Setting the stage in KMT2A rearranged acute myelogenous leukemia in the era of menin inhibitors Free

Lysine methyltransferase 2A gene rearrangements (KMT2Ar) typically occur via several translocations involving the 11q23 locus. KMT2Ar acute myeloid leukemia (AML) confers a poor prognosis and is associated with therapy-related AML. The menin inhibitors represent a novel class of targeted therapy among these patients (pts). The recent AUGMENT-101 trial led to the approval of revumenib, a first-in-class drug, in relapsed/refractory KMT2Ar AML, however there is still limited data on outcomes of KMT2Ar AML. Therefore, a historical benchmark is needed to further guide drug development.

We identified pts with confirmed diagnosis of KMT2Ar AML (n=85). Patients were then stratified into two groups according to treatment intensity. We described baseline characteristics, response rates to first- and second-line therapy, and overall outcomes. Therapies were divided into low intensity treatment (LIT) and intensive treatment (IT). Low intensity treatment included hypomethylating agents and targeted treatments while intensive treatments included standard dosing chemotherapy.

The median age was 56 years (Range: 12-83). There were 47 female pts compared to 38 male pts. At the time of diagnosis, the mean blast percentage was 61.2%. The mean WBC was 43.1 × 10⁹/L and the mean platelet count was 56.0 × 10⁹/L. Fifteen pts (17.6%) were classified as treatment-related AML. The most common translocation partners were chromosomes 9 (n=22), 19 (n=17), 6 (n=15), 10 (n=11), and 17 (n=4). Twenty-five out of 73 pts (34.2%) had RAS mutations, 6/73 had FLT TKD mutations (7.7%), and 6/73 had FLT ITD (7.7%). Coexisting gene mutations in IDH1 (n=2), NPM1 (n=1), and TP53 (n=1) were less common.

First-line therapy included IT (n=69) and LIT (n=12). The mean age for pts receiving LIT was 69.3 years, while in the IT group, the mean age was 48.6 years. Ten pts (83.3%) were over 60 years old in the LIT group compared to 23 pts (33.3%) in the IT group. Among those who received LIT, 5 pts were treated with a hypomethylating agent (HMA) alone and 7 pts received an HMA in combination with venetoclax. The composite complete response (cCR) rate was 86.6% (58/67) for IT and 36.4% for LIT (4/11). None of the LIT pts without venetoclax achieved cCR, while 4/7 pts (57.1%) in the LIT group who received venetoclax did. Among the IT group, only 7 pts received venetoclax. Fifty-three out of 60 pts (88.3%) who did not receive venetoclax achieved cCR, compared to 71.4% (5/7 pts) for those who received venetoclax achieved cCR.

Thirty-four pts received allogeneic hematopoietic stem cell transplant (AHSCT) after first line treatment. The median overall survival (OS) for this cohort was 93.8 mo vs 11.5 mo for those who did not (p = <0.001). Progression-free survival (PFS) for this cohort was 82.1 mo vs 5.3 mo (p = <0.001). Only 1/12 pts (8.3%) in the LIT group underwent AHSCT while 33/69 pts (47.8%) in the IT group underwent AHSCT.

Forty-seven pts (58.0%) relapsed after first-line treatment. Among those who relapsed, 15 pts (31.9%) had received AHSCT while 32 pts (68.1%) had not. Thirty-seven pts went on to receive second-line salvage treatment. Eighteen pts received LIT while 19 pts received IT as second-line treatment. The cCR rate of the LIT group was 23.5% compared to 61.1% in the IT group. In the LIT salvage therapy group, the addition of venetoclax did not impact response rates (22.2% cCR with venetoclax vs 25% without). Patients who relapsed had overall poor PFS (4.3 mo) and median OS (5.6 mo).

AHSCT offers the best outcome for KMT2Ar AML. Intensive treatment yielded higher response rates, with more pts proceeding to AHSCT. The addition of venetoclax to LIT in first-line therapies but not in salvage therapies improved responses. Strategies to incorporate menin-inhibition treatment should focus on improving response rates in LIT, bridging to AHSCT, improving outcomes in non-transplant candidate pts, and implementing maintenance strategies to prevent relapse.