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By MedHelp Editors
Chronic myelogenous leukemia (CML) is a rare type of slow-progressing cancer of the white blood cells that is almost always associated with a chromosomal abnormality called the Philadelphia chromosome.
MedHelp talked with CML expert Matt Kalaycio, MD, director of the Chronic Leukemia and Myeloma Program at the Cleveland Clinic, about current and new treatment options for CML. (Dr. Kalaycio receives speaking fees and research money from Novartis and research money from Bristol-Meyers Squibb.) Here is an edited version of the conversation:
Q: CML is most often diagnosed through a routine blood test in people who have no outward symptoms of the disease. Would you suggest that this gives people another reason not to skip their regular physicals exams with their doctors?
A: Well, it's interesting. There's no advantage to catching this leukemia early as far as we currently know. So unlike breast cancer where early recognition is important, it's not as important in CML.
Even though CML treatments are the most effective when they're started during the chronic, or first, phase of leukemia, it's not likely that a chronic phase will end up progressing to the more advanced blast crisis phase without coming to medical attention somewhere along the way. At least 80% of patients get diagnosed in the chronic phase versus the accelerated or blast crisis phases. That's because patients will eventually develop symptoms and it's almost always in the chronic phase.
This cancer is relatively rare. Only about 5,000 new cases of CML are diagnosed each year in the United States. Therefore screening and prevention are unnecessary and unwarranted because it's so unlikely that an individual will develop CML.
Q: Gleevec (imatinib), the standard first-line treatment for CML, has changed not only the way we treat CML, but it has also changed our approach to developing new cancer drugs. Can you explain?
A: CML and imatinib is the success story in cancer treatment. It's Nobel Prize-winning work that hasn't won the Nobel Prize...yet.
For investigation into cancer treatments, the "holy grail" is to identify the cause of the cancer, develop a treatment that interferes with that cause, and cure the cancer. In CML, we've basically done that. Brian Druker [of the Oregon Health and Science University] and his colleagues knew what the pathway was, the BCR-ABL protein [which is caused by the Philadelphia chromosome], worked with the pharmaceutical company Novartis to find a compound that interfered with that protein and developed the drug Gleevec to put the disease in remission indefinitely in the vast majority of patients.
You can't stop taking the drug Gleevec because it's not clear that the disease is ever cured, it's only in remission. But with treatment, the disease keeps people in remission for as long as we've been following them.
Gleevec is not perfect: 20 percent of cancer patients either can't take the drug or can't tolerate it. But it is pretty close to a homerun. And it is proof of principle that you can identify the pathophysiologic pathways that lead to cancer, interfere with that pathway and induce remission.
That's called a targeted therapy — meaning you target the pathway that causes the cancer. And Gleevec was the initial treatment that proved it could actually be done. Since Gleevec was invented, just about all cancer research has moved away from chemotherapy and to these targeted therapies.
Q: Will there be drugs that improve upon Gleevec?
A: Those patients who fail Gleevec, in other words, the 20 percent of patients who either can't tolerate or don't respond to Gleevec treatment, are given either the drug dasatinib (brand name Sprycel) or nilotinib (brand name Tasigna) as second-line therapy. And in the majority of cases, patients respond to these drugs and the cancer remains in remission.
But just recently, the New England Journal of Medicine published two studies in which these drugs were directly compared to Gleevec in newly diagnosed patients. The results suggest that these drugs are better than Gleevec in terms of inducing remission and keeping patients in remission.
These new trials show that if you use dasatinib and nilotinib upfront, before Gleevec, they work even better than Gleevec itself. In the next five years or so, it is likely that Gleevec will be replaced by one of these two drugs as initial therapy. It's really unbelievable — how could you improve on such great results? But these new drugs do.
Q: And yet a little more than 10 years ago, stem cell transplantation was the main course of treatment for CML.
A: It's paradoxic in a sense that a stem cell transplant is absolutely capable of curing CML. There's no question about it — the disease can be cured with transplant. But in order to have an opportunity for cure, there is a risk for early death. Untreated, the disease can go five or six years on average [while the disease is in the chronic phase] and things are OK. But with a transplant, you run about a one or two out of 10 chance of not surviving six months after the transplant. That's because the incoming marrow — the incoming immune system — rejects the recipient (not the recipient rejecting the marrow).
Plus, if a patient survives the transplant, there is the potential for a long-term immune reaction called graft versus host disease that never goes away. That's a high price to pay even if you're cured. That's why transplant has been relegated to second-line therapy - the toxicities of it are far greater than the potential benefit.
Q: The advances in this field have been quite remarkable in the last 10 years.
A: Absolutely. It's changed my practice. When I came in as a stem cell transplanter in 1994, when I had a patient with CML, I would transplant them. I had a clinic full of patients with chronic graft versus host disease. But since about 2001, when Gleevec was first introduced, the number of patients I've transplanted for CML has gone to almost zero and my clinic is full of people taking pills. It's completely changed the way we deal with CML. And I don't see as many patients anymore because the local doctors can take care of them on their own. They don't need to send them to see me to get pills. Whereas, they had to send them to me to get a transplant once upon a time.
Q: What new treatments do you foresee in the treatment of leukemia? Will there be better drugs than the ones we have now?
A: I wouldn't necessarily say better, but they are at least as good. The class of drugs that includes Gleevec is called tyrosine kinase inhibitors. There are other tyrosine kinase inhibitors under development. And there are other agents under development that work in a complementary fashion to the tyrosine kinase inhibitors. And perhaps most exciting, there are vaccines under development.
Q: Wow, a cancer vaccine? How does it work and who would be a candidate for vaccination?
A: These vaccines work by getting your own immune system to recognize the BCR-ABL protein as a foreign body and reject it. It would be a secondary vaccination. So you would be diagnosed with CML, then your immune system would be "vaccinated," for lack of a better word, and the disease would go away. So it's not primary prevention, it's secondary treatment. Because it is still immunologically-based we call it a vaccine.
The purpose of the vaccine is to stop the medicine, because otherwise you're on the pills forever. The problem with this is that, let's say you're on Gleevec and you're doing great, responding well to treatment, and you know that your long-term survival looks good. But in order to get the vaccine, you've got to stop the Gleevec. Who's willing to do that? That's the problem.
Q: In a field where there's not usually a lot of good news, is there a message of hope you give your patients?
A: I try to convince them that, yes they've got leukemia, and yes, untreated it's fatal, but with treatment, there's every expectation that their life span will be just as long as everybody else's. Now I can't say that with certainty because the drug hasn't been around long enough to say that with certainty.
And what do we mean by cure? If a pill keeps you in remission forever, you're cured. But if you stop taking the medicine, the disease comes back, so you're not really cured. We can't cure high blood pressure either, but if you take your medicine, you don't die of a stroke. Much like CML, where if you take your medicine, you won't die of the leukemia.