FLT3

Prognostic impact of FLT3 ligand plasma level in acute myeloid leukemia

The fms-like tyrosine kinase 3 (FLT3) receptor is activated by binding to the fms-like tyrosine kinase 3 ligand (FLT3L), which is expressed by acute myeloid leukemia (AML) cells and is thought to enhance proliferation through an autocrine process.1 The soluble FLT3L concentration (sFLT3Lc) has been shown to correlate with the extent of bone marrow aplasia following treatment, and this could provide a potential prognostic impact in outcomes for AML patients.2

In a letter to the editor of Haematologica, the authors outlined the prospective, monocentric, non-interventional FLAM/FLAL trial (NCT02693899) which aimed to assess the impact of the sFLT3Lc kinetic profile on outcomes in intensively treated adult patients with AML following 18-month first-line therapy protocols.3 Endpoints assessed in this trial were progression-free survival (PFS) and overall survival (OS). Patients recruited to this trial (n = 63), between May 2016 and January 2018, were treated according to the standard-of-care first-line therapy, in line with multicenter trial protocols. Plasma samples were collected on days 1, 8, 15, and 22 of induction for analysis of sFLT3Lc by ELISA (n = 62; median age = 59 years, range 29–71). Prognostic value was assessed according to refractory status following induction, relapse according to morphologic, cytogenetic, molecular, or immunophenotypic characteristics.

Key findings:
  • Median follow-up time: 541 days (range, 154–787)
  • Median sFLT3Lc at day 1 (n = 62): 2 pg/ml (range, 0–234)
  • Median sFLT3Lc at day 8 (n = 62): 321 pg/ml (range, 0–7750)
  • Median sFLT3Lc at day 15 (n = 59): 2952 pg/ml (range, 0–14284)
  • Median sFLT3Lc at day 22 (n = 59): 1390 pg/ml (range, 13–16088)
  • Three sFLT3Lc kinetic profiles were identified from the analysis of plasma samples
    • Sustained increase from days 1 to 22 (group 1): 42% (n = 26)
    • Increase from days 1 to 15, then decrease at day 22 (group 2): 35% (n = 22)
    • Consistently low levels from day 1 to 22 (group 3): 23% (n = 14)
  • Two-year PFS was significantly greater for group 1: 79.1% vs 54.9% (group 2) vs 11.4% (group 3), P < 0.0001
  • Two-year OS was significantly greater for group 1: 80.4% vs 58.6% (group 2) vs 18.6% (group 3), P = 0.09

The authors concluded that the sFLT3Lc kinetic profile during induction appeared to be an early prognostic marker which could help to classify patients with AML, although these results will need to be validated in a larger cohort study.

References
  1. Zheng R. et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004 Jan 1; 103: 267–274. DOI:https://doi.org/10.1182/blood-2003-06-1969.
  2. Prat M. et al. Kinetics of plasma FLT3 ligand concentration in hematopoietic stem cell transplanted patients. Leuk Lymphoma. 2006 Jan; 47(1):77–80. DOI:https://doi.org/10.1080/10428190500175122.
  3. Peterlin P. et al. FLT3 ligand plasma levels in acute myeloid leukemia. Haematologica. 2019 Jan 10. DOI: 10.3324/haematol.2018.209460. [Epub ahead of print].
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