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Rearrangements in the KMT2A (KMT2Ar) and mutations in the NPM1 gene occur in approximately 9–15% and 30%, respectively, of adult patients diagnosed with acute myeloid leukemia (AML), and are associated with poor outcomes.1 Patients with KMT2Ar are often refractory to standard treatments, leading to relapse, with a median overall survival rate (OS) of 2.4 months.3 Therefore, targeting the menin-KMT2A complex is a promising new approach to treatment in this population.
During the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, preliminary results from early phase trials of menin inhibitors were presented. The AML Hub is pleased to summarize presentations from Jabbour on JNJ-75276617,2 Aldoss on revumenib monotherapy, 3 Issa on the combination of revumenib + decitabine + cedazuridine plus venetoclax, 4 Basyal on menin inhibition-induced proteomic alterations,5 and Balasubramanian and Goldberg on ziftomenib combinations in patients with AML.6,7
Initial analysis from an ongoing phase I, multicenter, open-label trial (NCT04811560) assessing the safety and efficacy of JNJ-75276617 in patients with R/R AML harboring KMT2A or NPM1 alterations.
The most common treatment-emergent adverse event (TEAE) of any-grade was differentiation syndrome (12%), followed by neutropenia (12%)
Bone marrow blast reduction was observed in 71% of patients, with over half of patients reporting ≥50% blast reduction; and was similar in patients with KMT2Ar or NPM1 mutations.
A total of 33 patients receiving 45–130 mg of JNJ-75276617 twice daily were included in the efficacy subset analysis, with response rates shown in Figure 1.
Figure 1. Response rates in patients receiving escalated doses of JNJ-75276617*
CR, complete remission; CRh, CR with incomplete hematologic recovery; CRi, CR with incomplete recovery; MLFS, morphological leukemia-free state; ORR, overall response rate; PR, partial remission.
*Data from Jabbour.2
†Patients with mutated NPM1 (n = 14) and mutated KMT2A (n = 19).
In this interim analysis from the phase II AUGMENT-101 trial (NCT04065399) of patients with R/R KMT2A-rearranged acute leukemia aged ≥30 days, patients received RP2D of oral revumenib (163 mg every 12 hours) plus a CYP3A4 inhibitor in 28-day cycles.
At the data cutoff of July 24, 2023, patients in the efficacy analysis (n = 57) had a median age of 34 years (range, 1.3–75 years), 58% of patients were female, and 86% of patients had AML. Patients were heavily pretreated, with 72% having received prior venetoclax and 46% a hematopoietic stem cell transplant (HSCT).
Figure 2. Response rates in patients receiving revumenib monotherapy*
CR, complete remission; CRc, composite CR; CRh, CR with incomplete hematologic recovery; CRi, CR with incomplete recovery; CRp, CR with incomplete platelet recovery; MLFS, morphological leukemia-free state; ORR, overall response rate; PD, progressive disease; PR, partial remission.
*Data from Aldoss.3
†n = 10
‡CRc in MRD negative patients (n = 22).
Safety analysis (n = 94) found adverse events and TEAE as shown in Figure 3.
Figure 3. Most common Grade ≥3 TEAEs occurring in ≥10% of patients*
AE, adverse event; TEAE, treatment-emergent adverse event; QTc, corrected QT interval.
*Data from Aldoss.3
The SAVE trial (NCT05360160) is a phase I/II dose escalation study in patients aged ≥12 years with R/R AML or mixed phenotype acute leukemia, rearrangements in KMT2A or NUP98 or mutated NPM1, and an Eastern Cooperative Oncology Group score of ≤2.
Figure 4. Dosing schedule*
*Data from Issa.4
Figure 5. Most common Grade ≥3 TRAEs*
TRAE, treatment-related adverse event.
*Data from Issa.3
Plasma concentrations of revumenib in the SAVE trial were found to be comparable with revumenib monotherapy (mean concentrations 8.05 vs 7.11).
At a median follow-up of 6.4 months (range, 0.4–12.3 months), revumenib led to rapid responses with an overall response rate of 100% (Table 1). Response rates in the genetic subgroups are shown in Table 1.
Table 1. Response rates in patients receiving revumenib in combination with decitabine + cedazuridine plus venetoclax*
Patients, % |
All patients |
Patients with KMT2A rearrangement |
Patients with NUP98 rearrangements |
Patients with NPM1 mutations |
---|---|---|---|---|
ORR |
100 |
100 |
100 |
100 |
CR/CRh |
44 |
60 |
33 |
0 |
CRp |
33 |
40 |
0 |
100 |
PR |
11 |
0 |
33 |
0 |
MLFS |
11 |
0 |
33 |
0 |
MRD-negativity by MFC |
67 |
80 |
33 |
100 |
In CR/CRh |
100 |
100 |
100 |
100 |
6-month RFS |
62.2 |
0 |
0 |
0 |
6-month OS |
71.1 |
— |
— |
— |
CR, complete remission; CRc, composite CR; CRh, CR with incomplete hematologic recovery; CRi, CR with incomplete recovery; CRp, CR with incomplete platelet recovery; MFC, multiparametric flow cytometry; MLFS, morphological leukemia-free state; MRD, measurable residual disease; ORR, overall response rate; OS, overall survival; PR, partial remission; RFS, relapse-free survival. |
Leukemia-focused 51-parameter CyTOF panels were used pre and posttreatment in patients treated with revumenib in a phase I trial (n = 5).
This preclinical study assessed the synergistic growth inhibition of ziftomenib in combination with selinexor, a selective inhibitor of nuclear export, on AML cells. The impact on survival was assessed using xenografted mice.
The phase I KOMET-008 trial (NCT06001788) will evaluate the safety and preliminary efficacy of ziftomenib in combination with fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin (FLAG-Ida), or low-dose cytarabine in patients with R/R NPM1-mutated or KMT2Ar AML. The combination of ziftomenib + gilteritinib will also be investigated in patients with R/R NPM1-mutated AML with an FLT3 comutation.
These presentations demonstrate the potential of menin inhibitors in the treatment of AML. Revumenib was shown to be safe and effective in both pediatric and adult patients with R/R KMT2A-rearranged AML, demonstrating durable MRD-negative remissions and high transplant rates in responders. The SAVE combination of revumenib with decitabine, cedazuridine, and venetoclax suggests a good response rate and well tolerated safety profile. Furthermore, the proteomic analysis found that revumenib can cause proteomic alterations and changes to the leukemia proteomic landscape including downregulation of MEIS1, PBX3, BCL-2, and BCL-xL.
Also, JNJ-75276617 was found to have a well tolerated safety profile and efficacy in patients with R/R KMT2A-rearranged or NPM1-mutated AML, in an ongoing dose escalation study is ongoing.
Preclinical data suggest that the simultaneous inhibition of the menin-KMT2a interaction and nuclear export may be an effective treatment for patients with MLL-r AML. The KOMET-008 trial will determine the safety and preliminary clinical activity of ziftomenib in combination with standard-of-care therapies in patients with R/R KMT2A-rearranged or NPM1-mutated AML.
Several menin inhibitors in the preliminary stages of clinical development show promising initial results. Further studies are warranted to determine the full therapeutic potential of these treatments in patients with AML.
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