AUTHORS
Charles Foucar, MD, Deedra Nicolet, MS2, Preem Geeta Torlapati, MD, MPH3, Onyee Chan, MD4, Alice Scott Mims, MD5, Brittany Knick Ragon, MD6, Michael Jamie Hochman, MD7, Yazan F. Madanat, MD8, Bianca Barredo, BS9, Lauren G. Banaszak, MD10, Stephanie Begley, MS11, David Sallman, MD12, Rami Komrokji, MD13, Joshua F. Zeidner, MD14, Kieran Sahasrabudhe, MD15, Michael Walker16, Krzysztof Mrózek, MD, PhD17, Justice Ameyi, M.S.18, Alexander Joseph Ambinder, MD, MPH19, Ann-Kathrin Eisfeld, MD20
AFFILIATIONS
1 University of New Mexico, Albuquerque, New Mexico, United States
2 The Ohio State University, Columbus, Ohio, United States
3 The Ohio State University, Columbus, Ohio, United States
4 Moffit Cancer Center Tampa Fl, Haines City, Florida, United States
5 The Ohio State University, Columbus, Ohio, United States
6 Atrium Health Levine Cancer Institute, Charlotte, North Carolina, United States
7 Emory Winship Cancer Institute, Atlanta, Georgia, United States
8 Ut Southwestern Medical, Dallas, Texas, United States
9 University of Wisconsin-Madison, Madison, Wisconsin, United States
10 University of Wisconsin-Madison, Madison, Wisconsin, United States
11 Atrium Health Levine Cancer Institute, Charlotte, North Carolina, United States
12 Moffit Cancer Center Tampa Fl, Haines City, Florida, United States
13 Moffit Cancer Center Tampa Fl, Haines City, Florida, United States
14 UNC Lineberger Comprehensive Cancer Center, Hillsborough, North Carolina, United States
15 University of Wisconsin-Madison, Madison, Wisconsin, United States
16 The Ohio State University, Columbus, Ohio, United States
17 The Ohio State University, Columbus, Ohio, United States
18 The Ohio State University, Columbus, Ohio, United States
19 Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, United States
20 The Ohio State University, Columbus, Ohio, United States
ABSTRACT
Background:
Patients with AML harboring FLT3 mutations (FLT3-mut) who receive less intensive therapy due to age and/or comorbidities have shorter disease-free survival (DFS) and overall survival (OS), leading to FLT3-ITD being designated as an intermediate-risk feature in the ELN 2024 risk stratification. Based on the improved outcomes demonstrated in randomized controlled trials of the addition of FLT3 inhibitors to intensive chemotherapy (IC) regimens such as 7+3, there has been much interest in combining FLT3 inhibitors with less intensive therapies to improve outcomes. One such promising combination is hypomethylating agents (HMA), venetoclax (Ven), and gilteritinib (Gilt) which has been studied in phase I/II trials in both the frontline (1L) and relapsed/refractory (R/R) setting. These studies show promising response rates, including in pts ≥ 75 years of age, suggesting tolerability of this triplet even in older pts. These results have led many providers to adopt this triplet as standard of care, but randomized controlled trial data demonstrating superiority over HMA/Ven for 1L is lacking, as are outcomes data comparing its administration in academic vs community settings.
Methods:
We analyzed the clinical and molecular features of adult FLT3-mut AML patients unfit for IC who were treated at 8 major academic US Centers (Myeloid Malignancy Association on Rapid Research Outcomes Working Group (MARROW) Consortium) and in the community setting using the Flatiron Health electronic health record-derived and de-identified database. Data were centrally reviewed and analyzed at the Bloomfield Center for Leukemia Outcomes Research, and comparative clinical, molecular, and survival analyses were done for pts who received 1L HMA/Ven/Gilt, 1L HMA/Ven, and HMA/Ven/Gilt for R/R AML.
Results:
Our analysis included 279 FLT3-mut AML patients (MARROW, n=123 and Flatiron, n=156). Of these pts, 35 received 1L HMA/Ven/Gilt, 156 received 1L HMA/Ven, and 88 were treated with HMA/Ven/Gilt for R/R AML. For patients who received 1L HMA/Ven/Gilt, median age was 73 years with 34% ≥ 75 years compared to 74 years with 45% ≥ 75 years for 1L HMA/Ven. The percentage of pts with ECOG ≤ 1 was 55% for 1L HMA/Ven and 96% for 1L HMA/Ven/Gilt (p=0.003). According to the ELN 2024, 1L HMA/Ven pts had 31% favorable-risk disease and 60% intermediate-risk disease vs. 14% and 86% respectively for pts who received 1L HMA/Ven/Gilt.
CR/CRi was 69% with both 1L regimens (p=0.49). Median DFS was 8.41 months with 1L HMA/Ven/Gilt versus 12.84 months with HMA/Ven (p=0.076), while median OS was 25.03 months versus 15.40 months, respectively (p=0.854). OS with HMA/Ven/Gilt in 1L did not differ when patients were stratified by age ≥ 75. Exploratory molecular analyses suggested longer median DFS with HMA/Ven among patients with NPM1 mutations or FLT3-TKD, although neither comparison reached statistical significance.
For pts receiving HMA/Ven/Gilt for R/R AML, the CR/CRi rate was 76% and median OS was 20.27 months. The previous 1L therapy, whether Ven-based or 7+3-based, had no effect on the response rate, DFS, or OS of patients receiving HMA/Ven/Gilt for R/R AML. Rates of allogenic stem cell transplant (alloSCT) varied among the three treatment groups. 40% of pts who received HMA/Ven/Gilt in the R/R setting proceeded to alloSCT compared to 22% of pts treated with either 1L HMA/Ven/Gilt or 1L HMA/Ven. OS did not significantly differ between patients treated in the academic vs community setting for 1L or R/R HMA/Ven/Gilt.
Conclusion:
In this first multicenter real-world comparison of HMA/Ven and HMA/Ven/Gilt across academic and community settings, frontline triplet therapy did not improve CR/CRi or DFS and demonstrated no statistically significant OS advantage over HMA/Ven. In contrast, HMA/Ven/Gilt showed substantial activity in R/R FLT3-mut AML, with high response rates, encouraging survival, and a high rate of alloSCT, irrespective of prior frontline regimen. Comparable outcomes across academic and community settings support the feasibility of broader implementation of HMA/Ven/Gilt. However, prospective randomized studies are needed to better define the optimal role of 1L HMA/Ven/Gilt.
DISCLOSURES
Charles Foucar, MD: Binaytara, BMS, Stemline, Taiho - Honoraria; Novartis, Ascentage ,Kura Oncology, Janssen - Research Funding; BMS, Stemline, Taiho - Consultancy (Includes expert testimony)