Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Diseases, Myeloid Malignancies
Methods: We conducted a single-center retrospective cohort study to investigate the impact of KMT2A mutations on overall survival (OS), event-free survival (EFS), and clinical response rates in adult patients with AML (≥18 years) treated at the Cleveland Clinic Foundation, Ohio. Patients were categorized based on KMT2A status: KMT2A wild type (wt-KMT2A), re-KMT2A, SNV-KMT2A, and KMT2A-PTD. Mutated KMT2A (mt-KMT2A) included re-KMT2A, SNV-KMT2A and KMT2A-PTD. re-KMT2A were determined by cytogenetics, FISH, or RNA fusion next-generation sequencing (NGS) panel. SNV-KMT2A were determined using DNA NGS panel and KMT2A-PTD were determined using RNA fusion NGS panel. Baseline data included demographics, comorbidities, cytogenetics, NGS results, performance status, complete blood count, treatment lines, and responses to first-line treatment including complete clinical remission and cytogenetic response. OS was calculated from the date of diagnosis to the date of death or last follow-up, whichever came first. EFS was calculated from the date of treatment initiation to the date of first refractory disease, progression, or death from any cause. The Kaplan-Meier method was used to estimate survival probabilities, and the log-rank test assessed differences between groups. Multivariable regression was adjusted for confounders.
Results: From 5/2017 to 9/2023, 730 AML patients were treated at the Cleveland Clinic Foundation, Ohio. 353 patients were assessed for KMT2A abnormalities at baseline using cytogenetic analysis and DNA/RNA NGS. Of these, 310 patients (88%) were wt-KMT2A and 43 patients (12%) were mt-KMT2A. Among the mt-KMT2A group, 20 patients (5.7%) had rearrangement, 15 patients (3.2%) had point mutations, and 8 patients (2.3%) had PTD. The median ages were 66 and 65 years for the wt-KMTA and mt-KMT2A groups, respectively. Demographic factors such as age, gender, and race were not significantly different (p>0.05). Average bone marrow blasts were significantly higher in mutated than wt-KMT2A (64% vs 49%, p<0.05)
There was no significant difference in AML composite complete response (CCR) between mt-KMT2A (58%) and wt-KMT2A (58%) (OR=0.72, 95% CI: 0.34–1.52). Cytogenetic response to first-line therapy was also similar. The median follow-up time for survivors was 33.2 months, during which 235 patients died from any cause. On the multivariable Cox proportional hazards model, mt-KMT2A patients had a 63% higher risk of mortality compared to wt-KMT2A (HR= 1.63, 95% CI: 1.12–2.30, p=0.02). Similarly, mt-KMT2A had worse EFS than the wt-KMT2A group (HR=1.55, 95% CI: 1.06–2.26, P=0.03).
In subgroup analysis, re-KMT2A was seen in only 22 patients out of 729 patients who underwent conventional cytogenetics (3%). The 12-month OS was 50% (95%CI: 32%-78%) compared to 51% (95%CI: 48%-55%) in the non-rearranged subtypes. SNV-KMT2A was seen in 18 patients out of 395 patients who underwent DNA NGS panel (4.6%). SNV-KMT2A was not associated with a worse response rate, OS, or EFS compared to wt-KMT2A. Among the 353 patients who had RNA fusion NGS panel, KMT2A-PTD was seen in 8 patients. Their 12-month OS was 44% (95%CI: 21%- 92%).
Among mt-KMT2A AML patients, 29 patients were analyzed for allogeneic transplant using a 6-month landmark analysis. 14 patients underwent allogeneic transplant and 15 did not. The 6-month OS was 70% (95%CI: 49%-100%) for those who received the transplant and 53% (95%CI: 33%-86%) for patients who did not (P=0.3).
Conclusion: Despite KMT2A mutated AML having similar responses to first-line therapy to KMT2A wildtype AML, it was associated with worse long-term OS and EFS, likely due to late relapses. Future prognostic studies will determine the impact of the use of menin inhibitors on the response rate and long-term survival of KMT2A mutated AML.
Disclosures: Jain: Rigel: Other: Teaching and Speaking. Molina: Autolus: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gerds: Agios: Consultancy; Disc Medicine: Consultancy; PharmaEssentia: Consultancy; Rain Oncology: Consultancy; GSK: Consultancy; AbbVie: Consultancy; BMS: Consultancy. Advani: Glycomimetics: Research Funding; MJH Life: Honoraria; PER: Honoraria; American Society of Hematology: Honoraria; Kite: Consultancy, Research Funding; MD Education: Honoraria; Wolters Kluwer: Honoraria; Immunogen: Research Funding; Springer: Honoraria; Web MD: Honoraria; Incyte: Research Funding; BEAM: Other: Research support, Research Funding; OBI: Research Funding; Amgen: Research Funding; Pfizer: Other: Manuscript help, Research Funding; Macrogenics: Research Funding; Servier: Research Funding; Seattle Genetics: Research Funding; Wiley: Honoraria; Emmes: Honoraria; Kura: Research Funding; Novartis: Consultancy. Carraway: Stemline: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees. Mustafa Ali: Daiichi Sankyo: Consultancy.
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