TKI Dosage Considerations

Dr. Kalaycio: Now we touched a little bit on the side effects of nilotinib and dasatinib. We've talked about progressive disease, perhaps with or without mutations. Dr. Mauro, could you comment on where you think bosutinib might play a role in patients with relapsed or progressive CML?

Dr. Mauro: I think bosutinib remains an underutilized TKI. It is potent and thus offers good salvage activity. I think it offers a fairly distinct side effect profile making it a good choice for cases of intolerance. I think we've learned more about how to initiate bosutinib and manage its side effects; one element of this is that current trials start at slightly lower doses of bosutinib to avoid some of the early gastrointestinal toxicity.

Bosutinib continues to seek a place as a first-line therapy. I think this may be worthwhile as we are looking for the right balance of safety and side effect risk to maximize early response. Regarding the salvage setting—intolerance and resistance to other agents—I find myself speaking to patients about bosutinib as a potent and viable alternative. Bosutinib offers a similar spectrum of activity as dasatinib but can allow us to avoid cardiovascular toxicity and/or allow clearance of pleural and pericardial toxicity occurring with dasatinib.

The one place I would say bosutinib may not hold up as strongly to its competition would be as a third-line therapy after failure of a second-generation TKI. I think while there is reasonable activity with bosutinib in this setting of somewhat fairly drug-resistant CML, the performance of ponatinib is better. There is likely often a struggle with the long-term safety question of ponatinib, making some feel that a trial of bosutinib is often a worthwhile, logical, or even necessary step before ponatinib. My concerns about this approach are related to treatment decision-making based on safety and theoretical risk of adverse effects rather than efficacy and risk of progression; these have to be weighed carefully and appropriately against each other.

Dr. Kalaycio: That's an interesting perspective. You mentioned starting with a lower dose. Dr. Deininger, I'd like to ask you your thoughts about dose modifications of the TKIs in general. It used to be anathema to either start with a low dose or to maintain patients on a lower dose.

I'm aware of at least some data suggesting that those patients who tolerate these TKIs poorly particularly with regard to myelosuppression can be treated long term at lower than typically prescribed doses without adverse effect. What are your thoughts surrounding dose modification of the TKIs?

Dr. Deininger: I would stratify according to TKIs. I think imatinib at 400 mg is probably just rightly dosed, maybe not even at the optimal dose. It could be 600 mg. If you go to 300 mg, that is still acceptable.

If you go to 200 mg, I think I would make double sure that I monitor patients very frequently. People should be, in my mind, in a major molecular response to treat them with 200 mg long term. With the second-generation TKIs, it's a little different.

I cannot really speak to bosutinib because I'm not aware of a lot of data on those modifications. What seems to be clear from dasatinib is that the initial recommended dose of 100 mg is quite high, especially in older people.

I believe that's been corroborated by a study that hasn't been published yet. Apparently the drug excretion in the older individuals is quite a bit slower than in younger people. I think in our practice and in other people's practices as well, about 50% of those people end at doses substantially lower than 100 mg, maybe 50 mg, maybe 40 mg, some even 20 mg per day.

I think in the case of dasatinib you have a lot of maneuvering space. You can adjust the dose according to tolerability and molecular response. With nilotinib I think it's kind of similar. We have a few patients who are on maybe 150 mg twice a day because they have issues in terms of side effects at the higher doses.

I should again thoroughly qualify that by saying if you give up through dose reductions the goal of a major molecular response, then I think you really have to think about the strategy in general because at that point, I think you basically say "this patient is not ever going to be reaching a safe haven and is not tolerating inhibitors well enough to get him there."

That's quite a significant statement to make. Myelosuppression is frequently a situation where you cannot deliver enough dose but you also don't get a good response, whereas other side effects like pleural effusions or excessive fluid retention may well be cause for dose reduction and yet responses may be acceptable. Maybe Dr. Mauro could chime in here and share his experience.

Dr. Mauro: I agree. I think some patients, based on their disease status, may not tolerate the dose that is going to—at least in theory—get them to a deep molecular remission. The biggest problem we often face is myelosuppression. Some patients may have indolent disease and still have a good outcome, at least in the short to medium term, with lower doses of drug. In general I try to work through myelosuppression, especially early, as the combination of myelosuppression and suboptimal or response failure is dangerous.

I think treatment shouldn't be too chaotic and change too much, if possible. That was a very nice summary of the way we view the doses. There's still a fair bit of flexibility amongst the TKI doses, although I don't advocate for starting low and titration up.

In general I think, with regard to optimal TKI dose, we might have overshot; for example, with dasatinib. I think we might have overshot with bosutinib. Trials ongoing now initiate bosutinib at 400 mg rather than 500 mg. That's what I was alluding to.