Dr. Kalaycio: I'm starting with the less controversial questions to begin with. I think the next set have the potential for some more controversy. Before we leave the initial assessment of CML, do either of you have observations regarding referrals that you get about which you would like to either dispel myths or remind practitioners about best practices in patients newly diagnosed with CML?

I think, moving forward it would be really important to have documentation of concomitant risk factors such as smoking and so on that are essentially driving outcomes more than the TKI treatment or the CML itself. – Michael Deininger, MD, PhDDr. Mauro: I can mention one thing. I think when thinking about initial molecular diagnostic results, it is important to point out that testing should screen broadly for different fusions, namely P190 and P210, or variant (p230) transcripts. There are rare patients in chronic phase with non-p210 fusion who need to be followed with specific PCR. On this same topic, the measurement of transcripts at presentation (ie, before treatment) has become quite important and whereas formerly had not been emphasized, presently all patients should have ”baseline” transcript levels.

Dr. Deininger: I think one issue that comes up once in a while is that spleen measurements are done by ultrasound. Technically it's more accurate, but all the clinical risk scores and the prognostication is based on the old fashioned—but probably highly inaccurate—technology of palpation. This is what counts, this is the value to document. I think, moving forward it would be really important to have documentation of concomitant risk factors such as smoking and so on that are essentially driving outcomes more than the TKI treatment or the CML itself. Getting a good handle of those risk factors at diagnosis is also important.

Dr. Kalaycio: I think that's a very important point. That's where I was going to go next with this conversation. I was going to avoid the conversation about which TKI to choose as initial treatment. I think that's a debate unto itself.

I would like to ask you how you might assess cardiovascular risk before placing a patient on nilotinib. You got to that a little bit, Dr. Deininger. Could you expand on what else you might review as far as whether or not you feel a patient is a good candidate to start on nilotinib?

Dr. Deininger: Specifically, with regard to nilotinib, we would always get a baseline electrocardiogram. We would do a clinical exam. We would not do an echocardiogram just routinely in the absence of a cardiovascular history or any clinical evidence for heart failure or other cardiovascular issues.

We've adopted the practice of doing a lipid panel. Of course we would include fasting glucose as well. Some of these recommendations are probably somewhat on the soft side, because it's not yet clear what to do with the information.

On the other hand, I think for a patient who is being considered for nilotinib one wants to make sure that one really does the best to minimize the cardiovascular risk factors. Of course that would include smoking history and taking blood pressure and making sure that these risk factors are controlled.

If people have a presentation that is really out of whack in terms of their risk factor management, I would send them to an internist or even a cardiologist to help me optimize the cardiovascular prevention strategy.

Dr. Kalaycio: Great. Similarly, Dr. Mauro, how do you assess pulmonary risk before placing a patient on dasatinib?

Dr. Mauro: I think here we are focused on the less frequent and also less well understood potential toxicity of pulmonary hypertension, coupled with the more common risk of pleural and pericardial effusions.

I'm not sure how much we've learned in clinical studies looking at baseline chest X-rays or timing of X-rays during treatment. I think our best tool in the prevention and management of pleural and pericardial effusions is full discussion with patients about risk and what to look for, attention to any and all symptoms, and appropriate deployment of diagnostics as indicated.

It's interesting to consider whether baseline echocardiography for measurement of pulmonary pressures is warranted. I would say now we're on probably somewhat softer ground, first because on routine echocardiogram pulmonary pressure can't be measured readily unless there is some valvular regurgitation. As well, it is stated that pulmonary hypertension is only properly diagnosed by right heart catheterization. While I'm tempted to do routine echocardiogram studies, I think that such a recommendation still may be perhaps the realm of a clinical study. We need to explore that further. I think with dasatinib there may be certain patients at higher risk, although the data are somewhat limited. There seem to be certain conditions potentially associated with more pleural and pericardial toxicity, including cardiovascular disease and autoimmune disease. There may be circumstances during treatment—lymphocytosis, for example—that may be associated with greater risk. I think expectant management may still be the right approach and echocardiography and more aggressive diagnostics be reserved for patients in whom there might be much more clinical consequence.

Dr. Kalaycio: I'd like to pursue that a little bit further because sometimes the patients will come to us having already had an echocardiogram that may actually show some mild pulmonary hypertension and maybe they've got significant cardiovascular risk factors where you would otherwise be thinking about using dasatinib. Here's someone with pulmonary hypertension, at least by echocardiographic criteria, would that be enough to dissuade you from the use of dasatinib?

Dr. Mauro: I think it would certainly require significant consideration, understanding what the basis of the pulmonary hypertension is for that patient, and risk with adding dasatinib. I think the good news is the low incidence and the reversibility for the most part of dasatinib-associated pulmonary hypertension.

Again, I think the mechanism of action and the pathophysiology isn't completely understood, although there is the intriguing notion that imatinib has been reported to potentially mitigate pulmonary hypertension whereas dasatinib triggers it—a ”closed loop” if you will and an area ripe for research.

I would probably think that a patient with preexisting pulmonary hypertension in the new diagnosis setting might be the kind of patient for whom you really might weigh the pluses versus the minuses of a second generation TKI versus imatinib.

E-mail: kalaycm@ccf.org

Testing, Risk Factors & Considerations of Treatment: Nilotinib & Dasatinib