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

The integration of the menin inhibitor revumenib (Revuforj) into the relapsed/refractory setting provides patients with KMT2A-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.

On November 15, 2024, revumenib received FDA approval for the treatment of adult and pediatric patients aged 1 year and older with relapsed/refractory acute leukemia and a KMT2A translocation.1 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 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,” Stein explained in an interview with OncLive®.

In the interview, Stein expanded on the significance of the approval of revumenib for relapsed/refractory acute leukemias harboring KMT2A rearrangements; detailed toxicities of note and key safety considerations for revumenib administration; and discussed the potential integration of revumenib 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.

OncLive: What are the implications of the FDA approval of revumenib for patients with relapsed/refractory acute leukemia harboring a KMT2A translocation ?

Stein: It's important to remember that patients with KMT2A 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 KMT2A rearrangements] who have received 2 or more lines of therapy for their relapse can be measured in a few months at most.2 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 KMT2A 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 Journal of Clinical Oncology [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.3 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 revumenib?

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

What is the prevalence of KMT2A rearrangements in acute leukemias, and why is timely testing critical for initiating targeted therapies like revumenib?

The prevalence [of KMT2A 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 KMT2A 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%.

The implication is that [KMT2A 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 revumenib [if appropriate] and potentially get them toward a CR.

What are the potential future roles for revumenib 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 revumenib, the median duration of CR/CRh is certainly not long enough.

Trials are ongoing [evaluating] revumenib [in combination with] standard-of-care therapies in the frontline setting. There's a [phase 1 trial (NCT06313437)] combining revumenib with induction chemotherapy and 7+3 [chemotherapy in NPM1- and FLT3-mutated AML]. Another phase 1/2 trial [Beat AML (NCT03013998)] is combining revumenib 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.

References

1. FDA approves revumenib 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
2. Issa GC, Zarka J, Sasaki K, et al. Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements. Blood Cancer J. 2021;11(9):162. doi:10.1038/s41408-021-00557-6
3. Issa GC, Aldoss I, Thirman MJ, et al. Menin inhibition with revumenib for KMT2A-rearranged relapsed or refractory acute leukemia (AUGMENT-101). J Clin Oncol. Published online August 9, 2024. doi:10.1200/JCO.24.00826