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2852 Predictors of Relapse and Post-Relapse Outcomes in Patients with Newly-Diagnosed Acute Myeloid Leukemia Treated with Venetoclax + Hypomethylating Agent

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

Azeem Elbeih, MD1*, Nour Ghosoun, MD1*, Kristen B. McCullough, PharmD2, Isla Johnson, MD3, Maymona Abdelmagid, MD4*, Aref Al-Kali, MD5, Hassan B Alkhateeb, MD5*, Kebede Begna, MD4, Michelle A Elliott, MD1, Abhishek A. Mangaonkar, MBBS1, Aasiya Matin, MD6, Antoine N. Saliba, MD5, Mehrdad Hefazi, MD5, Mark R. Litzow, MD5, William J. Hogan, MD5, Mithun V Shah, M.D., Ph.D.5, Mrinal M. Patnaik, MD, MBBS1, Animesh D. Pardanani, MBBS, PhD4, Talha Badar, MD7, Hemant S. Murthy, MD8, James M. Foran, MD9, Jeanne Palmer, MD10, Lisa Sproat, MD11, Nandita Khera, MD11, Cecilia Y. Arana Yi, MD12, Ayalew Tefferi, MD5 and Naseema Gangat, MBBS5

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

Background

Venetoclax + hypomethylating agent (Ven-HMA) therapy has demonstrated improved outcomes in elderly/unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML) (N Engl J Med 2020;383). However, ~50% of patients who respond to Ven-HMA, eventually relapse (Am J Hematol 2024;99). In the current study we examined the prognostic contribution of gene mutations, karyotype, measurable residual disease (MRD) status and clinical risk factors for relapse in patients with ND-AML treated with Ven-HMA therapy.

Methods

Our study population of ND-AML was retrospectively recruited from Mayo Clinic (MN, AZ, FL), after institutional review board approval and based on documentation of complete remission with/without count recovery (CR/CRi) following Ven-HMA therapy. Relapse-free survival was determined from the time of remission to relapse or last follow-up. Survival analysis was censored for transplant. The 2022 European LeukemiaNet (ELN) criteria was used to assign cytogenetic risk and classify treatment response (Blood 2022;140). Standard statistical analyses were performed using JMP Pro (Version 17.0.0).

Results

247 ND-AML patients treated with Ven-HMA (median age 73 years, 62% male, 64% de novo) who achieved CR (n=153), or CRi (n=94) were included. MRD by multiparameter flow cytometry (sensitivity 0.01%) performed at the time of CR/CRi, was negative in 117 (70%) of 166 informative cases. ELN cytogenetic risk categories at diagnosis included favorable 2%, intermediate 69%, or adverse 29%. Mutations involved TET2 21%, SRSF2 21%, TP53 19%, ASXL1 18%, DNMT3A 18%, NPM1 17%, IDH2 15%, RUNX1 15%, K/NRAS 12%, IDH1 8%, FLT3-ITD 7%, and DDX41 in 6% of informative cases.

Relapse was documented in a total of 99 (40%) patients who achieved CR (39%) or CRi (41%) after a median remission duration of 6 months (1-31). Patients that relapsed within the first-year vs those that did not, were more likely to be males (75% vs 55%), MRD positive (44% vs 24%), and harbor TP53 mutations (23% vs 16%). Univariate analysis for RFS identified male gender (12 vs 29 months; p=0.02), secondary AML (10 vs 21 months; p<0.01), adverse karyotype (9 vs 22 months; p<0.01), TP53 mutations (6 vs 18 months, p<0.01) and MRD positive remission (13 months vs not reached; p<0.01) as risk factors for relapse; on the other hand, IDH2 mutations (not reached vs 15 months; p<0.01) were associated with a lower risk of relapse. Multivariable analysis confirmed male gender (HR 2.2), TP53 mutations (HR 3.0) and MRD positive remission (HR 1.7) as unfavorable predictors of relapse. Subsequently, in a three-tiered relapse prediction model, RFS was significantly inferior in the presence of three risk factors (male gender, TP53 mutations, MRD positive remission) (n=10, median 4 months), vs two (n=34, median 10 months) vs ≤ 1 risk factor (n=122, median 31 months) (p<0.01); 1-year cumulative incidence of relapse was 100%, 56%, and 26% in the presence of three, two and ≤ 1 risk factors, respectively.

50 of 99 (65%) patients received salvage therapy which included cladribine-cytarabine-Ven (n=19), intensive induction chemotherapy (n=9), FLT3 inhibitors (n=5), Ven-HMA-FLT3 inhibitor (n=1), IDH1/2 inhibitors (n=5), glasdegib-cytarabine (n=4), gemtuzumab (n=3), lenalidomide (n=1), or investigational therapies (n=3); in addition, Ven-HMA was resumed in 14 patients in whom treatment had been discontinued for a median of 5 months (2-12). Overall, 20 (31%) of patients achieved second CR/CRi and response rates were similar with intensive vs less intensive therapy (CR/CRi; 44% vs 29%; p=0.37).

Median follow up after relapse was 3.4 months (1-66), during which 73 (74%) deaths, and 4 (5%) ASCT were recorded. Median transplant-censored survival was 4.2 months (1-year; 22%), and inferior in patients with adverse karyotype (median 4.6 vs 3.4 months; p=0.02), and TP53 mutations (3.6 vs 4.4; p=0.11); on the other hand, male gender (3.5 vs 6.8 months; p=0.51), MRD positive remission (4.6 vs 4.2; p=0.56), and IDH2 mutations (6.7 vs 4.2; p=0.28), did not influence post-relapse survival.

Conclusions

The current study identifies male gender, TP53 mutations, and MRD status as powerful predictors of relapse and proposes a relapse prediction model for ND-AML patients receiving Ven-HMA therapy. Furthermore, relapse following Ven-HMA was associated with uniformly poor outcomes, regardless of salvage treatment strategy.

Disclosures: 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: Epigenetix: Research Funding; StemLine: Research Funding; Polaris: Research Funding; Solu therapeutics: Research Funding; Kura Oncology: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Badar: Takeda: Other: advisory board ; Morphosys: 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. Gangat: DISC Medicine: Consultancy, Other: Advisory Board ; Agios: Other: Advisory Board.

*signifies non-member of ASH