When to Perform Molecular Testing in Relapsed AML
Harry P. Erba, MD, PhD, discusses the need to retest for mutations including IDH1, IDH2, FLT3, NPMI, and KMT2A rearrangement for patients with relapsed or refractory acute myeloid leukemia.
Transcript:
Naval G. Daver, MD: Dr Erba, when do you do this testing? I think that’s the big question, right? We all agree, in the frontline setting, we’re going to do it for all our patients. When else should we be doing it? Should we be doing every bone marrow? Should we do it at relapse? Should we do it post transplant? When do you do testing and what tests do you do at those time points?
Harry P. Erba, MD, PhD: Thank you, Naval. What we’ve learned over time is that the response of leukemia to chemotherapy can vary … For example, a patient may be cured. On the other hand, when the patient has a relapse of disease, they may relapse with the same mutations. And quite frankly, I find that most common in certain mutations. For example … NPM1 tends to be a stable mutation at the time of relapse. KMT2A rearrangements tend to be stable at the time of relapse. But other mutations may come and go and some of these are amenable to targeted therapies, such as FLT3, IDH1, and IDH2. And so, at the time of a suspected relapse or a patient having refractory disease, I think it is important to repeat the mutational profile.
The challenge is sometimes you’re doing bone marrows, you don’t know, you’re not certain. We have the ability here at Duke [Cancer Institute] to do a DNA extract and hold and then wait for the results and then cancel any or order a myeloid gene panel or PCR if needed, if the marrow does show persistent disease, as opposed to, for example, marrow that’s still hypoplastic from prior therapy. It gets a little bit complicated predicting when a patient is going to have relapse or refractory disease after initial therapy. But, in general, we strongly advocate that those tests be repeated and then, especially, I would say, for the mutations for which we now have targets, the targeted therapy. So FLT3, IDH1, IDH2. And I would add to that KMT2A rearrangements and NPM1, which tend to be stable but need to be tested for because there are a number of clinical trials and, hopefully, soon there will be availability of menin inhibitors in those subsets of patients. So those are the things I look for at the time of relapse refractory disease. My final point there would be, how about post transplant?
And we’ve always thought about allogeneic stem cell transplant as the end of the therapeutic algorithm for the patient even though we have known for decades that one of the major challenges that these patients face besides graft-vs-host disease will be relapse, despite the allogeneic graft vs leukemia effect. And so, maintenance therapies have really become forefront in our minds. And there have been a number of trials that have looked at maintenance therapies after allogenic transplants. But the only ones that have shown some benefit in terms of relapse-free and overall survival would be with the FLT3 inhibitors. The RADIUS trial [NCT01883362] of midostaurin vs placebo did not show a statistically significant improvement in survival, but on the other hand, the SORMAIN main trial from Germany [German Clinical Trials Register DRKS00000591] did show a relapse-free and survival benefit for sorafenib vs placebo after allogeneic transplant. And then to bring this right up to the current day, just 2 days ago, we saw the results of the MORPHO trial [NCT02997202] of gilteritinib vs placebo post-allo[geneic] transplant. And although as a whole population, we didn’t quite see a statistically significant improvement in relapse-free survival, when you look at the patients who had MRD [minimum residual disease] for the FLT3 mutation, those patients did seem to benefit as you might expect. And so, I think targeting, doing mutational analysis post transplant for mutations for which we have targeted therapies—FLT3 and I would add in the IDH inhibitors, even though we have [fewer] IDH mutations, even though we have much less data there.
Naval G. Daver, MD: I think we’ll talk more about the FLT3 inhibitors and how we use those, especially post transplant. But I think … checking at baseline for the broader mutational panel, especially rushing the FLT3 core binding factor and APL [acute promyelocytic leukemia] 15;17 have a very direct impact on treatment whether you’re going to add gemtuzumab in core binding [or] add FLT3 inhibitor for FLT3-mutated disease. And then getting to Dan’s point, I do think there’s more … movement going toward lower-intensity HMA-based therapies for TP53, chromosome 17, these very high-risk groups where we know intensive chemo[therapy] is going to give you a similar response and probably more time in the hospital, myelosuppression. Of course, with the caveats that all TP53 are not made equal, we must look at the variant allele frequency [VAF]-associated cytogenetics, but we are moving toward HMA-based [treatments] and I think more and more that’s something across the [United States] that is happening commonly.
I think for relapse testing, for sure, FLT3 is the most important one just because it has such a kinetic shift. You can see an FLT3 mutation at relapse in up to 40%, 50% of [patients] now based on the RATIFY study [NCT00651261] and [the] study with sorafenib intensive chemo[therapy] that Andrew Wei[, MBBS, PhD,] did. And you can also see it being gained. I think that’s important, Just to highlight, I think we also are learning that a lot of things we thought were static … we may see some of these emerge. For example, IDH. [Individuals] always said that if you have an IDH1, you almost never will have an IDH2. And now [increasingly] we’re seeing with the use of combinations [such as] HMA+IDH [inhibitor or] HMA+VEN[venetoclax]+IDH [that there is] better survival, that in fact there can be clone switching of these and it’s not as rare. So, I do think more checking for all of these—FLT3, IDH1, IDH2, NPM1—at relapse or progression from MDS to AML is really going to be critical.
Transcript is edited for clarity and readability.
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