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4249 Comprehensive Analysis of KMT2A Alterations in Acute Myeloid Leukemia and Their Impact on Survival and Response Rates; A Single Center Experience

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Diseases, Myeloid Malignancies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Ameed Bawwab, MD1*, Daniel P. Nurse, DO2*, Jessica El-Asmar, MD, MPH3, Yomna Abu-Farsakh, MD4*, Moath Albliwi, MD2*, John Hanna, MD2, Asad Rauf2*, Heya Batah, MD2*, Hasan Abuamsha2*, Emily C. Zabor, DrPH5*, Yohana B. Bedelu5*, Mark Jinan Chen, PhD6*, Joy Nakitandwe, PhD6*, Akriti G. Jain, MD3, John C. Molina, MD, MEd3, Sophia Balderman, MD3*, Abhay Singh, MD, MPH3, Aaron T. Gerds, MD, MS3, Sudipto Mukherjee, MD, PhD, MPH3, Anjali S. Advani, MD3, Hetty E. Carraway, MD, MBA3 and Moaath K. Mustafa Ali, MD, MPH3

1Department of Internal Medicine, Cleveland Clinic, Akron, OH
2Department of Internal Medicine, Cleveland Clinic, Cleveland, OH
3Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
4Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, North Canton, OH
5Department of Quantitative Health Sciences, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
6Department of Pathology and Laboratory Medicine, Cleveland Clinic Diagnostics Institute, Cleveland, OH

Background: Acute myeloid leukemia (AML) is an aggressive form of leukemia with poor outcomes. Understanding the molecular abnormalities in AML is crucial for effective treatment and prognostication. The KMT2A (lysine methyltransferase 2A) regulates hematopoiesis, cellular development, and gene expression. KMT2A mutations including genetic rearrangements (re-KMT2A), point mutations (SNV-KMT2A), and tandem duplications (KMT2A-PTD), are found in AML and may impact disease progression and treatment response. This study examines the frequency of these alterations and their impact on survival in AML patients.

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.

*signifies non-member of ASH