CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: October 17, 2022
Expiration: October 16, 2023
In this module, Eytan M. Stein, MD, discusses emerging data on menin inhibitors for the treatment of MLLr/mNPM1 acute leukemias.
Please note that the key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be downloaded here or by clicking any of the slide thumbnails in the module alongside the expert commentary.
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Although the definition of acute myeloid leukemia (AML) is having 20% or greater blasts in the blood or in the bone marrow, how a patient gets to 20% or greater blasts can occur in a variety of different ways. There are different gene mutations and cytogenetic abnormalities that can lead to the diagnosis of AML or, similarly, acute lymphoblastic leukemia (ALL). Among these gene mutations and cytogenetic abnormalities are either a rearrangement of the MLL gene (MLLr), which can occur both in AML and ALL, or mutations in the nucleophosmin gene (or NPM1), which occur in patients with AML.1,2 MLL rearrangements and NPM1 mutation analysis are part of the standard panel performed for patients with newly diagnosed AML and ALL.
MLL-rearranged acute leukemias are more common than one might think. They occur in 4% to 10% of patients with AML and in 10% to 15% of patients with ALL, and there is a type of ALL that occurs in infants where 80% of those cases have MLLr disease.1-5 The 5‑year overall survival (OS) rate for adults diagnosed with MLLr leukemia is unfortunately quite poor, at less than 25%.2,4
NPM1 mutations occur primarily in AML. It is the most common molecular genetic alteration and is found in approximately 30% of patients with newly diagnosed AML. The survival of patients with NPM1-mutated (mNPM1) AML is variable because the survival outcome depends on co‑occurring mutations. However, as a group, the 5‑year OS rate in patients with mNPM1 disease is about 50%.2-5
Clearly, these are 2 specific subsets of patients with acute leukemia who really would benefit from new and improved treatments. There are currently no FDA-approved targeted therapies to treat MLLr or mNPM1 acute leukemias.
Fortunately, we now understand the basic biology of how these MLLr and mNPM1 abnormalities lead to the development of leukemia. For an NPM1 mutation or MLL rearrangement to lead to the development of acute leukemia, there is a complex that needs to interact with a protein called menin. Menin binds to this MLL complex, which leads to the upregulation of leukemogenic genes such as HOX and MEIS1 and the development of acute leukemia.6
A small-molecule inhibitor, such as revumenib (SNDX-5613), can block the interaction between menin and this MLL complex. The blocking of that interaction turns off those leukemogenic genes. By turning off the leukemogenic genes, the cells or the malignant myeloblasts start to differentiate, and patients achieve a CR.6-9
Preclinical modeling of menin inhibition was investigated using a mouse model of mNPM1 AML. In this study, the mice that received a menin inhibitor had a survival of more than 1 year, whereas mice that were not given the menin inhibitor, and were instead given an inactive compound, died relatively rapidly in 50-100 days.7 This led to the development of several clinical trials investigating the use of menin inhibitors in patients with ALL and AML, particularly with MLL rearrangements and NPM1 mutations.
The AUGMENT‑101 trial is a phase I/II trial that evaluated revumenib in patients with relapsed/refractory (R/R) acute leukemias. At study initiation, the primary objectives were to determine the safety, tolerability, and recommended phase II dose and to characterize the pharmacokinetic properties of revumenib. Revumenib was administered orally twice a day in continuous dosing, with the trial having a standard 3-by-3 dose escalation design.
The trial started in patients with R/R acute leukemia; it did not restrict enrollment to patients with MLL rearrangements or NPM1 mutations. However, it became clear relatively quickly that patients without these mutations were not necessarily benefiting from revumenib. After the first 8 patients who did not have MLL rearrangements or NPM1 mutations were enrolled, the trial was amended to restrict enrollment only to patients with MLLr and mNPM1 acute leukemias, as that was the group of patients hypothesized to benefit from this targeted drug.9
Revumenib has an interaction with CYP3A4 inhibitors; therefore, there were 2 parallel dose-escalation cohorts, one for patients not on strong CYP3A4 inhibitors and one for patients who were receiving concomitant strong CYP3A4 inhibitors.9
The median age of the patients treated in this study was 47 years. Of note, the trial enrolled patients 30 days of age or older; it includes both pediatric patients and adult patients. Among the enrolled patients, 83% had AML, 15% had ALL, and 2% of patients had mixed-phenotype acute leukemia.
This is a very poor–risk patient population, as is evident from the median number of 4 prior therapies and the 42% of patients who had relapsed after prior allogeneic stem cell transplant.9 Patients who relapse after a transplant are incredibly difficult to get back into remission.
Revumenib is well tolerated. The most common adverse event thought to be related to the study drug is the prolongation of QTc. Grade ≥3 QTc prolongation was noted in 12% of patients, but patients were asymptomatic. QTc prolongation of any grade was noted to be present in 49% of patients on the study.
Any time that a patient is receiving a medication that can cause myeloid differentiation, one worries about differentiation syndrome. A total of 14% of the patients had a differentiation syndrome, although all cases were grade 1/2. There was no differentiation syndrome that was grade ≥3 in severity.9
The responses to this drug are truly remarkable in my opinion. The ORR in the 51 patients of the efficacy-evaluable population—the patients with MLL rearrangements or NPM1 mutations—is 55%, whereas the rate of CR and CRh is 24%.
Potentially the most impressive thing about this study is the MRD negativity rate in patients who achieved a CR or a CRh. A total of 92% of those patients were MRD negative. We do not typically see this robust degree of MRD negativity with small-molecule inhibitors in patients with AML.
Similarly, if you look at the MLL-rearranged patient population, the ORR is 61% with a CR/CRh rate of 24%.9
Correlative studies were performed for this trial showing that morphologically, the mechanism of action is myeloid cell differentiation. Looking at bulk populations of gene expression profiles by RNA sequencing, it is evident that leukemogenic genes (eg, MEIS1, HOXA9) are downregulated when patients are given a menin inhibitor, whereas genes that are associated with myeloid differentiation are upregulated.9
Looking at the duration of patients on therapy, it is evident there are some patients who are able to remain on therapy for close to 1 year. The median time to response for a CR or a CRh was 2 months. 9 of the 51 patients went on to receive an allogeneic stem cell transplant.9
The median duration of response has not yet been reached. These early results show that 6 of 12 patients who achieved a CR or CRh have a duration of response that is greater than 6 months.9
There are some new trials with revumenib. There is now a study of azacitidine/venetoclax in combination with revumenib for older patients with newly diagnosed MLLr or mNPM1 AML (NCT03013998). AUGMENT-102 is also ongoing, which is a study of revumenib in combination with chemotherapy in R/R MLLr or mNPM1 AML (NCT05326516). We are looking forward to seeing data from these studies at future meetings.
The only other menin inhibitor for which clinical data have been presented is a compound called ziftomenib (KO-539), which is in an ongoing phase I/II study of patients with R/R AML (NCT04067336). Oral ziftomenib was administered once daily in a continuous fashion. Data presented at the 2020 Annual Society of Hematology meeting showed clinical activity in 6 out of 8 evaluable patients. Interestingly, there is a patient in this trial who achieved a complete remission, albeit MRD positive, who had neither an NPM1 mutation nor an MLL rearrangement.10 This observation raises the question of whether one could expand the use of menin inhibitors outside of the patient population where these inhibitors are expected to be most efficacious.
No doses were discontinued due to treatment-related adverse events with ziftomenib. It should also be noted that there were no electrocardiogram (ECG) changes reported with ziftomenib, and there does not appear to be an interaction with CYP3A4 inhibitors.10 The recommended phase II dose for ziftomenib is hoped to be identified in the near future.
There are several other menin inhibitors currently under development in phase I/II trials for patients with R/R acute leukemias: DS-1594b, JNJ-75276617, DSP-5336, and BMF-219. DPS-5336 and BMF-219 are currently being studied as monotherapy (NCT04988555, NCT05153330), and DS-1594b is being studied as monotherapy and in combination with other chemotherapeutic agents (NCT04752163). JNJ-75276617 is being investigated both as monotherapy and in combination with azacitidine/venetoclax (NCT04811560, NCT05453903).
Menin inhibition in combination with targeted therapies is also appealing. In mice that harbor MLLr FLT3-positive AML, preclinical data have shown potential synergy when a menin inhibitor is combined with a FLT3 inhibitor. Concurrent administration was noted to decrease leukemia cell proliferation and prolong OS.11
As I mentioned previously, analyses of MLL rearrangements and NPM1 s are performed at the time of diagnosis; oncologists know at the beginning whether these are present. These particular abnormalities do not tend to disappear when a patient relapses. In my practice, I actually receive a list of patients with NPM1 mutations and MLL rearrangements. I have that information ready, and if they are going to need a trial during later lines of therapy, I can introduce the trial to them.
In conclusion, the data we know for revumenib indicate that it is well tolerated and has a favorable adverse event profile. It showed very high rates of response, with an ORR of 55% and a rate of MRD negativity of 92% in those patients who achieved a CR or a CRh. We are waiting for more data and more mature data presented for the menin inhibitors, hopefully soon.
I think that we are going to be hearing a lot about menin inhibitors over the next 1‑2 years. I anticipate that it is likely that these drugs will be approved for some subset of patients with AML in the future. It is exciting that we now have another area of leukemia, another subset of patients who can be given a targeted therapy that appears to have promising efficacy along with a good safety profile.
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