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Emerging Therapies in CML

Posted Aug 24 2008 1:49pm

ANNOUNCER: Imatinib, also known as Gleevec, is an effective treatment for patients diagnosed in the chronic phase of CML. However, some patients cannot tolerate its side effects.

JORGE CORTES, MD: Intolerance to Gleevec, fortunately, is not a common phenomenon. And I'm talking about intolerance to the point where you really just cannot take imatinib despite dose adjustments and management, etc. It's about 3 to 4% of the patients who really cannot take it at all.

ANNOUNCER: A small minority of patients may not respond well to imatinib from the start. This is called primary resistance. Other patients may develop secondary resistance, a relapse after a period of good control of the disease. Resistance may be caused by point mutations. Changes in the DNA lead to small changes in the BCR-ABL protein and imatinib can no longer fit in the binding site and the abnormal growth of white blood cells resumes.

JORGE CORTES, MD: Mutations occur in about 40 to 50% of patients who develop resistance. So in at least half of the patients, we don't know what the mechanism of resistance is.

ANNOUNCER: Dasatinib, also known as Sprycel and nilotinib or Tasigna are FDA approved for patients who have become intolerant or resistant to imatinib. Like imatinib, both drugs are tyrosine kinase inhibitors.

STEPHEN NIMER, MD: Dasatinib inhibits BCR-ABL, but it also inhibits another class of kinases or enzymes in the cell and those are called SRC family kinases.

NEIL SHAH, MD: We now know with approximately 15 months of follow up that 49% of patients on the phase II chronic phase study have achieved a complete cytogenetic response on dasatinib.

ANNOUNCER: Cytogenetic testing showed no detectable disease.

STEPHEN NIMER, MD: Nilotinib is a drug that's very similar to imatinib. It does not inhibit the SRC family of kinases that dasatinib does and it does not seem to cause the same degrees of fluid accumulation as dasatinib.

NEIL SHAH, MD: There was an update of nilotinib presented at the recent ASCO meeting which showed complete cytogenetic response rates on the order of 40% in after a median of approximately 12 months of follow up.

ANNOUNCER: Dastinib and nilotinib are generally well tolerated but some patients may experience side effects.

MICHAEL MAURO, MD: Blood count suppression is also more common on newer drugs, but that's probably more a function of a rapid treatment effect in a person who's probably had a bit more treatment and maybe has a bit more of an abnormal marrow underneath their CML. And we don't think that it's a new and heavy side effect from the drugs. And also, salts and electrolytes in the blood need to be monitored, and liver and kidney function tests, as we had with imatinib.

ANNOUNCER: Some side effects are serious and should be monitored closely.

STEPHEN NIMER, MD: There can be fluid retention that's found on dasatinib, sometimes fluid accumulating in some unusual places. So on imatinib as well, sometimes patients will notice swelling in their legs or swelling around their eyes, what we call periorbital edema. But, on dasatinib, some of the patients develop fluid accumulation, either around their lungs, which we call a pleural effusion, or sometimes even around their heart, called a pericardial effusion.

ANNOUNCER: Dasitinib and nilotinib are effective against most mutations. However they are not effective against the mutation T315I.

NEIL SHAH, MD: MK0457 is perhaps the most exciting agent thus far for the treatment of patients who have the T315I mutation. And some complete cytogenetic responses have been seen in patients with advanced phase CML and Philadelphia chromosome-positive ALL who were resistant to prior therapies and had the T315I mutation. So it's certainly very encouraging. It's preliminary data for the most part, but it's certainly more encouraging than anything else we've seen thus far.

JORGE CORTES, MD: We are looking at other drugs specifically targeting this mutation. Homoharringtonine and LBH, we're also looking at their efficacy in this mutation. And then we are looking at other drugs that are similar to the MK in some ways, like K -- one that's called KW2449, another one that's called XL228.

ANNOUNCER: Researchers hope to find better treatment strategies and more potent drugs to manage CML and hopefully find a cure.

STEPHEN NIMER, MD: The issue of the optimal dose of Gleevec is also something that's being intensively studied. Initially, Gleevec was approved at 400 mg/day for the chronic phase and 600 mg for the more advanced phases, but it may be that 600 or even 800 mg could turn out, over time, to be better than 400 in terms of treating even the chronic phase of this disease.

JORGE CORTES, MD: We have a couple of studies where we are using in one study nilotinib and in another study dasatinib as the first line of therapy for patients newly diagnosed with CML. And the results have been actually very good so far. At six months, almost 100% of the patients already don't have the Philadelphia chromosome.

ANNOUNCER: New second generation tyrosine kinase inhibitors SKI-606 and INNO-406 that target and inhibit different kinases than imatinib, dasatinib and nilotinib are also under investigation.

MICHAEL MAURO, MD: We have a lot of patients in very good remission, perhaps with very minimal levels of residual disease. So the questions we're beginning to ask for that population, which is really the largest, is, How can we complete the job? How can we reduce minimal residual disease? And one approach has been immune-based therapy.

STEPHEN NIMER, MD: The idea would be, with these new drugs, that you can get patients who have complete cytogenetic responses and even complete molecular responses and that would be the ideal situation to introduce the vaccine and maybe the vaccine could allow the immune system to get rid of the last few remaining cells in the body. We're learning a lot about cancers and we're learning a lot about how to develop new treatments. So I'm incredibly optimistic. It's a wonderful time to be a physician treating these diseases and, hopefully, at some point, we'll learn what causes these things and we'll be able to decrease the incidence of these diseases. But we do have a lot more to offer patients than we've ever had before.

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