First-Line Treatment Options for NPM1-mutant AML


Eunice S. Wang, MD, shares first-line treatment approaches for patients with NPM1-mutant AML, discussing current clinical data.


Naval Daver, MD: Let me turn this here to Eunice. So, intensive chemo[therapy]…that’s a bucket term, but we know intensive chemo[therapy] is not intensive chemo[therapy]. The MD Anderson intensive chemo[therapy regimen] is different from a lot of other centers… so let’s break this down little bit more. NPM1-mutated or MLL-mutated [AML], what would you do for intensive chemo[therapy]? And these may be different for the 2 different groups, so let’s start with NPM1. Would you do 7+3? Would you do the FLAG-IDA [fludarabine, cytarabine, and filgrastim, and idarubicin] + VEN [venetoclax]? Would you do FLAG-IDA + GO [ozogamicin]? You may have seen very nice data from the British MRC [Medical Research Council] at the EHA [European Hematology Association Congress] showing FLAG-IDA + GO is very, very effective [for treatment] NPM1. What’s your thinking there today, Eunice, for a fit patient [with NPM1-mutated disease]? Or even HMA-VEN [azacitidine or decitabine, and venetoclax]? You have 4 options really.

Eunice S. Wang, MD: I think right now we don’t. As we know, we have a lot of randomized trials that we’re all eagerly waiting for to look at whether HMA-VEN may be equivalent to 7+3 in many different subtypes. At this time…say you have a 40-year-old patient with NPM1-mutant [AML], I’m not 100% sure that outside of a clinical trial, all of us…would feel comfortable giving that individual a non-7+3 cytarabine-anthracycline based regimen. I think that the data are still out on that. I think if there was some significant comorbidity, a cardiomyopathy of 20%and that’s something that occurs in[patients with] KMT2A-rearranged [disease] and is therapy related [in] patients who have prior topoisomerase inhibitor [treatment].

But aside from that situation, for an NPM1 mutation, I would look to see whether it’s FLT3 mutant. If it’s FLT3 mutant, which happens about 40% to 50% of the time, I’m going to go with a FLT3 inhibitor-based therapy. In the absence, you’re talking about NPM1, FLT3 negative, maybe IDH1, IDH2 co-mutated, I would do cytarabine-anthracycline based therapy. I was impressed by the FLAG + GO data, where they’re adding GO. I think that I would potentially look at, for those [patients with] NPM1-mutated [AML], the addition of GO. We know GO added to 7+3 can improve event-free survival. We saw with the recent data that FLAG-IDA + GO based therapy also improves the event-free survival, while maybe not the overall survival. I think I would consider currently in my practice a GO-based therapy if I wasn’t thinking about necessarily going to transplant.

I think there’s some hesitation in people adding GO to an up-front regimen if they’re going to a myeloablative [stem cell transplant]. Now in our center we haven’t seen that in all of our GO-treated patients, but I think I would consider something like that. I think the benefit of FLAG-IDA vs 7+3…we haven’t completely switched over to a FLAG-IDA- or CLAG [G-CSF, cladribine, cytarabine]-based regimen for up-front therapy, though there is very promising data in that regard. I think a very young fitter patient whether you want to give a 7+3 standard [of care treatment] or a FLAG-IDA, CLAG-IDA type of regimen is really up to the individual clinician. I would think about GO. Our practice in the past has been when they get into remission as we mentioned previously, following the NPM1 MRD [minimal residual disease] by molecular PCR [polymerase chain reaction] is really validated.

I think that’s a really great way to determine whether somebody that has an NPM1-mutant disease has achieved your therapeutic goal, which is an MRD-negative response, and to use that for monitoring. That I think would be my thought process. I would try to avoid, if I use that up-front therapy, transplant automatically in those patients because we know that they do have excellent overall response rates, but I would be tracking that NPM1-mutant fraction very closely at the time of consolidation. And subsequently, I’d be interested in knowing what everybody else would do, since of course you give me the tricky case.

Naval Daver, MD: [All cases are] getting tricky… Just to highlight the data from the UK MRC group and Nigel Russell[, MD,] and his colleagues, what they showed was in NPM1- mutated [disease, using] either FLAG-IDA + GO or DA + GO, and then they also had a second randomization of 1 or 2 doses of GO…the summary was that FLAG-IDA + GO with 1 dose didn’t matter; [with] 1 or 2 [doses], there was no difference. [It] gave you a very good DFS [disease-free survival], but also gave you quite a good OS [overall survival benefit] in the NPM1-mutated subset.

Eunice S. Wang, MD: And decreased the risk of relapse.

Naval Daver, MD: To me what was really interesting is [the researchers] then looked at people who got just the 2 inductions, so FLAG-IDA + GO, FLAG-IDA + GO, 1 dose of GO each time, and did not get consolidation. And there was no difference in survival. The 4-year survival is close to 80%. I think now we have competing issues. One is HMA-VEN may be very effective, may be very good, but it’s a continuous therapy. That may be OK for some patients. But then you have things like FLAG-IDA + GO and FLAG-IDA + VEN or experiences quite similar that you may just need 2 or 3 cycles to achieve NPM1 MRD clearance. You may not need a transplant for a young, 35- to 40-year-old [patient]. You’re done, [the patient] goes back to work, [the patient] goes back to school. I think these choices are going to be very, very tricky. And I don’t know if you’ll have all the randomized studies to answer all of them. But, Harry, go ahead.

Harry P. Erba, MD, PhD: All I was going to say is I wish all the phase 3 data actually was congruent and [gave] you the same conclusion. The Germans did a study in NPM1-mutated AML, where they added GO to chemo[therapy] with ATRA [all‐trans retinoic acid]. Remember they showed data that ATRA might be important in NPM1 for a subset of patients, although the UK group did not see that benefit. But when they added the GO there was no improvement in event-free survival and it was mostly due to a higher induction toxicity, having grown up in SWOG [Cancer Research Network], showing a higher induction toxicity or death rate than GO with 7 + 3 in a cooperative group setting. It’s the kind of data that makes me worried about maybe being too heavy handed in a patient who’s likely to get into a deeper remission and be cured with what we have. And then, of course, if I find that that patient needs to go to transplant, we haven’t really seen the details of how receiving the GO may impact on their outcomes after transplant. I guess, I completely agree with Eunice and I would say I’m still on the fence, but I haven’t been pushed over the fence to give GO. And we actually get a PCR test for NPM1 back in 3 days, so I could do it. I’ll have to think more about it. Eunice, thanks for making me think about it.

Naval Daver, MD: I think it’s a great question.

Eunice S. Wang, MD: We noticed no increased VOD [veno-occlusive disease] with our regimen and we think it’s helpful. You want to give everybody the best chance up front and that SWOG data, despite the increased toxicity with GO, in the end when they looked at the trial there was no increased toxicity in the final analysis.

Harry P. Erba, MD, PhD: No, in the end there was increased induction death, but here’s the caveat. [The mortality rate] was 5% with GO induction and it was 1% with just daunorubicin, which is lower than any prior or current trial in a cooperative group setting. And the FDA congratulated us on our excellent care of the patients who got daunorubicin in the SWOG study.

Naval Daver, MD: Which was never replicated. I will say that we are starting to think between FLAG-IDA + GO and FLAG-IDA + VEN for these isolated NPM1, non-FLT3[-mutated cases] because FLAG-IDA + VEN as well as CLIA [intensive chemotherapy with cladribine, idarubicin, and cytarabine] + VEN, [it has been] shown are giving you close to 95% to 100%, the 3-year survival is very similar. It’s a plethora of riches. But I do think the GO data are getting more and more compelling for those isolated NPM1 without the FLT3 [cases] without any other adverse features.

Transcript edited for clarity and readability.

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