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Slide #1
SANDRA HORNING, MD: It's my pleasure to introduce Dr. Auayporn Nademanee, known affectionately as Dr. Nadee to many. Dr. Nademanee is currently the Associate Clinical Director of Hematology and Bone Marrow Transplantation at the City of Hope. She's a very experienced transplant physician, and we're lucky to have her here today to speak to us on transplantation for non-Hodgkin's lymphoma, autologous, allogeneic and mini-allo. Dr. Nadee. [APPLAUSE]
AUAYPORN NADEMANEE, MD: Thank you very much, Sandra. I would like to thank the organization for inviting me to participate in this educational symposium.
What I'm trying to do is try to talk to you about stem cell transplantation for non-Hodgkin's lymphoma, different types of transplants that we do, and the what's the risk-benefit for each approach.
Slide #2
You know, a lot of times when we see the patients, the most common question the patient asks us is, "What's the difference between bone marrow and stem cell?" Why we are using bone marrow. Are you using stem cell? So basically there are three different cells of stem cell. One is from the bone marrow. This is like when you the bone marrow test done. The bone marrow can be collected from the large needle inserted into the hip bone. The bone marrow can be frozen and given back to the patient, and this cell can grow back in the body and start making blood cells in the body.
Another sort type of stem cell, as we have learned more, is something called peripheral blood stem cell, which is also the bone marrow precursor cell that starts in the bone marrow, and then circulating in the peripheral blood, and we can collect these cells using something called a phoresis machine, where we take your blood into the machine and separate the blood into different layers, and taking the stem cell portion, and that can be frozen and can be given back to the patient. This cell will grow back in the body, as well as bone marrow.
Another type of stem cell that we have used lately is something called cord blood, which is obtained from the cord during the birth of a child. Cord blood transplants mostly are used in children because the volume is small, and the volume is dependent on the size of the patient. So even though the size is too big, sometimes cord blood is not possible.
Slide #3
Now, the potential advantages of using peripheral blood stem cell are several-fold. This can be done as an outpatient, as compared to bone marrow, where we have to put the patient under anesthesia to collect bone marrow. So we don't have to do anesthesia. We collect the cell through the peripheral blood, using a needle, or we put in the Hickman catheter, a double lumen Hickman catheter, and collect the cells for that procedure.
The most important thing is, when we give these cells back to the patient, they grow back much faster than the bone marrow. It takes about only a week or ten days for the cells to grow back, for the white cells to grow back, and the platelets can recover. It's also much faster than when we use the bone marrow. There is also potentially the advantage of not having the tumor cell contaminant in the peripheral blood when compared to the bone marrow. This is more of the concern of patients who do have bone marrow involvement at diagnosis or at the time of transplantation.
When we start using peripheral blood stem cell ... mostly we use it in patients who have bone marrow disorders -- i.e., they have radiation to the bone where we cannot harvest the bone marrow, or they have tumor involving the bone marrow, so therefore we can't harvest the bone marrow for transplantation.
Slide #4
When we talk about stem cell transplantation, we divide it into the type of donor that we use. Autologous means we can use a patient's own blood stem cell or bone marrow. Allogeneic means the stem cells come from a different person. It can be either from a matched sibling donor, like a brother or sister that happens to be identical, or it could be from matched family members, like a father or mother, aunt, uncle, or it could be from matched unrelated donors, someone that's not related to you but happens to share the same -- have identical markers. And another thought that would be added on this is cord blood, which mostly would be either a sibling or unrelated donor. If you have a twin, then we call it syngenic transplantation. This is, the bone marrow is from identical twin transplant.
Slide #5
There are advantages and disadvantages of autologous and allogeneic stem cell transplantation. For autologous, because this procedure is simple, basically what we do is we give a patient a very high dose of chemo and radiation, give them back their cells so they can recover from the side effects of a low blood count. So this procedure can be done in older patients, age up to 70 years old, and sometimes nowadays, sometimes we go up to higher, depending on the patient's condition and functional status. We don't have to have a donor in order to do this kind of transplantation. Because the cells are coming from the patient's own blood stem cell, there is no risk of graft versus host disease, because the patient, it's their own stem cells.
The disadvantages of autologous stem cell is that there is a phenomenon that we have observed after transplantation, something called graft versus lymphoma effect. When you have someone else's cells in your bone marrow, that cell helps fight the lymphoma from coming back and prevents relapse of that lymphoma. And the risk of relapse is lower when we use a brother-sister transplant than when they use their own stem cell transplant.
And another possible risk would be that we can have the possible tumor cell contamination in the stem cell or bone marrow, so we might be infusing the cells back to the patient. But that risk is very, very small, because most of the failures after transplant are due to disease resistance rather than tumor cell contamination.
A benefit of using allogeneic transplant and clearly with using the normal cells, and the graft versus lymphoma effect, which I will show later, that the risk of relapse is much lower when we use allogeneic stem cell transplantation. But a major disadvantage of this approach is that you don't have a donor. Only about a third of patients would be able --
AUAYPORN NADEMANEE, MD: Okay, thank you. Sorry. For allogeneic transplantation, only about a third of the patients will have a donor, especially in this day when most families will have one child. Therefore, the chance of finding a donor and a family member is very limited, and only 30% of patients will find a donor for them.
As mentioned earlier, the older the patients get, the harder it is to do this kind of transplantation for them, because of the risk of graft versus host reaction and the transplant-related complications. Even in the younger age patients, there is a significant rate of graft versus host reaction, and because of that is increased risk of complications from transplantation.
Slide #6
This slide shows that lymphoma is the most common transplant that we do compared to other diseases. This is from the International Bone Marrow Transplant Registry. ... lymphoma compared to leukemia and other disease. About 45,000 patients undergo autologous or allogeneic transplantation per year.
Slide #7
Now the rationale why we're doing high-dose therapy in patients with lymphoma, these are the following rationales: In the animal studies, in which we have observed that the lymphoma cell, the ... lymphoma cell, survival of this cell inversely related to the dose of alkylating agents administered, meaning that the higher the dose the animals receive, the higher the chance that animals survive. We also observed this in clinical presentation. In the clinical trial, in patients with aggressive non-Hodgkin's lymphoma, when we used CHOP or intensive CHOP chemotherapy, if we increased the dose of Cytoxan-adriamycin, or if we give it more frequently -- every two weeks instead of three weeks -- we observe a higher chance of achieving complete remission. But the side effect is toxicity from the treatment.
And there, also, the principle that the resistance to standard therapy can be overcome by increasing the dose of the drug delivered and the radiation given to the patient. So based on that ... why stem cell transplantation is being performed.
Slide #8
This is a list of agents that we use in the high-dose regimen. This is based on multiple studies and the experience of what was done in phase I and phase II trials. Each drug has side effects and a dose-limiting toxicity, so if we use them together, we have to be very concerned about the combination of side effects together. Etoposide, or VP-16, Cytoxan, cyclophosphamide, are the two most common ones. Carmustine, or BCNU, total body irradiation is a very common regimen. High-dose melphalan and busulfan. And these are the side effects associated with those agents.
Slide #9
Very commonly, when the patients come to us, they often ask, "What regimen do you use? What are the best combination regimens in the transplant setting? Is radiation important?" So there are regimens that use total body irradiation in combination with chemotherapy, and the regimens that use chemotherapy alone.
Now, the choice of the regimen is mostly based on the transplant center experience and their preference and their research interests at that center. Radiation is very difficult to deliver. You need to have very good radiation oncology support at the hospital. The delivery is time-consuming, and it takes a lot of planning. So some centers prefer not to use radiation at all. There is also a concern that radiation may be causing more long-term toxicity, especially second malignancies or risk of other malignancies. So some centers shy away from using radiation. But radiation is also very important. Drug is a very important anti-lymphoma therapy. Some more centers do use some radiation.
But at the present time, there is no study to say that any one of these regimens are better than the others. There have not been any randomized studies comparing radiation-based versus chemotherapy-based. They have started looking at the ISH Center, looked at the outcome of radiation-based versus chemotherapy-based, and basically there is no difference in terms of outcome. But you may also see that sometimes radiation is not given as a total body irradiation, but as involved-field irradiation incorporated into the transplant regimen.
For example, if the patient had bulky mass in the abdomen or in the chest that had not responded well to chemotherapy, we often give involved-field radiation to that mass either before or after transplant, with the idea to provide local control and to prevent relapse after transplantation.
Slide #10
Now, the major indication to do stem cell transplant for non-Hodgkin's lymphoma include patients who have relapse or refractory non-Hodgkin's lymphoma. These are the patients who have achieved initial remission after induction chemotherapy, and then six months later, a year later, the disease comes back.
The second group of patients, this is the worst group of patients, these are the patients who are diagnosed with aggressive lymphoma, was getting chemotherapy. While getting chemotherapy, the disease started to grow back, or they still finish the chemotherapy and a month later the disease starts growing back. This is what's called induction failure. Transplantation is the only curative approach for this group of patients.
And then there are a subset of patients with aggressive non-Hodgkin's lymphoma who may benefit from transplantation during first complete remission, if they have poor risk factors at the time of their diagnosis. And there are certain types of lymphoma -- you probably heard from some of the meeting in different areas -- like patients with mantle cell lymphoma. This is a very bad lymphoma. Advanced stage, very poor prognosis, and transplantation is now being studied in this group of patients. And there are a certain percentage of lymphoma that there may be a role for transplantation, such as patients with a rare presentation in the central nervous system where the chemotherapy doesn't penetrate very well to that because of the blood-brain barrier, so there might be a role of high-dose therapy in order to penetrate the blood-brain barrier.
Slide #11
This is a study from a European group looking at the value of transplantation in patients with relapsed non-Hodgkin's lymphoma. This is a large study. Patients with relapsed lymphoma were treated with -- some with chemotherapy called DHAP, which has dexamethasone, cisplatin and ara-C. After two cycles, if they achieved remission or partial response they were then randomized to either to undergo high-dose chemotherapy and stem cell transplant or receive conventional chemotherapy with four more cycles of the same chemotherapy. This slide showed that those patients who had received transplant had a better chance to survive, both event-free survival and overall survival, compared to a conventional chemotherapy.
Based on these studies -- and there are some other studies -- the value of transplantation for relapsed aggressive non-Hodgkin's lymphoma has been confirmed, and therefore during the year 2002, there is no question that you have aggressive lymphoma that has relapsed after initial chemotherapy treatment, that transplant should be done in this group of patients.
Slide #12
Now, for patients with aggressive non-Hodgkin's lymphoma who had poor risk factors at diagnosis, the value of transplantation is being studied. These are prognostic factors that have been compiled in more than 5,000 patients with aggressive lymphoma. Several factors have been identified as poor risk factors, including age, older patients don't do as well; patients who presented with poor performance status, very sick from their disease, don't do as well as people who don't have symptoms. Patients who have elevated tumor markers for lactate dehydrogenase or LDH at diagnosis don't do as well as people who have normal LDH. Extranodal involvement -- i.e., lung, liver involvement -- bone marrow involvement and advanced stage disease.
Based on this, in fact, we can put the patient into several risk groups based on a number of their risk factors. If they have -- 0 to 1 is called low risk. 2 means low intermediate. 3, high intermediate, and high risk at 4 and 5 respective. And this can predict how the patient is going to do after conventional chemotherapy. Patients in the low-risk group do very well with chemotherapy. We'd have very good overall survival, and very low risk of dying from lymphoma per se. However, patients who have very high risk or high intermediate risk group had very poor survival, and the risk of dying from lymphoma in the first couple years is very high. Therefore, something needs to be done for this group of patients in order to improve their survival.
Slide #13
Since age is the very most important factor which predicts for survival, in another model they're using the same factors, but delete the age from the model. This is called the Age-Adjusted International Index. It has similar predictive value. If a patient has three risk factors, these patients don't do very well with conventional chemotherapy, and this is the group of patients that -- autologous stem cell transplant patients as consolidation therapy during first remission is being studied.
Slide #14
There have been several studies looking at the value of autologous stem cell during first complete remission versus conventional chemotherapy in this group of patients. This is a study from Italy looking at using very high-dose chemo and sequential chemotherapy and autologous stem cell compared to conventional chemotherapy, and this study showed that for these very high-risk patients, one can improve the prognosis by doing early stem cell transplantation.
There are a couple other studies that show the same findings. However, not all the studies confirm the benefit of transplantation during first complete remission. There's also a lot of questions about the patient selection. Those who go to transplant may be those who are going to do well already -- those in better performance status, therefore they can go to the high-dose treatment, and maybe there might be a selection bias in the transplantation group. So in order to try to answer this question, we in the United States have conducted studies.
Slide #15
This is SWOG-9704, which has now become an intergroup study, trying to answer this question, whether we really need to do autologous stem cell transplantation in these poor risk patients, including high intermediate and high risk groups. In this study, the patients were treated with conventional chemotherapy, CHOP regimen, and after five cycles the patient would be staged. If they're in complete remission, then they'd be either randomized to receive three more cycles of CHOP, a total of eight cycles, or one more cycle of CHOP followed by stem cell collection, and then go to autologous stem cell transplantation using either a total body irradiation-based regimen or a chemotherapy regimen in those who cannot receive TBI, and then followed by autologous stem cell transplantation.
But those who don't have remission, then, were off studies. We hope that by completed these studies, we'll be able to answer whether stem cell transplantation needs to be done in this group of patients. So we would encourage you to participate in these studies. If not, we also have another protocol that looks at the value of transplantation in those patients who are not able to undergo these studies.
Slide #16
Another patient asks, "How am I going to do after transplantation? What are my chances of curing this lymphoma?" There are many factors that one can look at at the time of transplantation and sort of predict how a patient is going to do. If the patient is in remission after transplant, clearly they'll do better than those who are not in remission. If they have chemosensitive disease, the prognosis is better than chemoresistant, because you're dealing with this tumor, cancer that is chemosensitive. Therefore we increase the dose of chemo and we might be able to eradicate the disease for a long, long time.
Patients who take a long time to relapse have a better prognosis than those who relapse very shortly after completion of chemotherapy. The same thing, if you have elevated LDH at the time of relapse, this means the tumor is very aggressive, and the chance after transplantation may not be as good.
Age is a very important factor. Younger patients do better than older patients, because they're able to tolerate the treatment better, and the biology of the disease in the older patients is different from the young patients. Performance status is important, and bulky disease is important, because if the patient is going to fail, there is often failure in the area of where they had bulky disease before.
Slide #17
This slide from the International Bone Marrow Transplant Registry compiling all the data over five, six years that were reported to the registry looking at the outcome of transplantation in diffuse large-cell lymphoma based on the status at the time of transplantation. Patients in first remission do the best. Second remission, about 60%. Induction failure, about 50%. And relapse is about 40%. Now, those in this induction failure can be difficult to interpret, because there's different definitions used at different centers. Nevertheless, transplantation offered the best chance of cure in this group of patients.
Slide #18
This is the result from our centers. We do a lot more transplants in first remission. There's about an 80% for cure and no relapse, whereas for patients the induction failure, the curve dropped to about 50%. And the problem is, sometimes when we do patients who had had multiple courses of chemotherapy, sometimes they suffered late complications from transplantation, from toxicity, from previous chemotherapy or radiation.
Slide #19
There's many issues that have not been answered and resolved in the autologous stem cell for non-Hodgkin's lymphoma. Relapse is a major cause of treatment failure, and we need to do something to prevent relapse after stem cell transplantation. Regimen-related toxicity is significant. Most of that we can manage, but some of the long-term toxicity is very concerning. The timing of transplantation, when should we do the transplantation? Whether patients should be referred earlier on instead of waiting for them to have multiple relapses before they're referred to us for transplantation. We need to educate the oncologists in the community to send the patients sooner rather than try everything in the world before they send the patients to us, because that impacts the outcome of transplant.
Every patient always asks, "Do I need -- Do you do the purging? Do you do something to the stem cell before you give it back to me? Do we need to do purging? Is that necessary?" And I will try to answer that question. A very common question, what is the best high-dose regimen? Do I need to have radiation? Is it as good as a non-radiation regimen? The answer is unknown at the present time.
And the major question we are thinking about every day and every time we talk to patients is the risk of second malignancies. We have observed this phenomenon in patients with Hodgkin's disease who are treated with chemotherapy and cured their disease -- chemo and radiation, and then 10, 20 years later develop solid tumor or other malignancies. So we are now doing the same thing, and we do transplantation for lymphoma. We try to ... every possible thing to try to get rid of these second malignancies.
Slide #20
So what can we do to prevent relapse after transplantation? One way of doing that is to intensify the regimen. Now, with the introduction of radioimmunotherapy, or targeted therapy, to the lymphoma, we can incorporated that radioimmunotherapy in the high-dose regimen, and perhaps we can be more effective, because we target the radiation or the antibody to the lymphoma cells, and we spare the normal tissue from the side effects of radiation or of the chemotherapy.
Some centers elect to use something called tandem transplant, or double transplant, where we do one transplant, get the cells back, let the patient rest, and do the second transplant. The problem with the tandem transplant is that sometimes the toxicity from the transplant is more, and the risk of liver complications is significant, and the study hasn't shown that this is the way to go yet for transplantation.
There are many approaches tried to do post-transplant to prevent relapse. One approach is to use interleukin-2. As you know, IL-2 is a very effective anti-lymphoma therapy. So we have a study going on right now looking at giving IL-2 post-transplant to see whether we can prevent relapse after transplant. Several studies using rituximab, or Rituxan, during the stem cell collection -- and again, as maintenance therapy post-transplantation to try to mop up those lymphoma cells left in the body, too. Preliminary data showed that perhaps these patients do better than without rituximab. A randomized study needs to be done to confirm that.
Interferon has been tried. We have done T cell infusion to try to activate the patient's own T cells to mop up the lymphoma cells. This is a phase I study, so we don't have the long-term results yet. And there are some studies going on using idiotypic vaccine in mantle cell local lymphoma, where the patient's lymphoma was removed before the transplant, make the idiotypic vaccine, and then after transplantation the patients get vaccinated with their own idiotypic vaccine. So that study is ongoing, and I think it will be interesting to see whether we do something to the relapse.
Slide #21
This is a study that we are the major institution. That is SWOG, SWOG-9438, which is looking at the value of post-transplant IL-2. The patient with relapse, intermediate-grade or low-grade non-Hodgkin's lymphoma, and doing salvage chemotherapy followed by stem cell collection, then undergo autologous stem cell transplant using TBI, Cytoxan, VP-16 regimen, and then after a month or so, at day 28, if they have no evidence of disease progression and have recovered from their graft function, and the patients randomized received either interleukin-2 in hospital for over four days followed by low-dose IL-2 infusion for over 10 days versus no IL-2. This is a group ... study. Many centers participated in this study, and we hope by next year, maybe in another six months, we'll be able to have the answer, will the IL-2 do anything for transplant.
Slide #22
With the era of radioimmunotherapy, this is targeted therapy in lymphoma cells with antibody attached to the cell and attacked with the radiation. There are two different types of target therapy.
Slide #23
I think Dr. ... as we talked about this afternoon is to use either yttrium-90 or I-131. The yttrium-90, that was what we used at our hospital. It's easy to do. It can be given as an outpatient. It's a shorter half-life, 64 hours, and minimal urinary excretion. Therefore, the patient can be home with their family and it can be done as an outpatient, and there's no concern about radiation exposure to the employee or the nursing staff.
I-131 is another type of iodide that is being used in combination with targeted radiation. It is a beta and gamma commuter. It has -- can be done in a low dose as an outpatient, but the high dose has to be done as in inpatient. It has a longer half-life, and it is excreted in the urine, so the patient needs to be in isolation and be careful with the family members. They can't go home until the excretion is below a certain level.
Slide #24
There are two types of studies now incorporating this radioimmunotherapy into the high-dose regimen. The first study was reported by Dr. Vose from the University of Nebraska using the beam regimen that we use for transplant, but add the Bexxar or I-131 anti-CD20 antibodies into the regimen. Start with the trace dose, and then give the dose of the Bexxar about ten days before the high-dose treatment, and then the patient goes to the usual regimen that we use for beam, and then the stem cell infusion. The data was presented last year. The treatment is well tolerated. There's no addition of toxicity by adding the Bexxar, and this treatment seems to be very effective. A longer followup is needed.
Slide #25
Another study was done at the Fred Hutchinson Cancer Research Center by Dr. Oliver Press using a higher dose of Bexxar instead of total body irradiation. So replace high-dose Bexxar with TBI, and then give it in combination with the same high-dose etoposide, high-dose Cytoxan, followed by autologous stem cell infusion. It's a little bit more complicated. The patient was given I-131 for dose symmetry, and then ten days later the patient is then given the higher dose Bexxar targeted to about 2,000 centigray to the normal L organ, and then about ten days later they receive chemotherapy with VP-16 and Cytoxan, and followed by stem cell infusion.
The result of this study was reported a couple years ago, and then what he does is he compares it with the regimen that he used at the same center. This is the high-dose Bexxar and chemotherapy compared to total body irradiation with high-dose chemotherapy. So in this, it's not a randomized trial, but it is a case controlled study. It looks like the Bexxar and the high-dose chemo might be more effective in inducing -- have more impact on survival and progression-free survival.
Slide #26
At City of Hope, we're more interested in using the high-dose Zevalin, because it's easy to do, and our radiation oncologist is more familiar with Zevalin than I-131. It's more easy to do. So we decided to use high-dose Zevalin in our transplant regimen, and this is a molecule of Zevalin. We have B cell Rituxan attached to that plus yttrium-90.
Slide #27
At the present time we have two different protocols we do now for patients with relapse lymphoma. One protocol is to use a very high dose of Zevalin in combination with VP-16 and Cytoxan, the same thing that Dr. Press is doing, but we use Zevalin instead of Bexxar in patients with relapse intermediate-grade and low-grade non-Hodgkin's lymphoma.
The study includes -- first give the patient Rituxan and indium to see the lymphoma distribution in the body. A week later we give the patient Rituxan followed by a high dose of Zevalin calculated based on the distribution of the lymphoma in the body, where it is targeted to the lymph node, and also to the dose to the normal organ not to exceed 1,500 centigray.
Then a week later we do the bone marrow biopsy to see how much radiation we have left in the bone marrow to estimate when it is safe to give the patient back their own stem cells. Then at day minus-4, they receive VP-16, and at on minus-2 Cytoxan the same way we've done before. And we give this, the TPA, which is a chelating agent, to remove the residual radiation from the bone marrow, and then we give the stem cell infusion and start the growth factor.
Now, this study has been going on for the last couple years. We will present this result in December at the American Society meeting. So far, 25 patients have been treated and we saw very encouraging -- What we've seen is that engraftment is no different using the high-dose Zevalin, and the patients have done extremely well without additional toxicity from the high-dose Zevalin, so we are very encouraged by this result, but we need more patients and more time to say this is the best way to go, and not --
Slide #28
Another study we have ongoing right now is similar to what Dr. Vose is doing, but instead of using Bexxar, we use Zevalin in combination with beam, so patients who are not able to receive high-dose Zevalin will go on these studies. This one uses a regular dose of Zevalin, which is 0.4 mCi/Kg. The same principle, the patient receives Rituxan, gets the imaging to see where the distribution of lymphoma cells are, then a week later gets a regular dose of Zevalin than used for relapse lymphoma, and then wait for a week, and then give the same chemotherapy with beam regimen and stem cell infusion. We also observed the same phenomenon as Dr. Vose has seen, that engraftment is very quick. Adding Zevalin to beam does not cause any delay in the engraftment, and doesn't increase any toxicity to the lung, liver or bone marrow so far. So these two studies are ongoing, and we hope that using targeted radiation might be better for the patient than to use chemotherapy alone or total body irradiation.
Now, most of that data that I presented were intermediate-grade or aggressive lymphoma, and some patients have low-grade lymphoma, as well. But the problem with low-grade lymphoma is different from the intermediate-grade lymphoma, because these diseases are more common in elderly patients. The median age must be 50 or older. Therefore, some of them might not be a candidate to undergo autologous stem cell transplant.
The natural history of disease is also different. Patients can live for ten years or five or longer without any treatment, so it's very hard to convince them to say, "You know, you need to have transplantation done," unless we can prove that we can alter the natural history of this disease. In addition, with the new antibodies coming up, with the Zevalin, with the rituximab, the patient has more options when the disease comes back. Maybe they don't need to go through a transplantation. Maybe rituximab alone would be adequate, or Zevalin would give them a better chance with less toxicity than going through stem cell transplantation.
There's always of selection bias for autologous patients, because they have to pass all the functional tests -- their heart, their lungs, their kidney, their liver have to be in good shape in order for them to undergo autologous stem cell treatment. So we've already selected a group of patients that might be better because they're in better shape than the other group of patients.
And unlike intermediate-grade lymphoma, there are no randomized studies comparing transplantation with this regular chemotherapy or regular salvage treatment in patients with low-grade non-Hodgkin's lymphoma. So if you have low-grade lymphoma, I think it's very difficult to understand. Ask all these questions when you see the doctor, and ask about your options and whether transplantation is really indicated for you.
Slide #29
Now, the other question that's commonly asked is, "Is bone marrow purging or stem cell purging necessary?" Purging means that we take the patient's stem cell and we treat that in vitro after we take it out, and we pass it through a cocktail of antibodies, of chemotherapy or chemical agents to try to kill the bad lymphoma cells in the product before we give it back to the patient.
Slide #30
And some centers do purging, and some centers do not do purging. There have not been any randomized studies to confirm that purging is important. But the rationale for purging is that a lot of disease, a lot of lymphoma patients have bone marrow involvement, and that certain lymphomas have a higher incidence of bone marrow involvement than the others. Common ones include follicular lymphoma. 95% of patients may have bone marrow involvement. Mantle cell lymphoma has a very incidence of marrow involvement. High-grade non-Hodgkin's lymphoma, lymphoblastic or bulky lymphoma, about a third of the patients will have bone marrow involvement at the time of diagnosis.
There's some evidence that if we purge the bone marrow and become molecular negative without any evidence of residual lymphoma cells by molecular typing, that seems to improve disease-free survival in that group of patients. This is study from Dana-Farber, and there is also evidence, for example, from Nebraska that you're able to culture the tumor cells from the marrow that had no evidence of lymphoma involvement. What's the meaning of this tumor cell? What does it do? So that's why some centers prefer to use purging.
Slide #31
This is data from Dana-Farber Cancer Center in patients with B cell lymphoma looking at the outcome, the impact of purging. Those who become -- purging become negative by molecular typing have much better survival than those who have evidence of residual lymphoma cells or PCR positive in the bone marrow. Now, there have not been any other studies to confirm this, and again, like I mentioned earlier, there are no randomized studies, and it's probably impossible to do the randomized studies. We would need a large number of patients.
But in general the thinking is that most patients relapse not because we're infusing the contaminated cells. Most relapses occur because the disease becomes resistant to chemotherapy, or we are failing to eradicate the disease because the regimens that we use are not good enough or not effective enough to kill the lymphoma cells, and only a very small fraction of that, that live ... is due to infusing of the lymphoma cells, and that's why this question cannot really be answered.
Slide #32
Now, let's shift to allogeneic stem cell transplantation for lymphoma. We do transplantation for lymphoma, but this cannot be done in older patients. In general, the maximum age is 55, but now we're moving up to 60 and higher, and I will show you how we do that. But in general, if we do full marrow ablative allogeneic stem cell transplantation, age is very important. When they're older than 55, they clash. The minute they get radiation they get sepsis, they have GVHD. So it's very difficult to do full transplantation in people older than 55 years old. There's very high transplant-related mortality in younger patients, maybe 20, 30%, which is still very high, and generally it's about 40, 50%, and this is mainly due to infectious complications, graft versus host reaction or complications of transplantation.
The most important thing is the high-dose regimen that we deliver may not be able to eradicate the disease, because the disease may be resistant. We cannot use a lot of high-dose treatment because -- for this type of transplantation. And there is a clear-cut phenomenon, that if one uses allogeneic bone marrow or stem cell, there is a clearcut graft versus lymphoma effect, and the risk of relapse is much lower when we use this kind of transplantation compared to autologous transplantation. And there's clearly a benefit of not having tumor cell contamination in the products that we give to the patients.
Slide #33
Now, in general, the indication, when the patients come to us, which patients are we going to recommend allogeneic, and which patients are we going to recommend autologous? We generally only reserve allogeneic stem cell transplantation for those patients with high-grade lymphoma, such as lymphoblastic lymphoma and Burkitt's lymphoma, because these lymphomas have a very, very high incidence of bone marrow involvement. It's almost like acute lymphoblastic leukemia.
And the ability to collect cells or to do transplants from their bone marrow stem cells is very, very minimal in patients with low-grade lymphoma, follicular lymphoma or small lymphocytic lymphoma, for two reasons: because the bone marrow is often involved in this disease. Secondly, these are the types of lymphoma that have the most graft versus lymphoma effect. The risk of relapse is extremely low in patients with low-grade lymphoma if they undergo allogeneic stem cell transplantation.
Another type of lymphoma that we're now doing allogeneic stem cell transplants in are patients with mycosis fungoides. Advanced stage, patients with tumor stage, Sézary syndrome. With these patients, we do a peripheral blood. We almost always demonstrate gene rearrangement or peripheral blood involvement, so therefore it's impossible to do autologous stem cell in these patients. And clearly, patients who have persistent bone marrow, peripheral blood involvement by their lymphoma will be unable to use their stem cells, so we have to look for allogeneic stem cell transplant for those patients.
Now, when we do allogeneic stem cell transplantation, it's not as simple as autologous. It has many steps involved. First, we have to give them high-dose chemotherapy or chemo and radiation for two purposes: one, as an anti-lymphoma therapy to eradicate the disease from the body; and second, as an immunosuppressive therapy to prepare the body for the new bone marrow. Otherwise, the body may not accept the new bone marrow.
Once we've done that, we still have to deal with graft versus host disease. The body is very careful. Even though the brother might be identical to you by testing, but your body recognizes this not your own stem cell, and the patient will develop a reaction called graft versus host disease. There are two different types of graft versus host disease, the acute form within the first treatments, and the chronic form that occurs later on and sometimes can be debilitating for a long time.
So we have to give the patient medication to prevent graft versus host disease. There are two ways of doing that, either to use drugs such as cyclosporin, Prograf or methotrexate, or a combination of all of these; or to remove the T lymphocyte, which is a cell that initiates graft versus host disease from the product, and that's called T cell depletion. The problem with T cell depletion is that removing a lot of lymphocytes can also remove the immune system, so patients have more problems with infectious complications, and also because the T lymphocyte also is a cell that exercises graft versus lymphoma effects, therefore the risk of relapse is higher in the T cell depletion because you don't have those cells to initiate the graft versus lymphoma effect.
Because of all this immunosuppression from the high dose itself, from the drugs that we have to give to prevent the reaction, the patient is very, very immunocompromised, so they are set up to develop infections that normally we don't see in a normal person -- cytomegaloviral infections, fungus infections, opportunistic infections, herpes infection reactivation, Pneumocystis carinii pneumonia, sort of like people who have HIV infection. So we have to treat and prevent all these infections. And infection actually is one of the most common causes of treatment failure in allogeneic stem cell transplant.
Slide #34
So the bottom line is, if you do -- What is the better way of doing it, whether we do autologous or do allogeneic? And this is an attempt to try to answer the question. There haven't been any randomized studies, because it's very hard to randomized based on the donor, because this is biological randomization. This is one way of looking at it. This is a case-controlled study from European bone marrow transplant studies. Tried to match the patients with the same disease, the same histology, who underwent allogeneic stem cell transplantation or allogeneic bone marrow transplant compared to those who underwent autologous bone marrow transplant, and there's no difference in the outcome. Basically, patients with autologous die from relapse, and patients with allogeneic, they still have the same survival, but we lost them from infectious complications or from graft versus host disease.
This is the data from Detroit, Wayne State, a single-center study looking at patients with lymphoma and patients who do have a matched sibling donor undergo allogeneic stem cell transplant. Patients who do not have not have a matched sibling donor undergo autologous stem cell transplantation. This is a typo. It should be autologous. And it seems that the autologous might be better in a single-center study. However, the risk of relapse is much lower in a patient who receives allogeneic stem cell transplantation, really clearly illustrating the impact of graft versus lymphoma effect. The relapse is only 20% compared to 60% if you use autologous bone marrow.
Slide #35
And this is much more pronounced in the patients with low-grade non-Hodgkin's lymphoma, small lymphocytic and follicular lymphoma. This is data from European comparing allo versus autologous stem cell for patients with low-grade non-Hodgkin's lymphoma. There no relapse, or risk of relapse is less than 10% in which you use allo stem cell compared to autologous, and that translates into better progression-free survival. So there's clearly a role for allogeneic stem cell transplantation for a certain subset of patients because of the benefit of the graft versus lymphoma effect.
This is just trying to compare the toxicity from the two types of transplants. In general, the transplant-related mortality during the first year for allogeneic ranged between 30 to 40%, and if you divide them as to what are the causes of the toxicity, the majority were due to infection, organ toxicity and graft versus host disease, and the risk of relapse, about 20, 30%. When compared to autologous, relapse is a major cause of treatment failure, and regimen toxicity and infection is much less common than with the allogeneic stem cell transplant.
Slide #36
So in order to improve the transplant for allogeneic stem cell, we have developed a new transplant depending on which center you go to, this terminology either mini- allogeneic stem cell transplant or mini-transplant, non-myeloablative allogeneic stem cell transplantation, or reduce intensity allogeneic stem cell transplantation. They are the same, but the drug might be different. The mini-transplant is really mini. The patients get very minimal treatment.
Slide #37
And the rationale for doing this is that if we can reduce the early transplant-related morbidity and mortalities in the first hundred days from 30, 40% to 10% or lower, then we can get the patients through the transplant more, and therefore the chance for survival will be better. If you don't use a very high dose of chemotherapy and radiation in the regimen, you're likely to reduce it's long-term toxicity from this regimen from radiation or from chemotherapy. So we reduce both the early transplant toxicity, and we also aim at looking at trying to reduce long-term toxicity.
And since the regimen is much more milder or less toxic, therefore we can extend this -- try transplant in older patients. We have done that up to, say, 68 or 70 years over this approach. And we know that there is a clearcut graft versus lymphoma effect. Therefore, we can use that as way to prevent relapse and use that instead of using a heavy dose of chemotherapy and radiation.
Slide #38
And we're able to accomplish this from several approaches. One is to use a regimen that is designed to be immunosuppressive to facilitate donor engraftment and limit systemic toxicity. We can do this because of this new drug, fludarabine, or 2-CDA. Ten years ago we didn't have this drug. This other drug that's used for treatment of low-grade lymphoma or CLL, very effective therapy for patients with lymphoma, and at the very same dose that we give to patients it's also immunosuppressive. It reduces the T lymphocyte, it's both T cell and B cell depletion. Therefore it can be used to induce engraftment.
We can also add monoclonal antibody to remove to T cells if they use antithymocyte globulin, which has been used for treatment of graft versus host disease, or for patients who receive T cell depletion as an in vitro T cell depletion. There's a new drug called Campath-1H, which is a very effective therapy for patients with B cell CLL. This is very, very immunosuppressive. It kills both B and T cells, and it can be use in conjunction with transplant to allow engraftment.
A study from Seattle has shown that you don't need to give 1,200 centigray in order to get engraftment. In animal studies, we can give one single dose of radiation at 200 centigray, and that can be enough to allow the engraftment.
The second approach is to add some agents that can prevent graft versus host disease and at the same time enhance engraftment. For the last year or so, there's a new -- not a drug, but a drug that had been used in renal transplant or organ transplant called mycophenolate mofetil. This is a very, very effective anti-immunosuppressive therapy, and this had been done -- is shown in animal models, is synergistic with cyclosporin. When given with cyclosporin, it potentiates a section of cyclosporin, therefore this can be added to cyclosporin to prevent graft versus host disease and allow engraftment.
The next approach we do is, instead of using the bone marrow, we know that stem cell grow much faster in the body. We could then use a stem cell instead of bone marrow. The stem cell can be collected with a large volume, so the graft can come back very quickly, and then after that, once the patient engrafts, if they don't respond, there's also an idea of giving back the patient donor lymphocyte to exercise graft versus lymphoma effect by inducing them to have graft versus host reaction, which in turn exhibits graft versus lymphoma effect. So that's the principle of the nonmyeloablative approach.
Slide #39
There are several regimens that are being used now at several centers. We use fludarabine, single-dose TBI at City of Hope, and this is a consortium study with Seattle, Stanford, the University of Colorado in patients with lymphoma and myeloma. Fludarabine melphalan was developed at MD Anderson, and we are using that when people have tumor burden. Combination fludarabine, Cytoxan, Rituxan is very effective for patients with small lymphocytic lymphoma and low-grade lymphoma at MD Anderson. The English group used -- added Campath in addition to fludarabine-melphalan as anti-T cell therapy or in vivo T cell depletion. The group at Boston used combination fludarabine, busulfan and ATG. So depending on which center you go to, these are the regimens commonly used. Most of them have fludarabine, since it's a very effective immunosuppressive therapy.
Again, these are still ongoing studies, and we don't know yet which is the best combination. The patients, all the patients should be enrolled on -- ... This is a constant experimental study, so you should be enrolled on all the studies at each center.
This is an example of the regimen that we use. It's combination fludarabine and TBI. The dose of fludarabine is the same as we use for patients for treatment of low-grade lymphoma or CLL. It's 90 mg/m2 given over three days, a single dose of radiation, 200 gray, cyclosporin begun at day minus-2, and MMF begun after we give the patient stem cell infusion.
Slide #40
So far the experience shows that the transplant-related mortality during the first 100 days can be reduced to about 10 to 15%. We still have to deal with graft versus host disease, but so far, preliminary results suggest that this approach might be better than regular transplantation. This is a slide from Dr. Khouri from MD Anderson. For patients with low-grade non-Hodgkin's lymphoma who underwent transplantation and using molecular high-dose treatment with TBI, Cytoxan, VP-16, compared to the nonmyeloablative approach using fludarabine, Cytoxan with or without Rituxan, and the risk of relapse is much lower and the outcome is much better. But again, this is a small number of patients, short followup, so we still need to define this approach. There's still a lot to be learned, what the best regimen to use, how much cell we have to give, how we can combat graft versus host disease without altering the graft versus lymphoma effect.
Now, another approach is also being explored, and this is being done a lot more done for patients with multiple myeloma and now being explored in patients with lymphoma, as well. It is to do something called autologous stem cell followed by mini-allogeneic stem cell transplant. The idea is to do autologous stem cell to try to achieve maximum tumor response giving the high-dose therapy, giving the cells to rescue the side effects. Let the patient rest for about two or three months to allow them to recover from the side effects of high-dose treatment, allow the graft to recover.
Then patients who we fear might be at higher risk of relapse because they have these symptoms, high LDH, big, bulky mass, extranodal involvement, if they have a matched sibling donor, instead of waiting for them to relapse we then advise them to undergo something called mini-allo as a way to exercise immunotherapy to export the graft versus lymphoma effect. So a study is being carried out. A protocol has been developed to try to identify which patients might benefit from this type of approach.
I'll just show you one study from Professor Carrell from Italy in patients with refractory Hodgkin's disease. He identified from the beginning that these patients are not going to do well with autologous stem cell transplantation, so he subjected the patients to autologous stem cell, let them recover. Those who had matched siblings, two or three months later, then undergo a mini-allo using fludarabine, Cytoxan and allogeneic stem cell transplantation from their sibling. So far the results are encouraging, and there might be benefit for a subset of patients. But again, this remains experimental, and larger studies need to be done in order to make sure that this is the best way to go.
Slide #41
There's a lot of complication of transplantation, that every time we talk to the patient we need to prepare them for these short-term and long-term complications. Most of the short-term complications can be treated, can be prevented and can be resolved with treatment. These include low blood count from the effects of high-dose chemo and radiation, mucositis, a mouth sore from the side effects of chemo and radiation, diarrhea, infectious complications because of the low blood count, skin rashes, fever, some liver complications.
And then there are long-term toxicities that are of concern, especially sterility in young persons. If you use total body irradiation in that person, almost 99 to 100% of the patients become sterile. They won't be able to have children, so this is a major issue for young adults. Because of the accumulating toxicity of the drug that we use before treatment and during the transplant, some patients do develop lung or heart complications ten years or 20 years later -- i.e., cardiomyopathy from adriamycin plus high-dose Cytoxan plus ... radiation, so this is something that we did to follow the patients along. We make sure their heart-lung function is normal before the transplantation. We follow the long-term followup on these organ functions.
The risk of second malignancy is a major, major concern as per leukemia and solid tumor. We try to avoid using drugs that might cause leukemia. If we do transplant early on before their exposed to too many cycles of chemotherapy, then we can perhaps reduce the risk of this leukemia. If we don't use radiation in the regimen, there are some studies showing that maybe the radiation is the caused more solid tumors than without radiation, but the data are not 100% supported.
Basically, most data show that the amount of chemotherapy that the patient had before the transplant is probably the leading cause of leukemia rather than the regimen that we use in the high dose itself. And the quality of life is a major concern. We have long-term follow-up studies, and at our hospital we send a questionnaire to the patient. We interview them at frequent intervals to see how they do, how the marriage is doing, about the sex life, whether they go back to work, what's the quality of life after transplantation. This is very important, because when we talk to the patient about transplant, they often ask, "How am I going to be a year from now? Am I going to go back to work? What's going to happen to my family? What's going to happen to my life?" So doing this kind of study will be able to help answer those questions.
Slide #42
This is very exciting. It's by the Amgen company.
That has been studied using IL-2 during transplant in the allo setting. We have done amifostine, because amifostine has been shown to reduce mucositis in patients with head and neck cancer who receive local radiation to head and neck, but in the transplant setting we have not see the benefit of amifostine. Lisofylline has also been used in the transplant setting. The initial result looks good, but long-term followup did not turn out to be more prevention of infectious complications.
So in the future we're going to need to try to improve the regimens that we use. We need to reduce the toxicity. We need to prevent long-term and short-term complications in order to cure more patients with lymphoma. Thank you very much for your attention. [APPLAUSE]
SANDRA HORNING, MD: While we're getting set up for our next speaker, I'm going to ask Dr. Nadee to take a question or two from the table. I think that first mike will be on.
Q: Is it just important to have a good match for a mini-allo as an allo?
AUAYPORN NADEMANEE, MD: Yes? It's very important to have six out of six match, although one antigen mismatch can be done, but not advisable. In order to do one antigen mismatch, we have to intensify the regimen, like add Campath or do something to the graft. But we would prefer to have a six out of six match.
Q: What preparation does the donor in an allo have to go through?
AUAYPORN NADEMANEE, MD: Usually for this -- either way, what you have to do is, we have to see them, do a routine physical, lab work, chest x-ray, kidney function test, hepatitis, HIV and all the usual tests to make sure they're healthy, they don't have any contraindication to donate the blood or bone marrow. So the same principle as used for blood donation, but we do a chest x-ray, EKG and so on.
Q: Are they given any drugs to --
AUAYPORN NADEMANEE, MD: Yes. If they do the bone marrow, they don't get any drugs. We just take them to the operating room and harvest the bone marrow under general anesthesia. It takes about 30 minutes to one hour, and they recover and usually go home the same day. The long-term side effects mostly a pain in the hip area, like someone really punched hard on the hip.
Now, for the stem cell transplant, we give them growth factor the same way, the same growth factor they use for cancer treatment. It's called Neupogen. It stimulates the white cells to grow. We give the injection subcutaneously, underneath the skin, for five days before we do the stem cell collection. The immediate side effects, mainly flu-like illness, body ache, generalized body ache, back pains, and some people do get a little bit of headache, a little bit of fever. And during the stem cell collection, they do from the arm like we do with the blood donation. It's about four hours on the machine for one or two days.
There have not been long-term complications of using the growth factor in normal donors. This has been looked at in the National Marrow Donor Program. It's been going on for the last ten years or so. So some people are concerned that it may cause leukemia. We have not seen that. There have not been long-term risks of getting growth factor for the normal donor.
SANDRA HORNING, MD: I think in the interest of time that we'll move along in our program, and hopefully those of you who have not had an opportunity to ask your questions can do so during our question and answer or during the break. We're running a little over time. That's okay. Thank you.
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