Serum Flt3 ligand is biomarker of progenitor cell mass and prognosis in acute myeloid leukemia

Abstract

Fms-like tyrosine kinase 3 (Flt3) is a hematopoietic growth factor receptor expressed on lymphomyeloid progenitors and frequently, by AML blasts. Its ligand, Flt3L, has non-hematopoietic and lymphoid origins, is detectable during homeostasis and increases to high levels in states of hypoplasia due to genetic defects or treatment with cytoreductive agents. Measurement of Flt3L by ELISA reveals that Flt3 + AML, is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering CR, but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the BM. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 135 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney p < 0.0001). Day 26 Flt3L was also associated with survival: Flt3L ≤ 291pg/ml was associated with inferior event-free survival; and, Flt3L >1185pg/ml was associated with higher overall survival (p = 0.0119). Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML further illustrated the potential value of declining Flt3L to identify relapse. Together these observations suggest that measurement of Flt3L provides a non-invasive estimate of progenitor cell mass in most patients with AML, with the potential to inform clinical decisions.

Allogeneic FLT3 CAR T Cells with an Off-Switch Exhibit Potent Activity against AML and Can Be Depleted to Expedite Bone Marrow Recovery

“…The recent finding that FLT3 protein expression in Purkinje cells in human cerebellum is cytoplasmic 24 and the lack of apparent neurotoxicity observed in our studies and in non-human primates administered a FLT3/CD3 bispecific antibody 21 suggest that the off-tumor effects of FLT3 CAR T cells may be confined to the hematopoietic tissue. Although the expression level of FLT3 has been reported to be higher in AML versus normal HSPCs, 25 we did not find that HSPCs were less susceptible to FLT3 CAR T cells in in vitro assays. Thus, it is likely that FLT3 CAR T cell expansion and activity in patients responding to the therapy will be accompanied by some degree of hematopoietic toxicity.…”

“…24 FLT3 is found expressed at high density on the surface of AML blasts as well as in leukemic cells of B cell acute lymphoblastic leukemia (B-ALL) patients. 25,26 FLT3 is the most commonly mutated gene in AML patients 27,28 and is implicated in the pathogenesis and progression of the disease. Mutations involving an internal tandem duplication (ITD) in the juxtamembrane domain of FLT3 are particularly prevalent and result in ligand-independent overactive signaling that confers a survival and proliferation advantage to blast cells.…”

A new cytokine‐based dynamic stratification during induction is highly predictive of survivals in acute myeloid leukemia

“…In the latter, three FL kinetic profiles were delineated during induction: (i) sustained increase in FL concentrations between day (D) 1 and D22 (FLI group, n = 26, good‐risk); (ii) increase from D1 to D15, then decrease at D22 (FLD group, n = 22, intermediate risk); and (iii) stagnation of low levels (<1000 pg/ml, FLL group, n = 14, high risk). The impact of FL levels was confirmed independently by a retrospective analysis of the AML17 trial in the UK, showing that a single FL assay at day 26 also predicted survivals in AML patients 7 . Because serum samples from the FLAM/FLAL study have been frozen stored, we were able to conduct an ancillary study aiming at assessing the potential impact on survivals of the kinetics of other cytokines in the same cohort of AML patients.…”

FLT3 ligand in acute myeloid leukemia: a simple test with deep implications

“…Both of our studies 43,44 arrived separately at the conclusion that the evaluation of FLT3L level can provide a low cost, rapid and non-invasive assessment of chemo-sensitivity and blast clearance during intensive induction. Strikingly, these results were obtained in patients with wild type FLT3 AML (French study) as well as FLT3 mutated AML (UK study), strengthening the robust prognostic significance of this parameter.…”

“…Patients with sustained clinical responses maintained increased FLT3L levels, whilst treatment refractory patients showed persistently undetectable FLT3L concentrations, concluding that measurement of FLT3L is a non-invasive test that has the potential to inform clinical decision making in AML patients. 44…”