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New Treatments for Non-Hodgkin’s Lymphoma

Non-Hodgkin’s lymphoma includes approximately 20 different diseases and there are five times as many cases of non-Hodgkin’s lymphoma as there are Hodgkin’s disease.  Non-Hodgkin’s lymphoma has the much more typical age distribution that we are used to from solid tumors. So here’s the epidemiology, and there is a fifty-fold increase from childhood to late adulthood in the incidence of non-Hodgkin’s lymphoma for both genders. So this is a disease that much more frequently presents in the elderly patient. The other major epidemiologic trend is the steady increase in the number of cases. Between 1-3% rise in the incidence of non-Hodgkin’s lymphoma has been occurring for over the past 50 years. This is a very robust trend and seems to be continuing right through the present day. It obviously antedates the AIDS epidemic and is not explained simply by the addition that’s been made by age-related lymphomas. And goes on in both genders, as you can see from this slide here. As this happens, lymphoma has jockeyed its way up into the number four position for both genders.

There is a sub-trend. Look here at the young men more recently with this burst of incidence and that is probably related to AIDS and AIDS-related lymphomas. But what I want you to remember is that old people get lymphoma, not exclusively - young people do too - but it is a disease of the older patient population and there is this pressing need to understand why we are seeing more lymphomas - because we really are now - than we saw 20 and 50 years ago.

Risk factors for the development of lymphoma: immunodeficiency states, congenital acquired or induced by immunosuppressive agents, all of those situations lead to an increased risk of developing non-Hodgkin’s lymphoma. But interestingly, immuno-regulatory states or immuno-regulation defects in which the lymphoid system, the immunologic system, is overactive also contributes to an increased incidence of non-Hodgkin’s lymphoma. So when the system goes missing or when it is overactive you still wind up in both situations.

We have a collection of viruses that are either causative or tightly associated with the lymphomas. HTLV-1 which is an RNA retrovirus that has been shown to confer a risk of non-Hodgkin’s lymphoma. A handy thing to remember about this virus is that it only confers a risk of lymphoma when it is acquired congenitally. It almost certainly requires whole lymphocytes to be transmitted in milk. So breast fed babies are the ones that get this disease.

Some of the other problems; immuno-phenotype now was available and was still ignored. The folks in Europe were gaining major insights into lymphoma classification and there was a void or a block exchanging information across the Atlantic Ocean and they were being ignored. And finally, the reason why we needed to move on to something else, is that new entities such as mantel and marginal zone types of lymphoma were identified and needed to be worked into the classification scheme in some sensible fashion.

Now the classification scheme that we have to work with looks more complicated, but makes much more biologic sense and is actually worth spending the time to learn because it is a workable one based on biology. It splits, first, patients into primarily B and T-cell disease, but in the future you will hear more and more about rare NK-cell types of diseases. And then I think the clinician, to make some sense of these B and T-cell lists that the pathologists produce, can actually divide these patients up on the basis of the clinical behavior of the disease. But I would emphasize the pretreatment clinical behavior.

But what is new. This is first a look at what I would call the indolent types of lymphomas, the lymphomas that have a slowly unfolding natural history. To split things, I’ve put in white terms that we already know and are familiar with, and I will not be returning to, and in yellow the new insights and new ideas in classification. So for instance, we have a new name; lymphoplasmacytic, but that’s just plain old Waldenström’s macroglobulinemia or a small

For the follicular lymphomas there is a bit of collapsing. This will actually make our lives somewhat easier. Why are they collapsed? Well, here are the long-term results for treatment of patients with follicular lymphoma, broken down by cell type, at our institution. And I don’t see any stand-out difference in long-term outcome for these patients, whether they are called small-cleaved, mixed, or large cell lymphoma. So one change is that much less emphasis will be placed on sub-typing the follicular lymphomas and they will more reasonably be lumped together. You should realize that some authorities still think that it is necessary to segregate follicular large cell

First, this MALT-type, mucosa associated lymphoid tissue-type of lymphoma. This is now going to be called a sub-type of marginal zone lymphoma in the WHO classification. We used to call this "small lymphocytic lymphoma." It constitutes about 5% of all lymphomas and so it is one of the 12 or 13 most common lymphomas. The age is typical of the elderly patient with lymphoma.

The classic MALT-type of lymphoma; this is a disease that frequently can occur in association with a mucosal surface as it does near the stomach, here. And the special things about this that we need to remember are that because a substantial number of the patients present with limited stage disease, localized disease, irradiation remains a very potent tool for the management of

Then there is the special stand-out case of patients with Helicobacter-associated MALT lymphoma of the stomach. Since you know that story well, I’ll just remind you of it. Here we have a situation in which effective antibiotic therapy can take away the antigenic stimulus on which the lymphoma is still dependent and at least a substantial portion - perhaps 70% or 80% - of the patients effectively treated that way will go into remissions that appear durable through 5-10 years of follow-up. Watch the literature whether those patients maintain those responses for the long run.

When the marginal zone lymphoma presents in nodal tissue, lymph node tissue, rather than an epithelium-associated structure the name that has been applied to it is "nodal type". A name that used to be used and has now fallen out of favor is "monocytoid B-cell lymphoma" but you don’t have to go very far back in the literature to find articles with that kind of a title on them. This is a much more rare type of presentation, 1%. And this is in many ways similar to MALT-type of

Those are what I would consider the major insights in the indolent set of diseases, and I will switch now to what I will entitle the aggressive kinds of lymphomas, based again on how they behaved before they get into your hands. But these are diseases that tend to cause more aggressive problems and more rapidly unfolding natural histories. The major entity, mantle cell lymphoma, a collection of different possibilities for sub-types of diffuse large cell lymphoma, and then the T-cell lymphomas, are the ones I want to concentrate on today because they are the areas where there are new ideas and new insights into lymphoma. If we do that we’ll start out

Where are those treatments going to come from? I think it’s from insights such as have arisen from the cytogenetic and oncogenic evaluation of these diseases. As Peter emphasized, the large majority of these patients have a specific 11-14 translocation or its molecular equivalent in which the BCL-1 gene is translocated into the proximity of the immunoglobulin heavy chain gene, up-regulated, leading to over-expression of cyclin D1 which binds to inhibitors of cell cyclin in such a way as to shorten the G-phase in the growth of the cell. Right now our treatment for this

Shifting gears then to other insights from the more recent steps forward in classification of lymphoma, I wanted to emphasize that with this category, one-third of all the lymphomas that we see fitting into diffuse large B-cell, these can be sub-typed into many different types. Some old names over here in white, and a bunch of new names that have come along. At present for the treating clinician I don't think that any of these entities actually carries with it any implications

The major insight in the aggressive histology of lymphomas in the real or WHO classification is in the area of the T-cell diseases. I’m going to speed up here because Peter has covered some of this ground. The first one that I want to emphasize though is this anaplastic large cell entity. You hear the background of how this was found, using the antibodies that recognized the key 1 antigen. The large majority of these patients turn out to have T or null-cell disease. When the type says B-cell disease just lump it in with diffuse large B-cell lymphoma. These patients have a typical translocation, I’ll return to. And clinically the important thing about this is that just as you

If we go further into the sub-types of T-cell diseases, an area where clarity has been brought by the new classification scheme is in the one where we used to have a syndrome; angioimmunoblastic lymphadenopathy with dis-proteinemia and have come to realize that that syndrome with these symptoms that are listed for you here is in fact a T-cell non-Hodgkin’s lymphoma. When that is recognized it explains a lot about what’s going on. A small number of

The next sub-type that I want you to remember is going to go by the name of "intestinal T-cell lymphoma". I would have preferred the name "enteropathy-associated T-cell lymphoma" because it would have reminded me more about the background of the disease. But this is the kind of lymphoma that develops in patients on a background of gluten enteropathy, or celiac sprue. Sometimes the disease is unsuspected. That is, it isn’t clear that the patient actually has sprue. They’ve never had to go onto a special diet, although most of those patients spontaneously avoid gluten-containing foods. But often the patients are known to have gluten enteropathy and the signal that this particular disease is present is that the previously well-

The other couple of single insights from classification that I just want to remind you of is the, what I will call "affirmation of the behavior of lymphoblastic lymphoma" as the major very aggressive, or leukemia-like T-cell type of disease, and Burkitt’s lymphoma as the major very aggressive B-cell type of lymphoma. I put them down as acute leukemia-like to remind me that in fact often with time these do evolve into a leukemic phase. They frequently involve the

And finally the viral types that I already mentioned; primary effusion lymphoma, almost always seen in AIDS patients but occasionally in patients who don’t have HIV infection, presenting with effusions in the abdomen with ascites or the chest with pleural effusion. The malignant cell

Finally, HTLV-1 type of leukemia lymphoma; just remember that this disease follows an aggressive course. It tends to be seen more frequently in patients from Japan, from the Caribbean basin, from Native Americans and actually native dwellers throughout North America where there is an increased incidence of the disease, and in Morocco, of the places that I know

One slide with oncogenes on it just to emphasize this because this is a favorite kind of question to put onto Board examinations. And that’s the ALK or anaplastic lymphoma kinase gene, which is translocated and linked together with the NPM nuclear phosmine gene in a 2-5 translocation. The fusion gene leads to a fusion protein and it is unclear exactly what the effect of that gene product is. This is seen in association with anaplastic large cell lymphoma of T-cell-type in 50% or more of the patients. Finally, the PAX 5 gene, which codes for a B-cell

Two specific types then to talk about. I’m going to talk about the two common varieties of non-Hodgkin’s lymphoma seen in North America and Western Europe. First of them is the follicular types of lymphoma. This happens to be follicular small cleaved cell, or sub-type of lymphoma. This shows the kind of bright surface immunoglobulin staining that is seen with the malignant cells in this disease. A reasonable approach to treatment for these patients that is emulated in its

This is what happens. The patients with early stage disease do relatively well. This is a time scale out to 10+ years and the patients with more advanced disease do less well with time. Notice how this curve is almost linear and the death rate for these patients is somewhere around 5-7% per year from diagnosis, and holds up quite consistently over very long periods of follow-up, even with the best treatments that we have available today. To emphasize that point, these are data from Stanford University in which they have looked at survival for patients with advanced stage indolent lymphoma. Most of these patients have follicular lymphoma and what they were

Where are we going to go in the future? Well this is a part of the future that is already here. This is the chemical structure for two of the substituted purine analogs. So you have 2CdA cladribine and fludarabine. Each of these has a halogen substitution. One of them a chloride and one of them a fluorine stabilizing the ring structure. This gets stuck in the degradadive enzymes that break down nucleic acid structures and gum up the works, and injure the cells in such a way

I think in most people’s hands and practice today that initial management of the follicular lymphomas still relies on an alkylating agent, typically chlorambucil or cyclophosphamide. And most are relying on fludarabine as a second line therapy. But the time has come to think about moving it up into the first line because in both the first line situation and the first relapse situation fludarabine has been shown to - in randomized trials - to produce a superior outcome in terms of complete response rate, overall response rate, and disease-free survival for patients. So the likelihood of getting into and staying in a remission is higher with fludarabine than can be

Transformation. I list these particular warnings that transformation has occurred. It usually follows the setting of follicular lymphoma in which a large cell lymphoma arises. If any of these warning indicators are present you should strongly suspect it, and these patients will require multi-agent chemotherapy. If one does, this is the kind of results that you can hope to achieve. Disappointing in the sense that most of the patients eventually succumb to the disease but showing that a minority can have that large cell lymphoma brought under control, and switch