Poster Session II: Acute myeloid leukemia - Biology - translational research
Mutations of the gene encoding Fms Related Tyrosine Kinase 3 (FLT3), both at the tyrosine kinase domain (TKD) and the juxta-membrane level (ITD), represent the most common lesions found in Acute Myeloid Leukemia (AML),identifying a subgroup of patients with mainly unfavorable prognosis.FLT3 mutations are considered an unreliable tool for measurable (previously minimal) residual disease (MRD) monitoring, due to their intraclonal heterogeneity and instability during the course of disease. Instead, multiparametric flow cytometry (MFC) may represent a reliable tool to monitor MRD in this molecular subset. In fact,through the recognition and monitoring of leukemia associated immunophenotypes,MFC is applicable in up to 90% of AML patients with a sensitivity up to 10-4.
The aim of our study was to investigate the feasibility of MRD assessment by MFC in FLT3 mutated AML. Furthermore, we investigated if MRD persistence in FLT3 mutated AML affects prognosis in terms of overall (OS) and disease-free survival (DFS), as compared with FLT3 wildtype ones.
We retrospectively analyzed a series of 39 patients with de novo AML carrying FLT3 mutations (34/39,87% ITD, 2/39, 5% TKD, 3/39, 8% ITD/TKD). We compared MRD status and clinical outcome with a matched group of FLT3 wildtype AML (n = 128). Both groups were treated according to intensive EORTC/GIMEMA protocols. MRD was measured by MFC at the post-consolidation timepoint. Patients were defined as MRD-negative, when obtaining a residual leukemic cells (RLCs) count below the threshold of 3.5x10-4 (0.035%).
Overall median age was 47 (range 17-72). The 2 cohorts were balanced in terms of age and sex distribution. In the FLT3 mutated group, 22 out of 37 (59%) cases carried a concomitant NPM1 mutation vs 32 out of 124 (26%) of FLT3 wildtype ones (p <0.001). Furthermore, FLT3 mutation was significantly associated with a WBC count >50x109/L (20/39, 51%) vs 30/128 (23%) of those FLT3 wildtype (p < 0.001). Post remission treatment allocation was different between FLT3 mutated patients as compared to. FLT3 wildtype ones; 16 out of 39 (41%) FLT3 mutated patients were submitted to allogenic stem cells transplantation (ASCT) as compared to 34 out of 128 (27%) FLT3 wildtype ones (p = 001). At the post-consolidation time-point, MRD negativity rate was significantly lower in FTL3 mutated patients (4/39, 10%) as compared to those FLT3 wildtype (40/128, 31%), (p = 0.009). In particular, 32 out of 35 (91%) FLT3 mutated patients were above the ELN recommended threshold of positivity (0.1%) and 11/35 (31%) were above 1% of RLC.Among FLT3 mutated patients, OS was significantly longer for patients obtaining MRD-negativity as compared to those who did not (67% vs. 31%, p = 0.9). As for as DFS, we observed the same difference for MRD negative patients vs. MRD positive ones (67% vs. 29%, p = 0.8). The negative impact of MRD was proportional to the amount of RLC at post-consolidation time-point (Figure 1) (p = 0.045). However, among FLT3 mutated patients, ASCT was the only post remission treatment allowing a prolonged OS to be achieved as compared to autologous SCT or standard chemotherapy (4-years OS 63% vs. 0% vs. 15%, p = 0.019, respectively).
In conclusion, MRD as measured by MFC is a biomarker of response also in FLT3 mutated patients. In these patients, ASCT delivery is associated with a satisfactory long term outcome, however a longer duration of response can be pursued by administering FLT3 inhibitors before or after transplant, in order to improve the quality of remission and prevent leukemic recurrence.