Clinical Impact of Change of FLT3 Mutation Status in Acute Myeloid Leukemia (AML) Patients
Mikako Warren, Rajyalakshmi Luthra, Cameron C Yin, Farhad Ravandi, L Jeffrey Medeiros, Zhuang Zuo. Baylor Collage of Medicine, Texas Children's Hospital, Houston, TX; The University of Texas M.D. Anderson Cancer Center, Houston, TX
Background: FLT3 is one of the most mutated genes in AML. Internal tandem duplications (ITD) have been associated with worse outcome. The prognostic relevance of point mutations in tyrosine kinase domain (D835) remains controversial. Changes of FLT3 mutation status during disease course have been observed, but their clinical impact is not defined. With FLT3 inhibitors now in clinical trials, accurate assessment of FLT3 mutation status in AML patients is key.
Design: Retrospective review of AML patients tested for FLT3 mutation at our institution from 2002 to 2011. Based on test results at time of diagnosis and at follow-ups, they were divided into 4 groups: negative at diagnosis /negative at follow-ups (Neg/Neg), Positive/Positive (Pos/Pos), Neg/Pos and Pos/Neg, respectively.
Results: During review period, 680 (19.1%) patients were positive for FLT3 mutations in at least one instance: 541 ITD, 139 D835, and 42 showed a change of mutation statuses over time: 36 Neg/Pos and 6 Pos/Neg. To compare outcomes, we randomly selected 57 patients for Neg/Neg group and 49 for Pos/Pos group. All 4 groups had similar age and gender ratio (P=0.971 and 0.218, respectively). Bone marrow blast counts were higher in patients with FLT3 mutations (P=0.001). Cytogenetic clonal evolution was more frequent in the Pos/Pos and Neg/Pos groups (P=0.006). The complete remission rate in the Neg/Pos (94%) and Pos/Neg (100%) groups were similar to that of the Neg/Neg group (81%), and significantly higher than that of Pos/Pos (68%; P=0.003). The 5-year survival of patients in the Neg/Pos and Pos/Neg groups were not significant different than that of patients in the Neg/Neg group (P=0.464), but significantly better than patients in the Pos/Pos group (P<0.001). However, after the detection of FLT3 mutations in the Neg/Pos group, their survival tracked the curve of that of the Pos/Pos group (P=0.761). No significant difference in survival between patients with ITD versus D835 in either scenario.
Conclusions: These results suggest that FLT3 mutations are unstable and correlate with cytogenetic evidence of clonal evolution. Once FLT3 mutated clones emerge as dominant, the clinical course of patients is adversely impacted. These observations also suggest that FLT3 mutation status in AML patients should be monitored continuously, and that FLT3 inhibitor therapy may be of value in AML patients who initially have no evidence of FLT3 mutation.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 238, Monday Morning