A Comprehensive Analysis of FLT3 Mutation Profiles and Clinical Outcomes in Adult Patients with Acute Myeloid Leukemia: A Single Institution Experience
Authors: El-Asmar Jessica , Nurse Daniel P. , Bawwab Ameed , Abu-Farsakh Yomna , Albliwi Moath , Hanna John , Rauf Asad , Abuamsha Hasan , Batah Heya , Zabor Emily C. , Bedelu Yohana B. , Chen Mark Jinan , Nakitandwe Joy , Jain Akriti G. , Molina John C. , Balderman Sophia , Singh Abhay , Gerds Aaron T. , Mukherjee Sudipto , Advani Anjali S. , Carraway Hetty E. , Mustafa Ali Moaath K. 
Published: December 2024

Background: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy. The molecular profile of the disease at the time of diagnosis provides key information to determine treatment options and prognostic outcomes. One of the most common genetic alterations in AML is a mutation within the FMS-like tyrosine kinase 3 (FLT3) gene. There are two main mechanisms by which FLT3 mutations can occur: internal tandem duplication (ITD) or point mutations within the tyrosine kinase domain (TKD). FLT3-ITD mutations are generally associated with reduced overall survival and increased relapse rates. However, it is not well known if FLT3-TKD point mutations are associated with worse outcomes as well. We aim to explore how clinical outcomes differ among the different FLT3 mutational profiles in a large population of patients with AML.

Methods: We conducted a single institution retrospective cohort study to analyze treatment outcomes among adult patients aged 18 years and above with FLT3 mutated AML. The presence of FLT3-TKD mutations was based on Next-Generation Sequencing (NGS), while FLT3-ITD mutations were diagnosed by PCR testing or NGS. Baseline characteristics were collected for all patients, including age at diagnosis, gender, race, comorbidities, cytogenetics, performance status, blast percentage (peripheral blood and bone marrow), and peripheral blood counts at presentation. Response rates, overall survival (OS), and event-free survival (EFS) were calculated and compared among three groups: FLT3 wild type, FLT3-ITD, and FLT3-TKD. OS was calculated from date of diagnosis to date of death. EFS was calculated from the date of treatment start to date of first refractory disease, progression or death. Response was analyzed based on morphology and cytogenetics. Morphological Responses to first-line treatment were categorized as composite complete response (CCR) (complete response [CR] or complete response with incomplete count recovery [CRi]) and minimal residual disease (MRD) assessed by flow cytometry (MRD-FC) or real-time PCR. Multivariable regression was used to adjust for confounders. Kaplan-Meier method was used to estimate survival probabilities, while log-rank test was used to compare the differences.

Results: 730 patients were treated for AML between May, 2017 and September 2023 at the Cleveland Clinic Foundation in Ohio. 531 patients were tested for FLT3 mutations, among which 374 were FLT3 wild type (FLT3-WT) (70%), 127 had FLT3-ITD mutations (24%), and 30 had FLT3-TKD mutations (6%). The median age at presentation was 67, 65, and 61 years in the FLT3- WT, ITD, and TKD groups, respectively (P=0.2). Intermediate and High-risk cytogenetics per ELN 2022 were seen in 23% & 39% in FLT3-WT, 21% & 6.3% in ITD, and 27% & 10% in TKD groups, respectively (P&lt;0.05). Bone marrow blast percentages on average were higher in the FLT3-ITD group (75%) than WT (40%) and TKD groups (65%) (P&lt;0.01). Co-occurring mutational profiles will be included in the dataset.

Intensive chemotherapy +/- midostaurin and hypomethylating agents with venetoclax were given in 43% & 19% of FLT3-WT, 58% & 7.9% of FLT3-ITD and 63% & 10% of FLT3-TKD groups, respectively. The CCR rate was achieved in 52%, 54%, and 79% of FLT3-WT, ITD and TKD groups. On multivariable logistic regression, the FLT3-TKD group was more likely to achieve a CCR (odds ratio (OR): 3.12, 95%CI: 1.26-8.92) than FLT3-WT (reference) and FLT3-ITD groups (OR: 0.93, 95%CI: 0.59-1.46) (P=0.04). With a median follow-up period of 35 months (range: 1.8-90.2), the twelve-month OS probability was found to be highest among those with FLT3-TKD mutations at 63% (95%CI: 48-83), followed by FLT3-ITD mutations at 51% (95%CI: 43-60), followed by wild type at 48% (95%CI: 43-54), but not statistically different (log-rank P=0.08). The 12-month EFS was 63% (95%CI: 48-83) in FLT3-TKD, 46% (95%CI: 38-55%) in FLT3-TKD and 42% (95%CI: 37-48%) in FLT3-WT AML (log-rank P=0.03). On multivariable Cox proportional hazards regression, both EFS and OS were longer in FLT3-TKD but not statistically significant.

Conclusion: In our cohort, patients with FLT3-TKD mutated AML were shown to have improved response rates to chemotherapy and EFS compared to FLT3-ITD and FLT3-WT. Moreover, FLT3-TKD had a trend to higher OS but was not statistically significant. Further studies are needed to determine if this holds true with the use of FLT3 inhibitors upfront and in the relapsed/refractory setting.