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Pr Jorge Cortes: Refractory Chronic Myeloid Leukemia

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MD-FM INSIGHT Tuesday 2nd July 2013



Hello! You’re on MD-FM INSIGHT, the first medical web radio.

Clementine: Today we’re pleased to offer you a "Question & Answer" program devoted to the treatment of patients with refractory chronic myeloid leukemia (or CML).


Ponatenib might be the solution for chronic myeloid leukemia patients with a T315I mutation. These mutations are not very common but very resistant. At the 2012 meeting of the American Society of Hematology, which took place in December in Orlando, Florida, we met with Professor Jorge Cortes, from MD Anderson Cancer Center in Houston, Texas, who tested Ponatenib in CML patients.


First Dr. Cortes, tell us about the specificity of this new second generation tyrosine kinase inhibitor Ponatenib and its effect on T315I mutations


You know it’s been a mutation that’s been giving us a little bit of trouble, because we have great drugs for CML, but none of the ones that we had so far would work against this mutation. So this drug called ponatenib was engineered looking at how you can overcome this. This mutation, what it does: it has this bulky area that prevents all other drugs from binding. And ponatenib, I see it as having a long neck that allows it to accommodate that bulky area, and so it still binds and it still stops that enzyme from working abnormally, and if you block that enzyme the cells die. 


So you led a phase 2 pivotal trial testing this agent in CML patients. Tell us about it:


We gave this drug ponatenib, it’s an oral drug, and we gave it to patients with CML at all stages: chronic, accelerated or blast phase, whether they had the T315I mutation or not, we gave it also to other patients. They were all resistant or refractory to dasatinib or nilotinib –actually most of these patients had already received all three tyrosine kinase inhibitors. We found some outstanding results: the response rate was very high. In the chronic phase, for example, 2/3rd of patients have achieved some cytogenetic response and it’s been complete in almost half of the patients. Again, thinking that 2/3rd of these patients had failed three tyrosine kinase inhibitors –that’s outstanding. 


And what about side effect?


That drug is very well tolerated. We know that all these tyrosine kinase inhibitors have some side effects but they tend to be very minimal. With ponatenib, for example, what we have is a little bit of a rash and dry skin in some patients but usually very manageable, we have some headaches… The one side effect of concern in phase 1, at the highest doses, was pancreatitis. With the doses that we are using now, the incidence of pancreatitis is much lower: it’s about 6% of patients with grade 3 pancreatitis. It’s usually manageable, you adjust the doses and most patients can restart therapy so it is something that we can really manage in the clinic. 


Now if Ponatenib is accepted as standard therapy, does this mean it’s the end of the story –we’ll have all the mutations taken care of?


Well, all the mutations that we know today –yes. But you know cancer is smart, cancer develops tricks to try to overcome this. I think it’s likely that we are going to able to overcome it in the great majority of patients but I think there’s always going to be an occasional patient where perhaps this kinase is not their main driver and we are going to need to find another way to kill them.


So can we say you have transformed CML into a form of diabetes but for cancer?


I think we have. I have a large number of patients that I follow in my clinic –I follow probably more than 700 or 800 patients with CML, I have some of these patients that I’ve been following for more than 10 years, and these people lead normal lives, they do their jobs, they do their exercises, they have normal lives. 


Now what would be the correct way to approach any patient with chronic myeloid leukemia from now on?


Well I think that the important steps are at the very beginning. We have very good treatments and now we are going towards second-generation drugs as initial therapy and I think that with proper monitoring –if you follow your patients correctly, you minimize treatment interruptions and dose reductions that are not needed and all that –I think the overwhelming majority of patients will not die of this disease. So make sure that we follow the patients very closely, that we educate and help the patients overcome their side effects, because some will come but if we help them, I think that we will help patients stay with their treatment and get the best results possible. You know you can get a second opinion from someone who has familiarity, especially when things look a bit out of the ordinary, to make sure that we offer patients the best chance, so that we don’t loose patients from CML.



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