Abstract
Background:KMT2A-rearranged acute myeloid leukemia (KMT2Ar AML) is characterized by chromosomal translocation involving KMT2A gene at 11q23, resulting in fusion with variety of partner genes. It is usually associated with poor outcomes, high risk of relapses and suboptimal responses to conventional therapies. While NPM1-mutated (mt) AML is considered favorable risk, they are equally dismal in relapse refractory (RR) setting. Menin inhibitors have emerged as a promising therapeutic strategy, particularly in RR AML patients (pts) with KMT2Ar and NPM1-mt genotypes. While revumenib, a menin inhibitor approved for managing RR KMT2Ar acute leukemia, no menin inhibitor is currently approved for NPM1-mt AML. In this study, we evaluated clinical outcomes of adults with KMT2Ar AML and performed a comparative analysis of pts with RR KMT2Ar and NPM1-mt AML using data from the Mayo Clinic.
Methods: After screening 102 AML pts with reported KMT2A abnormalities, we identified 33 adults with confirmed KMT2Ar diagnosed between 2012 and 2024 for retrospective analysis. Clinical and molecular/cytogenetics data, induction type (intensive chemotherapy [IC] vs non-intensive chemotherapy [NIC]), response, transplant use, and survival outcomes were reviewed. A separate analysis was performed comparing 20 RR KMT2Ar AML pts with 20 propensity score matched RR NPM1-mt AML pts from a pool of 125 NPM1-mt RR pts.
Results: The median age was 50 years (yrs) (range [R], 19.0-75.0), and 60.6% were < 60 yrs. Most cases were de novo AML (64%), and the most frequent translocation was t(6;11)(q27;q23)/MLLT4 (27%), followed by t(10;11)(p12;q23)/MLLT10 (21%), t(9;11)(p21.3;q23.3)/MLLT3 (15%), and t(11;19)(q23;p13.1)/ELL (12%). Other KMT2A fusion partners were rare and collectively accounted for the remaining cases. The median follow-up was 57 months (mo) (R, 7.0-109.0).
The overall response rate (ORR) was 91%, and composite complete remission (CRc, , including CR, CRi, and CRh) was 73%. The CRc rates were comparable between IC and NIC (80% vs 62%, p=0.24). CRc were not significantly different by disease type (de novo [71.4%] vs secondary [sAML] [75%], p= 0.82) or KMT2A fusion partner gene (60% for t[9;11]/MLLT3 vs. 57.1% for t[10;11]/MLLT10 vs 55.6% for t[6;11]/MLLT4, p=0.069).
Seventeen (52%) pts received an allogeneic stem cell transplantation (allo-HCT). The median overall survival (mOS ) for the entire cohort was 16 mo (R, 11.0-34.0). In subset analysis, IC compared to NIC was associated with significantly longer mOS (30 vs 11 mo, p=0.014). The mOS was also superior in pts <60 vs ≥60 yrs (32 vs 8 mo, p=0.005). Similarly, de novo cases had better mOS than sAML (22.0 vs 9.5 mo, p=0.052). Among KMT2Ar subtypes, t(6;11)/MLLT4 showed the longest mOS (54 mo [R, 30.0-not reached (NR)]), while t(9;11)/MLLT3 had the shortest (11.0 mo, [R 9-NR]), but differences were not statistically significant (p=0.32). The mOS was significantly longer among allo-HCT pts (30 vs 11 mo, p=0.005).
Among 29 pts who experienced RR disease, the median relapse free survival (RFS) was 3 mo (R, 2.0-10.0). First salvage therapy yielded a CRc of 43.8% in 16 evaluable pts. When compared to a propensity matched cohort of 20 RR NPM1-mt AML pts, the CRc rates was 57.9% vs 50% in RR NPM1-mt and KMT2Ar AML (p= 0.68). The mRFS was not significantly different between RR KMT2Ar and NPM1-mt AML, (3 vs 4 mo, p=0.9). However, KMT2Ar pts had inferior mOS compared to NPM-mt AML (12 vs 65 mo, p=0.004). We further compared survival between NPM1-mt and KMT2Ar pts stratified by allo-HCT status. Among those who underwent allo-HCT, NPM1-mt pts had longer mOS (NR vs 22 mo, p=0.037). Among non-allo-HCT pts, mOS was numerically higher in NPM1-mt vs KMT2Ar (19 vs 8 mo, p=0.11).
Conclusions: This single institusion cohort of adult AML with KMT2Ar underscores the biological and clinical heterogeneity of this high-risk group. IC was associated with a survival benefit, particularly among younger and fit patients. However, the outcomes following relapse remained poor, highlighting the urgent need for improved post-remission and salvage therapies. Comparative analysis with matched RR NPM1-mt AML pts revealed similarly dismal survival outcomes. Emerging data from single-arm studies of menin inhibitors in both frontline and RR settings among pts with NPM1-mt and KMT2Ar AML are encouraging and may represent a paradigm shift in treatment.
