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778 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Novel Approaches to Risk Stratification and Optimization for Transplant
Hematology Disease Topics & Pathways:
Research, Clinical Research, Real-world evidence
Monday, December 9, 2024: 11:15 AM

Yomna Eissa1*, Hyeoung-Joon Kim, MD, PhD2, Joon Ho Moon, MD, PhD3*, Robert Zeiser, MD4, Francesca Biavasco4*, Christopher Lemieux, MD5, Mohamed Elemary, MD, MSc, PhD6*, Varun Mehra, FRCPATH, MRCP7*, Mili Shah7*, Ahmed Alotaibi8*, Yu Cai9*, Xianmin Song9, Jae-Sook Ahn, MD, PhD10, Sang Kyun Sohn, MD, PhD3*, Mohsen Al Zahrani11*, Muhned Alhumaid12*, Hee-Je Kim13 and Dennis Dong Hwan Kim, MD, PhD1

1Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
2Chonnam National University Hwasun Hospital, Hwasun, Korea, Republic of (South)
3Kyungpook National University Hospital, Daegu, Korea, Republic of (South)
4University of Freiburg Medical Centre, Department of Medicine I, Freiburg, Germany
5Centre intégré de cancérologie, CHU de Québec - Université Laval, Québec, QC, Canada
6Provincial Hematology and Blood and Marrow Transplant Program, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
7Dept. of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom
8King Faisal Specialist Hospital and Research, Cancer Center of Excellence, Riyadh, Saudi Arabia
9Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
10Chonnam National University Hwasun Hospital, Jeollanam-Do, Korea, Republic of (South)
11Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
12Medical City, Riyadh, Saudi Arabia
13Department of Hematology, Seoul St. Mary's Hospital, Seoul, Korea, Republic of (South)

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<0.0001), while the OS rate was 82.6% vs 54.8% (p<0.0001) at 3 years. The CIR was 15.3% vs 38.5% (p<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<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.

Disclosures: Zeiser: Incyte: Consultancy, Honoraria; Mallinkrodt: Consultancy, Honoraria; Neovii: Consultancy; Novartis: Consultancy, Honoraria; Medac: Honoraria; Sanofi: Honoraria; Ironwood Pharmaceuticals, Inc.: Consultancy. Lemieux: Astellas: Honoraria; Jazz Pharma: Honoraria; Amgen: Honoraria; Sanofi: Honoraria. Mehra: Gilead UK: Honoraria, Research Funding; Cidara: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Kim: AbbVie, AIMS Bioscience, AML-Hub, Astellas, BMS & Celgene, Boryung Pharm Co., Daiichi Sankyo, Janssen, Handok, LG Chem, Novartis, Pfizer, SL VaxiGen, VigenCell, Aston Bioscience, Ingenium, Amgen, Sanofi Genzyme, Takeda, Meiji Pharm Co. and GreenCross Phar: Consultancy; AbbVie, Astellas, BMS, Handok, Novartis, AML-Hub, Jazz Pharmaceuticals and Takeda: Honoraria, Speakers Bureau; BL&H: Research Funding; BMS & Celgene, Novartis, APLC, AbbVie, Astellas, Janssen, Handok, Pfizer, Sanofi Genzyme, AML-Hub, Daiichi Sankyo and APBMT: Membership on an entity's Board of Directors or advisory committees. Kim: Ascentage: Consultancy; Pfizer: Honoraria, Research Funding; Paladin: Honoraria, Research Funding; Novartis: Honoraria, Other: Advisory board, Research Funding.

*signifies non-member of ASH