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GREG BERK, MD:  Hello, I'm Dr. Greg Berk.  I am pleased today to welcome Dr. Andrew Zelenetz, Chief of the Lymphoma Section at the Memorial Sloan Kettering Cancer Center and Associate Professor of Medicine at Cornell Medical School.  Welcome, Dr. Zelenetz.
 

ANDREW ZELENETZ, MD:  Thank you.
 

GREG BERK, MD:  Dr. Zelenetz, today we're going to discuss mantle cell lymphoma.  The first question  I have for you is -- can you tell us where mantle cell fits into our general classification of lymphoma at this time?
 

ANDREW ZELENETZ, MD:  Mantle cell lymphoma is an entity that was recognized actually by Lennard, and  in the Lennard classification it was actually the centrocytic lymphomas.  In the more commonly used International Working Formulation that was in wide use in the United States until recently, most of these lymphomas were classified in the category of diffuse small cleaved cell lymphomas.  However, some of them, in fact, fell into the follicular lymphoma category and a small proportion also fell into the small lymphocytic lymphoma category.

In the International Working Formulation, however, it was simply just not recognized as a separate distinct entity.  The REAL classification for lymphomas has recategorized these as a distinct entity and they, in fact, are very pathologically quite distinct.  They're characterized by a monoclonal B-cell population. They uniformly express CD19 and CD20.  However, they do express the CD5 antigen as well like the CLL or small lymphocytic lymphoma of the CLL type.  What distinguishes them immunohistochemically and by flow cytometry is the lack of expression of CD23 and the presence of FNC-7.  Pathologically the tumor is characterized by the overexpression of the protein cyclin D1.  This overexpression occurs as a consequence of a chromosomal translocation juxtaposing the immunoglobulin heavy-chain locus on chromosome 14 to the cyclin D1 gene on chromosome 11.  So this is a distinct pathologic entity which is now well characterized, better able to be recognized particularly because of the availability of immunohistochemical reagents for CD5 and cyclin D1.
 

GREG BERK, MD:  Dr. Zelenetz, do most mantle cells actually have this well defined cytogenetic abnormality if you look for it?
 

ANDREW ZELENETZ, MD:  Well, the presence of the 11, 14 chromosomal translocation has been variably reported in series of mantle cell lymphoma patients from as low as 50% to as high as  90%.  I think part of it is the difficulty in obtaining mitoses from the population and knowing that you're, in fact, observing the malignant clone.

However, when you look at the protein product, the cyclin D1 gene, they're almost universally and certainly in excess of 90% of the cases that otherwise are characterized as mantle cell lymphoma on the basis of markers.  You will see the overexpression of the cyclin D1.  So that seems to be a more universal feature than the translocation itself.  And again, the reason – the difficulty detecting that translocation may well have to do with the difficulty in obtaining clean cytogenetics from these mantle cell lymphomas.
 

GREG BERK, MD:  Thank you.  And Dr. Zelenetz, can you comment on how we view mantle cell lymphomas, stage for stage, as far as prognostically... how do we view them in contrast to your typical, for instance, large cell lymphoma?
 

ANDREW ZELENETZ, MD:  Prognostically they actually unfortunately take features, the bad features from intermediate-grade lymphoma and the bad features from low-grade lymphoma.  In that with the current therapies they have a median survival of two to three years, typical of the intermediate-grade lymphomas.  However, they're incurable by conventional treatment so there is no survival plateau with the currently available treatments, although a number of investigational treatments are being used.

In terms of staging, this is a systemic illness.  There is a male predominance.  And bone marrow and GI tract involvement is very common.  In fact, GI tract involvement is so common that with the confirmed diagnosis of mantle cell lymphoma we have been recommending an evaluation of the GI tract with upper GI endoscopy and colonoscopy.

The colonic – the colonoscopic appearance of mantle cell lymphoma can be very unusual and can present as innumerable lymphoid polyps scattered throughout the colon.  And this is sort of a unique separate entity within mantle cell lymphoma.  Circulating cells are very common as is bone marrow involvement.
 

GREG BERK, MD:  Thank you.  Dr. Zelenetz, short of putting patients on specific protocols for mantle cell lymphoma, is there a standard of care of what type of chemotherapy we should be using for this disease?
 

ANDREW ZELENETZ, MD:  Well, I think that's a controversial point in that because we have failed to demonstrate a survival plateau in this disease, it's difficult to define a clear standard.  CHOP chemotherapy which many people will use as their first-line therapy can be highly active and response rates, overall response rates of 70-80% are very common.  The problem is that  responses tend to be of brief duration and re-treatment tends to be rather unsuccessful.  Fludarabine as a single-agent does not have substantial activity though there are some indications that fludarabine in combination with alkylators as in the Cytoxan-fludarabine regimen or in the FND regimen may have some activity.

The MD Anderson group has reported excellent results with high-dose alkylator-based therapy in their hyper-CVAD regimen and they feel that this has been highly beneficial. And that's probably currently the best published data for longevity of response though I think that needs to be confirmed.
 

GREG BERK, MD:  Andy, is there any data on incorporating any of the monoclonal antibody therapies into the treatment of mantle cell lymphoma.
 

ANDREW ZELENETZ, MD:  Well, rituximab has been used by the French group and reported by Coiffier in his study of intermediate-grade and mantle cell lymphoma.  About one in three patients with mantle cell lymphoma had major responses to a regimen of rituximab given actually for a period of eight weeks.  It's not clear whether or not eight weeks is required. That was just the study design in that particular study.
 

What it does show is that this antibody is active as a single-agent in the treatment of mantle cell lymphoma and actually is active in chemotherapy-resistant disease.  The role of rituximab in the combination with chemotherapy is clearly intriguing and is currently the subject of investigation in regimens like that described by Czuczman in the Journal of Clinical Oncology for the treatment of low-grade lymphoma.  And that's the combination of rituximab and CHOP.
 

GREG BERK, MD:  Is that combination being used in first remission or in consolidation therapy post-CHOP?
 

ANDREW ZELENETZ, MD:  The rituximab plus CHOP trial is actually a combination of rituximab integrated with the CHOP chemotherapy.  The post-remission rituximab therapy is another approach to studying the activity, and that is, to use the rituximab if I'm mopping up in first remission.  And there is a small trial actually with that study design going on in mantle cell lymphoma as well.  So there is both the combined chemo-antibody as well as chemo followed by antibody as an adjuvant.  But time will tell whether this is going to change the natural history of the disease.
 

GREG BERK, MD:  Thank you.  Dr. Zelenetz, the last subject that I'd like to discuss in relation to mantle cell is, does autotransplant have a role in this disease either in first remission or in relapsed disease?
 

ANDREW ZELENETZ, MD:  The role of autotransplant is controversial.  One of the largest studies, though it's still quite small, was reported by Arnold Freeman from the Dana Farber Cancer Institute and showed that transplant as second-line therapy was remarkably unsatisfying as a treatment with no survival plateau despite some responses.  They tended to be transient.

Others have found actually strikingly different results with and are reporting particularly the group from Nebraska reporting substantial more activity of transplant in mantle cell lymphoma.  Many groups across the country are exploring the role of transplantation as consolidation for initial therapy and that is conventional dose chemotherapy and when a remission is achieved to follow that with high-dose therapy and autologous stem cell rescue.  This is a promising area, though the jury is still out and we still have yet to determine if this is going to be an important treatment option.

The other bone marrow transplant approach that does appear to have some promise is that of allotransplantation. Again, the numbers here are very small, though in some series the relapse rate after allotransplant seems to be reduced, suggesting that there is a graft vs. tumor effect opening the way to a variety of treatment options including possibly mini-allotransplant as a treatment option.  But these all must be considered investigational and patients should be studied on these with these treatment programs.  But they should be studied in the context of a clinical trial.
 

GREG BERK, MD:  Dr. Zelenetz, I really very much appreciate your helpful comments today in our discussion of mantle cell lymphoma.  Thank you.
 

ANDREW ZELENETZ, MD:  Okay.  Thank you very much.