ONCAlert | Upfront Therapy for mRCC

Case 1: Treatment Recommendations for FLT3+ AML

Targeted Oncology
Published Online:12:35 PM, Wed June 19, 2019


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD: James, how would you approach this patient for treatment? Let’s say you’ve got this data, this patient is now sitting in front of you…. What would you discuss and offer?

James K. McCloskey II, MD: We have this patient, a 44-year-old woman with confirmed FLT3-mutated disease. She does have some other concerning mutational abnormalities, most notably the P53 mutation. Considering all that, this is a patient who’s not had therapy before, and this is a patient who we would certainly consider for induction with 7+3 [cytarabine/daunorubicin], plus midostaurin, based on the results of the RATIFY trial.

Naval G. Daver, MD: With these people you would do the midostaurin day 8 to 21 or would you do continuous? People have debated this.

James K. McCloskey II, MD: We would do the midostaurin according to the protocols on day 8 through 21. I think the rationale behind that was 2-fold. I think from a molecular standpoint, there was some concept that potentially inhibiting FLT3 upfront might reduce the cytotoxic effects of the chemotherapy. Additionally, when we gave the drugs in combination with chemotherapy continuously, there was some concern regarding toxicity, which was much more tolerable when we gave it for a 2-week period following the induction chemotherapy.

We would ideally start it on day 8. I think that when you talk to folks in the community, we already talked about the potential lag behind with molecular results, and then navigating, potentially, that patient’s insurance provider. It’s unfortunately not unusual that we might be starting midostaurin after day 8, and I think that’s not ideal, but given the data we have, I think it makes sense to add it when it’s available. So even if that starts on day 11, that would be our standard protocol and I think probably the best approach in the real-world setting.

Naval G. Daver, MD: I think that’s important because we get a lot of calls, and I’m sure you all do, that I got the results on day 10 or 11, and should I not do the midostaurin because I’m not fitting the protocol? I think, there’s no data, but we would just do it from day 10 for 2 weeks, because I think adding the TKI [tyrosine kinase inhibitor] is probably more important than doing it on day 8, which is optimal. Dr Rizzieri, what do you think?

David Alan Rizzieri, MD: I think it highlights the point of working with good pathologists to get the data back quickly, because there really seems to be more and more evidence that earlier addition of FLT3 inhibition is important.

Naval G. Daver, MD: Correct.

David Alan Rizzieri, MD: We want to push to get that data as soon as possible.

Naval G. Daver, MD: Yes. Dr Rizzieri, let’s have a little bit of a curve ball about something that we get asked in all these symposia. What if this patient had MRC [myelodysplasia-related changes], and this was a younger patient—let’s say she’s a little bit older, a 66-year-old—and has a FLT3, which we thought would be very uncommon, but about 20% of the people in the Vyxeos study had it. What would you do for this patient? Would you say, “I go for FLT3; the TKI is more important.” Would you consider Vyxeos? Would you consider [azacitidine/venetoclax]? There’s no right answer, but what do you think?

David Alan Rizzieri, MD: The short answer is yes. I could see doing any of the 3 scenarios you laid out depending on the patient conversation. That’s why I think we’re privileged in many of our clinics in academia to still have enough time to sit and have this shared decision making conversation with the patient to try to best understand their goals of care.

If we’re initially looking at this as a curative event, then right or wrong, I still feel that aggressive therapy today would be what I’m leaning to. In terms of aggressive therapy in the scenario you laid out, then I would choose a CPX-351 and lead to transplant. However, in this particular case, we see the P53 abnormality as well. That really concerns me. I’m not sure we’re benefitting these patients with aggressive chemotherapy very much, so I wouldn’t feel badly if, in consultation with a patient or another referring physician, they went a different path. A [venetoclax]/hypomethylator combination or something like that, I don’t think would be unreasonable in a number of these patients. I think any of those would be on the table in my view. I’d be curious as to what my colleagues think.

Naval G. Daver, MD: Anybody else feel differently about this?

James K. McCloskey II, MD: I agree. A lot of it, for me, would revolve around age, and what is the AML [acute myeloid leukemia] MRC? Is it just multilineage dysplasia? In that case, I don’t find that often as convincing of an argument to pursue Vyxeos. The data there are a little more conflicting, and I think the P53 mutation is really the most challenging. In a 44-year-old, I completely agree. I’m not often excited about the efficacy endpoints in these P53-mutated patients. I think we’re trying to use [venetoclax] and hypomethylators conservatively, acknowledging that the N [number] in those clinical trials where we are drawing this presumed better response from, is relatively small. If I’m on the fence, in an older patient, or maybe in a patient who has some other borderline comorbidities, I’m certainly much more inclined to think of that patient as a better candidate for less intensive therapy.

Naval G. Daver, MD: You both brought up some very interesting points for the audience. One is that this fit for [chemotherapy] is no longer purely being based on age. It’s really more on biology, because both of you said TP53 and I totally agree with that. A 40-year-old TP53 is not really much better off than a 60-year-old or 65-year-old. I think we’re starting to see where people are saying, even for younger ones, is there benefit to giving them [chemotherapy]?

The second thing you said, which we’re looking at too at [The University of Texas MD] Anderson [Cancer Center]: is all MRC the same? I think the feeling is that it’s not. Some of these softer MRCs may not be the same negative prognostic as the ones with true MDS [myelodysplastic syndrome] or secondary AML, but there’s not enough data for that, so we have to look more into that. The third thing is, could you combine these agents, which is something that people are going to look at? Can you add Vyxeos? There are trials ongoing for that, and that could be a good patient for those. There’s no right answer. This is where we’re privileged, where the right answer 5 years ago was always 3+7 [daunorubicin/cytarabine]. Today, we can have 3 right answers, so that’s good.

Transcript edited for clarity.

 


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD: James, how would you approach this patient for treatment? Let’s say you’ve got this data, this patient is now sitting in front of you…. What would you discuss and offer?

James K. McCloskey II, MD: We have this patient, a 44-year-old woman with confirmed FLT3-mutated disease. She does have some other concerning mutational abnormalities, most notably the P53 mutation. Considering all that, this is a patient who’s not had therapy before, and this is a patient who we would certainly consider for induction with 7+3 [cytarabine/daunorubicin], plus midostaurin, based on the results of the RATIFY trial.

Naval G. Daver, MD: With these people you would do the midostaurin day 8 to 21 or would you do continuous? People have debated this.

James K. McCloskey II, MD: We would do the midostaurin according to the protocols on day 8 through 21. I think the rationale behind that was 2-fold. I think from a molecular standpoint, there was some concept that potentially inhibiting FLT3 upfront might reduce the cytotoxic effects of the chemotherapy. Additionally, when we gave the drugs in combination with chemotherapy continuously, there was some concern regarding toxicity, which was much more tolerable when we gave it for a 2-week period following the induction chemotherapy.

We would ideally start it on day 8. I think that when you talk to folks in the community, we already talked about the potential lag behind with molecular results, and then navigating, potentially, that patient’s insurance provider. It’s unfortunately not unusual that we might be starting midostaurin after day 8, and I think that’s not ideal, but given the data we have, I think it makes sense to add it when it’s available. So even if that starts on day 11, that would be our standard protocol and I think probably the best approach in the real-world setting.

Naval G. Daver, MD: I think that’s important because we get a lot of calls, and I’m sure you all do, that I got the results on day 10 or 11, and should I not do the midostaurin because I’m not fitting the protocol? I think, there’s no data, but we would just do it from day 10 for 2 weeks, because I think adding the TKI [tyrosine kinase inhibitor] is probably more important than doing it on day 8, which is optimal. Dr Rizzieri, what do you think?

David Alan Rizzieri, MD: I think it highlights the point of working with good pathologists to get the data back quickly, because there really seems to be more and more evidence that earlier addition of FLT3 inhibition is important.

Naval G. Daver, MD: Correct.

David Alan Rizzieri, MD: We want to push to get that data as soon as possible.

Naval G. Daver, MD: Yes. Dr Rizzieri, let’s have a little bit of a curve ball about something that we get asked in all these symposia. What if this patient had MRC [myelodysplasia-related changes], and this was a younger patient—let’s say she’s a little bit older, a 66-year-old—and has a FLT3, which we thought would be very uncommon, but about 20% of the people in the Vyxeos study had it. What would you do for this patient? Would you say, “I go for FLT3; the TKI is more important.” Would you consider Vyxeos? Would you consider [azacitidine/venetoclax]? There’s no right answer, but what do you think?

David Alan Rizzieri, MD: The short answer is yes. I could see doing any of the 3 scenarios you laid out depending on the patient conversation. That’s why I think we’re privileged in many of our clinics in academia to still have enough time to sit and have this shared decision making conversation with the patient to try to best understand their goals of care.

If we’re initially looking at this as a curative event, then right or wrong, I still feel that aggressive therapy today would be what I’m leaning to. In terms of aggressive therapy in the scenario you laid out, then I would choose a CPX-351 and lead to transplant. However, in this particular case, we see the P53 abnormality as well. That really concerns me. I’m not sure we’re benefitting these patients with aggressive chemotherapy very much, so I wouldn’t feel badly if, in consultation with a patient or another referring physician, they went a different path. A [venetoclax]/hypomethylator combination or something like that, I don’t think would be unreasonable in a number of these patients. I think any of those would be on the table in my view. I’d be curious as to what my colleagues think.

Naval G. Daver, MD: Anybody else feel differently about this?

James K. McCloskey II, MD: I agree. A lot of it, for me, would revolve around age, and what is the AML [acute myeloid leukemia] MRC? Is it just multilineage dysplasia? In that case, I don’t find that often as convincing of an argument to pursue Vyxeos. The data there are a little more conflicting, and I think the P53 mutation is really the most challenging. In a 44-year-old, I completely agree. I’m not often excited about the efficacy endpoints in these P53-mutated patients. I think we’re trying to use [venetoclax] and hypomethylators conservatively, acknowledging that the N [number] in those clinical trials where we are drawing this presumed better response from, is relatively small. If I’m on the fence, in an older patient, or maybe in a patient who has some other borderline comorbidities, I’m certainly much more inclined to think of that patient as a better candidate for less intensive therapy.

Naval G. Daver, MD: You both brought up some very interesting points for the audience. One is that this fit for [chemotherapy] is no longer purely being based on age. It’s really more on biology, because both of you said TP53 and I totally agree with that. A 40-year-old TP53 is not really much better off than a 60-year-old or 65-year-old. I think we’re starting to see where people are saying, even for younger ones, is there benefit to giving them [chemotherapy]?

The second thing you said, which we’re looking at too at [The University of Texas MD] Anderson [Cancer Center]: is all MRC the same? I think the feeling is that it’s not. Some of these softer MRCs may not be the same negative prognostic as the ones with true MDS [myelodysplastic syndrome] or secondary AML, but there’s not enough data for that, so we have to look more into that. The third thing is, could you combine these agents, which is something that people are going to look at? Can you add Vyxeos? There are trials ongoing for that, and that could be a good patient for those. There’s no right answer. This is where we’re privileged, where the right answer 5 years ago was always 3+7 [daunorubicin/cytarabine]. Today, we can have 3 right answers, so that’s good.

Transcript edited for clarity.

 
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