Encyclopedia
Please note this is a comparison between Version 2 by Camila Xu and Version 4 by Camila Xu.
FLT3 is a member of the class III receptor tyrosine kinase family that exerts a key role in the proliferation and differentiation of hematopoietic progenitor cells. FLT3 inhibitors have dramatically altered the prognosis of the FLT3 mutant AML.
- FMS-like tyrosine kinase 3 (FLT3)
- acute myeloid leukemia
1. Introduction
Acute myeloid leukemia (AML) is the most common type of leukemia in adults [1][2]. It is a heterogeneous group of hematological malignancies characterized by the clonal proliferation of immature myeloid cells in the bone marrow [1]. In its most recent classification, the World Health Organization identified AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, and AML not otherwise specified [3]. The incidence increases with age, with 50% of the patients being older than 60 years old. Treatment of AML for younger and fit patients usually relies on chemotherapy. For older patients, the new standard of treatment is a combination of hypomethylating agents and venetoclax. In younger patients, the first round of chemotherapy usually yields a complete remission rate of 60 to 70%. The success of the AML treatment is mostly dependent on recurrent cytogenetic and genetic alterations. The 2017 European Leukemia Net classification has divided AML patients into three prognosis groups based on their oncogenetic characteristics [4].
Acute myeloid leukemia (AML) is the most common type of leukemia in adults [1,2]. It is a heterogeneous group of hematological malignancies characterized by the clonal proliferation of immature myeloid cells in the bone marrow [1]. In its most recent classification, the World Health Organization identified AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, and AML not otherwise specified [3]. The incidence increases with age, with 50% of the patients being older than 60 years old. Treatment of AML for younger and fit patients usually relies on chemotherapy. For older patients, the new standard of treatment is a combination of hypomethylating agents and venetoclax. In younger patients, the first round of chemotherapy usually yields a complete remission rate of 60 to 70%. The success of the AML treatment is mostly dependent on recurrent cytogenetic and genetic alterations. The 2017 European Leukemia Net classification has divided AML patients into three prognosis groups based on their oncogenetic characteristics [4].
Among these recurrent genetic alterations, the mutations or duplication of the FMS such as tyrosine kinase 3 (FLT3) is the most frequent.
FLT3 is a member of the class III receptor tyrosine kinase family that exerts a key role in the proliferation and differentiation of hematopoietic progenitor cells. Around 30% of newly diagnosed AML patients carry a genetic modification in the
FLT3
gene [5]. It can either affect the juxtamembrane domain and the activation loop of the tyrosine kinase domain (TKD) (~7% of AML cases), resulting in the constitutive activation of FLT3, or it can be an internal tandem duplication (ITD), leading to a disrupted juxtamembrane domain that has been shown to be crucial for kinase autoinhibition (~23% of AML cases) [6]. These activated mutations in
FLT3 are oncogenic and show transformation activity in cells. Before the rise of small molecule inhibitors, FLT3-mutated AML was associated with a poor prognosis with a high relapse risk [7][8][9] even after allogeneic hematopoietic stem cell transplantation (aHSCT) [10]. Many studies have now reported a link between the rate of ITD allelic ratio and prognosis, with a ratio higher than 0.5 associated with a higher risk of treatment failure and relapse [11]. The prognostic impact of
are oncogenic and show transformation activity in cells. Before the rise of small molecule inhibitors, FLT3-mutated AML was associated with a poor prognosis with a high relapse risk [7,8,9] even after allogeneic hematopoietic stem cell transplantation (aHSCT) [10]. Many studies have now reported a link between the rate of ITD allelic ratio and prognosis, with a ratio higher than 0.5 associated with a higher risk of treatment failure and relapse [11]. The prognostic impact of
FLT3
TKD mutation is still debated. The real breakthrough for these patients came with the use of FLT3 inhibitors either in monotherapy or in combination with standard treatment.
2. Pharmacological Inhibition of FLT3 in AML
2.1. TKI in the Treatment of AML Patients
The poor prognosis associated with FLT3-mutated AML has led to the development of pharmacological agents designed to inhibit FLT3. The development of FLT3-targeting drugs proved to be difficult initially as many of the available candidates had poor bioavailability, low potency, insufficient kinase specificity, leading to few responders [12]. Despite these setbacks, several FLT3 inhibitors have passed the preclinical development requirements and have been evaluated in clinical trials. Indeed, many improvements have been achieved with next-generation TKIs, as compared to sorafenib and Lestaurtinib. Past and present TKI especially have different spectra and do not inhibit the same kinases (
Table 1). These differences partly explain the drugs’ side effects and efficacy. Current FLT3 inhibitors are usually divided between first- (Sorafenib, Midostaurin, and Lestaurtinib) and second-generation TKIs (gilteritinib, quizartinib, crenolanib). Next-generation TKIs have fewer off-target effects leading to fewer and less severe side effects and a higher FLT3 specificity [13][14]. Most common side effects now include cytopenias and gastrointestinal effects such as nausea and vomiting. These toxicities are easily manageable through transfusions, antibiotic courses, and antiemetics. A brief overview of the different developmental phase of the
). These differences partly explain the drugs’ side effects and efficacy. Current FLT3 inhibitors are usually divided between first- (Sorafenib, Midostaurin, and Lestaurtinib) and second-generation TKIs (gilteritinib, quizartinib, crenolanib). Next-generation TKIs have fewer off-target effects leading to fewer and less severe side effects and a higher FLT3 specificity [13,14]. Most common side effects now include cytopenias and gastrointestinal effects such as nausea and vomiting. These toxicities are easily manageable through transfusions, antibiotic courses, and antiemetics. A brief overview of the different developmental phase of the
FLT3
TKI is displayed in
, whereas a summary of the clinical trials that led to the development of the most recent TKIs is provided in
.
Table 1.
FLT3 TKI spectrum activity.
| Agent | Type |
|---|---|
| Second generation, type I | |
Table 4.
FLT3 TKIs in combination with demethylating agents.
FMS-like tyrosine kinase 3 (FLT3), rapidly accelerated fibrosarcoma (RAF), vascular endothelial growth factor receptor (VEGFR), JAK Janus kinase (JAK), platelet-derived growth factor receptor (PDGFR), protein kinase (PK), spleen tyrosine kinase (SYK), fetal liver kinase 1 (FLK-1), protein kinase cAMP-dependent (PKA), Gardner–Rasheed feline sarcoma viral (FGR), VEGFR vascular endothelial growth factor receptor.
Table 2.
FLT3 TKIs. Treatment phase and available trials.
| Indication | Dose | Target |
|---|
| Agent | Trial |
|---|
| Sorafenib | First generation, type I | 400 mg BID | FLT3-ITD, RAF, VEGFR1/2/3, PDGFRβ, KIT, RET |
2.1.1. Midostaurin
Midostaurin, also known as PKC412 or CGP41251, is an orally administered inhibitor. Its kinome includes the wild-type (WT) and mutated FLT3, KIT, VEGFR, and PDGFR. After binding its target, Midostaurin inhibits the signaling pathways regulated by the kinase leading to a growth arrest. The drug is active on both
FLT3
-ITD and
FLT3
-TKD derived kinase. Its metabolism goes through CYP3A4, which may result in several drug interactions.
Midostaurin was first assessed in a phase II study of 20 relapsed/refractory FLT3-mutated AML patients who received 75 mg Midostaurin three times daily. No patients achieved complete remission (CR), but the drug showed some promise by reducing both the bone marrow and the peripheral blast cell counts in, respectively, 50% and 70% of the patients [15].
The inhibitor was then tested during a phase II trial in patients with R/R AML or high-risk MDS with WT or mutated FLT3. Patients received single-agent Midostaurin at a dose of 50 mg BID or 100 mg BID. There was no difference in terms of tolerability between the two dosage groups. Again, none of the patients achieved CR but the blast count decreased in 71% of the FLT3-mutated AML patients and 42% of the nonmutant patients [16].
A subsequent phase Ib trial was then designed [17]. This study enrolled adult patients, aged 18 to 60 years old, with untreated AML. Patients received several schemes of Midostaurin administration in combination with chemotherapy, including 100 mg BID and 50 mg BID, continuous administration or from day 8 to day 21. The sequential treatment from day 8 to 21 was the best-tolerated regimen and did not yield severe gastrointestinal or liver complications. Regarding efficacy, 80% of all participants achieved complete remission (74% in the WT group and 92% in the FLT3-mutated group). In the FLT3-mutated group, the 1- and 2-year overall survival were, respectively, 85% and 62%.
These encouraging data led to the phase III, randomized, placebo-controlled RATIFY trial [18]. It enrolled newly diagnosed
FLT3
ITD or TKD AML patients. The primary endpoint of the study was overall survival. Secondary key endpoints were event-free survival, complete remission (CR), disease-free survival (DFS), and pharmacokinetics data. The study was designed to show that the combination of Midostaurin and conventional induction and consolidation chemotherapy, followed by one-year maintenance, would improve the OS of patients with FLT3-mutated patients. Of note, patients were not allowed to receive posttransplant Midostaurin maintenance in this trial.
The study included 717 patients, 360 in the Midostaurin arm and 357 in the placebo group. The
FLT3
subtype was ITD for 555 patients and TKD for 162 patients. The study achieved its primary endpoint by demonstrating a significantly longer survival for patients receiving Midostaurin (
p
= 0.0078). The probability of being alive at 3 years was higher in the Midostaurin group, compared to the placebo group (54% [95% CI: 0.49, 0.59] vs. 47% [95% CI: 0.41, 0.52]). There was no difference in the frequency of hematological and nonhematological adverse events. No difference was noted regarding CR rate 59% in the Midostaurin group and 54% in the placebo group (
p
= 0.15). The 4-year EFS rates were 28.2% in the Midostaurin group and 20.6% in the placebo group. The 4-year OS rates were 51.4% in the Midostaurin arm versus 44.3% in the placebo arm. The hazard ratio (HR) comparing Midostaurin to placebo was 0.78 for OS (one-sided
p
= 0.009) and 0.78 for EFS (one-sided
p
= 0.002). All
FLT3
subgroups (ITD and TKD) benefited from the addition of Midostaurin.
The RATIFY trial was the first time a new molecule ever demonstrated a real benefit in addition to chemo for first-line treatment of fit and young AML patients. This trial led to the approval of the drug by both the EMA and the FDA for the first-line treatment of adult patients with FLT3-mutated AML, in combination with the standard 7 + 3 regimen [19]. The EMA also granted Midostaurin authorization for maintenance therapy after complete remission. Following the RATIFY trial, the results of a phase 3b trial were reported at the ASH meeting in 2020 [20]. The aim of the study was to evaluate further the safety and efficacy of the combination of Midostaurin with chemotherapy both in younger and older patients with FLT3-mutated AML. This European multicenter open-label study enrolled 300 patients and confirmed that the combination of Midostaurin plus chemotherapy is safe and results in high response rates regardless of patient age or induction regimen, with a CR/CRi rate of 80.7%.
2.1.2. Lestaurtinib
Lestaurtinib is another FLT3 inhibitor candidate that was studied in two randomized trials the UK AML15 and AML17 trials, comparing the outcome of newly diagnosed FLT3-mutated AML patients with or without the addition of Lestaurtinib to conventional chemotherapy [21]. The patients were started on Lestaurtinib or placebo 2 days after the completion of their induction and consolidation courses for a 28-day period. No significant differences were seen in either 5-year overall survival or 5-year relapse-free survival. Subgroups’ analysis demonstrated large interpatient differences in FLT3 inhibition, with a survival advantage for patients with a stronger rate of inhibition.
Aside from these first-generation TKIs, several second-generation have been developed, among which Gilteritinib and Crenolanib are type I inhibitors that target both the inactive and active conformational states of the FLT3 kinase domain, whereas Quizartinib is a type II inhibitor that is specific for the inactive conformation [22]. These drugs were developed to have a better FLT3 affinity and specificity.
2.1.3. Quizartinib
Quizartinib is a once-daily, oral, highly potent, and selective, second-generation, type II FLT3 inhibitor that has shown antitumor activity in
FLT3
-ITD acute myeloid leukemia in animal models [23]. Its spectrum includes cKIT, another type III receptor tyrosine kinase. This special spectrum characteristic explains Quizartinib’s increased bone marrow toxicity. Quizartinib is not active on
FLT3
TKD AML.
Quizartinib clinical results were first evaluated in a phase I trial of Quizartinib monotherapy in R/R AML patients [24]. In this trial, the drug was administered orally as a single dose. Out of 76 patients included in the study, responses occurred in 23 (30%), including 10 (13%) CR and 13 (17%) partial remissions (PRs). The response rate was higher among patients with
FLT3
-ITD-positive patients, with a 53% overall response rate. The median duration of response was 13.3 weeks; the median survival was 14.0 weeks. The drug regimen was well tolerated since few patients exhibited adverse events (10%). The most common drug-related adverse events were digestive (nausea, vomiting, dysgeusia) and prolonged QT interval.
Following this trial, two phase 2 trials investigated Quizartinib in R/R FLT3-mutated AML patients. In an open-label, multicenter, single-arm, phase 2 trial, 333 patients were divided into two independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukemia within 1 year after first-line therapy (cohort 1) and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or hemopoietic stem cell transplantation (cohort 2). The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete hematological recovery) and the proportion of patients who achieved a complete remission. Tolerability was also recorded. A total of 56%
FLT3
-ITD-positive patients and 36%
FLT3
-ITD-negative patients achieved composite complete remission, with three (3%)
FLT3
-ITD-positive patients and two (5%)
FLT3
-ITD-negative patients achieving complete remission in cohort 1. In cohort 2, 46% of
FLT3
-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 30% of
FLT3
-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. The drug exhibited few adverse events, mostly linked to myelosuppression and QT prolonged interval, already described during the phase I trial.
Another phase IIb trial evaluated the safety and efficacy of two regimens of Quizartinib monotherapy in patients with relapsed/refractory (R/R)
FLT3
-ITD AML who previously underwent transplant or 1 s-line salvage therapy. A total of 76 patients were randomly assigned to receive either 30 or 60 mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral Quizartinib. Similar to the other phase 2 study, co-primary endpoints were composite complete remission (CRc) rates but also the incidence of QT interval. CRc rates were 47% in both groups, similar to earlier reports with higher Quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30 and 60 mg groups, respectively. The median OS in this trial were 20.9 and 27.3 weeks in the 30 mg group and 60 mg group, respectively.
Following these good results on efficacy and tolerability, Quizartinib was assessed in the QuANTUM-R multicenter, randomized, controlled, open-label, phase 3, comparing Quizartinib versus salvage chemotherapy [25]. The study randomized a total of 367 R/R
FLT3
-ITD patients. Overall survival was longer for Quizartinib than for chemotherapy (hazard ratio 0.76 [95% CI 0.58–0.98;
p
= 0.02]). Median overall survival was 6.2 months (5.3–7.2) in the Quizartinib group and 4.7 months (4.0–5.5) in the chemotherapy group. The most common toxicity in the Quizartinib group was hematological, whereas, in this trial, very few prolonged QT were recorded.
Aside from its use in the R/R AML setting, Quizartinib has been evaluated in combination with intensive chemotherapy during induction and consolidation courses, in a phase 1, open-label, sequential group dose-escalation trial [26]. This study was the first to evaluate the safety and tolerability of Quizartinib in combination with chemotherapy in newly diagnosed AML. Starting on day 4 after chemotherapy, 19 patients received Quizartinib. The tolerability was not different from the one already reported in the previous trials with only one case of the prolonged QT interval. In total, 16 patients (84%) achieved a response, from which 14 (74%) achieved composite complete responses. Following the publication of the QUANTUM R results, a retrospective French multicenter study reported the efficacy and safety of Quizartinib in R/R FLT3-mutated patients enrolled in the Quizartinib early access program [27]. Patients received Quizartinib monotherapy (83%) or in combination with either azacitidine (13%) or intensive chemotherapy (4%). The data from this study revealed that Quizartinib was safely administered with only one case of prolonged QTc and 7% of the patients experiencing differentiation syndrome. Regarding the outcome, the data confirmed the efficacy of Quizartinib, with 15 patients achieving CR or CRi (26%), 2 patients partial response (PR) (4%), 1 patient morphologic leukemia-free state (MLFS) (2%), 9 patients hematological improvement (HI)(16%), or 17 patients in stable disease (30%). These interesting results on R/R need to be confirmed on a larger real-life cohort and in first-line therapy.
The combination of Quizartinib with chemotherapy as a first-line treatment for FLT3-mutated AML patients is currently under investigation in the QuANTUM-First phase 3 trial [28]. If the results of this trial will change the current standard of care chemotherapy plus Midostaurin remains to be seen as the control arm of the QuANTUM-First trial used a placebo instead of Midostaurin, making it harder to draw any conclusion on the ability of Quizartinib to challenge Midostaurin in first-line treatment in combination with chemotherapy.
2.1.4. Gilteritinib
Gilteritinib is a second-generation TKI, and its spectrum includes FLT3, AXL, and ALK. Several in vitro studies have highlighted the pharmaceutical properties of Gilteritinib. A central point is that the drug targets both
FLT3
-ITD and TKD and has a strong affinity for FLT3, leading to sustained FLT3 inhibition [29]. Since it has no effect on c-kit, Gilteritinib does not yield myelosuppression as much as other second-generation TKIs. Moreover, the AXL inhibition leads to better control of the AML oncogenic pathways and decreases the risk of resistance [30].
The results of the open-label, first-in-human phase I/II trial were recently reported. A total number of 252 R/R AML patients were enrolled into one of seven dose-escalation (
n
= 23) or dose-expansion cohorts (
n
= 229) assigned to receive once-daily doses of oral Gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg or 450 mg). The primary endpoints were the safety, tolerability, and pharmacokinetic profile of Gilteritinib. Secondary endpoints included overall response, duration of response, and overall survival [31].
Overall, tolerance was good. The most frequent adverse effects were infections (febrile neutropenia, pneumonia, sepsis), anemia, and thrombopenia. Regarding the efficacy of Gilteritinib monotherapy in this R/R AML population, the ORR rate was 40%, with 19 patients achieving CR, 46 patients achieving complete remission with incomplete hematologic recovery, and 25 partial remissions. The median duration of response was 17 weeks, and the median overall survival was 25 weeks.
These results paved the way for further trials. Recently reported multicenter, phase 3 ADMIRAL trial reported the outcome of 247 R/R patients assigned to either Gilteritinib monotherapy (at a dose of 120 mg per day) or salvage chemotherapy at a 2:1 ratio [32]. Patients were required to have
FLT3
-ITD or TKD D835 or I836 mutations. The two primary endpoints were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Key secondary endpoints were event-free survival and the percentage of patients with complete remission. Regarding tolerance, the trial reported the same rate and type of adverse events, especially febrile neutropenia, anemia, and thrombopenia, as previously reported in the phase I/II trial. Of note, adverse events were less frequent in the Gilteritinib group, as compared to the salvage chemotherapy group. The median overall survival in the Gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83;
p
< 0.001). The median event-free survival was 2.8 months in the Gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the Gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4).
Based on these encouraging results, several phase 3 trials have been designed to evaluate the safety and efficacy of Gilteritinib in combination with conventional chemotherapy, compared to Midostaurin (in Europe: HOVON 156 AML/AMLSG 28-18, NCT04027309, in the USA: NCT03836209)
2.1.5. Crenolanib
Just as Gilteritinib, Crenolanib is a type II inhibitor. Crenolanib has a heightened binding affinity against the
FLT3
-ITD mutation (the most frequent
FLT3
aberration in AML) and TKD point mutations
FLT3
(D835H),
FLT3
(D835Y), and
FLT3
(D835V). Interestingly, Crenolanib has the ability to suppress all resistance-conferring TKD mutants [33].
Similar to other FLT3 ITKs, Crenolanib has first been studied among R/R FLT3 mutant patients. In the ARO-010 phase I/II trial, 28 heavily pretreated patients were included and received salvage therapy with Crenolanib. Crenolanib was well tolerated at a dose of 100 mg TID in combination with salvage chemotherapy. The main reported side effects were nausea, diarrhea, constipation, and fatigue [34]. A second multicenter phase I trial ARO-011 (NCT02626338) confirmed these results on 16 R/R FLT3-WT and -mutated AML patients [35]. Reported in 2019, the results of another phase II trial reported that Crenolanib when given with chemotherapy can achieve sufficient levels to inhibit multiple FLT3 mutations. The combination of Crenolanib and salvage chemotherapy seemed to improve outcomes in younger patients with newly diagnosed FLT3-mutated AML.