Prognostic significance of nucleophosmin mutations and FLT3 internal tandem duplication in adult patients with cytogenetically normal acute myeloid leukemia

Abstract The FLT3 is class III fms-like tyrosine kinase. FLT3 mutations are one of the most frequent genetic changes at diagnosis and have been reported to be of prognostic significance in acute myeloid leukemia. FLT3 internal tandem duplication of the juxtamembrane domain (FLT3 ITD) was analyzed by PCR of genomic DNA at diagnosis or during the follow-up in patients with acute myeloid leukemia (AML). Total 223 patients were diagnosed as AML from Mar. 1996 till Aug. 2005. Their median age was 34 years-old (range: 0–86). The number of male or female patients was 116 or 107. Their FAB classifications were M0/1/2/3/4/5/6/7/RAEB/biphenotypic in 6/23/85/20/32/21/13/16/2/5 patients, respectively. Cytogenetic data at diagnosis were available in 182 patients; good/ intermediate/poor risk in 51/107/24 patients, respectively. Among the 190 patients receiving induction therapy, 147 patients achieved hematologic remission with a remission rate of 77%. Median event-free (EFS) and overall survival were 9 (95% confidence interval: 8–12) months and 14 (95% CI: 11–14) months, respectively. The incidence of FLT3 ITD at diagnosis was 13% (29/223). FLT3 ITD was more prevalent in M0~4 subtypes and older age. Among non-M3 population (N=203), patients with FLT3 ITD had a significantly short EFS when compared with those without ITD (p=0.0454). Among the 52 relapsed patients, 9 patients had a FLT3 ITD at diagnosis. Six patients showed reappearing of ITD and 3 patients remained negative at relapse. One patient acquired new ITD at relapse among 43 relapsed patients who had not baseline ITD. Tested 100 samples of 92 patients at remission were all negative for FLT3 ITD. Among the 28 patients at induction failure, one patient showed persistent ITD, one another re-appeared ITD after relapse, and the other one newly-developed ITD. Two others showed disappearance of ITD despite of persistent disease. Leukemic clones with FLT3 ITD may be susceptible to conventional chemotherapeutic agents and have no value for minimal residual disease. Therefore, effective induction and consolidation therapy could convert the poor prognosis of AML with FLT3 ITD.

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Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia

Blood ◽

10.1182/blood-2005-08-3453 ◽

2006 ◽

Vol 107 (9) ◽

pp. 3724-3726 ◽

Cited By ~ 134

Author(s):

Derek L. Stirewalt ◽

Kenneth J. Kopecky ◽

Soheil Meshinchi ◽

Julia H. Engel ◽

Era L. Pogosova-Agadjanyan ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Tandem Duplication ◽

Prognostic Significance ◽

Juxtamembrane Domain ◽

Internal Tandem Duplication ◽

Southwest Oncology Group ◽

Flt3 Internal Tandem Duplication ◽

Tandem Duplications ◽

Acute Myeloid

FLT3 internal tandem duplications (FLT3/ITDs) in the juxtamembrane domain are found in approximately 25% of acute myeloid leukemia (AML) patients, ranging in size from 3 to hundreds of nucleotides. We examined whether the sizes of FLT3/ITDs were associated with clinical outcomes in 151 AML patients enrolled in Southwest Oncology Group studies: S9333 and S9500. FLT3/ITDs were identified in 32% of patients (median ITD size = 39 nucleotides; range, 15-153 nucleotides). The CR rates were 35%, 67%, and 52% for patients with large (≥ 40), small (< 40), and no ITDs, respectively (P = .19). Increasing ITD size was associated with decreasing OS (estimated 5-year OS: large = 13%, small = 26%, and no ITD = 21%, P = .072) and RFS (estimated 5-year RFS: large = 13%, small = 27%, and no ITD = 34%, P = .017). These studies suggest that ITD size may have prognostic significance.

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