, anaplastic lymphoma kinase negative. Has a veryfavorable prognosis in young people who are ALK-positive and there’s even new medicines that work onthe ALK kinase.



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Slide 47: Non-Hodgkin Lymphomas: Treatment Overview

With regard to treatment, you see how diverse the lymphomas are in terms of the types of diseases thatare possible. They all have different natural histories. Some with a long untreated survival, some moreaggressive but curable. And different natural histories, different response to therapies, differentprognoses. So how do you treat lymphomas? It depends on their unique features. And there’s a wholepalette of treatment options, starting with doing nothing. And that applies only for low grade or indolentlymphomas. Obviously if somebody has an aggressive lymphoma, you have to do something. Butindolent lymphomas that have low tumor volumes and are asymptomatic, are perfectly appropriate to justfollow and establish a tempo.

With chemotherapy therapy, radiation therapy, monoclonal antibody therapy, combinations of the above,radioactive antibodies, occasionally bone marrow and stem cell transplants, and a lot of very excitinginvestigational and new therapies that are beyond the scope of this talk, but as you learn about eachspecific diagnosis you’ll see what’s being done.

Slide 48: Standard Therapeutic Approaches to non-Hodgkin Lymphomas

For the indolent lymphomas, the approach is generally palliative, meaning you don’t do anything unlessyou have to. And if you have to, you can really achieve some spectacular results in patients andsometimes long-lasting results with current therapies. And early stage disease may be appropriate justfor radiation.

Aggressive lymphomas, we intend to cure. And the so-called R-CHOP regimen for B-cell large celllymphoma is the standard. That’s Rituxan plus a combination chemotherapy regimen called CHOP.Sometimes if it’s early stage we combine R-CHOP with radiation. And CHOP alone can be used for T-celllymphomas. You don’t use rituximab for T-cell lymphoma because that binds CD20.

Highly aggressive lymphomas are treated like the leukemias and frequently curable.

Slide 49: B cell malignancies: new therapeutic targets

This shows some of the new stuff that’s going on. If you look at the nucleus of the cell, which is this gray,purple-gray area, circular area in the center, all chemotherapy and radiation therapy aims at this DNA. Itdamages DNA, the cell senses the DNA is damaged, and then it dies. That’s how chemotherapy andradiation therapy work. Normal cells can recover from that DNA damage. Lymphoma cells can’t recoverso well. That’s how come chemotherapy and radiation therapy work.

But look outside of the nucleus. Look at all this stuff, okay? There’s CD19, one of these proteins. We’renow genetically engineering T-cells that can kill cells with CD19, and this was presented – we presentedour lymphoma data last week at the American Society of Hematology meeting. Vaccines have beenmade against proteins on the surface. Monoclonal antibodies like rituximab can target CD20. There’schemotherapy conjugated monoclonal antibodies can be used. We now have B-cell receptor kinaseinhibitors that target specific enzymes that make B-cells live. The list goes on. And we’re studying BCL2protein inhibitors and IMiDs like lenalidomide or Revlimid® have activity. PD1 blocking agents. All theseextranuclear targets are all being studies. Some, there’s already approved therapies based on, for DR.



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STEPHEN SCHUSTER:example, the PI3 kinase delta inhibitor, idelalisib, was approved in August for treatment of follicularlymphoma. And ibrutinib, which inhibits BTK or Bruton’s tyrosine kinase, was approved for chroniclymphocytic leukemia, small lymphocytic lymphoma, in February of this year.

Slide 50: The Future

So I’m just going to wind up by showing you my crystal ball. I think the future, we’re going to have moretargeted, more specific therapies that’ll be individualized by patient in terms of their tumor characteristics.We’ll be able to better predict what’s going to happen. And how to deal with what happens. And drugdevelopment is happening at a dizzying pace. So I just totally expect improvement.

What I’m going to do now is just stop and open up for questions.

Slide 51: Question and Answer Session

LAUREN BERGER:Thank you, Dr. Schuster, for a very clear and informative presentation.

It’s now time for the question and answer portion of our program.

We’ll take the first question from the web audience and this one is from Bonita. Bonita asks, “If you feelconfident with your oncologist’s diagnosis and it seems to agree with what you’ve read about, is it stilladvisable to get a second opinion?” And we’ve actually heard that question from a few people.

DR. STEPHEN SCHUSTER:It really depends a lot on the situation. I’m always in favor for a second opinion with any cancer diagnosis,okay, and by second opinion I don’t just mean going to see another oncologist because doing that, in theprocess of doing that, you also get a second review of pathology, a second review of radiology. Youknow, you get a second set of eyes that look at everything. And I think that that’s important with cancer.And particularly when you’re dealing with lymphomas, where pathologists can frequently disagree, etc.So it’s not a matter of just the oncologist, it’s a matter of the pathologist, who the patient never sees, andthe pathologist that the oncologist works with and even getting a second look at the staging information.So in general I recommend it, if there’s time.

If somebody needs treatment urgently in a highly aggressive lymphoma, you’re obviously not going towait. But for an indolent lymphoma, for example, there’s time. And not uncommonly even for aggressivelymphomas, there’s time to get a second opinion.

I generally recommend it and I think that most of us oncologists actually don’t mind it. We kind of likewhen our patients get a second opinion.

LAUREN BERGER:Thank you. Thanks for your question, Bonita. We’ll take the next question from the telephone audience,please.

OPERATOR:The next question comes from Cynthia in Florida. Cynthia, please state your question.



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CYNTHIA:Yes, I had received two rabies vaccinations. I’m a zookeeper and wildlife rehabilitator. And I just wantedto know, because I had the large B-cell lymphoma, could that have been the reason? This goes back tothe very beginning of the talk.

DR. STEPHEN SCHUSTER:I think chronic immune stimulation, you know, can recreate a milieu for development of lymphoma, butI’m not aware of the rabies vaccine being associated with the development of lymphoma. So I – probablynot. Would be my guess. But I can’t say with certainty.

LAUREN BERGER:Thank you for your question, Cynthia. We’ll take the next question from the web audience and this one’sfrom Katherine and she asks, “Dr. Schuster, please share information about vaccines for follicularlymphoma.”

DR. STEPHEN SCHUSTER:Okay, so as you may know, if you go on the internet, I was involved with an idiotype vaccine, whichappeared to have some activity. And is kind of exciting and it was, I think, at the time, you know, lookedlike, you know, this is the way to go. I think there – it’s hard to know right now with regard to the idiotypevaccine, where it would fall within the, you know, the palette of things that we have to offer.

There’s so many therapies now that are immunologic in origin and so good, that a therapeutic vaccine,you know, may be one approach. It may not even be necessary. It may be just some – that we’re nowworking on ways of blocking immune checkpoints, so that the body can see cancer and without evendoing an active vaccine, take out the cancer cells.

So I think – and I’m talking about a therapeutic vaccine, a vaccine used to treat cancer, not to preventlymphoma, okay, because that’s the kind of vaccine that I’d worked on. Preventive vaccines, there arepreventive vaccines, for example, you know, if you get a – if you’re vaccinated against hepatitis-B and itprevents hepatitis-B, it could prevent hepatoma. Similarly cervical cancer can be prevented byvaccination against HPV. We don’t have preventive vaccines for lymphoma.

But I think that the vaccine historically was something I was interested in. I think there is some activitythere. But where and how to apply therapeutic vaccines in the midst of all these other therapies is just anarea that needs further research.

LAUREN BERGER: Thank you for your question, Katherine. We’ll take the next question from the telephone audience,please.

OPERATOR:The next question comes from Sonja in North Carolina. Sonja, please state your question.



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SONJA:Thank you, Dr. Schuster, for taking our calls and thank you for this informative session. My husband hasfollicular lymphoma, Stage II-B, what do you think the likelihood would be that there would ever be atotal cure for this? Or does it matter where the location is in the body?

DR. STEPHEN SCHUSTER:Well, I mean, obviously it always matters where – all the specifics of a case determine whether in fact thepatient even needs to be treated for follicular lymphoma. If somebody has no symptoms and the tumorvolume is very low, you know, and it’s not in a vital organ, I mean, it may be appropriate to do nothing.

I’m optimistic that there will be people that are treated when treatment is necessary. And a portion ofthem will probably, even with our current immuno-chemotherapy approaches, probably be long-termdisease-free survivors. And yet there’ll be others that stay in remission for years and have recurrences.But with the pace of things and with the new immunotherapies and kinase inhibitors that are appearingalmost annually on the scene, I actually tend to think of follicular lymphoma as a disease that we will – ifyou have it, you know, and I think every year that you have it that you’re still alive, the probability existsthat you’ll continue to have it and you’ll continue to live because the therapies just get better and betterand it’s likely to be a manageable condition, much like hypertension or diabetes. May not be curable, butit may not shorten your life. And so I think that you need to have that attitude.

Yeah, some patients will be cured, meaning they’ll live the rest of their life and never see their disease.Others will be on and off treatments intermittently for years. But if it doesn’t interfere with your quality oflife and it doesn’t shorten your life, I think that that’s still good therapy. And so I think many patients willhave – with this diagnosis – will be successfully treated, cured or not cured.

LAUREN BERGER:Thank you for your question, Sonja. We’ll take the next question from the web audience and Jim asks,“What is the difference between NHL and CLL, how do they differ?”

DR. STEPHEN SCHUSTER:Well, they’re both cancers, as I showed you on that slide that showed the origins of blood cancers,they’re both blood cancers. They’re both derived from mature B-cells. The difference is when we seemore than 5,000 per microliter circulating malignant B-cells in the blood, we call it chronic lymphocyticleukemia. If we see those same cells in lesser numbers in the blood, but present in lymph nodes, we callit small lymphocytic lymphoma. They’re basically the same disease. So it’s semantic. It goes back to thedays when, you know, patients saw – or pathologists saw circulating cells. If it’s in the blood we called aleukemia. If it’s in a lymph node or in a tissue, we call it a lymphoma. Well, it just so happens that thecells of small lymphocytic lymphoma-slash-chronic lymphocytic leukemia, go back and forth andsometimes are in both places and so, you know, it’s semantic. But it’s the same disease.

And it is a very unique disease. It’s got unique immunophenotype, like I showed on the slides, meaningunique staining antigens, staining pattern. And it also has unique therapies that are very successfulnowadays and very exciting. I think there’s been more excitement in chronic lymphocytic leukemia thanany of the lymphomas in the last 12 months because of the success of the kinase inhibitors, the Brutontyrosine kinase inhibitor ibrutinib, or the PI3 delta kinase inhibitor idelalisib. I mean, these are oral



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DR. STEPHEN SCHUSTER:therapies that are not chemotherapeutic in the sense that they don’t damage DNA and they’re very welltolerated and the responses are spectacular. Even in patients who’ve had multiple other prior therapiesand are no longer responding to conventional therapies.

So I think the treatment of this disease is clearly going to change over the next couple of years and theprognosis is much, much brighter than it’s ever been.

LAUREN BERGER:Thank you for your question, Jim. We’ll take the next question from the telephone audience, please.

OPERATOR:The next phone question comes from Patty in Missouri. Patty, please state your question.

PATTY:Yes, I am a nine year survivor of diagnosis and treatment for follicular lymphoma, Grade I, Stage IV,although, well, on the borderline really with III and IV. And I wondered for those of us who are long-termsurvivors and have not had to be retreated, is there any value in going back and having the original slide,especially if you didn’t get a second opinion, reevaluated? Is there any progress that would benefit?

DR. STEPHEN SCHUSTER:I think if you have no evidence of lymphoma right now and you’re in remission

PATTY:Not complete remission. I’ve been stable.

DR. STEPHEN SCHUSTER:Oh, oh, okay. I was going to say, you know, it never hurts to get another opinion, as I said, so – andagain, it’s been years and so it’s certainly not an urgent thing. But I suspect if you have active lymphomaand you’ve not needed to be treated and it’s been stable, it probably is one of the low grade B-celllymphomas. And follicular lymphoma is the most common. So statistically, you know, that’s probably whatit is. But I’m always for second opinions. It gets the primary doctors off the hook, you know.

LAUREN BERGER:Thank you for your question Patty. We’ll take the next question from the web and this one’s from Nike,“Is there an increased risk of lymphoma for people with rheumatoid arthritis?”

DR. STEPHEN SCHUSTER:Absolutely. Patients with autoimmune diseases have an increased incidence of lymphoma. Patients, forexample, with Sjogren’s syndrome and rheumatoid arthritis, may have up to like a 40-fold increase in risk.So not everybody with rheumatoid arthritis gets lymphoma, or Sjogren’s gets it, they have a substantiallyhigher risk than the average person. Because these are autoimmune diseases and the immune system ischronically stimulated.



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DR. STEPHEN SCHUSTER:Now there’s a lot of talk about the immunosuppressive drugs that are used to treat rheumatoid arthritis,causing lymphoma. These would be the antibodies that inhibit TNF and – or the low dose chemotherapydrugs like methotrexate. These immunosuppressive drugs have some risk of increased – for causinglymphoma. And that may be in fact true, however, I think everything’s a risk-benefit decision. I mean, ifyou have severe rheumatoid arthritis, do you want to accept a slight – even slightly higher – you alreadyhave a higher risk of leukemia, do you want to accept a slightly higher risk or do you want to haveirreversible joint destruction, which the new drugs can prevent? So I think, you know, there’s a risk-benefit decision and it’s acceptable sometimes to take an increased risk.

But yeah, clearly there’s an increased risk of lymphomas both in untreated and treated patients withrheumatoid arthritis.

LAUREN BERGER:Thank you for your question, Nike. We’ll take the next question from the telephone audience, please.

OPERATOR:The next question comes from Jean in New Mexico. Jean, please state your question.

JEAN:Yes, sir, I just wanted if you could go over the acronym BIG again.

DR. STEPHEN SCHUSTER:Oh, yeah, that’s just how we should think of making a diagnosis. B would be biopsy, looking under themicroscope at the histology; I would be immunophenotype, that’s staining for the CDs, either on tissuesections or by what they call flow cytometry; and the G is genetics, genotype, that’s the DNA analysis tolook for specific chromosomal changes. So the biopsy, the B in BIG, what it looks like under themicroscope helps you make the diagnosis. The I, which is the immuno-staining for the CD pattern, helpsyou make the diagnosis. And the G, the genetics, helps you make the diagnosis. And to do the WorldHealth Organization approach to making a diagnosis, we have to do all three of those things.

LAUREN BERGER:Thank you for your question, Jean. We’ll take the next question from the web audience and. Carltonasked, “How do you decide when to treat indolent lymphoma?”

DR. STEPHEN SCHUSTER:If an indolent lymphoma is causing symptoms, that’s easy, you know, we can relieve symptoms and putpatients into remission. If the lymphoma is causing organ dysfunction, that’s obvious, even if it’sasymptomatic, we may want to treat. And organ dysfunction would be like, for example, bone marrowsuppression causing anemia. That may be enough – patient may not feel the anemia, but there’s organdysfunction, so there’d be an indication to treat. So symptoms that a patient has like night sweats, fevers,organ dysfunction like anemia, you know, or sometimes just in the course of following a patient’s diseaseand its anatomical locations and its growth rate, an oncologist may decide that he wants to prevent the



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DR. STEPHEN SCHUSTER:development of symptoms or organ dysfunction and jump in at some point in time with a preemptivestrike. But in general, in asymptomatic patients whose organ function is good, who don’t have impendingproblems from a large tumor volume, there’s no advantage to jumping in with an early treatment. Andcertainly with the pace of change of recommended therapies and new therapeutic options, I think there’seven some benefit to waiting to treat until you have to be treated.

LAUREN BERGER:Thank you for your question, Carlton. We’ll take the next question from the telephone audience, please.

OPERATOR:The next question comes from Teresa in Washington. Teresa, please state your question.

TERESA:I had a bone marrow transplant, mantle cell lymphoma, Stage IV, at Seattle Cancer Care Alliance. I wentthrough R-CHOP times six, radioimmunotherapy and then a stem cell transplant. I’ve been in remissionfor four years, yay, and I’m – when and if I fall out of remission, I don’t know if aggressive treatmentwould have been selected for me back then, knowing what we know now, maybe they would havewaited a little longer, ibrutinib maybe as a first-line, who knows. But what my question I guess really is, iswhen and if my mantle cell lymphoma, I fall out of remission, I understand that cancer usually comesback with a roar.

DR. STEPHEN SCHUSTER:No, not necessarily, not necessarily. I mean – and with regard to mantle cell lymphoma, you know, it’s avery heterogeneous disease and can be quite aggressive or even quite indolent. And sometimes thebest approach is treatment like you’ve had. And the fact that you’re in remission for four years is great.There are additional options now for patients with mantle cell that fall out of remission and these arethings like ibrutinib or lenalidomide, which are spectacular drugs, and even partner with rituximab. So itmay be that if you ever suffer relapse, your next treatment’s even less aggressive than your first. But itsounds like you’ve done very well and, you know, that four years in remission is great. I think that youhave every reason to believe you’ll stay in remission.

LAUREN BERGER:Thank you for your question, Teresa. We’ll take the next question from the web. This one’s from Lorettaand Loretta asks, “How effective is rituximab alone for indolent lymphoma? And then after two years ofmaintenance treatment, what happens then?” So two–part question.

DR. STEPHEN SCHUSTER:Yes, so it’s variable. Meaning there are some patients who you can give four doses of Rituxan to andthey’ll have a complete response. And other patients you give four doses of Rituxan to, four weeklydoses, and they have less than a complete response, a partial response. Or other patients that have noresponse. So I tell you that the outcome depends on factors that we don’t quite understand. There’spatients that can have, you know, two years of Rituxan maintenance, Rituxan without any chemotherapy,



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DR. STEPHEN SCHUSTER:and stay in remission for – I have patients five, six, seven years in remission with just Rituxan alone. Nowthat’s not most patients, but it’s some patients.

So statistically it won’t be the majority that’ll stay in remission for more than five years with – after twoyears of Rituxan monotherapy – but some patients will.

So the answer is if I look at statistics I’d tell you that there – I could give you percentages, but they’rekind of meaningless. It depends on the individual patient, how well they responded to it. And the kineticsof that response. And then you could make a better guesstimate.

LAUREN BERGER:Thank you for your question, Loretta. We’ll take the next question from the telephone audience, please.

OPERATOR:The next phone question comes from Gary in Pennsylvania. Gary, please state your question.

GARY:Hi, Doctor. Thanks for the advice. On the Rituxan with Zevalin, why aren’t they using that any more?

DR. STEPHEN SCHUSTER:It’s still available, Gary.

GARY:Did it fall short of their goal, or what?

DR. STEPHEN SCHUSTER:No, no, it’s still – Zevalin is still available, it’s an FDA approved therapy. It even has – it has a label forpart of initial therapy as consolidation following chemotherapy, or for relapsed follicular lymphoma, andCD20-positive lymphoma. It’s just not – it doesn’t tend to be as widely used or as high profile as yearsago because now there’s just so many things out there.

LAUREN BERGER:Okay, thank you for your question, Gary. We’ll take the next question from the web audience and this isfrom Venki. “Dr. Schuster, do you have any specific treatment plans for double-hit lymphoma?”

DR. STEPHEN SCHUSTER:There was a great session at the ASH meeting that we were just at, on double-hit lymphomas, and so thedefinition is becoming more precise and if we accept that as somebody that has a C-MYC rearrangementand a BCL2 rearrangement, you know, then I’ll say yes, that’s a double hit as I understand it.

The best results in double hit that we’ve seen and we’re actually working on a manuscript, is usingsomething a little more aggressive than R-CHOP as an induction. And then we try to get patients to atransplant. I think that things are going to change. There’s a drug now that’s being developed thatinhibits the BCL2 protein, it’s called ABT199, and it’s being used together with standard chemotherapy on



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DR. STEPHEN SCHUSTER:clinical trials for B-cell large cell lymphomas. And I think that would be theoretically a spectacular agentfor double-hit lymphoma. So if I had a patient with a double-hit lymphoma, I would either use a moreaggressive regimen than R-CHOP, I’d probably use R-EPOCH, something like that, and try to get thepatient to a transplant procedure in first remission. Or I would, if possible, I’d try to get them onto theprotocol that includes the BCL2 inhibitor with R-CHOP. So that would be my approach to somebody thathad double-hit.

LAUREN BERGER:Okay, thank you, Venki, for your question. We’ll take the next question from the web audience and thisone is from Kay and Kay asks, “I’m on Medicare and was just informed that I have reached my lifetimelimit of PET scans.” And just as a commentary, Medicare will cover up to three PET scans after the endof treatment for cancer and any subsequent PET scans must be preapproved. But the question then, thefollow-up question she then asks is, “How much less accurate are CAT scans?”

DR. STEPHEN SCHUSTER:Well, I don’t think there is a lifetime limit on PET scans if there’s an indication for the scan. So if they’reusing the scans for surveillance, for recurrence of disease, in someone who has no symptoms, then Ithink there’s an imposed limit. But if somebody develops a new symptom or a new problem that needsto be investigated, then a PET scan can be ordered.

In general, we’re getting away from all this radiologic surveillance. Most of the aggressive lymphomaslike large cell lymphoma, we’re done at about two years, large cell and Hodgkin lymphoma, and follicularlymphoma similarly, you know, although many people are doing surveillance imaging even out to fiveyears, I think that it’s really overdone. Most relapses or recurrences, the patients come to you and tellyou they have a symptom, you know, or there’s a finding on physical exam or there’s a new laboratoryabnormality on routine screening. And we analyze this in our own practice and I’m sure that this iscorrect. So I’m actually getting away from a lot of surveillance imaging. But if you have symptoms, thereis no limit on imaging procedures that you can have. It’s just they’ll limit it based on indication. In yearspast, a lot of oncologists were just doing scans every three months for five years. I think it was excessive.

LAUREN BERGER:Thank you for your question, Kay. And if patients have additional questions about insurance or otherthings that we might be able to be helpful for, the Information Specialists at The Leukemia & LymphomaSociety would be happy to help you. The toll-free number is 800-955-4572. Thank you for your questionagain, Kay, and thank you all for your questions. Dr. Schuster, we really, really appreciate the informationthat you’ve provided. And we hope that this information will assist patients and their families in theirnext steps.



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Slide 53: LLS Resources

LAUREN BERGER:The Leukemia & Lymphoma Society also offers online chats for patients and caregivers to help shareexperiences and support each other. And these chats are moderated by oncology social workers. Wespecifically have a lymphoma chat and it’s held on Monday and Wednesday evenings. There’s a flyer inyour packet and feel free to call an Information Specialist or go to www.LLS.org/chat.

And if we were not able to get to your question today, please call the Information Specialists at TheLeukemia & Lymphoma Society. We are open from 9 AM to 9 PM Eastern Time. Or you can reach us byemail at [email protected] and the phone number again is 800-955-4572. They can also help you withclinical trial searches and other financial assistance information.

DR. STEPHEN SCHUSTER:Can I just add one thing? Patients, everyone out there, feel free to ask your doctor, too. I meanoncologists are by and large very much open to questions and patients should not feel inhibited.Just, you know, ask your doctor these questions, too.

LAUREN BERGER:Absolutely, thank you.

And as a reminder, you can download and print Dr. Schuster’s slides and you can also download andprint a booklet from The Leukemia & Lymphoma Society on non-Hodgkin’s lymphoma, and it’s on ourwebsite at www.LLS.org/programs and remember to click on today’s program and you’ll get thatinformation.

Dr. Schuster, thank you so much for volunteering your time with us today. On behalf of The Leukemia &Lymphoma Society, thank you all for joining us. We wish you well.

END



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nhl: keys to an accurate diagnosisthis slide is just to illustrate the lymphatic circulatory system....

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