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4247 Response-Stratified Genetic Risk Model for Newly-Diagnosed Acute Myeloid Leukemia Treated with Venetoclax + Hypomethylating Agent

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

Naseema Gangat, MBBS1, Azeem Elbeih, MD2*, Nour Ghosoun, MD2*, Kristen B. McCullough, PharmD3, Isla Johnson, MD4, Maymona Abdelmagid, MD5*, Aref Al-Kali, MD6, Hassan B Alkhateeb, MD1*, Kebede Begna, MD5, Michelle A Elliott, MD2, Abhishek A. Mangaonkar, MBBS2, Aasiya Matin, MD7, Antoine N. Saliba, MD1, Mehrdad Hefazi, MD1, Mark R. Litzow, MD1, William J. Hogan, MD1, Mithun V Shah, M.D., Ph.D.1, Mrinal M. Patnaik, MD, MBBS2, Animesh D. Pardanani, MBBS, PhD5, Talha Badar, MD8, Hemant S. Murthy, MD9, James M. Foran, MD10, Jeanne Palmer, MD11, Lisa Sproat, MD12, Nandita Khera, MD12, Cecilia Y. Arana Yi, MD13 and Ayalew Tefferi, MD1

1Division of Hematology, Mayo Clinic, Rochester, MN
2Mayo Clinic, Rochester, MN
3Division of Hematology, Mayo Clinic Hospital-Rochester, Rochester, MN
4Mayo School of Graduate Medical Education,, Rochester, MN
5Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
6Mayo Clinic, Rochester
7Hematology, Mayo Clinic, Rochester, MN
8Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
9Mayo Clinic, Jacksonville, FL
10Division of Hematology & Medical Oncology, Mayo Clinic, Jacksonville, FL
11Mayo Clinic - Arizona, Scottsdale, AZ
12Mayo Clinic, Phoenix, AZ
13Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ

Background

Venetoclax + hypomethylating agent (Ven-HMA) therapy results in favorable response rates (CR/CRi 66%) and overall survival (OS; median 14.7 months) in unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML; N Engl J Med 2020;383). However, there is substantial heterogeneity in individual patient outcomes based on response to treatment. The objective of the current study was to develop a genetic risk model to predict survival outcome in treatment responders and non-responders, analyzed separately, and also account for allogeneic stem cell transplant (ASCT).

Methods

Treatment-naïve AML patients receiving Ven-HMA, outside of a clinical trial, at the Mayo Clinic, USA (MN, AZ, FL) were retrospectively recruited. Molecular studies (48-gene panel) were performed by next-generation sequencing. Response was assessed according to the 2022 European LeukemiaNet (ELN) criteria (Blood 2022;140). Standard statistical analyses were performed using JMP Pro (Version 17.0.0).

Results

400 ND-AML patients (median age 73 years, 64% male, 60% de novo) received Ven-HMA. ELN cytogenetic risk included favorable 2%, intermediate 60%, or adverse 38%. Mutations involved TP53 in 26%, TET2 19%, RUNX1 19%, SRSF2 18%, ASXL1 18%, DNMT3A 15%, K/NRAS 13%, NPM1 12%, IDH2 12%, FLT3-ITD 10%, IDH1 7% and DDX41 in 4% of informative cases.

153 (38%) patients achieved CR, 94 (24%) CR with incomplete count recovery (CRi), resulting in CR/CRi in 247 (62%) patients. CR/CRi rates were higher with NPM1 (86% vs 59%), IDH2 (77% vs 60%), and DDX41 mutations (93% vs 61%) and lower with TP53 (45% vs 67%), FLT3-ITD (41% vs 64%), RUNX1 (49% vs 65%) mutations and adverse karyotype (48% vs 71%), with all retaining significance in multivariable analysis. CR/CRi rate was highest (87%) in 75 patients with one or more favorable mutations (NPM1, IDH2, DDX41) and no unfavorable mutation (TP53, FLT3-ITD, RUNX1). CR/CRi rate was lowest in 171 patients with at least one unfavorable mutation and no favorable mutation (44%; p<0.01).

After a median follow up of 10.5 months (0.5-66), 105 relapses (43% of patients in CR/CRi), 248 (62%) deaths and 65 (16%) ASCT were documented. Univariate analysis for transplant-censored OS disclosed superior survival in patients achieving CR/CRi (median 21 vs 3.6 months; HR 5.4, 95% CI 4.1-7.1). Among patients achieving CR/CRi, IDH2 mutation was associated with superior (median not reached vs 20.5 months) and male gender (median 17.6 vs 29.2 months), TP53 mutations (median 11.9 vs 24.3 months) and adverse karyotype (median 12.6 vs 29.4 months) with inferior survival; multivariable analysis resulted in HRs (95% CI) of 2.1 (1.3-3.4) for male gender, 2.1 (1.2-3.8) for adverse karyotype, and 2.5 (1.1-5.7) for absence of IDH2 mutations. Male gender did not show an association with karyotype, or TP53 mutations (p>0.1). Accordingly, an HR-weighted genetic risk model was generated with assignment of one point each to male gender, adverse karyotype, and absence of IDH2 mutation: high risk = 3 risk factors (n=38; median 9.6 months; 3-year survival 0%); intermediate risk = 2 risk factors (n=129; median 22 months; 3-year survival 38%); and low-risk = ≤1 risk factor (n=78; median not reached; 3-year survival 69%; p<0.01). In patients bridged to ASCT (n=60), post-transplant survival was inferior in the presence of ≥ 2 risk factors (n=42; median 46 months) vs. ≤1 risk factor (n=18; median not reached; p=0.1).

In patients not achieving CR/CRi, risk factors for OS included male gender (median 3.4 vs 6.1 months), adverse karyotype (median 3.3 vs 4.5 months) and TP53 mutation (median 3.1 vs 4.5 months) while those with IDH2 mutations lived longer (median 8.4 vs 3.4 months). In multivariable analysis, HRs (95% CI) were 1.9 (1.3-2.9) for male gender, 2.0 (1.4-2.9) for adverse karyotype, and 2.1 (1.1-4.3) for absence of IDH2 mutations. OS was shortest for non-responders harboring 3 risk factors (n=45; median 3 months; 1-year survival 0%) and longer for those harboring two (n=80; median 6 months, 1-year OS 15%) or ≤ 1 risk factor (n=25; median 14 months; 1-year OS 56%; p<0.01).

Conclusion

The current study describes a molecular profile for predicting response to Ven-HMA in ND-AML and also introduces a novel approach to survival prediction that considers treatment response as the starting point. In both responders and non-responders, male gender and adverse karyotype were identified as unfavorable and IDH2 mutation favorable risk factor for OS.

Disclosures: Gangat: DISC Medicine: Consultancy, Other: Advisory Board ; Agios: Other: Advisory Board. Begna: Novartis: Membership on an entity's Board of Directors or advisory committees. Mangaonkar: BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Litzow: Abbvie: Research Funding; Amgen: Research Funding, Speakers Bureau; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Sanofi: Research Funding; Beigene: Speakers Bureau; Biosight: Other: Data Safety Monitoring Committee. Patnaik: Polaris: Research Funding; Kura Oncology: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Epigenetix: Research Funding; StemLine: Research Funding; Solu therapeutics: Research Funding. Badar: Morphosys: Other: Advisory Board; Takeda: Other: advisory board ; pfizer: Other: Advisory board. Murthy: CRISPR therapeutics,: Consultancy, Membership on an entity's Board of Directors or advisory committees; Senti Bioscience: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH