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447 Impact of Time from Diagnosis to Treatment on Outcomes of Adults with AML Treated with HMA and Venetoclax: A US-Based, Multi-Center, Real-World, Retrospective Analysis from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND)

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Frailty, Age, and Care Provisions-Impact on AML Outcomes
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Adult, Elderly, Clinical Research, Diseases, Real-world evidence, Myeloid Malignancies, Study Population, Human
Sunday, December 8, 2024: 10:00 AM

Samuel J. Yates, MD, MSc1, Julian J. Weiss, MD2*, Abigail Sneider, MD3*, Emily Geramita, MD, PhD4, Guru Subramanian Guru Murthy, MBBS5, Talha Badar, MD6, Annie Im, MD7, Chenyu Lin, MD8, Wei Cheng, PhD9*, Eric S. Winer, MD10, Yasmin Abaza, MD11, Mark R. Litzow, MD12, Ehab L. Atallah, MD5, Alok Swaroop, MD, PhD13*, Anand Ashwin Patel, MD1 and Rory M. Shallis, MD14

1Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
2Department of Internal Medicine, Duke University Medical Center, Durham, NC
3University of Chicago Pritzker School of Medicine, Chicago, IL
4UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
5Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI
6Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
7UPMC Hillman Cancer Center, Univ. of Pittsburgh Cancer Institute, Pittsburgh, PA
8Duke University Cancer Institute, Durham, NC
9Department of Biostatistics, Yale School of Public Health, New Haven, CT
10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
11Northwestern University, Chicago, IL
12Division of Hematology, Mayo Clinic, Rochester, MN
13Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL
14Department of Internal Medicine, Section of Hematology, Yale School of Medicine - Yale Cancer Center, Killingworth, CT

Introduction: Acute myeloid leukemia (AML) has been considered by many to be an oncologic emergency often leading to hospital admission for expeditious evaluation and treatment. Previous studies reported that time from diagnosis to treatment (TDT) does not impact outcomes (Sekeres, Blood, 2009), (Bertoli, Blood, 2013), (Rollig, Blood, 2020), however these analyses were restricted to intensively treated and/or non-United States (US) patients (pts). We report on a multi-center, retrospective analysis of TDT in adults with newly diagnosed AML receiving Hypomethylating agent (HMA) + venetoclax (Ven) using real-world data from the COMMAND.

Methods: Eight US academic medical centers with AML expertise performed a review of adult pts within their center treated with HMA+Ven for newly diagnosed AML. TDT was defined as days from diagnosis of AML to initiation of treatment with HMA+Ven. Cytoreduction with hydroxyurea or leukapheresis was included to control for the effects of severity of presentation on TDT. The primary outcome was impact of TDT on overall survival (OS) (defined as date of diagnosis to date of death). TDT was treated continuously for time-to-event analyses. Secondary outcomes included measurable residual disease (MRD) by flow cytometric analysis (sensitivity <0.1%), complete response (CR), complete response with incomplete count recovery (CRi), defined by European LeukemiaNet (ELN) 2022 Guidelines (Dohner, Blood, 2022), and early mortality (death within 30 and 60 days of initiation of HMA+Ven). Pre-planned subgroup analyses included those based on disease biology (FLT3 ITD, IDH1/2, TP53 mutation, ELN 2022 risk), HMA used (azacitidine vs decitabine) and age (<75 vs ≥75 years). For those analyses where TDT was significant in univariable analysis (P=0.1), multivariable analysis was conducted controlling for the following: ECOG performance status (PS), age, receipt of cytoreduction, ELN 2022 risk, and presence of individual pathogenic variants detected on broad myeloid gene next generation sequencing panels used at each institution. All analyses were conducted by a central statistician using RStudio statistical package.

Results: 488 pts were included in the analysis. Median age was 76 (interquartile range: 70-80) and the majority of pts had an ECOG PS of 0 or 1 (56%). Most pts (67.6%) had adverse risk with 9.4% and 18.6% of pts having favorable and intermediate risk disease by ELN 2022, respectfully. The most common mutations identified were TP53 (27.5%), IDH1/2 (19.3%), NPM1 (16.4%), DNMT3A (16.8%), ASXL1 (15.4%), and FLT3-ITD (13.7%). Twenty-eight percent of pts received cytoreduction prior to initiation of HMA+Ven. Azacitidine+Ven was the most common regimen utilized (53.9%). Median number of cycles of HMA+Ven was 3 (IQR: 1-6). MRD (-) CR, MRD (+) CR, and CRi was achieved in 21.5%, 10.5%, and 16.4% of pts after one cycle of HMA+Ven. Median OS for the cohort was 10.4 months (95% CI: 9.4-12.6). Median TDT for the cohort was 9 days (IQR: 5-17). In univariate Cox model, longer TDT was associated with improved OS (HR: 0.989, 95% CI: 0.981 to 0.998; p = 0.013). In multivariable analysis, longer TDT was still associated with improved OS (HR: 0.987; 95% CI: 0.973-0.999; p=0.049). TDT and presence of bZIP in-frame CEBPA mutations were the only factors associated with improved OS, while ECOG PS of 2 or 3-4, when compared to ECOG PS=0 (p=0.035 and 0.0002, respectively) and therapy-related AML (p=0.002), were associated with worse OS. Notably, ELN 2022 risk and IDH1/2 or NPM1 mutation status did not impact OS.

Discussion: In this real-world, multi-center, US-based analysis of pts with newly diagnosed AML treated with HMA+Ven we show that longer TDT is associated with improved OS even when controlling for severity of presentation, ELN 2022 risk score, ECOG PS, and age. This finding is consistent with data in pts treated with 7+3. Similar to results published in an electronic medical record-based analysis out of Germany (Baden, Haemotologica, 2024) in pts treated with lower-intensity Ven regimens, our results show that pts with newly diagnosed AML eventually treated with HMA+Ven are best served with a complete appraisal of disease biology and treatment planning before initiation of induction therapy. Given the consistent negative impact of ECOG PS and the findings of our study, future consideration for potential patient optimization strategies to improve ECOG PS prior to therapy initiation are warranted.

Disclosures: Guru Murthy: Syndax: Other: Advisory Board; Autolus: Other: Advisory board; Pfizer: Other: Advisory board; BMS: Other: Advisory Board; Amgen: Consultancy, Speakers Bureau; Gilead Sciences/Kite: Other: Advisory board, Research Funding; Schrodinger: Research Funding; Merck: Research Funding; Stemline: Speakers Bureau; Zentalis: Research Funding; LOXO/Lilly: Research Funding; Rigel: Speakers Bureau; BeiGene: Other: Advisory board, Research Funding. Badar: Morphosys: Other: Advisory Board; pfizer: Other: Advisory board; Takeda: Other: advisory board . Lin: Autolus: Consultancy; Rigel: Consultancy; ADC Therapeutics: Consultancy. 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. Atallah: Novartis Pharmaceuticals Corporation: Honoraria. Patel: AbbVie: Honoraria; Sumitomo: Research Funding; Bristol Myers Squibb: Honoraria; Pfizer: Research Funding; Sobi: Honoraria; Kronos Bio: Research Funding. Shallis: Gilead Sciences, Inc: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Steering Commitee; Rigel: Consultancy, Honoraria; Kura Oncology: Consultancy, Honoraria.

*signifies non-member of ASH