Very High Rate of Leukemic Transformation and Poor Survival in Patients with Lower Risk Myelodysplastic Syndrome (MDS) Who Dynamically Acquire FLT3 Molecular Alteration (FLT3m): Study of 290 MDS Patients with Sequential Mutation Analysis
Authors: Takahashi Koichi , Jabbour Elias J. , Wang Xuemei , Ghanem Hady , Pemmaraju Naveen , Ravandi Farhad , Cortes Jorge E. , Faderl Stefan , Kadia Tapan M. , Borthakur Gautam , Wierda William G. , Pierce Sherry A. , Estrov Zeev , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: October 2019

Abstract
Abstract 3802

Background and Aims:
Molecular alterations of FLT3, in particular internal tandem duplication (ITD) in the juxtamembrane domain or point mutation in the tyrosine kinase domain (TKD), are found in approximately 30% of acute myeloid leukemia (AML). In contrast, FLT3 molecular alteration (FLT3m) is not commonly detected in MDS patients with reported incidence of 0.6–6%. Limited data is available for its prognostic significance in MDS, especially when it is dynamically acquired during the follow up. The aims of this study were to evaluate: 1) the incidence of dynamic acquisition of FLT3m in lower risk MDS patients; 2) the association between FLT3m acquisition and other molecular/cytogenetic aberrations and 3) the prognostic impact of dynamic FLT3m acquisition on AML transformation and survival.

Methods:
We analyzed 290 patients with low and intermediate-1 (Int-1) risk MDS by IPSS (lower risk MDS), who were tested for FLT3m by semi-quantitative DNA-based PCR capillary electrophoresis assay on at least two occasions (at time of diagnosis and at least once thereafter) between 1/2000 and 1/2010.

Result:
Median age of the analyzed cohort was 64 years (range, 23–91), and 62% were female. Seventy five (26%) patients were IPSS low risk and 215 (74%) were int-1 risk. RAEB was the most frequent WHO diagnosis (N = 107, 37%), followed by RCMD (N = 78, 27%) and RA (N = 74, 26%). Sixty three percent (N = 183) of the patients had diploid cytogenetics at diagnosis. FLT3m was detected in total of 15 (5%) patients, of which 4 (1%, ITD = 3 and TKD = 1) were detected at initial diagnosis and 11 (4%, ITD = 9 and TKD = 2) were acquired during the follow up. Median time to FLT3m acquisition was 10 months (range, 1–53). Positive statistical association was observed between acquisition of FLT3m and NPM1 mutation (P = 0.004), while negative association was observed against RAS mutation (P = 0.013). Statistical association was not observed between FLT3m acquisition and other covariates that include: age, WHO classification, initial bone marrow blast, cytogenetics, cytogenetic evolution, and molecular mutations other than NPM1 and RAS. Eight (73%) patients with FLT3m acquisition had diploid cytogenetics at diagnosis while 3 had abnormal karyotype at the beginning: inv(3)(q21q26.2), del(11)(q13q23) and dup(2)(p15p23), respectively. Of those 8 patients whose initial cytogenetics were diploid, 4 acquired cytogenetic evolution (of which 3 acquired trisomy 8) concomitantly with FLT3m acquisition. Other 2 patients acquired NPM1 mutation and another patient acquired NRAS mutation in addition to FLT3m. There was only 1 patient whom we could not identify any other genetic alterations accompanied by FLT3m acquisition. After median follow-up duration of 31 months (range, 2–147), 75 [26%] patients transformed to AML in the entire cohort. Median transformation free survival (TFS) and OS of the entire cohort were 34 months (range; 1–147) and 36 months (range; 2–147), respectively. Strikingly, all 11 patients who acquired FLT3m experienced AML transformation (100%), with a median time to transformation of 11 months (range; 4–53). Acquisition of FLT3m was detected prior to transformation in 3 patients and at the time of transformation in 7 patients. One patient acquired FLT3m after the transformation. Log-rank test showed that median TFS and OS were both significantly shorter in the FLT3m acquired group than in the non-acquired group (Figure: TFS = 11 vs. 35 months; OS = 13 vs. 38 months, both P < 0.001). By fitting FLT3m acquisition and cytogenetic evolution as time-dependent covariates, Cox proportional hazard regression showed that age > 60 years (vs. ≤ 60, HR = 1.5, P = 0.008), having cytogenetic evolution (vs. no, HR = 5.3, P < 0.001), and FLT3m acquisition (vs. no, HR = 3.4, P < 0.001) independently predicted worse TFS.

Conclusion:
Approximately 4% of patients with lower risk MDS acquired FLT3 molecular alteration during their follow-up, and acquisition of such alteration was strongly associated with AML transformation (100%), with significant impact on TFS. Additionally, in 88% of the patients who acquired FLT3m and transformed to AML, other molecular and cytogenetic aberrations were accompanied, that may account for the classical “2-hit” model of AML transformation. This result supports the importance of monitoring for FLT3 mutation in lower risk MDS patients upon or even before disease progression, especially in the new era of FLT3 inhibitors.

Disclosures:
No relevant conflicts of interest to declare.