PB1750 ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IMPROVES SURVIVAL IN AML PATIENTS WITH HIGH FLT3‐ITD ALLELIC RATIO
Authors: Papalexandri A. , Kika F. , Varelas C. , Paleta A. , Marvaki A. , Mouratidou E. , Konstantinidou G. , Syrigou A. , Papathanasiou M. , Tsompanakou A. , Athanasiadou A. , Boussiou Z. , Touloumenidou T. , Sakellari I. , Lalayianni C. , Anagnostopoulos A. 
Published: June 2019

Background:

The prognostic significance of FLT3‐ITD mutations in patients with intermediate risk AML has been widely recognized. Until recently, FLT3‐ITD mutated (FLT3‐ITD+) patients were considered high‐risk and allogeneic hematopoetic cell transplantation (allo‐HCT) was performed whenever possible. ELN guidelines published in 2017 proposed risk stratification of FLT3‐ITD+ patients according to the allelic ratio of mutated/wild type FLT3 transcripts in combination with NPM1 mutational status.

Aims:

To retrospectively analyze the outcome of FLT3‐ITD+ AML patients, in relation to the FLT3‐ITD/FLT3 wild type allelic ratio.

Methods:

All FLT3‐ITD+ patients treated in our clinic with available data were included in the study. Patients were treated uniformly, according to our protocol; regardless of the NPM1 mutational status they were considered high risk and allo‐HCT was performed in eligible patients. FLT3‐ITD mutational status was defined by allele specific PCR (sensitivity 10‐3). Allelic ratio was calculated by PCR and Fragment analysis.

Results:

Twenty‐seven FLT3‐ITD(+)AML patients (13 females, 14 males), with a median age 51 years (range 17‐67) treated between 2002‐2018 were included in the study. Morphology revealed in the majority (9/27) myelomonocytic or monoblastic/monocytic AML. WBC at diagnosis ranged from 1,9‐200K/μL (median:40,7) and LDH was usually elevated (median 825, range 67‐2120IU/L). Cytogenetic risk was intermediate in most patients (24/27). FLT3‐ITD allelic ratio ranged from 0.07‐1.29 (median 0.67). Twenty out of 27 patients had high ratio FLT3‐ITD (>0.5). NPM1 mutation status was available in 20 cases: 12/20 were NPM1 mutated (NPM1+). We could stratify them according to ELN (2017) as of good risk: 3/20 (NPM1+/FLT3low), intermediate: 10/20 (1 NPM1‐/FLT3low, 9 NPM1+/FLT3high) and poor:7/20 (NPM1‐/FLT3high). Fourteen out of 27 patients had received allo‐HCT from a suitable donor. Median progression free survival (PFS) and overall survival (OS) were: median 430 (95%CI: 130‐729) and 603 (95%CI: 115‐1090) days respectively. FLT3‐ITD allelic ratio was not correlated to relapse (0.67 vs 0.62 in patients who relapsed vs patients who did not p, p = ns) but a higher ratio (0.72 vs 0.55, p = 0.053) was correlated to worse OS. Morphology, age or WBC at diagnosis didn’t differ among different allelic ratio. PFS and OS were significantly better in patients who underwent allo‐HCT vs those who didn’t {PFS(median): not reached vs 148d, OS(median): 1194 vs 260days p = 0,005}. When patients were stratified according to their allelic ratio (low vs high), the significant difference in PFS and OS was confirmed only for patients with FLT3‐ITD high. ELN stratification could not distinct groups with better PFS or OS, probably due to small numbers, although none of the NPM1+/FLT3low patients relapsed or died.

Summary/Conclusion:

High mutational burden of FLT3‐ITD in AML patients seems to confer worse prognosis. In patients with high ratio of FLT3‐ITD allo‐HCT improves PFS and OS. Recent ELN stratification identifies a category of patients that could benefit from intensive treatment.