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
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".