Multicenter, Real-World Experience Study of FLT3-Inhibitor Post-Transplant Maintenance Therapy Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia with FLT3-ITD
Authors: Eissa Yomna , Kim Hyeoung-Joon , Moon Joon Ho , Zeiser Robert , Biavasco Francesca , Lemieux Christopher , Elemary Mohamed , Mehra Varun , Shah Mili , Alotaibi Ahmed , Cai Yu , Song Xianmin , Ahn Jae-Sook , Sohn Sang Kyun , Al Zahrani Mohsen , Alhumaid Muhned , Kim Hee-Je , Kim Dennis Dong Hwan 
Published: December 2024

Introduction
Patients of acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD) carry a considerably higher risk of relapse, even after allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant maintenance (PTM) using FLT3 inhibitors (FLT3i) is known to reduce the risk of relapse and to improve long-term outcomes significantly. Although there are randomized trials analyzing the outcomes of the different FLT3i PTM, real-world experience data is still lacking. Accordingly, we performed a multicenter retrospective study to analyze the survival benefit of FLT3i PTM, its tolerability and treatment duration. This is the largest real-world experience data on FLT3i PTM to date.
Patients and method
We conducted a retrospective multicenter study on 440 patients from 12 centers who received an allogeneic HCT from 2007 to 2024 for AML with FLT3-ITD. The primary endpoint was relapse-free survival (RFS). The use of FLT3i PTM was treated as a time-dependent covariate. The Mantel-Byar test (MBT), which will avoid immortal bias, was conducted to compare outcomes between those who received FLT3i PTM vs those who did not. Kaplan-Meier method was used to analyze RFS, overall survival (OS) and graft-versus-host disease-free, relapse-free survival (GRFS), while cumulative incidence of competing event function was implemented for the analysis of cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and chronic graft-versus-host disease (cGvHD). Multivariate analysis was conducted using either Cox's or Fine-gray model, appropriately.
Results
Out of 440 patients, 389 (87.7%) were in complete remission (CR) and 52 (11.8%) had relapsed/refractory disease prior to HCT. PTM with FLT3i was started in 171 (38.9%) patients either with Sorafenib (n=138, 80.7%), Gilteritinib (n=32, 18.7%) or Midostaurin (n=1). Four pts received Sorafenib PTM subsequently received Gilteritinib, while 4 pts received Gilteritinib subsequently received Sorafenib, mainly due to toxicity.
The median time to start treatment with PTM was 91 days (17-685). In most of the patients, Sorafenib was mainly started either 200mg daily (n=72) or 400mg daily (n=61), while Gilteritinib was started 80 mg daily (n=14), followed by 120mg daily (n=8) and 40mg daily (n=6). Dose modification was required in 46% of pts.
With a median follow-up duration of 17.5 months following PTM in all the patients who received PTM, 97 (56.7%) patients had discontinued FLT3i PTM with the most common cause being planned treatment completion (usually within 2 years, n=39), followed by FLT3i-related toxicity (n=32) and relapse (n=21). Out of the 171 PTM patients, 30 pts (17.5%) relapsed at a median of 17 months after starting PTM. The median duration of FLT3i PTM was around 2.2 years. The incidence of relapse was 21.8% (14.2-30.3%) at 3 years after PTM with the relapse curve plateauing after 3 years.
In univariate analysis, the RFS rate in patients on PTM was 79.8% vs 48.2%for no PTM (p&lt;0.0001), while the OS rate was 82.6% vs 54.8% (p&lt;0.0001) at 3 years. The CIR was 15.3% vs 38.5% (p&lt;0.0001), while the NRM was 4.9% vs 12.7% (p=0.005) at 3 years. However, these analyses did not take into account FLT3i PTM starts as a time-dependent covariate; we conducted a time-dependent analysis and compared PTM vs no PTM using MBT. FLT3i PTM was found to reduce the risk of death by 63% (HR 0.371 [0.243, 0.567], p&lt;0.0001) and reduced the risk of RFS by 42% (HR 0.578 [0.395, 0.847], p=0.004). There was no difference in OS (p=0.5) or RFS (p=0.453) between the Sorafenib and Gilteritinib PTM groups. The incidence of relapse post Sorafenib PTM was 13%, whereas that of post Gilteritinib PTM was 9.4%.
Multivariate analysis also confirmed the clinical benefit of FLT3i PTM for OS (HR 0.315, p=0.0005), RFS (HR 0.540, p=0.029) and GRFS (HR 0.605, p=0.010), but not for NRM or cGvHD.
Conclusion
The present study confirmed the clinical benefit of FLT3i PTM in the patients of AML with FLT3-ITD following allogeneic HCT. Following FLT3i PTM, the incidence of relapse was 21.8% at 3 years, which looked to plateau after 3 years, suggesting that FLT3i PTM can be stopped after 3 years following FLT3i PTM started. Both Sorafenib and Gilteritinib seems similar outcomes although toxicity profiles are different. Further study is warranted to identify the high-risk patient for relapse following FLT3i PTM, for which additional therapeutic intervention would be required to reduce the risk of relapse.