A Strong Immune Effect by Allogeneic Stem Cell Transplantation May Improve Survival in AML Patients with a High Ratio of the FLT3-ITD Mutation to the Wt-FLT3 Allele: Results from an Analysis of 257 Patients Treated in the SAL AML-2003 Trial
Authors: Ehninger Gerhard , Bornhauser Martin , Kramer Michael , Röllig Christoph , Wandt Hannes , Hanel Mathias , Einsele Hermann , Aulitzky Walter E. , Schmitz Norbert , Berdel Wolfgang E. , Stelljes Matthias , Kienast Joachim , Thiel Eckhard , Mackensen Andreas , Platzbecker Uwe , Schaich Markus , Schetelig Johannes , Mayer Jiri , Serve Hubert , Ho Anthony D. , Thiede Christian 
Published: October 2019

Abstract
Abstract 497

Background:
The ratio of the FLT3-ITD mutation to the wt-FLT3 allele has significant prognostic importance in FLT3-ITD mutated acute myeloid leukemia (AML). Patients with a high mutant/wt ratio above 0.78 have significantly shorter overall (OS) and disease-free survival (DFS), whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations (Thiede C et al, Blood 2002).
There is still uncertainty about the role of allogeneic transplantation (allo-SCT) in the treatment of patients with FLT-ITD mutations (FLT3-ITD+). In order to prove the presence of an allogeneic effect, we compared the survival after allo-SCT in first remission in patients with a mutant rate < 0.8 with those ≥ 0.8. For comparison, the results in patient cohorts treated with chemotherapy alone were analyzed.

Patients and Methods:
Patients diagnosed with AML, aged 18–60 years, and treated in the AML-2003 trial of the SAL Study Alliance Leukemia were analyzed. According to the risk-adapted treatment strategy of the trial, cytogenetically intermediate-risk (IR) and adverse-risk (AR) patients should receive an allo SCT as consolidation treatment if an HLA-matched-sibling donor (IR) or HLA-matched related or unrelated donor (AR) was available. Patients with no available donor received high-dose cytarabine-based consolidation or autologous SCT. Survival analyses were performed using the Kaplan-Meier method including log-rank tests for significance testing.

Results:
Of 1182 patients enrolled in the AML-2003 trial between December 2003 and November 2009, 257 were FLT3-ITD+ (22%). The ratio of the FLT3-ITD mutation to the wt-FLT3 allele was < 0.8 in 182 patients (low-ratio) and ≥ 0.8 in 75 patients (high-ratio). 47 (26%) of the low-ratio group and 30 (40%) of the high-ratio group received an allogeneic transplantation.
In the cohorts having received an allogeneic transplantation, the 3-year DFS in the low- and high-ratio groups was 58% and 50%, respectively (p=0.53). The 3-year OS was 61% and 59%, respectively (p=0.47).
In the cohorts having chemotherapy as consolidation, the 3-year DFS in the low- and high-ratio groups was 36% and 10%, respectively (p<0.001). The 3-year OS was 43% and 11%, respectively (p<0.001).

Conclusions:
According to our results, allo-SCT in patients with a high allelic ratio of FLT3-ITD mutation led to an overall and event-free survival comparable with those with a low allelic ratio. In patients who received chemotherapy as consolidation and no allogeneic transplantation significant differences in DFS and OS could be shown between patients with a high vs. low ratio confirming our results obeserved in the previous AML96 study. These data point towards a strong graft versus leukemia effect after transplantation thus abrogating the negative impact of a high allelic ratio seen after conventional therapeutic appoaches.

Disclosures:
No relevant conflicts of interest to declare.