Hair loss Treatment Center

GREG BERK, MD:  Hello, my name is Dr. Greg Berk from Cornell Medical Center.  And I'm happy to have Dr. Madeleine Duvic, Chief of Dermatology and Professor of Medicine at the MD Anderson Cancer Center in Houston, Texas, today with us to discuss the treatment of cutaneous T-cell lymphoma.  Welcome, Dr. Duvic.
 

MADELEINE DUVIC, MD:  Hello.  How are you?
 

GREG BERK, MD:  Very good thanks.  Dr. Duvic, can you tell us a little bit about how we classify and stage cutaneous T-cell lymphoma?
 

MADELEINE DUVIC, MD:  The term cutaneous T-cell lymphoma is an umbrella that includes a lot of different kinds of T-cell lymphomas that begin in the skin.  Some of them are predominantly CD4 so that using cell markers helps us to classify them.  And those are like the mycosis fungoides variety which is the most common form of CTCL, and there is a spectrum of involvement in that disease that ranges from just a few pink patches on the skin all the way to leukemic involvement with a Sézary syndrome.  And that has its own staging classification, 1 through 4B, which we could talk about.

And then there are other forms of cutaneous T-cell lymphomas.  One that's HIV – HTLV-1 associated.  The large anaplastics, CD30 positive T-cell lymphomas.  The CD8 positive lymphomas.  Then there are peripheral T-cell lymphomas that come into here like subcutaneous T-cell lymphomas or angiocentric T-cells.  Also the ones that are more NKT-like, can be classified and start in the skin.  There are a lot of different lymphomas that might be under the heading of cutaneous T-cell lymphoma.

We stage MF in terms of how much skin is involved.  Whether it patches or plaques, what the nodal involvement is and whether it's in visceral organs or not.  Is that what you want?

GREG BERK, MD:  That's very helpful.  Thank you.  Are there any evolving concepts as to the pathogenesis of this disease in specific relation to viral infections or cytogenetic abnormalities?  Any clearcut associations?
 

MADELEINE DUVIC, MD:  In general, the CTCLs are a lot of different diseases so let's talk about mycosis fungoides. This is a disease that overlaps with other inflammatory skin diseases, especially when it starts.  And it can come – you can come to MF through eczema or through psoriasis.  These diseases are HLA-restricted.  We've found that MF is HLA-restricted and there is a high association of DRW-5 -- or DR-5 alleles in that disease.  I believe that a subset of patients with MF are actually, their T-cells are at least initially stimulated by staphylococcus which is a skin organism.  So in my opinion some patients with MF are SALTs which is like a MALT but it's in the skin so we call it a SALT.  And staphylococcus, as you know, is a good super antigen provider for T-cells to be stimulated.

There is also mounting evidence that the T-cells in this disease aren't undergoing normal apoptosis.  So once they're stimulated, they don't die normally.  But they're indolent cells and they don't grow especially quickly.  They just don't die.  And I think that this is probably – MF is probably a reaction pattern and a number of different causes can lead to an MF phenotype.  So as far as having one cytogenet ic abnormality, there hasn't been one found for this disease.

In some of the other T-cell lymphomas like anaplastic large cell lymphoma, there are translocations like t25, translocation creating a protein that is an oncogenic protein.  But in MF we don't have that yet.  It seems like there is a defect in cell signaling and apoptosis.

GREG BERK, MD:  Very good.  Dr. Duvic, getting right into the treatment aspects.  Can you go through sort of a step-wise approach to how we treat these patients?  What our treatment goals are in the typical type of scenario?  I know many of these patients are on and off of different modalities for many years.
 

MADELEINE DUVIC, MD:  Well, this is a rare disease.  So we don't have the kind of information that would be helpful to us as we do in other lymphomas.  And at the current time there is no cure for the cutaneous T-cell lymphomas so the goal of therapy at this point is palliation and to prevent progression of disease, if possible.  So initially when the disease is limited to the skin, we tend to use skin-directed therapies and those include topical agents, like steroids, light, some of the vitamin A/vitamin D steroid analogs, nitrogen mustard, carmustine, BCNU.  And then there is a lot of use of biological response modifiers, oral retinoids, and interferon being the major ones, although there are some others that are coming along.

And then as the patient has more involvement with nodes or blood, people tend to switch to chemotherapy.  However, at least mono-agent chemotherapy, where it has a high response rate, has a very, very short duration of response and accumulative chemotherapy creates immunosuppressed patients and they often succumb to infections.
So we don't have a lot of experience with bone marrow transplants.  In this patient population there is very little experience there.

GREG BERK, MD:  Dr. Duvic, can you comment on some of the newer treatment protocols with the purine analogs?
 

MADELEINE DUVIC, MD:  With the purine analogs...
 

GREG BERK, MD:  I'm aware of some data, some recent data with pentostatin for—
 

MADELEINE DUVIC, MD:  Right.  Pentostatin or Nipent or deoxycoformycin is an old agent that was really used in Hairy cell leukemia--
 

GREG BERK, MD:  Correct.

MADELEINE DUVIC, MD:  --initially.  And it has probably about a 60% response rate, especially in the erythrodermic Sézary patients.  Dr. Kurzrock and I have a paper coming out that shows some complete responders that are durable to pentostatin but in our hands, it works best in the erythrodermic Sézary-like MF patients or Sézary patients.
 

GREG BERK, MD:  I see.
 

MADELEINE DUVIC, MD:  There are other agents like 2-CdA which are used.  We did a study a couple of years ago and didn't really find a high response rate with 2-CdA, but other studies are now ongoing.  Ara-G is another one that's being looked at.  We're doing a Gemzar study right now as another agent--

GREG BERK, MD:  I see...  And lastly, Dr. Duvic, you know the ONTAK antibody was recently approved for this disease.  I'm curious as to what your experience has been with this and in what patients would we consider this therapy?
 

MADELEINE DUVIC, MD:  Okay.  Well, ONTAK is not an antibody.  It's actually recombinant IL-2, the binding domain of IL-2 which is linked to diphtheria toxin.  And so it's a fusion toxin protein and it's taken up by cells that bear the IL-2 receptor and it kills them by blocking protein synthesis.  And I was part of the pivotal trial for registration of this agent.  And I am very impressed by its potential to help patients who have tumor stage MF for which have been refractory to other agents.  I've had several patients with tumor stage who have gotten almost to complete remissions with it.  And the drug is attractive because it targets the tumor cells specifically and kills them as opposed to other forms of chemotherapy which kill a lot of other things.  The bone marrow toxicity is not a problem with this drug, fortunately.
 

GREG BERK, MD:  Is there any experience using ONTAK with chemotherapy in conjunction?
 

MADELEINE DUVIC, MD:  Not so far.
 

GREG BERK, MD:  I see.
 

MADELEINE DUVIC, MD:  It may not – you may not need it with chemotherapy although it may be advantageous to combine it with other therapy.  This agent just came out last year and it's approved for refractory lymphomas that are CD25.  Now the question is how much CD25 do you have to have on your cell surface?  How many IL-2 receptors do you have to have on your cell surface for this to work?  And we really don't know that answer?

The immunohistochemistry screening that we do is very coarse measurement of IL-2 receptors so there is another ongoing study for ONTAK that's accruing patients in a placebo blinded fashion for earlier patients.
 

GREG BERK, MD:  Right. Dr. Duvic, your comments today have been really extremely helpful in this relatively rare form of lymphoma which the general oncology community is still quite interested in.  I really appreciate you being with us today.  Thank you.
 

MADELEINE DUVIC, MD:  You're welcome.