Importance of Genomic Testing Increasing in the AML Field

James M. Foran, MD

Gradually, treating acute myeloid leukemia has improved for oncologists. The advances in the field are partly related to a better understanding of genomics in AML, and the more innovations for the disease are in the pipeline to improve survival. 

According to James M. Foran, MD, an oncologist with the Mayo Clinic, progress has mostly been in FTL3 and IHD mutations. Agents like midostaurin (Rydapt) and gilteritinib (Xospata) are now being tested for efficacy in first-line trials. With that, sequencing has become more important, with turnaround times going down.

Even with these innovations, unmet needs still remain, according to Foran. Treatment for patients with a tP53 mutation is a major unmet clinical need, as there is no treatment outside of allogeneic transplantation.

In an interview with Targeted Oncology^TM, Foran discussed how recent research has caused a paradigm shift in AML, and which ongoing clinical trials have the potential to change treatment in the near future.

TARGETED ONCOLOGY: What changes have you observed in the AML landscape in recent years?

FORAN: It was frustrating a few years ago to see all the advances in targeted therapy in chronic lymphocytic leukemia. And even some of the new therapies and chronic myeloid leukemia. And we've had a number of chemotherapy-based treatments that we evaluated in AML, that had not met their endpoints. And so, we were a little bit stuck. And there have been some major innovations in AML through better understanding of sequencing, the development of targeted therapies. And then an agnostic therapy, venetoclax [Venclexta]. I think the big innovations were the routine use of sequencing at diagnosis and at relapse to identify patients with FLT3 mutation and now IDH1and IDH2 mutations. We have the RATIFY [NCT00651261] trial that was published a couple of years ago that showed a survival advantage for adding midostaurin into intensive therapy. And since then, we have a relapse/refractory excellent and possibly even better FLT3 inhibitor gilteritinib [Xospata, which are now being tested head-to-head in a first-line trial.

So, for patients with FLT3-positive AML, in the range of 30% of younger patients and about 15% of older patients, we can now add targeted therapies that improves survival in the first line setting and significantly improved response rates and survival in the second line setting. With IDH inhibitors, they've really been an extremely important palliative treatment that are now FDA approved in the relapsed/refractory setting for both IDH1 and IDH2. And in a small phase 2 study in the first-line setting for IDH1, we're trying to learn how to incorporate those into intensive chemotherapy to get better results. So that was really the first of the waves. 

The second was a revaluation of gemtuzumab [Mylotarg]. That drug had been around from 2000 to 2010 but withdrawn from the market for toxicity and because the pivotal trials were negative, but it was really a follow-up trial that showed a survival advantage, particularly for those patients on meta-analysis who had favorabl- risk AML. So gemtuzumab came back into play and particularly for those with core bonding factor leukemia where it's extremely useful. 

The third major innovation, which I think is going to complicate our landscape for a while, in a positive way is venetoclax. Some single agent responses in the relapse setting, but when you add it to low intensity therapy, specifically azacitidine [Vidaza] for older unfit patients with AML in the first-line setting significantly increases the complete remission rate, and overall, improves the median survival by almost 50%, taking it from about 10 months to about 15 months, with a pretty respectable 2-year and beyond overall survival compared to what we used to see with azacitidine alone. Now that's a targeted drug, it targets BCL-2, not all AML is BCL-2 dependent, we're looking for a better understanding and a better biomarker for those that are not or maybe MCL-1 dependent maybe that can be exploited. But it's been a major innovation.

There are now studies including venetoclax with intensive therapy to see if that can be tolerated. And that has now become the doublet upfront of choice for patients over the age of 70 or 75 with newly diagnosed AML based on the higher remission rate and the improvement in overall survival. There are some groups that may not benefit as much those with unfavorable cytogenetics, those with tP53 mutations just as examples, and that's an area where we've had some disappointments and we're still waiting for trials to come forward that better target tP53 or get better results in that population.

The last innovation isn't really a new innovation. It's just new data looking at allogeneic transplantation in older patients. We've known for those with adverse genetics or adverse karyotype, that we get better survival without genetic transplant in younger patients. We now know from a prospective study, that patients with a donor over the age of 60 have a better survival than patients without a donor. So that's increasing the focus on transplant. I think we're going to look for ways to extend that more and more for patients over 65 or 70. And try to capitalize on the remissions by adding venetoclax, to try to take the patient's past just a 15-month median survival, but maybe onto a curative pathway, at least 10% can do it in retrospective studies, but I think that number is going to be higher. And those were the donor, especially those that get to transplant do better. And I think that's going to be increasingly used.

What is being investigated in ongoing AML research?

We can get sequencing results in 7 days to stratify patients into specific risk categories based on their mutation profile. And so, the innovation there is that we can move more quickly to get cytogenetics and to get next-generation sequencing results faster. And we've also learned in parallel from some European trials and from experience in North America, that you can wait in most patients to get those results before you start treatment. So, the paradigm shift is now patients are urgently transferred into the hospital, these urgent phone calls on Friday afternoons of a new patient with acute myeloid leukemia, and then suddenly, you're seeing them and you're slowing things down for 3 days, or 5 days, or 7 days. Or if they're stable, you're discharging them to see them a few days later in clinic because when we have those results, we can much better stratify on the treatment strategies. Those were the tP53 mutation who may not benefit from intensive chemotherapy, or those with a FLT3 mutation where we can get those back often in 48 hours now, for an FLT3-ITD mutation, where we can stratify them on the treatment more quickly. So, that's the paradigm shift, is that the focus is much more on rapid turnaround of genetics.

What have stratification patterns in clinical trials revelaed about oncoogists’ approach to treatment?

One size does not fit all. We're now trying to stratify this specific genetic subgroup, to try to be much more targeted about it. It may not matter in the end; those studies are being designed now. It may not matter what gets you in remission, it may matter just that you get a remission and possibly an MRD negative remission, whichever way you measure that typically flow cytometry, with leukemia associated immunophenotype. But it may not matter how you get there. And it could be that azacitidine and venetoclax can get nearly as many into remission, or to MRD negative remission if you keep them on long enough. Then it's the consolidation strategy that may matter, particularly if you're thinking about transplants. So that's the question that we're scratching our heads about. We've known for a long time, particularly in older adults, you can cure someone with intensive therapy, you just can't get everybody through it. And now we're looking to see should we be de-escalating to something slightly less intense, not that Venetoclax is easy for everybody. But should we be deescalating a little bit or adding a targeted therapy to get the best possible remission and then try to do some maintenance strategy or some other consolidation, or allogeneic transplant? I would be remiss if I did not mention a liposomal cytarabine called CPX-351. Where if somebody has therapy-related AML or AML with MDS-related changes, has a higher complete remission rate and a higher overall survival and even a higher overall survival of patients in remission to go on to transplant. I was a skeptic at first and I've really learned that that is an important innovation for patients with therapy-related AML or with MDS-related changes. 

What investigational treatments appear promising for AML right now?

I'm very excited about the CD3 bispecific T-engaging compounds. It's been shown in acute lymphoblastic leukemia, that there's activity of blinatumomab [Blincyto], a CD19/CD3 bispecific T-engaging compound. Now, there are a number of similar concepts being evaluated in acute myeloid leukemia, we've been part of a trial of a CD123, CD3 bispecific to try to get an immune response against myeloid blasts. There's another one in development that looks very exciting. There's a CD33, it's in development. And there are some new NK-cell based cell therapies. And bispecific or trispecific compounds that are being evaluated to try to generate an immune response to those patients who can't or shouldn't, or don't go to transplant or even after transplant. And so, I think we're really trying to harness immune therapy and AML.

I guess the other area, closely related or somewhat related, is CD47 as a potential target in AML. CD47 looks very attractive based on an antibody called magrolimab and some studies that have been run through Moffitt Cancer Center & Research Institute and has shown impressive phase 1 and phase 2 results in AML. Particularly those with high-risk cytogenetics and tP53, we're really lacking a good therapy. I'm hopeful that studies targeting CD47, not just with magrolimab, but other compounds will lead us on to a measurable clinical benefit for patients and an option for patients because it looks like it can be tolerated. I think those are very exciting.

For those who are transplant eligible, and over the age of 55, and who have a donor, but have refractory leukemia, there's also randomized study called the Iomab-B study (NCT02665065)., and that study has recently finished accrual and we're going to wait to see what the clinical results are. But I'm hopeful that can establish disease control in patients who have refractory AML and who may then be able to go on and get a transplant afterwards to try to augment those results or capitalize on that disease control.

What should we be considering in order to advance the field in the future?

There are definitely unmet needs. I'm going to just start with the obvious low hanging fruit. tP53 is our greatest unmet need. We have yet to find a therapy outside of allogeneic transplant, which is pretty inadequate, even for those who get it. That makes a major impact on the disease, low intensity therapy helps a little bit, allogeneic transplant helps a little bit, we need to understand that better, we need better ways to target that. And that's a major unmet need. The second is for frail patients to have some kind of therapy that can at least get a meaningful disease control. The third I would say is in reestablishing myelopoiesis. We have therapies that can control blasts. But we really, and I'm talking about AML and MDS together here, we need a better understanding about what we can do to improve myelopoiesis, to get blood counts better, even in the patients where we've eradicated the blastic phase of their disease. Adverse side genetics remains a problem. And the other area is really, we need to continue to innovate an allogeneic transplant and cell therapy and immune therapy. There are some consortia that are looking at some National Cancer Institute consortia, they're looking at trying to leverage PD-1 with pembrolizumab or in the right setting to get higher MRD rates. I mentioned the CD3 based by specifics targeting myeloid antigens, there are car T strategies trying to do the same thing with T cell-based strategies. And we really need a better immune based approach that shows efficacy in patients because allogeneic transplant is a little bit of a sledgehammer approach and not for everybody. We need to make that immune therapy that’s more effective.