Background: 11q23/KMT2A rearrangements (11q23/KMT2A-r) are associated with a poor prognosis and a high risk of relapse when treated with intensive chemotherapy. Given its overrepresentation in pediatric and younger adult pts, little is known about pts with 11q23/KMT2A-r AML who are older, underrepresented minorities, or who have received lower intensity regimens. To close this critical knowledge gap, we set out to define real-world treatment patterns and outcomes for pts with 11q23/KMT2A-r AML treated at both academic and community sites.

Methods: For comprehensive analyses reflective of both academic centers and community practice, we performed independent and combined analyses of 11q23/KMT2A-r pts treated at centers from the US MARROW consortium (10 US academic Comprehensive Cancer Centers; n= 175 pts, 2015-2024) and the Flatiron database (n=150 pts, 2014-2024), which includes pt data derived from a nationwide network of cancer centers, including many community sites. Statistical analyses were performed in SAS v9.4.

Results: A total of 325 pts with newly-diagnosed 11q23/KMT2A-r AML were included. No significant differences in characteristics or survival outcomes were observed between pts in the two datasets and the analysis was therefore pooled. The median age was 55 years (y; range 18-84y), and 132/325 (41%) pts were older (aged ≥60y). Of note, 11% of pts self-identified as non-Hispanic Black and 11% as Hispanic. The most common 11q23/KMT2A translocation observed was t(9;11) in 147/325 (45%) pts. For pts with available molecular data the most frequent co-mutations included NRAS (24%), KRAS (22%), TP53 (12%), TET2 (12%), FLT3-TKD (9%), and FLT3-ITD (8%). Ras pathway mutations were identified in 41% of pts and myelodysplasia-related (MR) mutations in 25%. Overall, 214 pts (71%) received intensive induction chemotherapy (IC), 54 pts (17%) were treated with venetoclax/hypomethylating agent (VEN/HMA) combination, and 35 pts (11%) received HMA monotherapy. A total of 138 pts (42%) underwent allogeneic stem cell transplant (SCT).

Among all pts, the 3y disease-free survival (DFS) was 33% and the 3y overall survival (OS) was 28%. Those receiving IC had superior outcomes compared to pts receiving VEN/HMA or HMA (composite complete remission [CRc], IC: 75%, HMA/VEN: 37%, HMA: 20%; 3y DFS, IC: 34%, HMA/VEN: 18%, HMA: 0%; 3y OS, IC: 36%, HMA/VEN: 19%, HMA: 0%; P≤0.001 for all comparisons). The OS benefit for IC was sustained when restricting the analyses to pts who did not receive SCT in CR1. For pts receiving IC, the CRc rate was similar in Black pts compared to White (72% v 80%, P=0.58). However, Black pts had significantly shorter DFS and OS compared to White pts (3y DFS, 14% v 40%, P=0.006; 3y OS, 14% v 41%, P=0.01).

Next, we compared outcomes of pts harboring t(9;11) versus those with other 11q23/KMT2A translocations in the different treatment groups. While the CR rate was higher for t(9;11) pts who received IC (82% vs 67%, P<0.001), there were no significant differences in DFS or OS, even when the analysis was restricted to pts < 60y. Similarly, in additional subgroup analyses no differences in survival by treatment type could be found for 11q23/KMT2A-r pts harboring RAS pathway mutations or for pts with AML-MR. Subsequent multivariable analyses for DFS and OS showed TP53 mutations were associated with shorter DFS (P<0.001), after correcting for SCT and treatment type, with IC associating with longer DFS and OS (P<0.001).

Among older pts (≥60y), the 3y DFS rate was 22% and 3y OS was 14%. Those receiving IC had a CRc of 77%, 3y DFS of 28% and 3y OS of 30%. For pts treated with VEN/HMA, 33% achieved CRc, with 3y DFS of 12% and 3y OS of 13%. For pts treated with single agent HMA, the CRc rate was 20%, with a median OS of 2 months and no patient was alive 3y post diagnosis. Comparing outcomes for VEN/HMA v. HMA monotherapy, there was no significant difference in DFS (P=0.09) but OS was significantly longer in the VEN/HMA group (P=0.001).

Conclusions: This large, real-world study demonstrates that overall outcomes are poor in pts with 11q23/KMT2A-r AML, including those who are treated with IC and who have t(9;11) rearrangements. Black pts had worse DFS and OS compared to White pts. For older and unfit pts, response rates are low for pts treated with HMA-based regimens, including HMA/VEN, highlighting the urgent need for the ongoing investigation of combination therapies with menin inhibitors in this pt population.

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2025
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