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GREG BERK, MD:  Hello, my name is Dr. Greg Berk from New York Hospital Cornell Medical Center, and I am pleased to have Dr. Bruce Cheson from the National Cancer Institute today to discuss various aspects of the treatment of indolent lymphomas.  Dr. Cheson is Clinical Professor of Medicine at Georgetown Medical Center and he is also Head of the Medicine Section at the Cancer Therapeutic and Evaluation Program at the NCI.  Thank you, Dr. Cheson, for joining us today.
 

BRUCE CHESON, MD:  It's a pleasure to be here.

GREG BERK, MD:  Dr. Cheson, can you discuss some of the changes in our new classification system which is coming out this year in regards to what we've referred to in the past as the indolent or low-grade lymphomas?
 

BRUCE CHESON, MD:  Well, the non-Hodgkin's lymphomas have been traditionally divided into low, intermediate and high-grade by the Working Formulation that was published about 16 or so years ago.  And what was found at that time was that a number of the diseases didn't fit quite right into their designated categories and, as the years went on, a number of new entities were identified which hadn't fit in either because they weren't recognized at the time that the Working Formulation was designed.

In about 1994 an international group of pathologists developed what was called the REAL classification, the Revised European-American Lymphoma classification, which has become over these years universally adopted as the new way to classify lymphomas.  It will be modified in the very near future to a WHO or World Health Organization classification with just some very minor changes.  And what this has done is categorized lymphomas into a large number of individual diseases but more precisely based on their lineage, that being B-cell, T-cell or Hodgkin's disease, and by whether they are indolent or aggressive and based on immunological and biological features.

Now as I mentioned, a number of the diseases which we now encounter weren't recognized a number of years ago.  For example, we were talking about the indolent lymphomas.  The MALT lymphomas, the mucosa associated lymphoid tissue lymphomas, which account for a large proportion of, for example, gastric lymphomas.  They were unknown at the time of earlier classifications and they are now put in the group of indolent lymphomas.  And there are other groups of lymphomas as well that fall into this category.

The mantle cell lymphoma which is more of an aggressive lymphoma previously got mixed up in with small lymphocytic lymphoma with diffuse small cleave lymphoma and in a variety of other categories.  It's now been separated out unto itself as perhaps the worst of all possible lymphomas.

So what the new classifications have done has been to provide order by categorizing lymphomas not just by what they look like under the microscope but also by their immunological, biological and clinical features.  And it will hopefully in the future make these lymphomas easier to direct our therapies against.
 

GREG BERK, MD: Thank you, Dr. Cheson.  Since you mentioned the MALT or gastric lymphomas of MALT origin, I was wondering if you could comment on some of the current evolving concepts in the treatment of this disease...
 

BRUCE CHESON, MD:  Well, the MALT lymphomas are one in a string of very interesting lymphomas that appear to have an infectious agent as the etiology of the tumor.  There are a number of lymphomas for which infections appear to be, at least in some way, associated with disease.  Way back when, there was the Mediterranean intestinal lymphoma....  And this was found to be caused by some still yet poorly characterized pathogen.  There was Burkitt's lymphoma and the Epstein Barr virus, and Hodgkin's disease and the Epstein Barr virus.

And then there was the MALT lymphomas that you've mentioned and what has been found is that this, when it occurs in the stomach, often occurs in association with an infection with the microorganism called Helicobacter pylori. And what is impressive is that the majority of patients who get treated with appropriate antibiotics for this Helicobacter infection experience total regression of their MALT lymphoma.  And in many of these patients it never comes back.  So it's kind of cute that we now have a series of lymphomas, and I didn't go through the whole list for which there are some infectious associations and perhaps this may lead to a new and innovative way of approaching the therapy of these lymphomas.
 

GREG BERK, MD:  Very good.  Can you comment specifically Dr. Cheson on how we're treating the MALT lymphomas of the GI tract at this point?
 

BRUCE CHESON, MD:  Well, the MALT lymphomas if they are isolated to the stomach, initially -- and you can identify the presence of this Helicobacter pylori organism ­- then we're using a triple antibiotic regimen.  And the antibiotics vary from group to group, but the use of these antibiotics has resulted in complete remissions in about 80% of the patients in some series, 60% or so in others.  And of these, recurrence happens in fewer than half of the patients.
 

GREG BERK, MD:  Very good.  Getting more to the more typical type of patient with indolent lymphoma, and obviously this is a field where oncologists have always felt there is very much an art to take care of patients, especially in the decision to treat or not to treat.  You know, the watchful waiting approach vs. treatment.

Once a decision is made to treat patients with indolent lymphoma and perhaps we should break down, perhaps an elderly age group population, can you comment on the certain treatment trends?  I know you follow these very closely.
 

BRUCE CHESON, MD:  Let me first reinforce a point that you made.  And that is, not every patient with an indolent lymphoma requires therapy.  And there have been several trials looking at early intervention into those patients who could be "watched and waited."  And none of these studies has shown any benefit from early intervention using primarily alkylating agent-based regimens.

But once a patient does need therapy, either because there is bulky or massive adenopathy or hepatosplenomegaly or rapidly progressive disease, disease-related symptoms, bone marrow compromise or other organ compromise because of lymphomatous involvement or other reasons, then there is a whole long list of therapeutic options -- from single alkylating agents to alkylating agent-based regimens such as CVP or Cytoxan, vincristine, prednisone to anthracycline containing regimens such as CHOP.  None of these seem to be any better than any other.  You may get quicker responses with some such as CVP or CHOP compared with an alkylating agent alone, but the responses don't tend to be any more durable.

What's happened over the past few years is there has been an enormous amount of excitement based on several new classes of compounds which are very active in the treatment of the indolent lymphomas.  Probably the first class of drugs has been the purine analogs, such as fludarabine which is the most active drug for the treatment of chronic lymphocytic leukemia and has now been shown to be highly effective for the treatment of indolent lymphomas.  For example, in patients with indolent lymphomas when fludarabine as a single-agent is used as the initial therapy, it has a complete remission rate of close to 40% and an overall response rate of almost 70%.  And that's higher than we've generally seen with alkylating agent-based regimens alone.

I mean when you combine fludarabine with other agents such as cyclophosphamide or mitoxantrone, then the overall response rate and complete remission rate gets even higher. Unfortunately despite the fact that you can get astonishing response rates, no one seems to be cured.  The incurability of the indolent lymphomas remains a mystery.

Another important class of drugs that has stimulated lots of enthusiasm have been the monoclonal antibodies.  And there are now several of these available either commercially or in the clinical research setting and rapidly approaching commercial availability.

The first of these was IDEC-C2B8 which now is called rituximab or Rituxan or if you happen to be in Europe, it's called Mabthera.  This is an anti-CD20 monoclonal antibody which when used to treat patients who have relapsed or refractory follicular low-grade lymphoma will get about a response at about 50% of patients including about 6% complete remissions.  And the drug can be used repeatedly and get responses on more than one occasion.

It has now been combined with other chemotherapy agents and combination regimens with very impressive results particularly, for example, the combination of CHOP and rituximab for indolent lymphomas in a study published earlier this year by Dr. Czuczman and coworkers in the Journal of Clinical Oncology.  The response rate to the CHOP-rituximab [regimen] in mostly previously untreated patients was 100%, about two-thirds of which were complete remissions and the duration of these responses was impressively long.  Whether this is any better than CHOP alone will be clarified by some ongoing randomized trials but the data are better than we've ever experienced with CHOP alone.  But in phase II trials, there is always the possibility of such things as selection bias or other issues.

Other antibodies which are of a high level of interest include Bexxar which is an I-131 conjugated monoclonal antibody which in patients who receive it as treatment for relapsed or refractory disease will get a response rate of over 70% including about 30% complete remissions.  When used as front-line therapy in a small number of patients, the response rate was 100% including over 60% complete remissions.

A third antibody rapidly approaching the FDA is Y2B8 which is the rituximab antibody conjugated to yttrium, yttrium-90 which is another radioisotope which has some advantages over I-131, particularly you can give it more readily as an outpatient in all states.  There are some restrictions in some states on the use of I-131 as an outpatient.  And this antibody has also shown impressive results.

Now where these various drugs will fit in with each other, the fludarabines, the Bexxars, the Y2B8s, the rituximabs  -- how we can combine them? how we can sequence them?  what we do with them to take advantage of their different characteristics is the subject of innumerable ongoing clinical trials but it's provided an enormous amount of enthusiasm and optimism that we may finally be pushing the survival curve for patients with indolent lymphomas ahead.
 

GREG BERK, MD:  I see.  Very interesting.  Thank you.  Dr. Cheson, to back track a little bit on your comments on the purine analogs...  Do you view in the indolent lymphomas the activities of the three available purine analogs that we have on the market now – fludarabine, cladribine, and pentostatin as very different?
 

BRUCE CHESON, MD:  Let me take it from the bottom up.  I think the data with pentostatin or deoxycoformycin or Nipent are very sparse and it makes it hard to compare to the other drugs.  These studies were done a number of years ago and they're sort of hard to interpret.  A lot of histologies were lumped together.  So I don't think we can really comment on that drug.  I know its current pharmaceutical sponsor is enthusiastically pursuing it in a number of B-cell malignancies and perhaps we'll have more data.

When you compare the results with fludarabine and cladribine particularly in previously treated patients, the response rates are relatively similar although the duration of responses seems to be somewhat longer with fludarabine albeit there are no head-to-head comparisons.
 

GREG BERK, MD:  Right.
 

BRUCE CHESON, MD:  Upfront you find sort of the same thing.  You may get a few more complete remissions with fludarabine but that's probably within confidence intervals of response rates.  And the overall response rates are about the same, but again it appears that fluda – fludarabine may be associated with a somewhat longer duration of response.  But again, it's hard to compare these different studies because of differences in eligibility criteria, differences in patient characteristics and what have you.

Are there major differences?  I don't think the differences are major.  There are certainly major differences in expense.  Cladribine is about four times the price of fludarabine and there is some increased toxicity with cladribine compared to fludarabine.  There has been a lot more experience with fludarabine, not only as a single-agent but also in combination with other compounds.  So I think that the fact that we need to be moving forward into combinations has led to a more wider use of fludarabine because it seems to be readily combinable with other drugs and there's just a lot more experience with it.  So people just seem to be using it more.
 

GREG BERK, MD:  I see.  Thank you.  Dr. Cheson, I have one more question for you today.  It relates to the upcoming trials, the ongoing trials and upcoming information on vaccines for indolent lymphoma, particularly in patients in first remission.  Can you comment?  Has lot of this work come out of the NCI?
 

BRUCE CHESON, MD:  Right.  The work that's come out of the NCI by Larry Kwak and his coworkers is very exciting and stems from his previous experience when he was with Ron Levy at Stanford University.

Both groups have provided data which suggests that you can immunize the patient against their lymphoma.  And that if a response, whether it is cellular and/or humoral response can be induced and those patients appear to have a longer survival.  Well, that's the old responder/ nonresponder problem and it makes it not clear as to whether it's really the drug that's doing it or whether it's the patient that's the factor in all of this.  So the only way you can resolve this issue is with a randomized trial.

And Dr. Kwak is about ready to activate a multi-center national study which will be coordinated from the NCI. A number of centers will be looking at the efficacy of this vaccine when added to patients who have experienced a response to chemotherapy as part of front-line treatment. And it may be that in the future these vaccines may provide another major important tool to the treatment of patients with indolent lymphomas.  But we're really not going to know until the randomized studies have been completed.  But the preliminary data are admittedly very exciting.
 

GREG BERK, MD:  Dr. Cheson, I very much appreciate your joining us today.  Your insights have been very helpful.  I thank you.
 

BRUCE CHESON, MD:  My pleasure.