Alexander E. Perl, MD, MS.
According to Alexander E. Perl, MD, MS, the acute myeloid leukemia (AML) treatment landscape includes emerging therapies and diagnostic strategies that simultaneously address previously unmet needs and raise further questions regarding the classification of diseases.
In 2022, the European LeukemiaNet (ELN) updated its AML recommendations based on a growing understanding of the molecular pathogenesis of the disease. This update includes revisions to genetic risk classification, response criteria, and treatment recommendations.1
“This is an exciting time in the AML therapy community,” Perl said in an interview with Live® according to 40th Annual CSA® meeting. “We are learning more about what drives this disease and, more importantly, how to use this information to guide our therapy.”
In the interview, Perl, an associate professor of medicine at the University of Pennsylvania Hospital in Philadelphia, discussed the implications of the updated ELN guidelines, how genetic testing is guiding the treatment of this disease and ongoing research into new AML targets such as MNP1 transfer or KMT2Atranslocations.
Live®: Could you trace the evolution of the ELN guidelines and how their current iteration affects the treatment of patients with low to intermediate risk AML?
pearl: The ELN has published guidelines for the diagnosis, risk prognosis, management and follow-up of patients with AML for the past 12 years. The first guidelines came out in 2010, and they were updated in 2017 [and again] in 2022.
The most recent guidelines are [substantially more complex than] which was previously released in 2017. [We had] difficulty with the 2017 guidelines because, while they incorporated many of the advances that were happening in the field based on the molecular genetics of AML, they were published just before the explosion of new drugs to treat patients with AML disease. It was difficult to review these guidelines and modify our therapies for patients based on what we saw. The new guidelines use multiple genetic mutations to stratify patient risk, along with traditional karyotyping, and they also recommend the use of minimal residual disease [MRD] surveillance.
[In my CFS® presentation], I provided an overview of how to approach diagnostic workup, timing of treatment initiation, and monitoring for MRD in patients at favorable or intermediate risk. Notably, [I focused on] patients with central binding factor rearrangements or MNP1 changes. With commercially available testing labs, we can better stratify our patients’ risk and assign treatment so that patients at more favorable risk are not overtreated and patients at less favorable risk, those with genetics to intermediate or favorable risk with MRD, can be directed to more aggressive approaches, such as transplantation.
Given the heterogeneity of AML, how does initial genetic testing help inform treatment?
Some of these differences with new therapies are huge. Gemtuzumab ozogamicin [Mylotarg]as a single agent, had activity but had no notable improvement in overall survival [OS] in the context of relapsed/refractory. When this drug was moved to the front line, it was difficult to see significant improvement from adding this drug to intensive chemotherapy until we started looking at beta analyzes with large numbers of patients separated by their genetic risk.
In patients with central binding factor [rearrangements]improving OS with the addition of gemtuzumab to induction and consolidation therapy [increased by at least] 20%, which is huge. These are patients who usually don’t have transplants, so that’s a big improvement. He argues that we should seek out these patients, so we can give them the best therapy and not use a one-size-fits-all approach.
Similar improvements, perhaps not as great, have been observed in patients with flt3 mutations, which saw substantial improvements in outcomes across multiple modalities. Two randomized, placebo-controlled studies show significant improvements in OS when FLT3 inhibitors are added to first-line chemotherapy.
The RATIFY phase 3 trial [NCT00651261] with midostaurin [Rydapt] led to the approval of this drug due to improved survival of patients with flt3-ITD and flt3-LAM TKD-positive. The [phase 3] QUANTUM-First study [NCT02668653] with quizartinib showed similar improvement in OS in a high-risk group. This trial included elderly patients and only those with flt3-ITD AML. [These results showed] better OS and flat survival curves, suggesting more cures.
It is important to determine a patient’s genetic risk profile and treatment targets so that the right therapy can be added early in treatment. This leads to long term gains.
What unmet needs still exist for this population, and how might they be addressed in future clinical trials?
We know how to perform MRD testing for patients with recurrent gene rearrangements, such as central binding factor rearrangements or MNP1 mutations, but for many patients we don’t have an ideal monitoring system. Flow MRD is nice, but it’s hard to give this to the masses or do it in multiple centers. If there was a better way to do MRD testing, we would be able to better divide intermediate-risk patients into those who need a transplant and those who don’t. This is an area where we are still trying to make progress.
The other question is: Do we need intensive chemotherapy for every patient? A question from the audience [at CFS®] was: What is the role of MRD testing in low-intensity therapy? There is an established role for MRD testing in high intensity therapy, but we can use a similar approach in patients treated with venetoclax [Venclexta] and azacitidine [Onureg] and show that there are high-risk and low-risk patients.
[However, we don’t know] whether we can change our therapies based on these results because the study from which these data were obtained treated elderly patients who were treated indefinitely, whether they responded to and tolerated the treatment. We don’t know yet if we can use a similar approach for younger patients and give them shorter, lower intensity therapy. [if they] become MRD negative. This question is being tested in randomized trials of high intensity vs low intensity therapy, 7+3 chemotherapy vs venetoclax and azacitidine, but this is an ongoing study, and we don’t have the data yet.
What current research on LAM intrigues you?
Some of the areas that interest me are the new targets that are emerging and the benefits of new agents targeting recurrent AML mutations. One of the classes that [many of us] are excited about drugs that inhibit a protein called menin, which is involved in a complicated transcriptional complex that regulates hematopoiesis through epigenetic mechanisms. This is especially important for patients who have translocations of the KMT2A gene, also known as MLL on 11Q23, or [those who have] mutations in NPM1.
Studies of many drugs that target menin and its interaction with MLL are ongoing. These are currently single-agent trials, but combinations are likely to happen soon. These drugs show clinical activity, including complete remissions, many of which are MRM negative, which is exciting in patients with aggressive, advanced disease that has been difficult to treat in the past. It’s promising.
Immunotherapy is an area in which we would like to see great progress, but which has been slow to establish itself. Some of the most promising drugs include those targeting CD47, such as magrolimab, which is currently in phase 3 testing in combination with hypomethylating agents. [with or without] venetoclax in myelodysplastic syndrome [MDS] and LAM. [We’re all] glad to see updates on this effort.
Finally, there are new emerging targets and increased use of IDH targeted therapy. A big question right now is: where should these drugs be used? Should they be used in the first line? Should they be used in relapsed and refractory diseases? There are many areas we can flag with exciting new drugs, and we should pay attention to ASH [Annual Meeting and Exposition] and other upcoming meetings for new data that comes out.
What is your main message for your colleagues regarding these AML treatment updates?
The new ELN guidelines are unfortunately still complicated. A complicating factor has been disagreement within the pathology community as to how to classify myeloid neoplasms. There are competing classification systems of the International Consensus Classification and the World Health Organization, and the ELN adds to this problem [the question]: Now that we have these classifications, how can we integrate them into our practice? These disagreements lead to many [of us wondering] how we should look at the data and use it in clinical practice.
The ELN guidelines present complexities that require examining the fine print. Whether this is how you define a CEBPalpha mutation, how do you define a TP53 mutation, or if you use an explosion percentage of 10% to say [a disease] is AML vs MDS, it becomes increasingly difficult to define how we use older literature to inform our current therapies with these changes in classifications. This will be settled, and there will be more agreements than disagreements, but it will take time.
What I like about the current ELN guidelines is that they are more detailed. For years we have had these reports saying [our patients have certain] changes, [but we haven’t known] how to integrate this into practice based on the data. This gives us a roadmap for how to use this data to better assign appropriate therapies to patients and ultimately achieve better outcomes.
- Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international panel of experts on behalf of the ELN. Blood. 2022;140(12):1345-1377. doi:10.1182/blood.2022016867
Editor’s Note: This interview was conducted prior to the 2022 ASH Annual Meeting.
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