Chronic Myeloid Leukemia - Episode 8

Case 2: Additional Treatment Considerations for T315I-Mutated CML

May 28, 2019


James K. McCloskey II, MD:Elias, can you talk a little bit about how frequently you monitor for mutations and when you check for them?

Elias Jabbour, MD:Well, I check them at the beginning of therapy and then if they’re responding, I don’t check them again. What matters for me is the response. If this patient is T315I mutation, I start with ponatinib. And then in 3 months when PCR [polymerase chain reaction] is down to 1%, anyway there’s no room for Sanger sequencing anymore; you can use other techniques, but we don’t have the evidence that it will help. So I will only check for mutations if they don’t have a response. Somebody in whom I have a diagnosis of a mutation and who is doing well, I would not do any mutation testing anymore.

James K. McCloskey II, MD:And for this patient now with a T315I mutation, is this a patient that you start working up for a stem cell transplant?

Elias Jabbour, MD:Well, any time I have somebody who is failing therapy with a TKI [tyrosine kinase inhibitor], I want to do the work-up for transplant, looking for a donor. It doesn’t mean I want to go for transplant. And in fact, I can tell you I saw somebody yesterday—he was a young man, a lawyer—and he’s telling me give to give him anything but transplant. So we’re going for asciminib and other new drugs. So I worked up this patient for transplant, of course. I will make sure I have the donor and then I will start ponatinib. If I have very good response to ponatinib and PCR is going down to 1% and maintained, I will put transplant on hold.

If I don’t have a good response and the PCR is going up or losing response, then I will go for transplant. But I think in the chronic phase, there are data from the PACE trial to the EBMT [European Society for Blood and Marrow Transplantation] registry showing that for a chronic phase patient with T315I mutation, ponatinib seems to be better than transplant. I think we know from the PACE trial that responses to ponatinib are durable. If you induce MCyR [major cytogenetic response] at 3 months, 80% of these patients maintain their response, and therefore I will not go for transplant even though they are a younger patient.

B. Douglas Smith, MD:Had the patient had a bone marrow biopsy at the time the white count was 140,000 and they were relapsing on frontline therapy and they had blast crisis, tell me how that might impact what you’d be thinking about after you put them on ponatinib?

Elias Jabbour, MD:That is a totally different scenario. I mentioned transplant for chronic phase. If there’s transformation to blast phase, I will not use ponatinib single agent. It does work, we have good responses, but they are short-lived. For this patient, regardless of the mutation, I will have used a combination of chemotherapy and ponatinib. If it’s a myeloblast phase, I will use AML [acute myeloid leukemia] regimen. She’s a young woman. I would use FLAG-IDA [fludarabine/ARA-C/G-CSF/idarubicin] /ponatinib and I would go for transplant.

B. Douglas Smith, MD:Michael, is that what you do in New York?

Michael J. Mauro, MD:I was just thinking what a dotted line we have between 15% blasts and 20% blasts. So that’s why I said there were a lot of alarms ringing with this case. And I think with careful monitoring, they still meet criteria for chronic or accelerated phase, and single-agent TKI is reasonable. And you should see the outcome relatively quickly, hematologic remission, any cytogenetic or molecular improvement relatively quickly. But I think you need to be careful that a blast phase patient A) needs different therapy, as Elias just mentioned, and B) is very likely to fall back into blast phase again and needs to move on.

Elias Jabbour, MD:And then meeting them with ponatinib post-transplant, not only offering transplant.

James K. McCloskey II, MD:Elias, can you talk about where you might use omacetaxine?

Elias Jabbour, MD:Well, it’s a very unfortunate drug. Every time this drug was close to an approval, we got other compounds or oral drugs. Omacetaxine is approved today for patients who failed two TKIs, and the way it’s given, it’s 1.25 mg/m2subQ [subcutaneous] twice daily for 14 days induction, and then during consolidation is once a week. I think at this dose it’s quite myelosuppressive. We’ve seen 10% CCyR [complete cytogenetic response], so I think between ponatinib and omacetaxine, I’m more in favor of course of ponatinib. That being said, I use omacetaxine usually in combination, not the single agent in blast phase where I have no other options to be given. But I think in chronic phase, I’m not quite sure where to fit this drug, especially. I think when I use it, I will use it for 3 days, 5 days max, not like 2 weeks as is in the label because of the myelosuppression. They will have to recover for 4 to 6 weeks.

B. Douglas Smith, MD:It is an interesting drug because it does have activity against T315I compared with all the other TKIs, but it is truly a chemotherapy drug. It’s delivered like a chemotherapy drug in spirit. It’s myelosuppressive. You get into the same myelosuppressive related problems with it. So it is a drug that we’ve been hesitant to use outside of the setting of blast crisis. We do use it there when we have other limited options at that point.

Elias Jabbour, MD:I think in a patient who failed TKIs, age is a factor. So say somebody who is 80 years old and on TKI, even if I don’t have the magical MMR [major molecular response], even if they have a partial response, I tend to keep them on TKIs. Don’t take them off TKI, put them on hydroxyurea. I will keep them on TKIs and let them be.

Michael J. Mauro, MD:That situation of maybe inadequate response or partial response in the patient who may not have any other options, I think Brian Druker MD, my mentor, always said the same thing, TKIs will always do better than hydroxyurea for the long-term, even with just hematologic responses.

Transcript edited for clarity.