Menin inhibitors such as revumenib (Revuforj) could address unmet needs in the treatment of patients with relapsed/refractory acute myeloid leukemia (AML) harboring 

 mutations, and the ultimate role for these agents could be in combination therapies to provide bolstered options for patient populations with generally poor prognosis, according to Maximilian Stahl, MD.

The first menin inhibitor joined the AML treatment paradigm on November 15, 2024, when 

 for the treatment of adult and pediatric patients aged 1 year and older with relapsed/refractory acute leukemia with a 

 This regulatory decision was based on data from the phase 1/2 AUGMENT-101 study (NCT04065399).

“Going with a targeted agent [such as revumenib] that specifically targets a pathophysiology of 

-rearranged leukemias has a lot of promise and has shown very good response rates,” Stahl explained in an interview with 

In the interview, Stahl discussed the unmet needs in treating patients with relapsed/refractory AML, highlighted the impact of the FDA approval of revumenib for patients with 

 rearrangements, and explained why combination therapies could represent the ideal use of menin inhibitors in AML.

Stahl is a physician of Hematologic Oncology and a member of the Adult Leukemia Program at Dana-Farber Cancer Institute, and he is also an instructor of medicine at Harvard Medical School in Boston, Massachusetts.

: What are the primary treatment challenges in the AML space? How could menin inhibitors add to the targeted therapy options for these patients?

: The treatment landscape for relapsed/refractory AML has changed for the better, but patients still have an overall poor prognosis if they experience a relapse. [One of the] options that we currently have approved and commonly use is a venetoclax [Venclexta] and hypomethylating agent [HMA]–based regimen, which is often used in the frontline setting as well. However, [this strategy] can be used after chemotherapy in patients with relapsed/refractory [disease].

Additionally, targeted therapies are also approved [in AML]. We have a FLT3 inhibitor [quizartinib (Vanflyta)] approved [in combination with chemotherapy for patients with newly diagnosed, 

-ITD–positive AML], as well as an IDH inhibitor [olutasidenib (Rezlidhia)] approved [for patients with relapsed/refractory AML with a susceptible 

[Looking at] menin inhibitors, this has always been a question: how [do we] target 2 other molecular abnormalities that have not been targetable thus far? This includes 

 rearrangements, and that's where menin inhibitors come into play.

How does the FDA approval of revumenib address the specific gap in care for patients with relapsed/refractory acute leukemia harboring 

Revumenib is a menin inhibitor by Syndax Pharmaceuticals and is now approved for patients with [relapsed/refractory] 

-rearranged leukemias. It's not yet approved for patients with 

-mutated leukemia, although the data look good as well for that subset of [patients]. We hope an approval [for patients with 

[The 2024 approval] fills a critical void for [patients with] 

-rearranged leukemias. Those are what we consider adverse-risk leukemias in the sense that many of those patients are resistant to classic, traditional chemotherapy. Generally, giving those patients more chemotherapy is not that helpful.

[In the data that supported the 2024 approval,] revumenib showed in [AUGMENT-101] that patients who have [

] rearrangements in the relapsed/refractory [setting] had a complete remission [CR] plus CR with partial hematological recovery rate of 21.2% [95% CI, 13.8%-30.3%]. The [overall] response rate was higher, and [23%] of patients were able to proceed to an allogeneic stem cell transplant.

 It is a critical part [of treatment for] patients with relapsed/refractory leukemia to get them to transplant because that is the only potentially curative approach for them.

What are the key considerations in identifying patients with relapsed/refractory AML who may be eligible for revumenib or other targeted therapies, particularly with respect to RNA vs DNA testing for 

Generally, for targeted therapies, we need to have in-depth genetic testing. This is a new realization in the field of AML, that one should wait for these test results before making a final treatment decision. For the menin inhibitors in particular, for the 

 rearrangement, you sometimes do pick them up on standard chromosome analysis—what we call cytogenetics. However, there can be rearrangements that are cryptic that we [therefore] cannot see on cytogenetics easily. Therefore, it is important to test for them with other techniques that are more sophisticated.

[In regard to] RNA-based tests, we use a fusion test that looks at multiple fusions using RT-PCR from RNA. That is an important test to run because otherwise, you might not find a patient who would be appropriate for [revumenib]. 

 mutations can be picked up by standard DNA sequencing via next-generation sequencing. Both [testing approaches] are important if we want to [identify] more patients who are potentially eligible for menin inhibitors.

 rearrangements is important for prognosis because most of them are associated with an adverse prognosis. This means that with chemotherapy alone, those patients can often not be cured, and that's why we do see a lot of relapses in this patient population.

Even the menin inhibitors are not curative per se, at least not as a single agent. What we have seen in the trial that led to the approval of revumenib is that although patients have a response—and there's a good population of patients who do have a response—this population of patients does not have a lasting response beyond several months. They respond for a couple of months, and then often they develop resistance mechanisms that make their disease come back and relapse. That's why transplant is such an important part of that treatment. When they have a response, try to get them to transplant.

For patients who are not transplant eligible, combination approaches with menin inhibitors will be even more critical. There have been several abstracts have looked at combining menin inhibitor with venetoclax- and HMA-based backbones, or intensive chemotherapy backbones. What we see is that patients generally have high response rates, and those responses seem to be very durable. The future of menin inhibition will be in combination therapy.

With the advent of more targeted therapies, it is essential to take that time and wait for genetic testing results. Often, that can take up to a week to get genetic testing back. However, it is time worth spending because it leads to better treatment options for patients.

What ongoing research with menin inhibitors could further illustrate the importance of timely identification?

The use of menin inhibitors as single agents marks only the start of their exploration in AML. The future is in combination therapies, and as we saw at the 2024 ASH Annual Meeting, and we will continue to see at future meetings is that it's a very busy field. There are several companies [developing] menin inhibitors, and they are testing those inhibitors in different ways with multiple different combination partners.

We saw promising data at ASH with [ziftomenib in combination with] the standard backbone of 7+3 chemotherapy. This was presented by Amer M. Zeidan, MBBS, MHS, of Yale University in New Haven, Connecticut. There are also other combinations with venetoclax and HMAs for patients who cannot tolerate intensive chemotherapy. Similarly, [these combinations have generated] high response rates, including high minimal residual disease–negative response rates.

Additionally, menin inhibitors will be explored [in combination] with other targeted therapies. There are now trials that combine them with a FLT3 inhibitor, including a trial that I lead at Dana-Farber Cancer Institute, which combines a menin inhibitor with intensive chemotherapy and a FLT3 inhibitor for patients who have both an 

 mutation. There will be many combinations [tested]. We'll have to see how those trials read out, but there is a lot of promise in this field.

FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. FDA. November 15, 2024. Accessed December 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation

Syndax announces FDA approval of Revuforj (revumenib), the first and only menin inhibitor to treat adult and pediatric patients with relapsed or refractory acute leukemia with a KMT2A translocation. News release. Syndax Pharmaceuticals. November 15, 2024. Accessed December 17, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-fda-approval-revuforjr-revumenib-first-and-only

Articles

Maximilian Stahl, MD, discusses unmet needs in relapsed/refractory AML, highlighting the potential utility menin inhibitors in select populations.

Menin Inhibitor–Based Combinations Are Central to Ongoing Research in KMT2A+/NPM1+ AML 

Dr Stahl on Key Genetic Tests for Menin Inhibitor Use in AML

“Both [RNA-based testing and next-generation sequencing] are important to do if we want to get more patients who are potentially eligible for a menin inhibitor to receive [revumenib].”

Maximilian Stahl, MD, physician, Medical Oncology, Dana-Farber Cancer Institute; instructor in medicine, Harvard Medical School, discusses key considerations when determining a patient’s eligibility for 

targeted therapies like revumenib (Revuforj)

 in acute myeloid leukemia (AML), particularly with respect to RNA vs DNA testing for 

Comprehensive genetic testing plays a critical role in identifying patients who may benefit from targeted therapies, Stahl begins. This is increasingly recognized in the field of AML, where waiting for genetic testing results before finalizing treatment decisions is becoming a standard approach, he explains. When considering the use of menin inhibitors for a patient with AML, testing for 

 rearrangements is essential, Stahl emphasizes. Although some of these rearrangements can be identified through standard cytogenetic analysis, others may not be readily detectable with conventional methods, Stahl says, adding that the use of advanced techniques to identify these rearrangements is therefore crucial. 

One such method involves RNA-based testing, he continues, which can detect multiple fusions through a technique known as reverse transcription polymerase chain reaction. This approach ensures that 

 rearrangements are not overlooked, thereby identifying patients who may benefit from menin inhibitor therapy, Stahl states. He notes that without such thorough testing, eligible patients may be missed. 

 mutation, which is another relevant target in AML, can typically be detected with standard next-generation sequencing, he continues. This method complements RNA-based testing and ensures a comprehensive evaluation of genetic alterations. Ultimately, incorporating sophisticated genetic testing techniques into standard practice is essential for optimizing patient outcomes in AML and expanding the pool of patients who can access menin inhibitors, Stahl concludes.

Videos

Maximilian Stahl, MD, discusses considerations for genetic testing to determine if patients with acute myeloid leukemia may be candidates for a menin inhibitor.

6366080824112

-rearranged leukemia, showing consistently the efficacy of revumenib, regardless of age…and this supports the label as a standard of care.”

Ghayas C. Issa, MD, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses key findings and clinical implications from the phase 2 AUGMENT-101 trial (NCT04065399) evaluating revumenib (Revuforj) in relapsed or refractory 

The AUGMENT-101 trial highlights the efficacy and safety of revumenib, a menin inhibitor, in patients with 

rearranged acute myeloid leukemia and acute lymphoblastic leukemia, Issa begins. This subset represents a high-risk population with limited treatment options, underscoring the importance of novel therapeutic agents, Issa explains.

 demonstrated consistent efficacy outcomes, supporting revumenib’s use as a standard of care treatment for patients with relapsed or refractory 

Specifically, revumenib achieved a complete remission (CR) or CR with partial hematologic recovery rate of 22.7%, with an overall response rate of 63.9%. These results were observed regardless of patient age, supporting the use of revumenib in both younger and older patients. Importantly, the durability of responses and minimal residual disease negativity observed in most responders further validate the drug’s clinical utility, he adds.

No new safety signals were reported, and no patients discontinued treatment due to cytopenias, differentiation syndrome, or QTc prolongation. Grade 3 or higher treatment-emergent or treatment-related adverse effects occurred in 91.4% and 54.3% of patients, respectively, of which 77.6% and 36.2% were serious.

The favorable safety and efficacy profile of revumenib positions it as a new standard of care for relapsed or refractory 

-rearranged leukemias, Issa concludes. This approval provides a new treatment option for patients with historically poor outcomes, addressing an unmet need in this population, Issa notes.

Ghayas C. Issa, MD, discusses the efficacy of revumenib in relapsed or refractory KMT2A-rearranged leukemias.

Dr Issa on the Efficacy and Safety of Revumenib in R/R KMT2A+ Leukemias 

Dr Stein on the Efficacy of Revumenib in KMT2A+ R/R Acute Leukemia

"What [the data] say to me is: [approximately] 23% of patients are clearing their blasts and having nice blood count recovery [with revumenib], but there's a large group of patients who are still able to clear their blasts. If those patients are eligible to receive [ASCT], the clearance of those blasts does allow those patients to proceed to transplant, [which will] hopefully be successful."

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, chief, Leukemia Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses key efficacy findings from the phase 1/2 AUGMENT-101 study (SNDX-5613-0700; NCT04065399), which supported the November 2024 

-rearranged relapsed/refractory acute leukemia.

In the efficacy portion of the study involving 104 patients with relapsed or refractory acute leukemia and a 

 rearrangement, 21.2% (95% CI, 13.8%-30.3%) of patients achieved a complete remission (CR) or a complete remission with partial hematologic recovery (CRh), meeting the FDA's regulatory bar for approval, Stein begins. The median duration of CR or CRh was 6.4 months (95% CI, 2.7-not estimable), with a time to response of 1.9 months (range, 0.9-5.6 months), he adds. Importantly, 14% of patients who were previously transfusion dependent achieved transfusion independence [TI]; 48% of patients at baseline remained independent. These findings highlight revumenib’s potential to improve not only remission rates but quality of life for patients by reducing transfusion dependency, Stein states.

 from a subset of 57 patients showed a similar trend, with an overall response rate of 63.2% and a CR/CRh rate of 22.8%, Stein notes. This dataset further reinforces the ability of revumenib to clear blasts, providing patients an opportunity to proceed to an allogeneic stem cell transplant (ASCT), which could offer long-term disease control, he explains. Although the CR/CRh rate produced by revumenib represents a significant achievement, the ability of additional patients to clear their blasts underscores the broader potential of revumenib in combination with subsequent treatments, offering hope for better outcomes in a patient group with historically poor prognosis, Stein concludes.

Eytan M. Stein, MD, discusses efficacy findings from the phase 1/2 AUGMENT-101 study of revumenib in KMT2A-rearranged relapsed/refractory acute leukemia.
 
 

) into the relapsed/refractory setting provides patients with 

-rearranged acute leukemia—a historically difficult-to-treat malignancy associated with poor survival outcomes—with an oral, targeted therapy capable of inducing durable remission and enabling more patients to proceed to allogenic stem cell transplantation (ASCT), according to Eytan M. Stein, MD.

 for the treatment of adult and pediatric patients aged 1 year and older with relapsed/refractory acute leukemia and a 

 The regulatory decision was supported by results from the phase 1/2 AUGMENT-101 study (SNDX-5613-0700; NCT04065399), in which 21.2% (95% CI, 13.8%-30.3%) of patients treated with the menin inhibitor (n = 104) achieved complete remission (CR) or a CR with partial hematologic recovery (CRh). Moreover, 14% of patients dependent on red blood cell (RBC) and platelet transfusions at baseline (n = 83) achieved independence during any 56-day post-baseline period; 48% of patients who were transfusion independent at baseline (n = 21) remained independent.

“This is a difficult-to-treat type of leukemia, and the approval of 

 gives these patients some hope that they'll be able to take a generally well-tolerated oral therapy that can put them back into remission,” Stein explained in an interview with 

In the interview, Stein expanded on the significance of the approval of 

 for relapsed/refractory acute leukemias harboring

 rearrangements; detailed toxicities of note and key safety considerations for 

 administration; and discussed the potential integration of 

 into frontline treatment or combination strategies through ongoing clinical trials.

Stein serves as director of the Program for Drug Development in Leukemia and chief of the Leukemia Service in the Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center in New York, New York.

: What are the implications of the FDA approval of 

 for patients with relapsed/refractory acute leukemia harboring a 

 It's important to remember that patients with

rearrangements with relapsed/refractory acute leukemia—whether it's acute myeloid leukemia [AML] or acute lymphocytic leukemia [ALL]—have very poor prognosis. We have retrospective data in AML [published in 2021] showing that overall survival [OS] for patients [with 

 rearrangements] who have received 2 or more lines of therapy for their relapse can be measured in a few months at most.

 In fact, if patients had 3 or more lines of therapy after relapse, the median OS was 2.4 months. 

What efficacy data from AUGMENT-101 supported this regulatory decision?

The FDA [evaluated data for] 104 patients with relapsed/refractory acute leukemia with a 

rearrangement in the efficacy portion of the study, and what they saw was that 21.2% of the patients achieved a CR/CRh. The median duration of CR/CRh was 6.4 months. A combination of CR/CRh is the regulatory bar for the FDA.

If you look at [data from] the paper published in the 

[in August 2024] before the FDA approval, we looked at a slightly earlier dataset, meaning we only looked at 57 patients who were [efficacy-evaluable] at the time of that data cutoff.

 When we looked at those patients, the overall response rate was 63.2%, the composite CR rate was 43.9%, and the CR/CRh rate was 22.8%.

What these [data] say to me is that [approximately] 23% of patients cleared their blasts and had a nice blood count recovery. However, there was a large group of patients who were still able to clear their blasts. If patients are eligible to receive [ASCT], the clearance of those blasts does allow those patients to proceed to transplant, [which will] hopefully be successful.

What are the key toxicities and safety considerations to be aware of when administering 

Most of the toxicities that [are reported] in the FDA label [for 

] and in the paper that we published are treatment-emergent adverse effects [TEAEs]. The 2 AEs to highlight that were related to revumenib are QTc prolongation and differentiation syndrome [DS]. Prolongation of the QTc interval is important because we often administer supportive medications to our patients that can also prolong the QTc interval. [Accordingly], the FDA has said in the label that you should be checking the QTc interval before starting a patient on revumenib. That QTcF interval should be less than 450 milliseconds. After you start the patient on revumenib, you should be sure their potassium and magnesium [levels] are repleted. I prefer [that the patient] has a potassium level over 4 mEq/L and magnesium level of 2 mg/dL or above. We should also check electrocardiograms weekly during the first month of treatment, and then monthly thereafter. There are a lot of details about how to handle things if the QTcF intervalis over a certain number. We can hold the drug [or] drop the dose of the drug. That’s important to pay attention to.

The second toxicity [of note] is DS, [which] is a capillary leak syndrome where patients can [experience] weight gain, edema, renal failure, pleural effusions, pericardial effusions, or pulmonary edema. The treatment for DS is steroids, [specifically] 10 mg of intravenous dexamethasone twice per day. There are instructions in the FDA label about how dexamethasone is supposed to be administered and how long it's administered for. [Notably,] the median time to the development of DS syndrome [with 

 in AUGMENT-101] was only 10 days. It seems to develop relatively rapidly, [and it is therefore] something that we should look out for during the first cycle of treatment.

In terms of other things to be aware of with [

], this drug interacts with strong CYP3A4 inhibitors, which tend to be azole antifungals such as voriconazole and posaconazole in our patient population. The dosing for revumenib is different if [a patient is] on a strong CYP3A4 inhibitor. This is all detailed in the FDA label.

 rearrangements in acute leukemias, and why is timely testing critical for initiating targeted therapies like 

 rearrangements] is different based on whether the patient has AML or ALL, and it is also based on the age of the patient. Pediatric patients under 1 year of age with AML or ALL have a very high rate of 

 rearrangements, upward of 50%. In the [remainder of the] pediatric population for both AML and ALL, the prevalence is [between] 20% to 30%. In the adult population for AML, the prevalence is [between] 5% to 10%; in ALL, it's approximately 5% to 15%.

 rearrangements] are not that rare. Now that we have an effective targeted therapy, everybody should be [testing] for it. This is generally part of the cytogenetics and fluorescence in situ hybridization panel that we send off as part of our standard bone marrow biopsies. However, it is important to get those results back relatively quickly, especially if we're sending these bone marrows to a commercial lab where we don't necessarily have control of how quickly something gets done. [The earlier we] get the results, [the faster we] can start the patient on 

 [if appropriate] and potentially get them toward a CR.

 in the acute leukemia treatment paradigm?

All drugs that work in the relapsed/refractory setting, in my opinion, should be moved into the frontline setting as quickly as possible because you don't want to wait for a patient to relapse. Once a patient relapses, it's difficult to get them back into remission. Even with 

, the median duration of CR/CRh is certainly not long enough.

 [in combination with] standard-of-care therapies in the frontline setting. There's a [phase 1 trial (NCT06313437)] combining 

 with induction chemotherapy and 7+3 [chemotherapy in 

-mutated AML]. Another phase 1/2 trial [Beat AML (NCT03013998)] is combining 

 with azacitidine [Vidaza] and venetoclax [Venclexta]. Data [from that study] have been presented at a couple of different meetings; so far, the data are actually quite good. The next step is to get [revumenib] into the up-front setting.

 for relapsed or refractory acute leukemia with a KMT2A translocation. FDA. November 15, 2024. Accessed December 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation

Issa GC, Zarka J, Sasaki K, et al. Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements. 

. 2021;11(9):162. doi:10.1038/s41408-021-00557-6

Issa GC, Aldoss I, Thirman MJ, et al. Menin inhibition with 

-rearranged relapsed or refractory acute leukemia (AUGMENT-101). 

. Published online August 9, 2024. doi:10.1200/JCO.24.00826

Eytan M. Stein, MD, discusses the significance of the FDA approval of revumenib for relapsed/refractory acute leukemia with KMT2A rearrangements. 

Revumenib Could Provide New Path to Transplant in R/R KMT2A+ Acute Leukemia

Dr Stein on the Impact of Revumenib on Survival Outcomes in KMT2A-Rearranged R/R Acute Leukemia

"This is a difficult-to-treat type of leukemia and the approval of revumenib gives these patients some hope that they'll be able to take a generally well tolerated oral therapy that can put them back into remission."

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, chief, Leukemia Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses how the FDA approval of revumenib (Revuforj) could improve survival outcomes for patients with 

-rearranged relapsed/ refractory acute leukemia.

The menin inhibitor received FDA approval

 in November 2024 for the treatment of adult and pediatric patients aged 1 year and older with relapsed/refractory acute leukemia with a 

 translocation. Data from the phase 1/2 AUGMENT-101 study (SNDX-5613-0700; NCT04065399), which demonstrated a 21.2% complete remission (CR) or complete remission with partial hematologic recovery (CRh) rate among those treated with revumenib (n = 104), supported this regulatory decision.

The approval of revumenib is particularly significant given the poor prognosis of patients with KMT2A rearrangements in relapsed/refractory acute leukemia, whether it be acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL), Stein begins. These patients, particularly those who have received multiple lines of prior therapy, face an extremely limited life expectancy. Retrospective data in AML, for instance, shows that the overall survival (OS) for patients with more than 2 lines of therapy after relapse is measured in mere months, Stein emphasizes. For patients who have undergone 3 or more lines of therapy, the median OS is approximately 2.4 months, he adds.

Revumenib's approval provides these patients with a new, generally well-tolerated oral therapy option that may offer a chance to achieve remission. Stein states. This is a hopeful development for a group of patients who have historically had few treatment options and poor outcomes, representing a significant advancement in the management of relapsed/refractory 

-positive acute leukemia, Stein concludes.