Mutational Sequencing Evolutions Drive Precision Medicine Approaches for AML

Eunice S. Wang, MD

Acute myeloid leukemia (AML) is a “dynamic disease” for which determining safe and effective treatments and improved mutational testing strategies is key, according to Eunice Wang, MD.

In November 2024, the FDA approved revumenib (Revuforj) for the treatment of adult and pediatric patients aged 1 year or older with relapsed/refractory acute leukemia harboring a KMT2A translocation.1 Importantly, patients are required to receive a karyotype cytogenetic analysis before they can be treated with revumenib, Wang noted during an interview with OncLive®.

“[Mutational sequencing strategies are] going to have to be part of our standard of care at diagnosis and at relapse,” Wang said. “We’re going to need to make efforts moving forward to get the results in a timely manner, because you don’t want to get them back 3 months or 3 or 4 weeks later and have the patient’s therapeutic options completely change.”

In the interview, Wang discussed current AML management updates stemming from the 2024 ASH Annual Meeting, the importance of performing mutational sequencing across AML subtypes, and future directions for targeted precision medicine in the AML treatment paradigm.

Wang is a professor of oncology, chief of the Leukemia Service, the Leukemia Clinical Disease Team leader, and an assistant member of the Tumor Immunology Program in the Department of Immunology at Roswell Park Comprehensive Cancer Center in Buffalo, New York. She is also an associate professor in the Department of Medicine at the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo.

OncLive: What clinical trial data have had the biggest recent effects on AML management?

Wang: One of the big topics [from ASH 2024] was the advent of a new class of targeted therapy for AML: menin inhibitors. Menin inhibitors target a pathway. The menin binds to an epigenomic complex—KMT2A, which drives the leukemogenesis in 2 specific AML subtypes: AML with KMT2A or MLL chromosomal rearrangements, and AML with NPM1 mutations.

[At ASH], there was an oral session devoted entirely to menin inhibitor therapy. We heard updates on the first-in-class, FDA-approved menin inhibitor revumenib. The long-term follow-up from the phase 1/2 AUGMENT-101 study [NCT04065399] evaluated and established the efficacy of revumenib in patients with KMT2A-rearranged leukemias, including pediatric patients and patients with acute lymphoblastic leukemia.2 These data confirmed that revumenib is an active compound that generated clinical benefit in [approximately] two-thirds of patients, with a complete remission [CR] rate of [approximately] 15%.

We also saw the advent of combination menin inhibitor therapy from an abstract [on the phase 1/2 SAVE study (NCT05360160)] presented by Ghayas C. Issa, MD, of The University of Texas MD Anderson Cancer Center in Houston. SAVE assessed the combination of revumenib with oral decitabine [Dacogen], cedazuridine, and venetoclax [Venclexta] in patients with relapsed/refractory AML. [The overall response rate in all patients was] high—greater than [those seen with revumenib] monotherapy—at [82%].3

I participated in another trial, [the phase 1 KOMET-007 study (NCT05735184)] evaluating ziftomenib combined with standard intensive induction chemotherapy in newly diagnosed patients [with NPM1-mutated or KMT2A-rearranged AML].4 In newly diagnosed patients with NPM1-mutated disease with adverse risk features, treatment with the ziftomenib regimen led to 100% of patients achieving a CR with full count recovery, no delay in hematologic adverse effects, no myelodysplastic syndrome, and no significant complications. These data suggest that moving menin inhibitors into the upfront therapy setting in combination with intensive and less-intensive regimens is what we’re going to be investigating in the next year or 2. Similar data were presented with a second menin inhibitor, bleximenib, plus intensive chemotherapy.

Other data [from a phase 2 study (NCT05177731) evaluated] the possibility of using venetoclax plus decitabine in younger patients [with newly diagnosed AML].5 [Venetoclax plus azacitidine (Vidaza), decitabine, or low-dose cytarabine] is FDA approved for patients aged 75 years and older [with comorbidities]. However, the tolerability and outcomes [associated with these regimens in older] patients have led many of us to use venetoclax plus azacitidine to treat younger patients with AML in the newly diagnosed setting, as opposed to using intensive chemotherapy. That combination, although associated with myelosuppression, may be much less toxic than intensive chemotherapy with cytarabine and anthracyclines.

[Findings from another phase 2 study (NCT05177731)] presented at ASH showed at least equivalency between venetoclax plus decitabine [and standard intensive chemotherapy in younger] patients with [newly diagnosed AML with] adverse risk factors. Additionally, a phase 2 study [NCT03573024] led by Daniel A. Pollyea, MD, MS, of the University of Colorado Cancer Center in Aurora; Justin M. Watts, MD, of the University of Miami in Florida; and colleagues found that among approximately 36 [younger] patients with intermediate- and adverse-risk [newly diagnosed AML who received] a venetoclax dose of 600 mg [in combination with azacitidine, patients achieved] similar CR rates [regardless of their fitness for intensive chemotherapy].6 [Venetoclax-based regimens are not more effective than intensive chemotherapy], but they are better tolerated, and [with the use of those combinations], one hopes for an easier transition of those patients to allogeneic stem cell transplant [allo-SCT].

Moreover, we saw additional data with FLT3 inhibitors, including the phase 2 PrECOG 0905 study [NCT03836209] with gilteritinib [Xospata] in combination with 7+3 [in patients with newly diagnosed, FLT3-mutated AML]. [This trial did] not meet its primary end point, which was minimal residual disease–negative CR after 1 cycle, but it showed deeper responses over time with [gilteritinib].7

We also saw some data with IDH inhibitors, [including] olutasidenib [Rezlidhia], a second-generation IDH inhibitor. Data [from a phase 1/2 study (NCT02719574)] suggested that this agent is effective—although it may need to be given for longer periods of time [compared with other agents]—and yielded encouraging data when combined [with azacitidine in patients with IDH1-mutant AML].8 Olutasidenib may be an additional agent we use in that patient population.

Why is it important for patients with AML to undergo mutational testing?

We’re all excited about menin inhibitors and the possibility of targeting NPM1-mutated and KMT2A-rearranged leukemias. However, we can’t apply any of our precision medicine approaches unless we know the individual profiles of patients with AML. For example, to [determine whether you should] use revumenib [in a patient], you have to perform a karyotype cytogenetic analysis; [that is different from sequencing] a mutational profile and is not under the next-generation sequencing [NGS] umbrella.

Similarly, to test for [mutations in] NPM1, IDH1, IDH2, ITD, and TKD, [as well as to look for] different FLT3 mutations, you have to run an extended sequencing panel to identify younger patients with adverse risk factors who may, down the line, receive venetoclax plus azacitidine instead of intensive chemotherapy. Based on some of those results, you’ll then need to look for some of those secondary adverse risk mutations that require a broader NGS panel. [These treatment decisions hinge on] individual oncologists diagnosing patients with AML, not only by morphology and flow, but also doing the extra step to get those patients’ NGS, mutational, and cytogenetic data as soon as possible.

Additionally, AML is a dynamic disease. If patients are treated up front and they have [undergone all those tests] when they develop relapsed or refractory disease or when their cancer recurs post-transplant, it’s extremely important to repeat those analyses. For example, approximately 50% of patients who receive a FLT3 inhibitor for FLT3-mutant disease at the time of relapse will lose their FLT3 mutation, and they may develop new mutations that may make them eligible for other therapies. Overall, the field is moving toward targeted precision medicine that is less toxic, includes agents that patients can take orally at home in the outpatient setting, and uses lower-dose backbones [of standard] agents. [We are] moving away from using inpatient chemotherapy and high-dose toxic myelosuppressive therapy.

What are the next steps for broadening access to these novel targeted therapies?

I was part of an interesting [ASH] abstract: a prospective, [multicenter] study investigating factors that can affect access to the implementation of allo-SCT for adult patients with AML. It demonstrated that patients with a lower socioeconomic status—including those with a lower median household income, those who don’t own their own homes but rent them, and those who are on food stamps—have a significantly lower ability to access curative allo-SCT. Their clinical outcomes with that intervention are the same as other patients, but accessing this potentially life-saving therapy for a life-threatening disease is [more difficult]. [We may see] similar results [regarding patients’ ability] to access some of the newer drugs, which have high out-of-pocket costs; this also may affect patients] abilities to enroll in some clinical trials. We need to keep that in mind as we move forward with all these wonderful developments and safer transplantations: there are other barriers we need to be cognizant of to ensure these interventions get to all our patients.

References

1. FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. FDA. November 15, 2024. Accessed April 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation
2. Updated results and longer follow-up from the AUGMENT-101 phase 2 study of revumenib in all patients with relapsed or refractory (R/R) KRT2Ar acute leukemia. Blood. 2024;144(suppl 1):211. doi:10.1182/blood-2024-194384
3. Phase I/II study of the all-oral combination of revumenib (SNDX-5613) with decitabine/cedazuridine (ASTX727) and venetoclax (SAVE) in R/R AML. Blood. 2024;144(suppl 1):216. doi:10.1182/blood-2024-204375
4. Ziftomenib combined with intensive induction (7+3) in newly diagnosed NPM1-m or KMT2A-r acute myeloid leukemia: interim phase 1a results from KOMET-007. Blood. 2024;144(suppl 1):214. doi:10.1182/blood-2024-198218
5. Venetoclax and decitabine compared with standard intensive chemotherapy as induction therapy in newly diagnosed acute myeloid leukemia: updated results of a multicenter, randomized, phase 2b trial. Blood. 2024;144(suppl 1):971. doi:10.1182/blood-2024-202801
6. Venetoclax plus azacitidine for newly diagnosed younger acute myeloid leukemia patients independent of fitness for intensive chemotherapy. Blood. 2024;144(suppl 1):969. doi:10.1182/blood-2024-199267
7. Gilteritinib results in higher remission and transplant rates than midostaurin but does not increase the post-induction mutational MRD negative rate: results of the phase 2 randomized precog 0905 study in newly diagnosed FLT3 mutated AML. Blood. 2024;144(suppl 1):221. doi:10.1182/blood-2024-201595
8. Combination of olutasidenib and azacitidine induces durable complete remissions in mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial. Blood. 2024;144(suppl 1):2886. doi:10.1182/blood-2024-201710