Case 3: Selecting Between TKI Inhibitors

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Michael J. Mauro, MD:So this patient was treated with imatinib. We’re getting a lot of referrals for patients where imatinib is still the king. And as we move them through time with response, perhaps the writing is on the wall because the initial transcript level was 89%, and then at 6-month follow-up we have an 11% transcript level, which is just shy of an early molecular remission. And if you look at the absolute reduction, it’s a somewhat even greater shortcoming. At 12 months, really little change and the patient does not have a cytogenetic complete remission, maybe a near cytogenetic complete remission. So we’re seeing with subsequent milestones this patient is really considered suboptimal or failing early molecular response, may be considered to be missing an optimal cytogenetic response at 12 months. And then at 18 months has a cytogenetic complete remission, which is encouraging, but transcripts are still at 1%.

James K. McCloskey II, MD:I agree with Elias that we would have probably selected a second-generation drug for this patient. But, Mike, as this patient started imatinib, would you have started with 400 mg? Would you have continued that dose, or might we have to have considered other doses for that patient, given their treatment history?

Michael J. Mauro, MD:I think they’re fairly old data now, but we know that 600 mg imatinib is more effective in accelerated phase by all definitions: clinical, clonal evolution, etcetera. I think we all worry about the patient with genetic instability and additional chromosome abnormalities and what might happen relative to BCR-ABL and ABL kinase domain mutations, other molecular changes.

So if I only had imatinib, I would have probably elected to use higher doses. I actually tend to favor higher doses of imatinib even in patients without these changes based on some data that if used optimally we can sometimes approach or even match the results of second-generation inhibitors with imatinib, for example, from data from the TIDEL I and TIDEL II trials. So I’m a big fan of, if you’re using imatinib, thinking about say 600 mg. But I agree with everyone’s comments that this is a high-risk patient. They have a very inferior survival and response expectation with standard therapy. They may still struggle with even a second-generation inhibitor because this biologically may be a different disease in some ways than just higher so-called risks even without clonal evolution.

Elias Jabbour, MD:So, Mike, for this case, at the end of the day this patient responded.

Michael J. Mauro, MD:Yes.

Elias Jabbour, MD:But then in retrospect at 6 months would you have changed therapy because of 11% or would you have maintained the imatinib?

Michael J. Mauro, MD:I think it’s a decision we’re all faced with in the clinic, what do we do with a patient in whom maybe we didn’t pay attention so much to the clonal evolution and we’re just focusing on response. Is that an inadequate response to be a near EMR [early molecular response]? I think there are definitely data looking at how patients can improve over time if they’re completely missing EMR at 3 months, how many correct to 6 months? This patient didn’t hardly have any correction, so I think some of the data would support the fact that this may not really turn out well, and how a change in therapy could be warranted. I tend to have patients and want to wait till 6 months because of those data, the fact that some patients can correct and look at the individual patients’ change. So I think I can’t ignore the cytogenetic abnormalities in this case. But if it was not on my radar and the patient was on imatinib, I probably would have said this is too slow.

B. Douglas Smith, MD:Michael, would you want information about what the marrow looks like now and whether that additional chromosome abnormality is changing, going away? Are there even more genetic abnormalities at that point? This is maybe somebody who at 6 months, marginal response, I might be looking at a bone marrow test early to repeat the formal karyotype to really understand what’s going on with that additional change.

Michael J. Mauro, MD:We heard it earlier. Reliably the only way to get a good karyotype is through bone marrow cytogenetics. So when you have a patient who has clonal evolution at diagnosis, I think that’s the patient who needs follow-up bone marrow studies to confirm clonal changes present, absent, evolving, confirm cytogenetic complete remissions. I agree completely that a follow-up bone marrow test would have been something I would have done, even if they had a beautiful response to it.

Transcript edited for clarity.