Classification System
Cytogenic Abnormalities
Pediatric Data
Role of Bone Marrow Transplantation
Role of Monoclonal Antibodies
GREG BERK, MD: Hello, my
name is Dr. Greg Berk from New York Hospital Cornell Medical Center.
Today I'm pleased to have with me Dr. Ian Magrath, Chief of the Lymphoma
Biology Section in the Pediatric Oncology Branch of the National Cancer
Institute. Welcome, Dr. Magrath.
IAN MAGRATH, MD: Thank you.
GREG BERK, MD: Today Dr.
Magrath is going to be discussing some of the specific diagnostic and treatment
aspects of the high-grade lymphomas. In particular we will be covering
Burkitt's lymphoma and lymphoblastic lymphoma. And I would like to start,
Dr. Magrath, by asking you some particular questions on our classification
system and how it's changed over the last few years, in particular relation
to the high-grade lymphomas.
IAN MAGRATH, MD: Well, the high-grade lymphomas
was a term that was really employed when the working formulation for clinical
usage was developed back in the early 1980s. And this was based simply
on the prognosis of the cases that were put into various different histological
categories, and those who had the worst five-year survival rate, which
was in the region of 25% or so, were categorized as high-grade lymphomas.
This is a bit of a fallacy because these are the lymphomas now that we
can cure most readily and so perhaps is a bit of a misnomer to call them
high-grade lymphomas at this point in history.
Those that we can't cure particularly things like mantle
cell and the indolent lymphomas actually ultimately, of course, do kill
patients and so perhaps we should be rethinking the way that we conceptualize
these tumors. Nonetheless, there were three histologic subtypes that
were categorized as high-grade in the working formulation. These
were the small non-cleaved cell lymphomas which were subdivided into Burkitt's
and non-Burkitt's lymphomas; lymphoblastic lymphomas which are predominantly
of T-cell type arising with a phenotype of precursor T-cells and, as opposed
to [the] predominant subtype of a small non-cleaved, which is [a] B-cell;
and then the immunoblastic lymphomas.
Now with the REAL classification things changed a little
bit because we are now referring to Burkitt's lymphoma which is exclusively
of B-cell origin by definition and Burkitt-like lymphoma which are tumors
which histologically are a little bit variant from Burkitt's lymphoma but
nonetheless resemble them fairly closely and particularly with respect
to their aggressive behavior.
And lymphoblastic lymphoma has remained, but lymphoblastic
lymphoma is not clearly a histological entity. There is controversy about
this, but pathologists in general have a hard time distinguishing immunoblastic
lymphomas from other types of large B-cell lymphoma. And so really
that has fallen by the wayside.
So now in the new World Health [Organization]classification
incidentally, there has been an additional slight change in the nomenclature
so that we have Burkitt's lymphoma, atypical Burkitt's lymphoma, and lymphoblastic
lymphoma remaining from these categories. But as I mentioned, we
have to be a little bit careful about the way we use the term, high-grade.
Grade is really something which is used more by pathologists than by clinicians.
But these tumors are certainly all characterized by their aggression in
terms of their very rapid growth rate and the rapid demise of patients,
if not treated appropriately.
GREG BERK, MD:
Dr. Magrath, are any of these particular high-grade lymphomas associated
with any well-defined cytogenetic abnormalities?
IAN MAGRATH, MD: Yes. Certainly Burkitt's
lymphoma characteristically in essentially all cases. I think it
may even be a better definition than the histology; [it] is associated
with an 8;14, or one of the variant, translocations in which the myc oncogene
is juxtaposed to immunoglobulin sequences, either heavy chain sequences
in the majority of cases (about 85%) or light chain sequences. So
this causes deregulation of the myc oncogene which is a gene associated
with cell proliferation and is probably the primary but not as sufficient,
I'm sure, abnormality in the small non-cleaved cell lymphomas. I'm
reverting to older terminology now and perhaps should say Burkitt's lymphoma.
This same translocation is seen in a small fraction of
large B-cell lymphomas (perhaps 5%-10%), particularly those that have extranodal
presentations. The lymphoblastic lymphomas have – not well studied
in this respect – [there] isn't a characteristic chromosomal translocation
or genetic, molecular genetic abnormality associated with them, but some
of them certainly do have translocations, often involving the T-cell receptor
in that particular case because, as I mentioned before, most of them are
of T-cell origin.
GREG BERK, MD: Thank you.
In relation specifically to Burkitt's lymphoma, Dr. Magrath, can you comment
on some of the new pediatric data that has come out? And how this
may apply to our treatment approach to the adult with Burkitt's lymphoma?
IAN MAGRATH, MD: Well, in recent years, it's become
clear that Burkitt's lymphoma is an eminently curable disease. Three
or four major groups have reported results of approximately 90% long-term
survival. This is a disease, incidentally, in which relapse is extraordinarily
rare, almost unknown after even just about eight months or so from the
time of presentation and the time of initiation of therapy. And so
these results certainly have stood the test of time. There is a very
stable plateau now. And I would say that well over a thousand patients
have been included in studies conducted by the French Society of Pediatric
Oncology, the German BFM Group. And we have a much smaller number
of cases in the National Cancer Institute, but again have achieved approximately
the same results. We've treated about 70-odd patients in the small
non-cleaved category. And others have used our protocol and have
obtained approximately similar results. So certainly Burkitt's lymphoma
and closely related tumors are eminently curable with modern treatment
approaches.
Similarly lymphoblastic lymphoma reports by the BFM Group
in the T-cell variant, which accounts for about 90% of them, are very similar
with a 92% long-term disease-free survival rate. Others have not
got quite as good results, but certainly 75% or above. So that these
high-grade, very aggressive lymphomas also happen to be among the most
curable of lymphomas.
GREG BERK, MD: I do still
think that in the adult population, the data is not as good as the pediatric.
And for instance, with lymphoblastic lymphoma we've always viewed that
in the adult population operationally very much like ALL.
IAN MAGRATH, MD: I think, here's the question that
you asked earlier, was how do these pediatric results apply to the adult
patients with these diseases, and I think this is a very important question.
We for some years at the National Cancer Institute have used these same
treatment regimens in the Burkitt and Burkitt-like lymphomas regardless
of age and have actually obtained essentially the same results.
The French and German protocols have been applied to small
numbers of patients in those countries in the adult age group and the results
appear to be similar. So I think there is a strong case to be made
in the case of the Burkitt and Burkitt-like lymphomas for at least exploring
further the use of the pediatric regimens in adults, with the possibility
that one may see the same kinds of long-term survival rates. Bearing
in mind that it tends to be younger adults who have these diseases.
In the lymphoblastic lymphoma group, I think it's much
less clear as to whether or not adults with these diseases would respond
as well as children. Certainly you mention the fact that you consider
it to be acute lymphoblastic leukemia, in disguise, as it were, and there's
no question that the dividing line between acute lymphoblastic leukemia
and lymphoblastic lymphoma is arbitrary.
And just as ALL in adults tends to do less well than ALL
in children, it may well be that lymphoblastic lymphoma in adults for biological
reasons does less well than lymphoblastic lymphoma in children. Certainly,
as I mentioned before, the molecular level lymphoblastic lymphoma is much
more heterogeneous than Burkitt’s lymphoma. So that although it may
be worth determining whether the same kinds of protocols used in children
are as effective in adults. And I don't mean by that simply applying
any acute lymphoblastic leukemia protocol, but perhaps the same protocol
as used in children because there may be something special about those
protocols. It's by no means clear that one would achieve in the lymphoblastic
lymphomas in adults the same results, as being achieved in children.
GREG BERK, MD:
In that regard, Dr. Magrath, can you comment on the role of bone marrow
transplantation, specifically in lymphoblastic lymphoma? And what
I'm specifically interested in is, is there any role for bone marrow transplantation
in first remission with this disease?
IAN MAGRATH, MD: I think that's an important question
because many people simply extrapolate from the fact that there are patients
with these diseases who can be cured by bone marrow transplantation and
patients who relapse who can be cured. Extrapolate from that information
to the upfront situation and argue that doing a bone marrow transplantation
at first remission may be a good way to go.
Well, it may. But I think one of the problems that
I have with that conceptually is the fact that the major problem in these
diseases in adults is getting the patients into remission. With CHOP,
for example, in the small non-cleaved cell lymphomas, maybe only 50% or
60% of patients enter remission. In lymphoblastic lymphoma, it's
not all that much different. So if one transplants, which is the
usual situation, those who achieve remission, but with chemotherapy, one
is still casting to one side, as it were, all of those patients who do
not achieve remission. So well even if you cured a 100% of patients
that you transplanted in first remission, you would still be left with
perhaps 40% of patients who never achieved remission and didn't have a
transplant and probably would do very poorly if you did give them a transplant
anyway. So I don't really think that transplantation is the solution.
In addition, of course, one has to bear in mind that those
who achieve remission with those regimens, and therefore would go on to
a transplant, a reasonable fraction of them – let's say half, if you like
– would be cured by the chemotherapy. And so you're actually subjecting
at least 50% of patients to a transplant that they don't need in terms
of cost and potential toxicities and so on. That's something to be
taken into consideration. So at this point I would view the role
of transplanting first remission as very experimental, and personally,
I would have thought it more important to try to get a higher fraction
of patients into remission. Then if one were to see that a higher
fraction of these were relapsing which I think is unlikely, because the
more you get into remission in general, the fewer relapse, one could very
seriously consider bone marrow transplantation for a subgroup of patients.
Of course, if one could define a very high-risk group
of patients and there are many ways to attempt to do that, such as the
International Prognostic Index, then it may be worth trying to transplant
that particular subset. But again, I think the problem is really
getting them into remission first.
GREG BERK, MD:
Thank you, Dr. Magrath. Lastly, in regards to some of the newer therapies
which are already in place for the low-grade and intermediate-grade lymphomas,
such as monoclonal antibody therapy, are there any new antibodies on the
horizon or any of the existing antibodies that are out there – do any of
these have a role in the high-grade lymphomas at this time?
IAN MAGRATH, MD: Well, again, I think it depends
which age group we're talking about. And obviously if we're talking
about the children, one has to be very careful because we're already getting
about 90% long-term survival rates. I think in that situation, the
question would be, might a monoclonal antibody reduce the need for toxic
chemotherapy or reduced toxicity or something?
As you know, for example, Rituximab in general used as
the sole therapeutic agent has not been very successful in the more aggressive
lymphomas, not nearly as successful as it has been in the indolent lymphomas.
But it could be that it would be a valuable addition to chemotherapy.
I don't think there are any new antibodies out there.
There is the anti-CD20, anti-CD19 and so on. I
certainly feel that it's worth exploring these approaches in conjunction
with chemotherapy, at least initially.
GREG BERK, MD: Dr. Magrath,
I very much thank you for joining us today.
IAN MAGRATH, MD: It's been a pleasure.
