ANNOUNCER: Doctors treating chronic myeloid leukemia now have 54 months of experience with imatinib. The drug, also known as Gleevec, is the standard of care for treating most people with the disease.
BRIAN DRUKER, MD: The most recent updates on Gleevec are showing that for newly diagnosed patients with chronic phase CML, they're doing extraordinarily well. Overall survival at four and a half years is 90 percent. What's really interesting about the most recent data is that the rate of relapse, in other words, the percent of patients or the numbers of patients relapsing per year, actually may be decreasing a little bit. And if that trend holds, there could even be a plateau on the survival curve, meaning that patients could live for decades, potentially. I certainly don't want to make too much of that, because it's early data, but at least there's a hint that we're headed in that direction.
ANNOUNCER: Effectiveness in treating CML can be measured by checking whether a sample of white blood cells, when viewed under the microscope, harbors the abnormal chromosome responsible for the disease. This is a test for what's called the "chromosomal response."
A major chromosomal response is good. A complete chromosomal response is better. The latest data, also from the so-called IRIS trial, shows improving responses by these measures.
MICHAEL DEININGER, MD, PhD: The rate of complete chromosomal [cytogenetic] responses in the latest update of the IRIS trial was 86 percent. So this is still improving, compared to last year, and the major chromosomal response rate is at over 90 percent .
ANNOUNCER: Doctors also monitor CML with more sensitive testing, called molecular testing, or PCR. When patients quickly achieve a significant reduction in their disease at one year, as measured by PCR, new data shows their prognosis may be very good.
MICHAEL DEININGER, MD, PhD: The patients who achieve very substantial reduction of their disease burden at 12 months continue to do extremely well with almost nobody going to blast crisis or accelerated phase. So it seems, for the majority of patients that are newly diagnosed, standard dose imatinib treatment is highly efficacious and relapse is the exception if not the rule.
ANNOUNCER: Scientists are also reporting on early, small-scale studies with new drugs that may prove valuable for the patients whose disease shows resistance to Gleevec. Data from a phase I study of dasatinib shows a significant response in many patients.
JORGE CORTES, MD: We found that, number one, in patients who failed imatinib, pretty much regardless of the stage of their disease, meaning chronic, accelerated or blast phase, the responses are very high. About 80 percent of patients had a hematologic response, meaning their counts go back to normal. And about half of the patients, and again, that was very constant throughout all these different stages of the disease, about 50 percent of patients had a cytogenetic response. Considering that all these patients had failed Gleevec already, that seems pretty impressive.
ANNOUNCER: Recent phase II data show similar responses, and there's a suggestion they may hold up over time. The phase II studies also show dasatinib is well tolerated in many patients, although there can be a drop in blood counts. In about 10 percent of patients, there can be fluid buildup around the lungs.
The other drug under study is AMN107. Testing is not quite as far along, and only phase I data has been released.
JORGE CORTES, MD: In this study, most of the patients were in the accelerated or in the blast phase. There were only a few (seventeen) patients that were in the chronic phase. But the responses were also very good in the different stages of the disease. Also around 80 percent of patients getting a hematologic response; some complete, some less than that, but still important. And, gain, cytogenetic responses in a high percentage of patients, in close to 50 percent, particularly in the chronic and accelerated phase; a little bit less, but about still 30 percent in the blast phase. So very good results.
ANNOUNCER: The study shows AMN107 is also well-tolerated. But it, too, can cause a drop in blood counts, and sometimes temporary increases in liver enzymes. When patients become resistant to Gleevec, it's usually because of a mutation in an enzyme called BCR-ABL. In CML, BCR-ABL leads to the uncontrolled replication of white blood cells.
Gleevec and the two new drugs under study inhibit BCR-ABL. One problem that's emerged is that none of the drugs are effective against one particular mutation, which is known as T315I.
JOHN GOLDMAN, MD: In patients who become resistant, within chronic phase, one finds a mutation in something between 40 and 70 percent of patients; say, about 50 percent. There are about 45 different mutations identified now. There are a lot of different mutations identified, and the incidence of each of these mutations varies quite a lot, but in different studies; I would guess that the T315I is found in about 5 or 7 percent of mutations.
ANNOUNCER: If a patient carries T315I, or fails on one of the new drugs for other reasons, or proves unable to take them because of side effects, treatment options still remain. There are trials with still other drugs. And doctors are likely to recommend a stem cell transplant, if the patient is young enough, and if a good tissue matched–donor can be found.
MICHAEL DEININGER, MD, PhD: Well, if a patient fails on one of the novel BCR-ABL inhibitors, then again, the question of an allogeneic transplant should be addressed. And really everybody who has a transplant option should go for it at this point. If not, then there are clinical trials out there that target other agents that are more specific than these novel inhibitors and there's a variety of trials out there.
ANNOUNCER: Yet Gleevec usually proves effective, especially in chronic phase CML. And sometimes the response is a reduction in leukemic cells below detectible levels, even with the very sensitive PCR testing. That raises the question of whether oral drug therapy in CML might ever lead to cure.
JOHN GOLDMAN, MD: The question of whether any patients at all are cured is pretty topical at the moment. My own feeling is that, even when you've got undetectable leukemia, there's probably a small amount of leukemia there in every case. But some of my colleagues have been arguing, even today, that once you have undetectable leukemia, in small numbers of patients, that really does mean eradication. And, if you stop the drug, it'll never come back. The leukemia will never come back.
ANNOUNCER: Today, most doctors say a patient with even a complete molecular response is still not cured. That's why residual disease is drawing much scientific attention.
BRIAN DRUKER, MD: There's a lot of research ongoing to try and figure out the precise mechanism whereby we can eradicate those last few cells so we can take a good remission with a drug like Gleevec or AMN-107 or dasatinib and turn that into a cure. And I see that as the most promising area of research for the future.
JORGE CORTES, MD: So there's been a lot of interest recently in trying to bring the disease down to a minimum and then to stimulate or train the immune system to try to control that little disease that's left, when it's just at the level of very few cells. Control it or, ideally, eliminate it. But, at the very least, control it so it'll never go out of those very few cells.
ANNOUNCER: Some research is suggesting the drug interferon might prove useful in fighting residual disease. Studies are also underway to see if vaccines might play a similar role.
The latest data on Gleevec shows a real survival benefit with the drug, especially for patients who begin therapy in the early, chronic phase of the disease. Doctors are monitoring patients to see if that trend continues. And researchers are launching new studies to better understand how to treat complications including resistance.
JOHN GOLDMAN, MD: Well the take-home message for a patient today is there's been a tremendous improvement in his or her prognosis in the last five years. From estimating a median survival of about five or six years, we're now looking at the possibility that a patient treated and responding to imatinib might live 15 or 20 years. It's difficult to be sure, but there's been an absolute revolution in the favorable prognosis for chronic myeloid leukemia.
BRIAN DRUKER, MD: The most recent updates on Gleevec are showing that for newly diagnosed patients with chronic phase CML, they're doing extraordinarily well. Overall survival at four and a half years is 90 percent. What's really interesting about the most recent data is that the rate of relapse, in other words, the percent of patients or the numbers of patients relapsing per year, actually may be decreasing a little bit. And if that trend holds, there could even be a plateau on the survival curve, meaning that patients could live for decades, potentially. I certainly don't want to make too much of that, because it's early data, but at least there's a hint that we're headed in that direction.
ANNOUNCER: Effectiveness in treating CML can be measured by checking whether a sample of white blood cells, when viewed under the microscope, harbors the abnormal chromosome responsible for the disease. This is a test for what's called the "chromosomal response."
A major chromosomal response is good. A complete chromosomal response is better. The latest data, also from the so-called IRIS trial, shows improving responses by these measures.
MICHAEL DEININGER, MD, PhD: The rate of complete chromosomal [cytogenetic] responses in the latest update of the IRIS trial was 86 percent. So this is still improving, compared to last year, and the major chromosomal response rate is at over 90 percent .
ANNOUNCER: Doctors also monitor CML with more sensitive testing, called molecular testing, or PCR. When patients quickly achieve a significant reduction in their disease at one year, as measured by PCR, new data shows their prognosis may be very good.
MICHAEL DEININGER, MD, PhD: The patients who achieve very substantial reduction of their disease burden at 12 months continue to do extremely well with almost nobody going to blast crisis or accelerated phase. So it seems, for the majority of patients that are newly diagnosed, standard dose imatinib treatment is highly efficacious and relapse is the exception if not the rule.
ANNOUNCER: Scientists are also reporting on early, small-scale studies with new drugs that may prove valuable for the patients whose disease shows resistance to Gleevec. Data from a phase I study of dasatinib shows a significant response in many patients.
JORGE CORTES, MD: We found that, number one, in patients who failed imatinib, pretty much regardless of the stage of their disease, meaning chronic, accelerated or blast phase, the responses are very high. About 80 percent of patients had a hematologic response, meaning their counts go back to normal. And about half of the patients, and again, that was very constant throughout all these different stages of the disease, about 50 percent of patients had a cytogenetic response. Considering that all these patients had failed Gleevec already, that seems pretty impressive.
ANNOUNCER: Recent phase II data show similar responses, and there's a suggestion they may hold up over time. The phase II studies also show dasatinib is well tolerated in many patients, although there can be a drop in blood counts. In about 10 percent of patients, there can be fluid buildup around the lungs.
The other drug under study is AMN107. Testing is not quite as far along, and only phase I data has been released.
JORGE CORTES, MD: In this study, most of the patients were in the accelerated or in the blast phase. There were only a few (seventeen) patients that were in the chronic phase. But the responses were also very good in the different stages of the disease. Also around 80 percent of patients getting a hematologic response; some complete, some less than that, but still important. And, gain, cytogenetic responses in a high percentage of patients, in close to 50 percent, particularly in the chronic and accelerated phase; a little bit less, but about still 30 percent in the blast phase. So very good results.
ANNOUNCER: The study shows AMN107 is also well-tolerated. But it, too, can cause a drop in blood counts, and sometimes temporary increases in liver enzymes. When patients become resistant to Gleevec, it's usually because of a mutation in an enzyme called BCR-ABL. In CML, BCR-ABL leads to the uncontrolled replication of white blood cells.
Gleevec and the two new drugs under study inhibit BCR-ABL. One problem that's emerged is that none of the drugs are effective against one particular mutation, which is known as T315I.
JOHN GOLDMAN, MD: In patients who become resistant, within chronic phase, one finds a mutation in something between 40 and 70 percent of patients; say, about 50 percent. There are about 45 different mutations identified now. There are a lot of different mutations identified, and the incidence of each of these mutations varies quite a lot, but in different studies; I would guess that the T315I is found in about 5 or 7 percent of mutations.
ANNOUNCER: If a patient carries T315I, or fails on one of the new drugs for other reasons, or proves unable to take them because of side effects, treatment options still remain. There are trials with still other drugs. And doctors are likely to recommend a stem cell transplant, if the patient is young enough, and if a good tissue matched–donor can be found.
MICHAEL DEININGER, MD, PhD: Well, if a patient fails on one of the novel BCR-ABL inhibitors, then again, the question of an allogeneic transplant should be addressed. And really everybody who has a transplant option should go for it at this point. If not, then there are clinical trials out there that target other agents that are more specific than these novel inhibitors and there's a variety of trials out there.
ANNOUNCER: Yet Gleevec usually proves effective, especially in chronic phase CML. And sometimes the response is a reduction in leukemic cells below detectible levels, even with the very sensitive PCR testing. That raises the question of whether oral drug therapy in CML might ever lead to cure.
JOHN GOLDMAN, MD: The question of whether any patients at all are cured is pretty topical at the moment. My own feeling is that, even when you've got undetectable leukemia, there's probably a small amount of leukemia there in every case. But some of my colleagues have been arguing, even today, that once you have undetectable leukemia, in small numbers of patients, that really does mean eradication. And, if you stop the drug, it'll never come back. The leukemia will never come back.
ANNOUNCER: Today, most doctors say a patient with even a complete molecular response is still not cured. That's why residual disease is drawing much scientific attention.
BRIAN DRUKER, MD: There's a lot of research ongoing to try and figure out the precise mechanism whereby we can eradicate those last few cells so we can take a good remission with a drug like Gleevec or AMN-107 or dasatinib and turn that into a cure. And I see that as the most promising area of research for the future.
JORGE CORTES, MD: So there's been a lot of interest recently in trying to bring the disease down to a minimum and then to stimulate or train the immune system to try to control that little disease that's left, when it's just at the level of very few cells. Control it or, ideally, eliminate it. But, at the very least, control it so it'll never go out of those very few cells.
ANNOUNCER: Some research is suggesting the drug interferon might prove useful in fighting residual disease. Studies are also underway to see if vaccines might play a similar role.
The latest data on Gleevec shows a real survival benefit with the drug, especially for patients who begin therapy in the early, chronic phase of the disease. Doctors are monitoring patients to see if that trend continues. And researchers are launching new studies to better understand how to treat complications including resistance.
JOHN GOLDMAN, MD: Well the take-home message for a patient today is there's been a tremendous improvement in his or her prognosis in the last five years. From estimating a median survival of about five or six years, we're now looking at the possibility that a patient treated and responding to imatinib might live 15 or 20 years. It's difficult to be sure, but there's been an absolute revolution in the favorable prognosis for chronic myeloid leukemia.