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Hairy Cell Leukemia Patient Forum

July 17, 2019

Hosted by the Hairy Cell Leukemia Foundation with Dr. Martin Tallman from Memorial Sloan Kettering Cancer Center

Transcript

Welcome and introductions

Dr. Kanti Rai: I feel that you ought to feel very privileged that you are having available to you one of the world's biggest authorities in this particular condition. Doctor Tallman will speak to you about wonderful developments which have changed the entire outlook for people who go on to have this diagnosis.

He and I were connected accidentally about thirty years ago. He was the head of the program at Northwestern University medical school in Chicago, and I was here in Long Island. At the Scripps Clinic, there was a wonderful scientist physician who ran into what is known as a wonder drug, which you will hear about from Doctor Tallman. When it was in the preliminary phases of development, Scripps doctors had treated, with huge success, a handful of patients, and the report made headlines. The doctor at the Scripps Clinic could not deal with the complete flood of care patients. So he called Doctor Tallman in Chicago and called me up in Long Island, and asked if he could he refer patients to us.

Each one of us would see approximately two to three newly diagnosed people in a year. In the course of the following eighteen months, Doctor Tallman treated approximately one hundred and twenty patients, and not only treated, but progressed the research and investigation in pathology and in the management of complications, and I suddenly had a flood of seventy patients over the course of fourteen months. From that time onwards, we collaborated and talked to each other and developed a great deal of camaraderie, friendship and trust, so that when I heard that Doctor Tallman from Memorial Sloan Kettering is coming to talk to you, I said, I owe it to Doctor Tallman to come and say thanks you. So this is my way of saying thank you, and it's a treat for you to have Doctor Tallman talk to you.

Presentation

Dr. Martin Tallman:   Thank you for your kind words. First of all, this is quite a rare disease. Less than a thousand people here in the United States. If you think of the most common malignancies like breast cancer and you have about two hundred and thirty, two hundred and forty thousand new cases per year. Lung cancer, two hundred and thirty thousand new cases, bone cancer roughly the same. Hairy cell leukemia, less than a thousand. This is what we call a clonal disease, that is one cell went haywire for some reason, acquired some genetic abnormality, the reason of which is unclear, and all of its progeny, all of its babies are derived from that single cell. It's what we call a B cell, and you can think of that as derived from the bone marrow.

Martin Tallman:      There are about fifteen percent of patients that have a variant you may hear about, some of you may have it or have a connection to someone who has the variant, and we'll talk a little bit about that, but I'm going to focus mostly on the classical form, which about eighty five percent of patients have.

The hairy cell derives its name from these hair-like projections from the side of the cell. Normally a cell is smooth and round, but these cells have these hair-like projections.

How they got there, what they're doing there, we don't know. The only major physical finding when we examine a patient... we don't find lymph nodes, we don't find skin rash very often... we find a big spleen.

When these cells accumulate in the bone marrow, they accumulate to the detriment of other cells. They sort of usurp the energy and the nutrients and the space of the bone marrow so healthy blood cells can't grow. They're weeds in the garden, and if there are weeds in the garden the flowers don't grow so well. That's why people have low blood counts, pancytopenia. For some reason, we don't know why, there is scar tissue that forms in the bone marrow. The scar tissue can be so tight that sometimes we have trouble getting the liquid portion of the bone marrow. It's called a dry tap.

Doctor Bertha Bouroncle is credited with the initial description of hairy cell leukemia. Her first paper on hairy cell was published in the Blood Journal in nineteen fifty eight.

This is a disease which has a unique genetic abnormality called the BRAF. It's a genetic mutation that is quite unique to hairy cell leukemia. Those of us that are in the field were very happy when this was described by several research groups, because it's seen in virtually every patient with hairy cell. Not the variant, but the eighty five percent of patients that have the classical form, and it's not seen in almost any other disease. Occasionally it can be seen in CLL, chronic lymphocytic leukemia and other things, but for all practical purposes every patient has the BRAF, and almost no other disease is associated with it. So that's very helpful for us because sometimes the diagnosis is very clear for hairy cell, but sometimes it's not so clear. Sometimes we have difficulty, but if they have the BRAF that's quite specific for hairy cell leukemia.

Martin Tallman: Now it's helpful to know a little something about how we got to such outstanding treatment that we have today. The mainstay of treatments are two drugs pentostatin and of course cladribine. It was discovered that kids with a certain immune deficiency lacked a certain enzyme and because they lack an enzyme, they had low lymphocytes. Some people said, why don't we deliberately inhibit the enzyme, maybe lymphocytes will go down. And that's what happened. Dr. Eloise Giblett at the University of Washington made that first observation. Doctor Dennis Carson made the observation to try to deliberately inhibit that enzyme and to see if lymphocytes would go down, and they did.

Dr. Ernest Beutler, a brilliant hematologist, and his group at the Scripps Clinic were among the first to test a drug that Doctor Dennis Carson helped develop called cladribine, in patients with too many lymphocytes, and in fact the lymphocytes went down.

Martin Tallman: There are studies that were carried out with pentostatin and with cladribine, and the overall survival at nine, ten years was ninety plus percent when treated with cladribine.

Audience member: When you say survival is that staying in remission or is that alive?

Martin Tallman: It's a good point. That is survival whether you have disease or not, which may be the most important question because this is a disease that people can survive for many, many years with a little bit of hairy cell. Other diseases you can't. This is overall survival whether you have a little hairy cell or not.

It's a general principle in oncology and hematology that if you have a patient that has a disease and they've been treated and they relapse, and they get treated again, the response rate is not as good as patients that are never treated before because the cells develop resistance. They outsmart our chemotherapy, so in many diseases if you treat a patient who's never been treated they respond well, they relapse, and then you try to retreat them again they may or not respond as well. But hairy cell is different. We've found and many others have found that if patients have been previously treated and get cladribine, who were never previously treated, they do the same and they do extremely well. It's an unusual concept.

What's also very true in oncology and hematology is that if you have a patient that has relapsed disease they may or not respond well, but their overall outlook is usually not as favorable as if the patient was treated for the first time. But, that also doesn't appear to be very true with hairy cell. So you have a patient with hairy cell, they get treated, they do very well, they relapse, we retreat them. I showed you they respond pretty well. Not only do they respond pretty well, it's quite durable. Again, ten, twelve, fifteen years. It's at eighty plus percent. So it's a remarkable disease in that respect.

Martin Tallman: Now, most of you have probably heard of cladribine. There are some possible side effects from cladribine. First of all, it does suppress the immune system, and it actually suppresses the immune system for one to two years, maybe even more. Most of the time that has no major consequence. Patients do well. There are occasionally second malignancies, perhaps contributed somewhat by cladribine. It's been difficult to study because patients with hairy cell leukemia and other lymphoproliferative disorders may have a very small inherent predisposition to a second malignancy without any treatment.

The other complication that we occasionally see are infections.

Audience member:     So I just have a question. Isn't it that most chemo drugs make you immunosuppressed anyway, or is this particular drug more so than the average person who goes through chemo?

Martin Tallman:          The latter. Cladribine is a very immunosuppressive drug. Lots of chemotherapy often temporarily suppresses the immune system, but this drug suppresses more of the complicated immune cells so it's more immunosuppressant than most chemotherapy.

Martin Tallman:          Patients with hairy cell and other lymphoproliferative disorders are predisposed to superficial skin cancers. We think there's some suggestive evidence, not hard proof. We do recommend that patients with hairy cell see a dermatologist twice a year, even if they feel fine. Usually if they develop something it's quite minor and easy to handle. Now there are some unique features of hairy cell that I want to mention, among the other lymphoproliferative disorders - lymphomas, chronic lymphocytic leukemia, prolymphocytic leukemia. Number one, hairy cell leukemia is among the most indolent of diseases. That is slow growing. It can sit there for years and years. Patients can have a little bit of hairy cell and it won't cause any trouble.

Martin Tallman:          If a patient is treated, or heavily pretreated, and they get cladribine for example, they respond equally well. It also stands to reason in medicine in general that if a tumor is smaller it's easier to treat than if it's bigger. Someone comes in with a small breast cancer it's easier to treat than someone that neglected it and has acute breast cancer. In hairy cell that doesn't apply. You can have a huge spleen and a very low count and the patient can respond as well as someone that has early hairy cell with minimal low counts. There seems to be no impact of tumor burden on response.

Martin Tallman:          For lymphoma we use six cycles of rituximab plus chemotherapy. Breast cancer we give four to six cycles of chemotherapy. With cladribine, as you may know, we give one cycle and it's highly effective. We almost never repeat it. One cycle is highly effective in hairy cell leukemia.

Chronic lymphocytic leukemia or other diseases can transform over time to a more aggressive disease. CLL can transform over time to lymphoma. Hairy cell leukemia never transforms. We don't know why. If hairy cell ever comes back, it comes back hairy cell. It doesn't come back with anything else.

This study was conducted by friends of mine at Scripps. This is a group of patients they treated between fifteen and twenty years earlier with a single cycle cladribine, and they had normal blood counts for up to twenty years. Completely normal blood counts. They called them back and they did a bone marrow. They did a bone marrow on twenty patients who had been treated up to twenty years before with normal blood counts, one cycle.

You'd think the blood counts were normal, and after up to twenty years there should be no hairy cell. In fact, fifty percent had no residual hairy cell, but about thirty seven percent were found to have a small amount of hairy cell by very sophisticated techniques. Another fifteen percent had actual evidence of hairy cell under the microscope. So this taught us that even patients with minimal residual disease, and even some with gross obvious disease, can live for many years without treatment. It's such a slow growing, indolent disease in most patients.

Martin Tallman:          It is true that about twenty to thirty five percent of patients relapse after a single course of cladribine, but not all patients who relapse need to be retreated. They may have a little bit of a dip in their counts that may sit there for years. So the relapse, in many diseases, someone relapses they need to be retreated, but in hairy cell leukemia someone who relapses doesn't necessarily need to be retreated.

Let me talk about some new strategies. I think cladribine remains the preeminent choice. It may change soon but it's still cladribine.

Martin Tallman:          There are the Immunotoxins, which is an antibody against a marker called CD22 on the surface of the cell, and it's linked to a certain toxin from a bacteria. It's like the booster and the rocket. The rocket serves to get the capsule into orbit, and this antibody grabs this toxin to the cell, and then like the rocket it goes away and leaves the orbiter, and that's what happens here. The anti-CD22 is the antibody that targets the CD22 on the hairy cells. It floats away and then leaves this toxin inside the cell.

Some people are combining rituxin with purine analogs. There's another drug called Bendamustine we give, and the hot area is the drug Vemurafenib. Remember we talked about this genetic abnormality called the BRAF? This is an anti-BRAF. It inhibits the BRAF mutation and it's an oral pill. So the rationale for BRAF inhibition with Vemurafenib is that its present in a hundred percent of classical hairy cell. It is an effective, selective BRAF inhibitor and it's administered orally. You don't have to give it intravenously.

The BRAF contributes and activates other genes and leads to the survival of hairy cells. If you inhibit BRAF, you inhibit these downstream molecular abnormalities, and that inhibits the survival and proliferation of hairy cells. Just to give you a feel of how we think about this. This is an example of a very early report of one patient that was treated with the BRAF, and this is a patient with refractory hairy cell. Not a patient of ours. They got Vemurafenib and within two days the spleen started to shrink, and the top is the white cells and neutrophils and you can see how dramatically they went up. This is the hemoglobin going up, and you can see the platelets went up.

Martin Tallman:          Some new strategies for hairy cell include this Vemurafenib, but we're combining it now with an antibody called obinutuzumab. This is an antibody against another marker... we talked about CD22, this is against another marker on the surface of the cell. The Italian group are giving Vemurafenib with rituximab. We're giving Vemurafenib and obinutuzumab to newly diagnosed patients, so we have an open trial in newly diagnosed patients. The first trial I talked about was in relapse and it worked that well in heavily treated patients, our hypothesis is that in untreated patients it will work even better. Because this trial is ongoing, I'm not at liberty to say, except we've been pleased with the results.

Martin Tallman:          Ibrutinib is a drug that's remarkably effective in chronic lymphocytic leukemia, and because chronic lymphocytic leukemia is so closely related to hairy cell we have treated a number of patients and it's been quite effective. Others have tried to combine it with rituximab or obinutuzumab or Vemurafenib. There's a new BRAF inhibitor that is thought to be even better than Vemurafenib called dabrafenib, and I've treated a couple of patients and they seemed to respond quite well, but no formal studies have been conducted with dabrafenib.

Audience member:     What key side effects did it have?

Martin Tallman:          I've only treated two people with it, and one of the benefits is that it says it has less side effects than Vemurafenib, but no one has studied it formally. It should be studied.

Some of you may have heard of Pentostatin. That's another purine analog. Cladribine is easier to administer. It's only one week and I think there are less side effects potentially. The ease of administration and potentially less toxicity suggests an advantage of cladribine over Pentostatin. It's remarkable because the pathogenesis of hairy cell is linked to that specific genetic mutation called BRAF. What I called immunobiologic treatments like antibodies, that CD22 drug and rituxin and obinutuzumab are effective treatments and the BRAF inhibitors appear to be very pronounced.

Martin Tallman:          These are the questions that those of us that are in the field are asking and trying to answer today. First of all, cladribine is the standard care today. So some physicians are giving rituxin after cladribine, and it's perfectly fine to do. Here's an example of why I would say it's a bit of a conundrum. If you treat patients with cladribine and their counts are low and they're doing great, by sophisticated techniques, in some patients you can find a few hairy cells. It's been shown that if you add rituxin after cladribine, you can get rid of those last few hairy cells.

That sounds like a good idea, but remember, this is a disease that patients can have a few hairy cells and live for years and years and don't die. So some people give rituxin and say yes, I want to get rid of every last hairy cell. Other people, and I'm one of them, say where is it shown that you have to get rid of every last hairy cell, and you may pay a price with rituxin. It suppresses the immune system and you can get infections and it has its own side effects. In our practice at Sloan Kettering we in general don't follow cladribine with rituxin, but it's certainly not wrong and there's an easy justification for it.

What about some of the relapses, what's the optimal treatment? Well we think if someone relapses within more than two years they should get another cycle of cladribine and we do add rituxin then, because the duration of that second remission may be shorter.

Audience member:     First of all, how do you quantify early versus late relapse? How many years?

Martin Tallman:          About twenty four months. We say that if someone relapses more than twenty four months they seem to go back into remission, but to relapse within a year, they don't do as well. This is an important question that we're all struggling with, is it important to get rid of every last cell? In many diseases it is. Breast cancer, colon cancer, many diseases, but in hairy cell it's not clear that you have to get rid of every last cell. What's the best treatment for the variant? Today, the best treatment is cladribine followed by, or given at the same time as rituxin, but we don't have the optimal for the variant.

Martin Tallman:          Finally, will the anti-CD22, that formula rocket, the drug that I told you about, or Vemurafenib, or dabrafenib, will they replace cladribine as the initial treatment of choice? More studies have to be done. Today cladribine for seven days is the treatment of choice. That's my last slide, so we have plenty of time for questions. Future directions, cladribine plus concurrent or sequential rituxin. Bendamustine is another drug that we're using. The excitement, again, is in BRAF inhibitors, like Vemurafenib with rituxin or obinutuzumab, we're trying it, as others are, in untreated patients. There’s Ibrutinib and then less critical I think, but a lot of people are interested in how important it is to treat and get rid of those last few cells.

Audience member:     If the blood counts are on the low side, but stable, and you've been carrying hairy cell for five or ten plus years, is it suggested that a bone marrow has to be done just to see how much hairy cells there are?

Martin Tallman:          Only if the blood counts are changing, so if the blood counts aren't changing we observe patients. If the blood counts are adequate, they may not be perfect, but they're adequate. If I did a bone marrow and they were twenty percent hairy cells, forty percent, seventy percent. It doesn't matter what the percentage is, it's all about keeping the blood counts okay. If the blood counts start to change, yes, we do a bone marrow.

Audience member:     In what time period, how imminent is it to get treatment?

Martin Tallman:         We have general criteria we agree upon, and I'm saying agree upon because I had the privilege of writing several chapters of established criteria that many people have agreed to. Another example of how this differs from other diseases, if someone has a heart attack they need treatment, someone has breast cancer they need treatment, someone has colon cancer they need treatment. You don't wait. In hairy cell, just because someone has the new diagnosis doesn't mean they need treatment. They need treatment when their blood counts drop, and we use less than a hundred thousand platelets, less than a thousand neutrophils, or less than 11 hemoglobin, so it's one, one, one.

Martin Tallman:          Hemoglobin less than 11, platelet count less than a hundred thousand, and neutrophil count less than a thousand. Also if they have a huge spleen that is bothersome, compressing their stomach. Patients may say, well come on, we're going to need treatment eventually, or why not treat them now. They may not need treatment eventually. I showed you the Scripps clinic data ages of fifteen, sixteen, seventeen years. They should do a follow-up report because that was published a number of years ago. I'd like to see what happens in twenty years, and twenty five years. Just because someone has a diagnosis, doesn't mean they need treatment. You wait until they fulfill the criteria.

Again, you may say, but if they need it then why not treat them now? Because there are side effects to even a single cycle of cladribine. We don't want to induce side effects in a patient that doesn't need treatment.

Audience member:     So what can happen? What's the danger of not treating?

Martin Tallman:         There's no danger as long as the blood counts were above those levels. There's no danger.

Audience member:     But if the count drops …I don't know what that time frame is of dropping. Is it a year, or month to month?

Martin Tallman:       Well, we watch patients to get a feel for the tempo of their change. So we may get a blood count CBC monthly, we may get it every four months. It's a very indolent disease in most patients. Most patients will take six, twelve, eighteen months to drop sufficiently to meet criteria. It's rare that someone has normal or minimally low blood counts and then two weeks later their blood counts are much lower. It's too slow of a disease.

Audience member:     What are immature granulocytes? How do they affect the disease?

Martin Tallman:          They don't affect the disease in any way.

Audience member:     So, someone that's never been treated for hairy cell in five years, and they need treatment today. Would you say go straight to cladribine? It depends on the patient?

Martin Tallman:         Well we and others are trying to make progress. As good as cladribine is, it's not perfect, and I talked about some of the side effects and progression for the survivor isn't perfect, so me and others are trying to do better in developing therapies. At our institution and when we diagnose patients, we're encouraging them to participate in Vemurafenib plus obinutuzumab. A BRAF inhibitor followed by the anti-hairy cell antibody, anti CD20. So that's why we encourage patients, it's a clinical trial. We hope it will be more effective and less toxic than cladribine, we're trying to prove that. Outside the context of the trial, the gold standard is cladribine.

So some patients want the newest and latest and they participate in the trial, and others say, you know what, I'll stick with the gold standard.

Audience member:     Are you recommending that for first line of treatment or relapse treatment?

Martin Tallman:         Vemurafenib plus obinutuzumab. We're recommending it at this time for newly diagnosed. I do not give it unless the patient signs the consent form.

Audience member:     There will be a point when the clinical trial closes, and new people can't come into it, and then there's a latency period, probably, between the time the trials close and it can start to be offered to patients. How much longer do you think that trial will be open, and then when it closes, what will be the period that you will then have to wait that you can actually get that, so that you can have that option as opposed to cladribine?

Martin Tallman:     It's a very good question. Hairy cell is an uncommon disease, and every new patient we get, we are trying to prolong the study. We hope to finish the study in eighteen, twenty four months, and then if it's as effective as we hope it will be, it will probably be another couple of years before it's available for untreated patients.

Now it doesn't mean that tomorrow, not on the study, I can treat someone with Vemurafenib plus obinutuzumab. You don't know the long-term effects of it, you don't know all of the side effects. We have to conduct a clinical trial first. The drugs are getting, they seem to be getting approved much more quickly than they ever have.

Audience member:    Is it global or US?

Martin Tallman:       Our trial is in the US. There is a trial in Europe, our colleagues, the Italians. The federal government, the FDA, food and drug administration, recognizes it's a rare disease. Cladribine was approved with forty patients, so they recognize that the public can't wait twenty years. Now colon cancer, lung cancer, breast cancer may kill hundreds of patients quickly, but this is such a rare disease. I think it got approved with twenty, thirty, forty patients.

Audience member:     I'm going to follow up on what she was saying earlier about, say your blood count has kind of drifted low, and you don't get treatment right away, is it right to say hairy cell won't kill you, but if your counts are low you're more prone to picking up something.

Martin Tallman:         I don't think that's correct, respectfully. I don't think that watching someone for a year or two with hairy cell low counts but not sufficiently low... yes they're a little bit immunosuppressed, but I don't know if they're predisposed to any higher incidence of secondary illnesses or infections without treatment.

Audience member:     A lot of people are on watch and wait it can go on for quite a while, but if everything's low, just not critically low. So they're a little bit anemic, red blood cells are low... do you recommend certain vitamins or iron or anything, or would taking iron not matter because there's no red blood cells for the iron to go into. Nutritionally, is there any vitamins or things that can be done to help you feel better.

Martin Tallman:       The problem with hairy cell is that the cancer overgrows like weeds in the garden and the flowers can't grow. They don't need water, they don't need nutrients, they need space to grow. So if you have the hairy cell, iron won't help. You can't make your blood cells, not because you lack iron, but because there's no space in the bone marrow. So the answer is not to get more iron, but to make more space so they can grow. It's more complicated than space alone but I'm using that example because it’s a conceptual way of thinking about it.

Audience member:    So, platelet counts. Would you recommend anything like vitamin K or anything like that?

Martin Tallman:        No. You can take it, but it won't do you any good.

Audience member:     For the folks that do have hairy cell that you've treated, do you recommend that they take a flu shot?

Martin Tallman:          Yes, if it’s not a live virus.

Audience member:     What about Shingrix?

Martin Tallman:          Yes I think that's not a live virus.

Audience member:     So, for the counts, how long would you be treated with cladribine, you mentioned saying immunosuppressed for a very long time. Do the counts themselves... how long do those take to come back?

Martin Tallman:          After a single cycle of cladribine... usually we like to give it by continuous infusion, platelets start to come back very quickly, within seven to ten days. The neutrophil is always up by four weeks, that lags behind. Platelets come on quickly, and the neutrophils come up a little slower, and by a month, the neutrophils over the thousand, that can take three to four weeks.

Audience member:     Does the rituxin keep that immunosuppression longer?

Martin Tallman:          Yes, it does contribute to further immunosuppression, but it's mild. Not enough that it's not worth giving. The benefits still outweigh the risks.

Audience member:     Are you finding the Vemurafenib less immunosuppressive than say cladribine, because it's not a real chemo?

Martin Tallman:         It's not chemotherapy, it's a small molecule inhibitor and it does not seem to suppress the system to the extent cladribine does.

Audience member:     So people can go out in public quicker in most weather.

Martin Tallman:        Yes.

Audience member:     Most patients in the trial seem to be doing pretty well with side effects. I'd rather listen to you, because when you go on Google, the list is long and scary, so I prefer to hear what you're saying so far.

Martin Tallman:         Because it's an ongoing clinical trial, I'm not able to say much, except to say that we've been quite pleased.

Audience member:     I had a lot of hair loss, which was not one of the symptoms on the box warnings, but I did lose a lot of hair. That was the worst side effect. I felt pretty good. I've been on everything, two cladribine, one rituxin, one Vemurafenib, one Ibrutinib. I've been on everything. Thirteen years. There were side effects, but we keep pushing through.

Audience member:     There are some patients who couldn't be here tonight, who have emailed me some questions. So you're saying that cladribine is very effective, these patients are asking would you say, is it okay to take cladribine first, because I think they're worried about the further immunosuppressive effects that rituxin can have... take the cladribine first, then do an evaluation, and then decide whether or not to take the rituxin?

Martin Tallman:          It's a major question. For newly diagnosed patients it is cladribine, for relapsed patients, because they've relapsed once, and once someone relapses the remissions tend to be shorter, we then do give rituxin, with cladribine. We actually give it sequentially, four weeks after cladribine we start rituxin, because then I think it may... although I haven't proven it, it may be important to eradicate every last cell, because we know the remission duration tends to be shorter, once they've relapsed.

Audience member:     Then the patients that want to take cladribine first and then decide later to take rituxin, that would be okay?

Martin Tallman:          Absolutely.

Audience member:     And that's just for the newly diagnosed?

Martin Tallman:          That's the newly diagnosed and relapsed we do follow with rituxin. Some people think the standard of care for once somebody relapses is another cycle of cladribine without rituxin. We haven't proven that adding rituxin, either newly diagnosed or once the patient relapses is better than cladribine on its own.

Audience member:     I know you're already immunosuppressed from taking the cladribine, but what's the time frame... what is the time frame when you can feel comfortable to go out and about?

Martin Tallman:          We think as soon as the neutrophil count and platelet counts go up. Platelets come up seven to ten days, neutrophils take three weeks, always by four weeks, so by a month we think patients can carry on.

Audience member:     But you said that for a couple of years you're still sort of immunosuppressed.

Martin Tallman:          There's some sophisticated testing you can demonstrate that the immune system isn't perfectly normal for a year or two, but it's not low enough that it poses any restrictions. Patients can travel and can go where they want and do what they want to do.

Audience member:     What about fertility?

Martin Tallman:          Good question. I've had patients that have mothered children, I don't know of any studies that have looked at fertility after cladribine.

Audience member:     But from a male perspective.

Martin Tallman:          I don't know of any studies. Interesting question, and I don't know of any studies... I'm trying to think if I've had any patients that have fathered children. Not that I can think of.

Audience member:     We're creating, or Anna's creating a patient chatroom, and there is going to be a chatroom for women who have HCL, so that might be a really great question to ask. See what the others have to say.

Martin Tallman:          Absolutely. It's not a regular chemotherapy, so my guess is fertility is less of an issue. I don't know for sure.

Audience member:     In the case of relapse treatment, cladribine with rituxin, whether it's determined that there are no hairy cells left, or there are just a few, does relapsing still occur again?

Martin Tallman:          Yes. The second time... in hairy cell with they get cladribine and do well for two, three, four, five years, and relapse and get cladribine with rituxin, and do well, can relapse again, yes.

Audience member:     So, it doesn't matter if you annihilate all hairy cells.

Martin Tallman:          No, we don't know. Maybe the relapse rate is less if you give cladribine.

Audience member:     Is hairy cell relatively easy to diagnose, can it be misdiagnosed? Does it look like it, or can it be something else?

Martin Tallman:          Good question. Most of the time the picture is pretty clear. Hairy cell leukemia basically... low counts, BRAF positive, we often see the hairy cells in the blood with the projections. There are other diseases which have hair-like projections too. So occasionally it's tough. The BRAF testing has helped a lot, because it's so specific for hairy cell, but there are cases that are tough. I would say that most of the time we are able to diagnose it pretty readily.

Audience member:     I have one other question, what happens physically if you cannot access the drugs?

Martin Tallman:          You mean your hospital doesn't have it?

Audience member:     Someone in another country where the drug's not available.

Martin Tallman:          What would I do?

Audience member:     I just wondered what would happen in most cases physically to the person who needs that.

Martin Tallman:          Well the spleen might get bigger and compress the stomach of that patient, and that patient will lose weight and have what we call early satiety, they get satiated, they take two bites of food and their stomach is compressed and they have left upper quadrant discomfort, their blood counts are low. If left untreated it's serious... it's readily treated, of course, but if left untreated there can be latter complications.

Audience member:     Is there a genetic connection between myelodysplastic syndrome and hairy cell leukemia.

Martin Tallman:          No, none that I know of.

Audience member:     In the clinical trial is it fifty fifty gender, male and female, is it older age groups, or is it specifically closed to one gender or another.

Martin Tallman:          In our study it is open to any patient with hairy cell.

Audience member:     Where is your study conducted, is it at Sloan?

Martin Tallman:          It's based at our institution. We invited four other institutions, partly for accrual, so we get more patients.

Audience member:     You may have said this, I'm not sure, but the secondary cancers, is there an understanding of whether they'd be coming from cladribine or the disease itself? Have you figured that out?

Martin Tallman:          We don't know that for sure. There's this very small increased risk, just by having hairy cell, and it isn't clear, we're not sure that if adding cladribine raises that risk, but even if it does, it's very, very slight. But it's present, we think. Hard to prove. It's hard to prove because the baseline level is so low, we'd really have to accrue hundreds, and hundreds of patients with hairy cell to answer your question, and it's such a rare disease that it's hard to do a clinical trial.

Audience member:     I would say that most hairy cell patients are under pretty continual physician care. They're being checked on a fairly regular basis, not quarterly, but something like this. That would result in CBCs and blood tests which should help with another cancer that might be festering in the body of somebody who may not going on regular blood tests, and you guys will pick up something in that blood test to lead you to believe that there is something else going on.

Martin Tallman:          Exactly. Important point.

Audience member:     In the newly diagnosed... the cladribine with rituxin, can I ask some of the reports that came out of the annual meeting when you reported on this, about a month ago, so are you saying that... well it does say in the reports that the disease free, or minimal residual disease, that's definitely being helped, or shown to be helping, that that may not have made a difference in the actual, with remission.

Martin Tallman:          You can get rid of almost every last little cell, but whether to do that is important enough or not and as far as I'm concerned at the moment, it's not wrong to do, but the survival is so good with a little dose of leukemia, that I'm not happy giving rituxin with a newly diagnosed patient.

Audience member:     The relapse free period, could it extend that? In the cases that it might come back, could it stop that?

Martin Tallman:          It hasn't been proven.

Audience member:     Any last questions for Doctor Tallman?

Martin Tallman:          Thank you all for coming out. [Applause]

Transcript has been edited for clarity.