Case 2: Ponatinib for T315I-Mutated CML

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Michael J. Mauro, MD:I have all kinds of alarms going off in this case because this is a really good presentation of early response and very deep response. I think statistically, based on clinical trial data, this would be a really unusual outcome. In backtracking, one might even want to inquire about adherence to therapy. Was there an inadvertent avoidance, or unknown to the practitioner that the patient might have been off therapy? Because this is a pretty clear case of resistance as you said, and I’d up the ante and say that the bone marrow test should have been done right at the time they walked in the door with the blood counts. You might say the same.

Elias Jabbour, MD:Correct.

Michael J. Mauro, MD:Because 12% blasts could be an iceberg with much worse disease. I see how someone might have said let’s try another second-generation TKI [tyrosine kinase inhibitor], but clearly more data could have been really helpful in this case.

Elias Jabbour, MD:That is correct. In fact, not in this scenario, but we’ve seen patients who responded so well that they have a blast phase but not CML [chronic myeloid leukemia]. They’re Philadelphia-negative.

Michael J. Mauro, MD:Some other disease.

Elias Jabbour, MD:Some other disease converting into full AML [acute myeloid leukemia], these are not transformations. And of course, as Mike alluded to, compliance is an issue here. It’s very surprising to have somebody responding so well, losing this response in this way. Now, this woman was offered dasatinib, and then when we did the Sanger technique afterward, we saw T315I mutation. We know with a second-generation TKI there’s higher prevalence of T315I because this suppresses all other mutations. Therefore, I would have checked for mutation right away, and I would not have gone to dasatinib. Even if there’s no mutation, I would have chosen for this patient, ponatinib. They failed a second-generation TKI. The rotation of second-generation TKI, unless you have intolerance, doesn’t give you good yield. This woman is almost blast phase, very close to transforming. I would have chosen ponatinib for this patient and not dasatinib.

B. Douglas Smith, MD:I’m going to ask you your own question. What dose would you have started her on in that setting? Because again, I agree that this is a very interesting and probably a good patient for ponatinib, no known risk factors that we’ve been shared in the history of cardiovascular or other vascular events. What dose would you have done knowing she’s resistant to a second-generation TKI after 4 or 5 years of good response?

Elias Jabbour, MD:That’s a great question that we don’t have the perfect answer to. But we know from the label the drug is approved at 45 mg per day with recommendation to reduce the dose as soon as you can. I would have done, if possible, NGS [next-generation sequencing] to see if I have compound mutations, more than T315I, documented or identified because if I have a compound mutation, I want to go of course with 45 mg per day. If I have no mutation whatsoever, I would have chosen 30 mg per day and reduce to 15 mg per day once the CMR [complete molecular response] is obtained. Otherwise, for this patient, with T315I mutation, I use 45 mg per day for a short period. As soon as I have a response, which it should be obtained within 3 months, reduce the dose and go for a lower dose.

B. Douglas Smith, MD:I want to talk a little bit about the additional mutations that Dr Jabbour wants to look for.

Adam Bagg, MD:Sure. Well, you alluded to the fact that just because you find 1 mutation, it doesn’t necessarily mean it’s the sole mutation that’s present. And the whole issue of finding more than 1 compound mutation sometimes in the same clone, sometimes in different clones, can be biologically relevant and obviously ultimately clinically relevant, too. We’ve just been talking aboutBCR-ABLmutations or more specifically,ABLmutations. But it also opens a discussion about if we should be doing mutational testing looking at other genes in CML. And there are emerging data there, too, looking for mutations ofASXL1or zinc finger or RUNX1 if that’s what you’re alluding to. They are found in CML and appear to be clinically relevant, too. So there’s more to CML than justBCR-ABLtesting.

Elias Jabbour, MD:There are good data from the Michael Deininger, MD, and Tim Hugh, MBBS, PhD team in Australia where they look at patients who have mutation identified by Sanger technique and then they give the appropriate TKIs based on the mutation profile. And they have MYE clones and progressed on to full resistance. And what we call myeclones, they are equivalent to full clones later on. That’s why in somebody failing second-generation TKI, I would favor more ponatinib than rotation of second-generation TKI, unless they have true intolerance, pleural effusion, I would go to nilotinib or vice versa.

Michael J. Mauro, MD:I like your answer, to start with the standard dose and lower the dose. Because we can’t settle the issue on what additional mutation, the compound mutations, exactly how to manage them. I think for the typical provider that might be looking at a case like this, all of us in the clinic when we only have basic tools available, I think we’ve got to use our best information. And clearly, we could have changed the outcome a little earlier in this case, but I think standard dosing and assuming the T315I could respond, I think we’ll maybe hear how things go in a bit.

James K. McCloskey II, MD:I think the key is, as was mentioned, regardless of what dose we start at, it’s remembering to reduce the dose when patients have responded.

Transcript edited for clarity.