Background – Activating mutations of the transmembrane receptor tyrosine kinase, FLT3, occur in approximately 30% of patient with acute myeloid leukemia (AML) and predict for a shorter relapse-free and overall survival. There is limited data on loss or persistence of the mutated clones at the time of complete response (CR) and their recurrence at the time of relapse.
To evaluate patterns of loss and recurrence of FLT3 mutated clones in relation to response and relapse in patients with FLT3 mutated AML treated with idarubicin and cytarabine (IA) with or without sorafenib (S), vorinostat (V), or tipifarnib (T). Bone marrow samples at diagnosis, CR and relapse were examined for the presence of FLT3 mutated clones using reverse transcription polymerase chain reaction.
Among 361 patients with AML treated from October 2004 to March 2010 on one of the 4 induction regimens of IA, IAS, IAV, and IAT, 321 had presentation bone marrow samples tested and 72 had FLT3 mutations (including 50 with ITD and 16 D835 with 6 having both). The median age for the entire group was 53 years (range, 17–73) and for the FLT3 mutated patients 52 years (range, 17 to 73). Cytogenetics at diagnosis in FLT3 mutated patients included normal karyotype in 48 (67%) patients, chromosome 5 and 7 abnormalities in 4(6%), trisomy 8 in 4(6%), 11q abnormalities in 2 (3%), insufficient metaphases in 3(4%), and miscellaneous in 11(16%). 271 (75%) patients overall, and 64 (89%) patients with mutated FLT3 achieved CR. Among the 56 patients with presentation FLT3-ITD, 51 achieved CR. Among 13 patients with available samples at CR, none had FLT3-ITD; 8 of these patients relapsed and 5 had FLT3-ITD positive clones at relapse (2 negative and 1 not done); Among the 38 patients with no samples at CR, 17 relapsed, 8 with a FLT3-ITD clone (1 negative and 8 not done). Among the 201 patients without FLT3-ITD at diagnosis, who achieved CR, 8 patients acquired a clone with FLT3-ITD at relapse.
FLT3-ITD mutant clones are unstable at follow-up. Relapse may occur in their absence and they may occur for the first time at relapse. Therefore, FLT3-ITD cannot be used reliably for minimal residual leukemia monitoring.
Ravandi:Bayer Onyx: Honoraria, Research Funding.
Asterisk with author names denotes non-ASH members.