New Biological Insights and Recent Therapeutic Advances in the Management of Acute and Chronic Leukemias and Myelodysplastic SyndromesClinical factors affecting the selection of tyrosine kinase inhibitors as initial therapy for CML
4:11 minutes.
TRANSCRIPTION:
DR LOVE: So Hagop, again, we’re talking outside a protocol setting right now. We know that your first choice and everybody’s first choice should be a trial, if there is one. But in general, Hagop, how would you think through a nonprotocol choice of a TKI? DR KANTARJIAN: As far as the initial treatment, as you know, 4 of the 5 TKIs are safe enough to be used in the front-line setting. Three of them are FDA approved, but when you look at the bosutinib data, the data is identical except that, in the study, they were unfortunate to miss their primary endpoint in the study. So if I were to choose the 3 tyrosine kinase inhibitors, imatinib, nilotinib, dasatinib would be excellent choices. To date, there is no differential in the price to allow you to choose one or the other. So you choose the drug that appears to have the safer profile and perhaps the more efficacious profile. So one could choose any of those three. In the ENESTnd, patients with low-risk Sokal did identically well whether they were on imatinib or the 2 doses of the nilotinib. But in the higher-risk Sokal, there were potential benefits from the nilotinib. Having said this, in all the randomized trials that compared the second-generation TKIs, dasatinib, bosutinib or nilotinib to imatinib, there are improvements in the early surrogate endpoints, but the survival is the same because salvage therapy is so effective that it neutralizes the negative effect in these patients. DR LOVE: Wendy? DR STOCK: I typically start in a standard-risk patient with imatinib. I still think that the drug, in my experience and looking at the data, is probably associated with the fewest toxicities, both short term and longer term. But I do consider, if the Sokal score is higher, I do think about a second-generation TKI to start with. In terms of choosing which one, then I look at toxicity profile for an individual patient. But in a patient with standard-risk CML, I start with imatinib, typically. In a higher-risk patient, I would consider a second-generation drug. DR LOVE: So Doug, again, about your general approach to selecting an up-front TKI, do you agree with the algorithm that’s kind of coming out here? Is that what you do? DR SMITH: That’s exactly the algorithm I follow. I think Wendy made it very clear. I follow a very similar pattern. DR LOVE: Charlie, again, do you buy into this algorithm? Is this what you do with your patients? DR SCHIFFER: Yes, I do. I use imatinib in virtually all people in chronic phase, except for people with higher-risk features, which can be defined by the Sokal score and sometimes, frankly, by your nose. The other thing that’s going to happen is this decision is going to be taken out of our hands when imatinib becomes generic. The insurers, in this case, I think appropriately are going to force us to use imatinib in newly diagnosed patients. And we are probably going to have to argue for the second-generation TKIs in newly diagnosed patients in whom we think it’s appropriate. DR KANTARJIAN: We are starting to see long-term toxicities with the second-generation TKIs, which are uncommon but bothersome. So we see people who have increased blood sugars on nilotinib, hypertension on the other TKIs, pulmonary hypertension with dasatinib, pleural effusion with the ponatinib. You get vaso-occlusive disease. You have a higher-than-expected incidence of vaso-occlusive peripheral arterial cardiac and transient ischemic attacks with nilotinib and ponatinib. And I’m concerned that today we are very happy with the results, but 15 or 20 years from now we could see something that resembles accelerated atherosclerosis. And so imatinib has not shown those side effects, and that may be an advantage in terms of the long-term side effects.
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