Survival and Prognosis Among 301 Patients with Newly-Diagnosed Acute Myeloid Leukemia Following Venetoclax Plus Hypomethylating Agent Therapy
Authors: Karrar Omer , Iftikhar Moazah , McCullough Kristen , Johnson Isla , Abdelmagid Maymona , Al-Kali Aref , Alkhateeb Hassan , Begna Kebede , Mangaonkar Abhishek A , Saliba Antoine , Hefazi Mehrdad , Litzow Mark R. , Hogan William J. , Shah Mithun V , Patnaik Mrinal M. , Pardanani Animesh D. , Badar Talha , Murthy Hemant S. , Foran James M. , Palmer Jeanne , Sproat Lisa , Khera Nandita , Arana Yi Cecilia Y. , Tefferi Ayalew , Gangat Naseema 
Published: December 2023

Background:

Venetoclax (Ven) in combination with hypomethylating agent (HMA) is the preferred treatment for elderly/unfit patients with newly-diagnosed acute myeloid leukemia (AML). Current prognostication for AML is based on European LeukemiaNet (ELN) genetic risk stratification which has limited applicability in patients treated with Ven-HMA ( Blood, 2022). Accordingly, our primary objective was to determine predictors of treatment response and survival outcomes in treatment-naïve AML patients receiving Ven-HMA.

Methods:

Our study population was recruited from Mayo Clinic (MN, FL, AZ), after institutional review board approval and based on documentation of newly-diagnosed AML treated with Ven-HMA outside of clinical trials between November 2018 and April 2023. Cytogenetic and molecular studies were performed by conventional karyotype, and next-generation sequencing, respectively. Response was assessed according to the 2022 ELN criteria

Results:

Patient characteristics

A total of 301 newly-diagnosed AML patients (median age 73 years, 66% male, 62% de novo) received a median of 3 cycles (range 1-48) of azacitidine 75 mg/m2 days 1-7 ( n=100) or decitabine 20 mg/m2 days 1-5 ( n=201) with Ven. ELN 2022 cytogenetic risk included favorable (1%, n=4), intermediate (61%, n=184) or adverse (38%, n=113). Mutations involved TP53 in 77/301 (25%), ASXL1 in 54/279 (19%), RUNX1 in 54/296 (18%), NPM1 in 44/299 (15%), DNMT3A in 40/296 (13%), K/NRAS in 41/296 (14%), IDH1 in 20/301 (6%), IDH2 in 30/301 (10%), FLT3-ITD in 25/301 (8%) and DDX41 in 9/247 (4%) of informative cases.

Predictors of response

Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients, including CR in 36% and measurable residual disease (MRD) negative by flow cytometry in 77% of 105 informative cases that achieved CR/CRi. Median time to CR/CRi was 1.4 months. In univariate analysis, CR/CRi was more likely to occur in the presence of NPM1 mutation, (86% vs. 56%; p &lt; .01), IDH2 mutation, (80% vs. 58%; p = .02), DNMT3A mutation, (78% vs. 57%; p = .01), or DDX41 mutation, (100% vs. 58%; p &lt;.01), and in the absence of adverse karyotype, (71% vs. 42%; p &lt; .01), TP53 mutation, (67% vs. 40%; p &lt;.01), FLT3-ITD mutation, (63% vs. 36%; p = .01), or RUNX1 mutation, (64% vs. 44%; p = .01); in multivariable analysis, adverse karyotype, ( p &lt; .01), FLT3-ITD ( p &lt; .01), RUNX1 ( p &lt; .01), NPM1 ( p = .03), IDH2 ( p = .04), and DDX41, ( p = .01) mutations remained significant.

Predictors of survival

After a median follow-up of 8.5 months (range 0.5-56), 13.2 months for living patients, 174 (58%) deaths, 73 relapses (40% of those achieving CR/CRi), and 41 (14%; including 35 in CR/CRi) allogeneic hematopoietic stem cell tranplants (AHSCT) were documented. In univariate analysis of pre-treatment variables, thrombocytopenia &lt; 100 x 10 9/l, (HR 1.5, 95% CI 1.03-2.2; p = .03), adverse karyotype, (HR 2.8, 95% CI 2.1-3.8; p &lt; .01) TP53 mutation, (HR 2.5, 95% CI 1.8-3.5; p &lt; .01), or absence of IDH2 mutation, (HR 3.5, 95% CI 1.7-7.6; p &lt; .01) predicted inferior survival. Failure to achieve CR/CRi (HR 4.5, 95% CI 3.3-6.1; p &lt; .01) was also associated with inferior survival and in multivariable analysis, failure to achieve CR/CRi, (HR 3.4, 95% CI 2.5-4.8; p&lt; .01), presence of adverse karyotype, (HR 1.6, 95% CI 1.1-2.6; p = .02), TP53 mutation, (HR 1.6, 95% CI 1.002-2.4; p = .04), and absence of IDH2 mutation (HR 2.2, 95% CI 1.004-4.7; p = .04) were identified as risk factors for survival. Subsequent HR-weighted scoring resulted in three-tiered risk stratification: low (0-1 point; n= 130), intermediate (2-3 points; n= 105), and high (4-5 points; n= 66), with respective median survival (3-year rate) of 28.9 (48%), 9.6 (6%), and 3.1 (0%) months ( p &lt; .01) (Figure). AHSCT had an independent favorable impact on survival (HR 0.3, 95% CI 0.1-0.6; p &lt; .01), most apparent in low ( p =0.04), and intermediate ( p &lt;.01), as opposed to high ( p = .06) risk.

Conclusions:

In the current single institutional series of Ven-HMA treated newly-diagnosed AML, response to Ven-HMA was the foremost predictor of survival. Additional risk factors for survival included adverse karyotype, presence of TP53 and absence of IDH2 mutations. These observations allowed for a three-tiered genetics-enhanced survival model with CR/CRi as a backbone, and also confirmed survival advantage from AHSCT, regardless of risk category.