FLT3 Mutations at Diagnosis and Relapse in Acute Myeloid Leukemia: Cytogenetic and Pathologic Correlations, Including Cuplike Blast Morphology

Abstract

Context.—Acquired mutations in the fms-like tyrosine kinase 3 gene (FLT3) adversely impact relapse risk after chemotherapy in patients with acute myeloid leukemia (AML). The FLT3 mutation status may differ at diagnosis and relapse, suggesting a potential role in chemoresistance, yet few reports have addressed the cytogenetic and pathologic correlates of FLT3 mutations in relapsed AML. Objectives.—To determine FLT3 mutations at diagnosis and relapse in a cohort of adult patients with chemoresistant AML and to correlate mutation status with multiple variables. Design.—We retrospectively determined FLT3 internal tandem duplication (FLT3/ITD) and FLT3 tyrosine kinase domain mutations in 50 diagnosis/relapse pairs. We correlated FLT3 status with karyotype, World Health Organization 2008 subtype, white blood cell count, biopsy cellularity, blast percentage, and the presence of invaginated (“cuplike”) blast nuclei. Results.—In 11 of 50 patients (22%) the FLT3 mutation status differed at relapse and diagnosis, with a trend toward gain of FLT3/ITD (n = 7) and loss of FLT3 tyrosine kinase domain (n = 5) mutations. FLT3-mutated AMLs correlated with the World Health Organization 2008 subtype, AML, not otherwise specified, hyperproliferative features at diagnosis and relapse, and cytogenetic evolution. FLT3-wild type AMLs correlated with the subtype AML with myelodysplasia-related changes and frequently had adverse presentation karyotypes. Cuplike blast morphology was associated with FLT3/ITD+ status and with high mutation levels. Four of 7 patients with relapse-only FLT3/ITD mutations exhibited cuplike blasts at relapse after being noncuplike at diagnosis. Conclusions.—In addition to well-known correlates in pretreatment specimens, FLT3 mutation status has pathologic and cytogenetic significance at relapse. A shift to cuplike blast morphology at relapse may herald emergence of a previously undetected FLT3/ITD mutation.

Involvement Value of FLT-3, c-Myc, STAT3, p27, and HOTAIR Gene Expression in Acute Myeloid Leukemia Patients: A Molecular Perspective to a Novel Leukemogenesis Mechanism

“…Grag et al indicated that the incidence of somatic mutations in FLT-3 is not enough for AML development, and other genetic factors are required to convert a myeloid progenitor into leukemic cells 18 . In another study, FLT-3 mutations were reported in relapsed AML patients and not in newly diagnosed patients 19 . In contrast, we found that among 41 newly diagnosed AML patients, 19 patients (46.34%) displayed over-expressed FLT-3.…”

Acute myeloid leukemia in elderly patients: New targets, new therapies

“…Comparative analyses of AML samples from patients at diagnosis and relapse have shown that FLT3-ITD mutations that were originally undetectable at diagnosis can become detectable later at relapse, suggesting that clones with FLT3-ITD mutations may undergo clonal expansion and become a dominant population at relapse after the selective pressure of chemotherapy. [27][28][29][30] Indeed, primary samples from relapsed AML patients demonstrated more significant sensitivity to FLT3 inhibitors than samples obtained from AML patients at diagnosis in vitro, suggesting that AML cells at relapse are more dependent on FLT3 signaling. 31 In addition, patients who had new FLT3-ITD mutation at relapse were shown to have shorter overall survival, 32 as well as significantly worse prognosis even after allogenic hematopoietic stem cell transplant (alloHSCT) than those who maintained wild-type FLT3.…”

Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia

“…However, other patterns have also been observed during the progression of the disease from diagnosis to relapse. Nearly 20% of patients with AML acquire either a newly detectable FLT3-ITD or FLT3-TKD mutation at relapse or lose the FLT3 mutation from the time of diagnosis [64].…”