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Molica, M.; Perrone, S.; Rossi, M. Gilteritinib. Encyclopedia. Available online: (accessed on 18 June 2024).
Molica M, Perrone S, Rossi M. Gilteritinib. Encyclopedia. Available at: Accessed June 18, 2024.
Molica, Matteo, Salvatore Perrone, Marco Rossi. "Gilteritinib" Encyclopedia, (accessed June 18, 2024).
Molica, M., Perrone, S., & Rossi, M. (2023, June 05). Gilteritinib. In Encyclopedia.
Molica, Matteo, et al. "Gilteritinib." Encyclopedia. Web. 05 June, 2023.

Gilteritinib is a next-generation tyrosine kinase inhibitor (TKI) primarily targeting FLT3FLT3 and AXL (an onco-genic tyrosine kinase) receptors. 

resistant/relapsed acute myeloid leukemia tyrosine kinase inhibitors gilteritinib miRNAs HSCT

1. Pharmacodynamics and Pharmacokinetics of Gilteritinib

Median maximum concentration is reached after 2–6 h following single and repeat dosing of oral gilteritinib (rapid absorption with or without food); mean elimination half-life was 113 h. Elimination was primarily via feces. Gilteritinib is primarily metabolized via cytochrome CYP3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) can significantly interfere with its pharmacokinetic profile [1]. Compared with first-generation multitargeted TKIs, it is more selective to FLT3FLT3 and has greater potency. It blocks FLT3FLT3 receptors’ ATP-binding site competitively, thus inhibiting receptor signaling and halting cell cycle [2]. Cellular experiments have shown powerful inhibitory effects on FLT3FLT3 mutations (FLT3FLT3–ITD and FLT3FLT3-D835Y point mutations in particular) [3]. Since both FLT3FLT3–ITD and FLT3FLT3–TKD mutations promote constitutive FLT3FLT3 kinase activity, sustaining leukemic cell proliferation and survival, gilteritinib-mediated inhibitory effects have the potential to lessen the leukemia burden of AML patients (Figure 1). It is classified as a type I inhibitor, generally unaffected by mutations in the activation loop (e.g., at D835) [4]. Moreover, gilteritinib promotes apoptosis in FLT3FLT3–ITD mutations carrying tumor cells in vitro [5]. In xenografted mice models, oral administration of gilteritinib lowered phosphorylated FLT3FLT3 levels by 40% after 1 h [3], while a single dosage was sufficient to reduce the phosphorylation of STAT-5, a known downstream FLT3FLT3 target [3]. Following successive 120 mg doses of gilteritinib in patients with R/R-AML, approximately 90% of FLT3FLT3 phosphorylation was decreased, with inhibition starting to take place 24 h after the first dosage [5]. When oral gilteritinib (1–10 mg/kg) was given to mice once every day for 28 days, tumor development was significantly suppressed by 63–100% (p = 0.05) [3]. Although gilteritinib did not influence the in vitro reduction in tumor growth or induction of apoptosis, stimulation of the FLT3 ligand can raise the chance of resistance to other FLT3 inhibitors [6]. Given that AXL activation is a known resistance mechanism to FLT3 inhibitors and that AXL inhibition can slow the growth of FLT3–ITD AML tumors, gilteritinib additional activity against AXL may also be advantageous [7]. In comparison with other less specific TKIs, gilteritinib may present a lower clinical risk of side events, such as myelosuppression [3]. Inhibition of c-KIT (an oncogene encoding KIT, a platelet-derived growth factor receptor essential for hematopoiesis) is expected to provoke severe myelosuppressive effects because FLT3 and KIT structures are remarkably similar [1]. Thus, the risk of myelosuppression with gilteritinib is anticipated to be lower than with other TKIs because it has no impact on c-KIT [1]. Based on in vitro findings, CYP3A4 primarily metabolizes gilteritinib [1]. The main metabolites identified in animal investigations are M17, M16, and M10 (all accounting for less than 10% of the parent exposure); it is unknown if these metabolites have any effect on FLT3 or AXL receptors [5]. Since gilteritinib is a P-glycoprotein (P-gp) substrate, a multidrug transporter that actively pumps substances out of the cell and away from their target regions [8], it might exert an inhibitory effect on BCRP, P-gp, and OCT1 in the small intestine as well as the liver [5]. In vivo, gilteritinib neither induces nor inhibits CYP3A4 or MATE1. Since gilteritinib may decrease the effectiveness of 5-HT2B or sigma nonspecific receptor targeting medications in vitro (such as escitalopram), it should only be used in rare conditions together with these medications [5]. Reduced gilteritinib plasma concentrations are caused by coadministration with a P-gp and potent CYP3A inducer, hence this should be avoided [5]. Conversely, gilteritinib exposure is increased when it is administered concurrently with a potent CYP3A and/or P-gp inhibitor [1]. For instance, coadministration of a single 10 mg dose of gilteritinib with 200 mg of itraconazole per day for 28 days raised Cmax and AUC in healthy individuals by 20% and 120%, respectively [5]. A concurrent strong CYP3A and/or P-gp inhibitor increased exposure in individuals with R/R-AML by about 1.5 times [5].
Figure 1. Schematic representation of FLT3 inhibitors’ mechanism of action: The type I family of FLT3 inhibitors (midostaurin, gilteritinib, and crenolanib) is able to bind the FLT3 receptor both in the active and inactive conformation, inhibiting FLT3–ITD and TKD mutations. Contrarywise, the type II family of FLT3 inhibitors (sorafenib and quizartinib) is able to bind the FLT3 receptor in the inactive conformation, acting only on FLT3–ITD. Overall, FLT3 inhibitors severely compromise leukemogenic activity of FLT3 (i.e., cellular proliferation, apoptosis inhibition, and impaired differentiation). Blue triangle: FLT3 ligands. Brown circles: extracellular membrane. Green arrows: FLT3-mediated leukemogenic activity in the absence of FLT3 inhibitors; red arrows: impairment of FLT3-mediated leukemogenic activity in the presence of FLT3 inhibitors. Abbreviations: FLT3, FMS-like tyrosine kinase; TKD, tyrosine kinase domain; ED, extramembrane domain; TMD, transmembrane domain; JMD, juxtamembrane domain.

2. Combination Regimens Including Gilteritinib in R/R and De Novo Acute Myeloid Leukemia 

2.1. Gilteritinib Plus Azacitidine in FMS-Related Tyrosine Kinase 3-Mutated Acute Myeloid Leukemia 

Wang et al. [9] proposed a randomized phase 3 trial aimed to assess the efficacy and safety of gilteritinib plus azacitidine vs. azacitidine in newly diagnosed FLT3-mutated AML considered not eligible for intensive chemotherapy. Patients were randomized (2:1) to be treated with gilteritinib (120 mg/day orally) and azacitidine at standard dosage or azacitidine alone on a 28-day cycle. In all, 123 patients were enrolled, 74 included in the gilteritinib–azacitidine arm (median age, 78 years) and 49 in the azacitidine arm (median age 76 years); among them, 47.3% and 32.7% had an ECOG performance status (PS) of 2 in the two arms, respectively.
Authors found no significant difference in OS between the two arms; the median OS was 9.82 months and 8.87 months, respectively (HR 0.916; 95% CI, 0.529–1.585; p = 0.753). The median EFS was 0.03 months in both treatment arms; the CRc rate was significantly higher in the gilteritinib–azacitidine arm than in the azacitidine arm (58.1% and 26.5%, respectively; p < 0.001). Furthermore, authors observed a numeric improvement in OS with gilteritinib–azacitidine in some patient subgroups, but statistical significance was not reached. In the subgroup of patients stratified as having an ECOG PS of 0 to 1, the median OS was 13.17 months and 11.89 months, respectively (HR, 0.811; 95% CI, 0.409–1.608; p = 0.549); among patients with an FLT3–ITD allelic ratio of 0.5 or higher, the median OS was 10.68 months and 4.34 months, respectively (HR, 0.580; 95% CI, 0.285–1.182; p = 0.134). AE rates were similar between the arms. AEs of any grade occurred in 100% of patients in the gilteritinib–azacitidine arm and 95.7% of those in the azacitidine arm. The rate of grade 3 or higher AEs was 95.9% and 89.4%, respectively [10]. According to these data, this combination approach did not improve survival outcomes in patients, with newly diagnosed FLT3-mutated AML unfit for intensive treatment. Therefore, the trial was closed based on the protocol-specified boundary for futility and recommendations from the independent data monitoring committee.

2.2. Gilteritinib Plus Venetoclax in R/R Acute Myeloid Leukemia

Venetoclax has been approved as a standard treatment in combination with low-dose cytarabine or hypomethylating agents for newly diagnosed AML ineligible for intensive chemotherapy [11][12]. Single-agent venetoclax showed limited activity in R/R AML [13]; however, in vitro reports demonstrated synergistic activity between venetoclax and FLT3 inhibitors in preclinical models [14][15].
In an American, multicenter study, 61 patients with R/R AML, including 56 with FLT3-mutated disease, were enrolled to receive a combination regimen based on venetoclax and gilteritinib; 15 patients were enrolled in the dose-escalation phase and 46 were enrolled in the dose-expansion phase. The trial provided 400 mg of venetoclax once daily and gilteritinib at 80 mg or 120 mg once daily during dose escalation, with the recommended phase II dose being venetoclax at 400 mg and gilteritinib at 120 mg. Among the 56 patients with FLT3-mutated disease treated at any dose, after a median follow-up of 17.5 months, the modified composite CR (consisting of complete response, complete response with incomplete blood count recovery, complete response with incomplete platelet recovery, and morphologic leukemia-free state) rate was 75% (the CR rate was 18%). The median time to response and median remission duration was 0.9 months and 4.9 months, respectively, with a median OS of 10.0 months. Modified composite CR was observed in 14 (67%, CR in 29%) of 21 patients with no prior FLT3 TKI exposure and in 28 (80%, CR in 11%) of 35 patients with prior TKI exposure. The median OS was 10.6 months and 9.6 months, respectively. Grade 3 or 4 AEs occurred in 97% of patients, mostly characterized by cytopenias (80%). AEs led to venetoclax and gilteritinib interruptions in 51% and 48% of patients and to discontinuation of treatment in 15% and 13%, respectively. Serious AEs occurred in 75% of patients, most commonly febrile neutropenia (44%) and pneumonia (13%) [16]. This combination approach produced a highly modified composite CR rate in patients with FLT3-mutated R/R AML; however, dose interruptions for cytopenias were very common, and this regimen showed a high toxicity profile.
The addiction of gilteritinib to azacitidine and venetoclax in FLT3-mutated AML was another fascinating triplet combination. In the phase I/II trial recently reported by Short et al., the ORR was 100% (27/27), with a 92% CR in newly diagnosed patients, a median OS that had not yet been attained, and an OS of 85% at 1 year. In R/R patients, the ORR was 70% (14/20), with a CR rate of 20% (4/20) and a median OS of 5.8 months. With a median OS of 10.5 months, outcomes were better in patients who had not previously received gilteritinib or venetoclax [17].

2.3. Gilteritinib Plus Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia

Recently, encouraging data on the association between gilteritinib and induction and consolidation chemotherapy were presented at the 10th Annual Meeting of the Society of Hematologic Oncology. Patients enrolled in this phase 1 trial (NCT02236013) were required to be at least 18 years of age with newly diagnosed AML and have an ECOG performance status of 2 or less; the presence of an FLT3 mutation at baseline was not required. Dose escalation of gilteritinib was assessed in part 1 of the study to identify the MTD. Induction regimen provided 3 days of idarubicin with 7 days of cytarabine and 14 days of gilteritinib at doses of 20 mg, 40 mg, 80 mg, 120 mg, or 200 mg, given on days 4 through 17 for up to 2 cycles. The consolidation approach included high-dose cytarabine plus the same dose of gilteritinib given daily for the first 14 days of each cycle for up to 3 cycles. Finally, patients received maintenance treatment based on gilteritinib daily for 28 days for up to 26 cycles. The dose expansion study (part 2) provided gilteritinib at 120 mg a day, with induction, consolidation, and maintenance following the same treatment pattern as dose expansion trial. In part 3 of the study, the gilteritinib dosing schedule during induction was modified to begin with the completion of chemotherapy, running from days 8 through 21, and the other receiving 3 days of daunorubicin and 7 days of cytarabine. Consolidation and maintenance followed the same treatment pattern as parts 1 and 2. In part 4 of the study, gilteritinib was given up to 56 consecutive days during consolidation. A total of 79 patients were enrolled; among them, 56.4% of patients harbored FLT3 mutations, 42.3% had FLT3–ITD mutations, and 41% had FLT3wt disease. At the end of treatment, the composite CR in patients with FLT3 mutation was 90.9%, with 70.6% of patients achieving a CR. The 26-week, 1-year, and 2-year OS rates were 92.4%, 82.1%, and 69.2%, respectively, in this subgroup. Additional data showed that while censoring for HSCT, the median disease-free survival (DFS) for patients with FLT3 mutations (n = 40) was 460 days (95% CI, 150–970), while the FLT3-negative population (n = 22) experienced a median DFS of 288 days (95% CI, 23–971). The MTD of gilteritinib was established to be 120 mg per day, and dose-limiting toxicities occurred in 15 of 78 (19.2%) patients given gilteritinib. AEs led to the discontinuation of gilteritinib in 24.4% of patients. Grade ≥ 3 treatment-emergent AEs were reported in 93.6% of patients [18]. According to these results, an effective antileukemic response was observed in terms of CR and OS, particularly in the FLT3-mutated subgroup in newly diagnosed AML who received gilteritinib in combination with intensive chemotherapy. These data support further trials to confirm the validity of this approach and to compare this regimen with the already approved treatment based on the combination of midostaurin with intensive chemotherapy in FLT3-mutated patients. Table 1 summarizes the trials including gilteritinib for the treatment of de novo AML. Table 2 summarizes the ongoing and recruiting studies including gilteritinib in combination with chemotherapy or other small molecules in R/R and de novo AML.


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