Prognosis of FLT3 ligand level in newly diagnosed FLT3-ITD negative Acute Myeloid Leukemia patients enrolled in the pethema QUIWI trial

Abstract Introduction FMS-like tyrosine kinase 3 (FLT3) plays a critical role in hematopoiesis. Circulating levels of its ligand, the soluble FLT3 ligand (FL), have been shown to correlate with the degree of bone marrow aplasia following cytotoxic treatments. Notably, FL can also be secreted by leukemic blasts, potentially promoting leukemic cell proliferation via autocrine signaling mechanisms, thereby potentially contributing to resistance. In this context, we aimed to investigate the impact of FL kinetic profiles during induction chemotherapy on clinical outcomes in newly diagnosed, FLT3-ITD negative acute myeloid leukemia (AML) patients enrolled in the QUIWI trial [NCT04107727]. In this trial median event-free survival (EFS) was 20.4 months and 9.9 months in the Quizartinib (Quiz) and placebo (PBO) arms, respectively (P=0.045). Median overall survival (OS) was not reached and 29.3 months in the Quiz and PBO arms, respectively (P=0.01). Methods This was a preplanned subanalysis conducted within the PETHEMA QUIWI trial, a multicenter, prospective, randomized, double-blind, placebo-controlled phase II study. The trial enrolled patients with newly diagnosed AML who received standard 3+7 induction chemotherapy (idarubicin and cytarabine), followed by quizartinib or placebo from day +8 to day +21, between September 2019 and October 2022. Plasma levels of FL (expressed in pg/mL) were measured by ELISA before starting and on day +15 of induction therapy. Based on the prior study by Peterlin et al. (2019), we defined two subgroups according to FL levels on +15: High Level (High, ≥1000 pg/mL) and Low Level (Low, <1000 pg/mL). Clinical outcomes evaluated included complete remission (CR) or CR with incomplete hematologic recovery (CRi), and measurable residual disease (MRD) after induction, EFS, OS, and duration of CR/CRi (DoR). Results A total of 111 out of 273 FLT3 -ITD negative AML patients enrolled in the QUIWI were included in this study, with a median age of 56 years (range 19–70). In total, 219 plasma samples were analyzed during induction (108 on day +1 before starting chemotherapy and 111 on day +15). Median baseline FL levels were 0.7 pg/mL (0–1116), and 1012 pg/mL (range 0–1176) on day +15. Overall Low FL on +15 was observed in 53 patients (48.2%) and High FL in 57 (51.8%). Median age was 59 years (range 25-70) in the Low FL group vs. 57 years (range 19–69) in the High FL group (p=0.19). Median bone marrow blast percentage was 42% (14–93) in Low FL vs. 44.5% (3–97) in High FL (p=0.71), and median white blood cell count was 4.23 ×10⁹/L (0.56–181.34) in Low FL and 3.1 ×10⁹/L (0.5–181.86) in High FL (p=0.37). ELN 2022 risk classification was unfavorable in 70.6% of patients with Low FL vs. 58.2% in High FL (p=0.37), MRC 2010 cytogenetic was adverse in 31.4% of patients with Low FL vs. 32.7% in High FL (p=0.99), and the diagnosis was secondary AML in 21.6% of patients with Low FL vs. 16.4% in High FL (p=0.66). The proportion of patients achieving CR/CRi after induction was higher in the High FL group (85.5% vs. 64.7%; p=0.0241), and among those patients, the MRD negativity was superior in the High FL vs. the Low FL group (65.8% vs. 33.3%; p=0.0127). The median OS was 19.8 months in the Low FL group and not reached in the High FL group (p=0.17). Patients with Low FL had a median EFS of 8.0 months and it was not reached in patients with High FL (p<0.01). Median DoR was 14.6 months in Low FL vs. not reached in High FL group (p=0.03). By treatment arm, 34/62 (54.8%) of Quiz and 21/44 (47.7%) of PBO patients showed FL ≥1000 pg/mL at day +15 (p=0.47). Among High FL patients, the 4-year OS, EFS, and DoR in Quiz vs. PBO arms were: 58.2% vs. 47.6%; p=0.29; 58.1% vs. 42.9%; p=0.60; and 68.2 vs. 74.9%; p=0.83, respectively. Among Low FL patients, the 4-year OS, EFS, and DoR in Quiz vs. PBO arms were: 48.1% vs. 39.1%; p=0.80; 33.3% vs. 21.7%; p=0.69; and 56.2 vs. 35.3%; p=0.24, respectively. Conclusion In this QUIWI trial subanalysis, plasma FL level ≥1000 pg/mL at day +15 of intensive induction chemotherapy was strongly associated with improved CR/CRi, OS, EFS and DoR. The Quiz arm showed a numerically higher proportion of patients achieving ≥1000 pg/mL FL level, and we observed a trend for prolonged DoR among Low FL patients randomized to Quiz. Larger studies are needed to elucidate the biology and prognostic impact of FL levels after chemotherapy in AML.