Prognosticating Survival Outcomes Within a Genetically Heterogeneous Population of KMT2A-Aberrant Acute Leukemia

KMT2A aberrations are frequently observed in both therapy-related and de novo acute leukemias and are often associated with a poor prognosis. However, significant heterogeneity exists among patients with KMT2A-aberrant acute leukemia. In this study, we attempt to further differentiate this heterogeneity by assessing the overall survival (OS) outcomes of 23 patients from the UMass Leukemia Registry with KMT2A-aberrant acute leukemia, stratified by leukemia type (lymphoblastic vs. myeloblastic vs. ambiguous lineage), concurrent mutations, and aberrancy type (translocation vs. other). For patients with KMT2A translocation, further stratification was performed to compare outcomes across various KMT2A translocation partners. Median age at diagnosis was 58 (IQR = 25.5 years), and median OS was 6.08 months (IQR = 28.7 months) for the entire group. No significant difference in OS was observed between KMT2A-aberrant acute myeloid leukemia (median OS 5.32 months), KMT2A-aberrant acute lymphoblastic leukemia (median OS 6.27 months), and KMT2A-aberrant acute leukemia of ambiguous lineage [(median OS 74.3 months), p = 0.77]. Additionally, no significant difference in OS was detected between patients with KMT2A translocation and other KMT2A aberrancy types such as frameshift mutation or amplification (p = 0.57). Among patients with KMT2A translocations, translocation partners included AF9 (n=5), AF4 (n=4), ENL (n=3), AF6 (n=3), ELL (n=2), AF10 (n=2), and SEPT2 (n=1). No significant difference in OS was detected based on KMT2A translocation partner (p = 0.91). Finally, the most common concurrent mutations observed were KRAS (n=6), NRAS (n=6), and TP53 (n=5). Patients with concurrent TP53 mutations had significantly decreased OS compared to those without (p = 0.0024), whereas no significant difference in OS was observed in patients with concurrent KRAS (p = 0.15) and NRAS (p = 0.62) mutations compared to those without. The above data supports that there are no significant differences in OS/prognosis of KMT2A-aberrant acute leukemia based on leukemia subtype, aberrancy type, translocation partner, or concurrent KRAS/NRAS mutation status, but co-mutation with TP53 results in significantly inferior OS. This is consistent with our prior reports from the UMass Leukemia Registry (Patel SA et al., Leuk Lymphoma 2021) (Patel SA et al., EJHaem 2023). Additional larger studies should be conducted to validate these findings and further develop menin inhibitors that might improve overall survival for this high-risk subset of patients.

Cerny:Actinium Pharmaceuticals, Bluebird Bio/2Seventy, Cellectar Sciences, Dynavax Technologies, aTyr Pharma, Gamida Cell Ltd, Novavax Inc, Ovid Therapeutics, Sorrento Therapeutics, TG Therapeutics, Vaxart, and Veru: Current holder of stock options in a privately-held company; Jazz Pharmaceuticals, Bristol Myers Squibb, MERIT CRO, Pfizer, and Amgen; ICON-AlloVir and ICON-Prolacta: Membership on an entity's Board of Directors or advisory committees. Patel:Bristol Myers Squibb: Consultancy, Honoraria.