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CC BY 4.0 · Indian J Med Paediatr Oncol
DOI: 10.1055/s-0045-1809991
Drug Review

Gilteritinib

Harini Raghunathan
1   Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
,
Parathan Karunakaran 
1   Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
› Author Affiliations

Funding None.
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Abstract

Introduction

Acute myeloid leukemia (AML) is a heterogeneous and aggressive form of blood cancer that affects the myeloid lineage of the cells. Among various genetic mutations associated with AML, the FLT-3 mutation is one of the most common and associated with poor prognosis. Gilteritinib (previously known as ASP2215) is the first tyrosine kinase inhibitor approved as monotherapy for treatment of relapsed/refractory AML.

Areas Covered

We review gilteritinib in detail, including its mechanism of action, pharmacology, efficacy, toxicity profile, and key clinical trials.


 

Keywords

FLT3 mutation - relapsed/refractory AML - TKI - gilteritinib

Introduction

Acute myeloid leukemia (AML) has an annual incidence of approximately 2 to 3 per 100,000 in adults in India. Fms-related tyrosine kinase 3 (FLT3) gene, which encodes type III receptor tyrosine kinase protein, is the most common gene that is mutated in AML.

FLT3-mutated AML is characterized by a younger age of onset, high white blood cell count, and high blast percentage at presentation, along with an elevated lactate dehydrogenase. It does achieve remission with conventional therapy, but has a pronounced tendency to relapse, relapse quickly, and die sooner.

Based on the interim results of the ADMIRAL study, gilteritinib was approved by the U.S. Food and Drug Administration (FDA) in November 2018 for the treatment of adults with relapsed and/or refractory (R/R) AML with a FLT3 mutation.[1] It has been available in India since April 2024. [Table 1] summarizes the drugs available with FLT3 activity.

Table 1

FDA-approved drugs for FLT3-mutated AML

Drug

Type

FLT3 activity

Generation

Selectivity

Upfront therapy

Relapsed therapy

Sorafenib

2

Only ITD

1

Multikinase inhibitor (FLT3, VEGFR, PDGFR)

Midostaurin

1

ITD and TKD

1

Multikinase inhibitor

As combination

Quizartinib

2

Only ITD

2

FLT3

As combination

Gilteritinib

1

ITD and TKD

2

FLT3, ALK, AXL

Monotherapy

Abbreviations: AML, acute myeloid leukemia; FDA, Food and Drug Administration; ITD, internal tandem duplication; TKD, tyrosine kinase domain.



 

Gilteritinib

Mechanism of Action

Gilteritinib is a highly selective FLT3 inhibitor, which has activity against both FLT3-ITD and FLT-TKD mutations. In comparison, midostaurin has slightly lower efficacy against FLT3-TKD. Gilteritinib also inhibits ALK and AXL, which is overexpressed in AML and has shown potential role in chemoresistance.[2]


 

Pharmacokinetics

Maximum plasma concentration achieved: 4 to 6 hours. High-fat meal delays it by 2 hours.

It is metabolized via CYP3A4, and it is excreted mainly via feces. It has a long elimination half-life of 113 hours, permitting once daily dosing.[2]


 

Drug Interactions

Strong CYP3A inhibitors (voriconazole, posaconazole) increase gilteritinib levels by 34.24%. Hence, dose reduction to 80 mg is advised. However, effect on efficacy is not known. It is pertinent to note that the ADMIRAL trial did not utilize these azoles for prophylaxis.[3]


 

 

Safety[1] [4]

Gilteritinib is generally well-tolerated compared with traditional chemotherapy. Its nonhematological toxicity includes:

  1. Aspartate and alanine aminotransferase elevation was the most commonly reported adverse effect (AE).

  2. QT segment prolongation

    Recommendation is for electrocardiogram monitoring on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. It is advised to withhold the drug if QTc > 500 ms, and restart at a lower dose once the QTc < 480 ms. Periodic potassium and magnesium monitoring is mandated.

  3. Differentiation syndrome (DS)[5]

    DS is a unique side effect initially reported with the use of all-trans retinoic acid in acute promyelocytic leukemia (APML). In the therapy of AML, gilteritinib shares this unique AE with the isocitrate dehydrogenase (IDH) inhibitors. Unlike DS seen in APML, DS occurs less frequently, has a later onset, and is associated with prominent skin involvement, in the form of Sweet's syndrome.

  4. Gastrointestinal (GI) disturbances, muscle pain, fatigue, dizziness, and peripheral edema have also been reported.

  5. Rare but serious toxicities include posterior reversible encephalopathy syndrome and Pancreatitis.


 

Clinical Efficacy

Approval for gilteritinib was obtained based on the results of CHRYSALIS and ADMIRAL trials.

CHRYSALIS Trial[5]

This is the first-in-human, open-label, phase I/II dose escalation, dose expansion trial in R/R AML.

Dose ranged from 20 to 450 mg, with maximum tolerated dose identified as 300 mg.


 

ADMIRAL Trial[1]

This global, open-label, phase III trial enrolled 371 adult patients with R/R FLT3-mutated AML. Assigned 2:1 to either gilteritinib or salvage chemotherapy (MEC/FLAG-Ida/azacitidine [Aza]/low dose cytarabine). The median overall survival was 9.3 months in the gilteritinib group compared with 5.6 months in the chemo group. The objective response rate was considerably higher in the gilteritinib group (67.6% vs. 25.8%). Similarly, gilteritinib demonstrated a longer duration of response (11 vs. 1.8 months).


 

MORPHO Trial[6]

This phase 3 trial by the BMT CTN group evaluated gilteritinib as maintenance therapy posttransplant. The strongest benefit was seen in patients who were MRD (measurable residual disease) positive in the peritransplant period, whereas no benefit was observed in patients who were MRD-negative.

The posttransplant relapse kinetics demonstrated that those who did not receive maintenance relapsed early (64.3% relapsed within 8 weeks and 93.9% by 16 weeks). Whereas clonal eradication due to graft versus leukemia occurred only by 3 to 6 months. Based on these kinetics in MRD-positive cases, it is advised that gilteritinib should be started soon after engraftment.


 

 

Current Uses

As Monotherapy

It is the only FLT3 inhibitor approved as monotherapy by the FDA in the relapsed setting.


 

As Combination Therapy

Combination therapy is preferred in the front-line setting. The Lacewing study initially included a monotherapy arm upfront, however, it was dropped midway through the trial, due to changing treatment paradigm. [Table 2] summarizes the trials with gilteritinib combination therapy.

Table 2

Trials of combination therapy with gilteritinib

Trial / Phase

n

Patient profile

ORR

CR

OS

PFS

Key message

Venetoclax plus gilteritinib[7]

phase IB

61

Failed > 1 line of AML therapy

-

mCRc- 75%a

10 months

−

Ven + Gilt had high mCRc, regardless of prior FLT3 inhibitor exposure

Triple therapy with venetoclax, FLT3 inhibitor, and decitabine for FLT3-mutated AML[9]–

Phase II trial

25

Newly diagnosed AML

and

R/R AML

Excl. favorable cytogenetics and prior venetoclax exposure

Newly diagnosed

67–92%

R/R AML 26–83%

Newly diagnosed

CRc- 92%

R/R AML

CRc- 62%

Newly diagnosed

OS not reached (2-year OS – 80%)

R/R AML

6.8 months

Newly diagnosed

18-month PFS-59%

R/R AML- 58%

Triplet therapy safe and effective

Lacewing trial[10]

Phase III trial

123

Newly diagnosed AML patients ineligible for intensive chemotherapy

Gilt + AZA-

CRc- 58%

CR- 16.2%

AZA

CRc–26.5%

CR-14.3%

Gilt + AZA

-9.8 months

AZA- 8.8 months

EFS

Gilt + AZA- 4.5 months

AZA-0.3 months

Negative study

Gilteritinib + 3 + 7 chemotherapy[3]

phase I B trial

80

Newly diagnosed, fit for intensive chemotherapy

Gilt in induction, consolidation, and maintenance

−

FLT-3 WT -CRc- 50%

FLT3–mutated

CRc-89%

mOS- 46.1 months

−

Gilteritinib can be safely combined with conventional 3 + 7 therapy.

It induced prolonged myelosuppression.

Gilteritinib maintenance well tolerated

Gilt plus CLIA chemotherapy (cladribine, idarubicin, cytarabine) ± venetoclax[11]

Phase II trial

18

Newly diagnosed, fit for intensive chemotherapy

CLIA + gilteritinib 80%

Vs.

CLIA+ gilteritinib +

venetoclax

88%

21. 9 months

For entire cohort

(not reached for CLIA + Gil arm and 22.4 months in CLIA + Gil + Ven arm

Addition of venetoclax produced similar results but prolonged the count recovery

Abbreviations: Aza, Azacitidine; AML, acute myeloid leukemia; CRh, complete remission; Cri, complete remission with incomplete hematological recovery; CRc, composite CR (CR + Cri + CRh); Gilt, Gilteritinib; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; R/R, relapsed and/or refractory; Ven, Venetoclax.


  1. Gilteritinib with venetoclax[7]

    It is hypothesized that targeting both FLT3 and BCL-2 pathways may enhance cell death in FLT3-mutated AML cells. Pharmacological modeling also suggests higher synergism between gilteritinib and venetoclax in comparison to midostaurin.[8]

  2. Gilteritinib with Aza[9]

    Aza is believed to enhance FLT3 inhibition by reducing cellular proliferation. The combination has shown manageable toxicity in elderly AML. However, the Lacewing study failed to demonstrate survival benefit for the addition of gilteritinib to Aza.[9] GI toxicity, especially, GI hemorrhage, was higher with gilteritinib + Aza.

  3. Triple therapy: Gilteritinib with Aza and venetoclax[10]

    It is the preferred combination and has proven to have the best efficacy. However, it is associated with higher toxicity with a 62% incidence of infection and 38% febrile neutropenia, More so with R/R AML.

  4. Gilteritinib and chemotherapy[3] [11]

    Adding gilteritinib to standard chemotherapeutic regimens can induce a deeper molecular response by targeting residual disease more effectively than chemotherapy. However, concern exists regarding the efficacy of gilteritinib in this setting, as there is rebound increase in wild-type FLT3, induced by the recovering marrow post-chemotherapy.


 

Use of Gilteritinib Post-Failure of Other FLT3i[12]

There is a concern that prior use of FLT3i can drive the expansion of clones with additional on-target mutations, which may confer resistance to gilteritinib. However, data from the Admiral trial and real-world data clearly demonstrated its efficacy in this population (composite complete remission [CR] rates of ∼50%).


 

Maintenance Therapy for Nontransplant patients[13]

Gilteritinib maintenance is more effective in preventing early relapse at 0.5 to 1 year. However, its utility is limited if the MRD is negative.


 

Myeloid Sarcoma[14]

Shatilova et al have reported superior efficacy of gilteritinib over other FLT3i for the therapy of extramedullary disease.


 

 

Dosing[1] [7] [9] [10] [11]

The dose of gilteritinib is 120 mg for monotherapy (only FDA-approved dose).

Dose escalation up to 200 mg was permitted if the patient is not in CR at 28 days of treatment.

Gilteritinib is used at a dose of 120 mg for doublet combination therapy (either Aza or venetoclax) and 80 mg for triplet combination therapy (Aza + venetoclax + gilteritinib).

Cost: Monotherapy with 120 mg of gilteritinib for 1 month will cost INR 6.3 lakh.


 

Ongoing Phase 3 Trials

Gilteritinib versus midostaurin in combination with intensive chemotherapy for upfront AML and MDS (HOVON 156 AML trial).[15]

Important Points about Gilteritinib[15]

  1. Inhibition of FLT3 needs to be near complete and sustained for days, not hours. Gilteritinib has a long half-life—hence, once daily dosing. It is important to minimize drug interruptions.

  2. Lower myelosuppression

    KIT and FLT3 are structurally similar. Gilteritinib selectively inhibits mutated FLT3, it has fivefold less activity against wild-type FLT3 and nil against KIT—hence, lesser myelosuppression compared with other FLT3i.

  3. FLT3-ITD AML evolves from diagnosis to relapse

    Leukemic cells are dependent on FLT3-ITD signaling for survival. This constitutes a small proportion of the total leukemic cell population at the time of diagnosis. However, it is of a large proportion at the time of relapse. Hence, monotherapy works well at relapse, whereas a combination regimen with synergistic cytotoxicity is a better option for therapy upfront.

  4. Gilteritinib acts by a combination of apoptosis and terminal myeloid differentiation

    Apoptosis of peripheral blood blasts results in rapid clearance. However, bone marrow (BM) blasts undergo differentiation. This tends to be a slower process. Hence, the attainment of CR is later than conventional chemotherapy and recovery of normal count is also delayed.

  5. Clinical endpoint: BM aplasia is avoided with gilteritinib monotherapy; however, count recovery is delayed. Cri + CRh (CR with incomplete hematological recovery + CR with partial hematological recovery) were included as a valid endpoint in clinical trials. This trend is seen with monotherapy with other targeted therapies like the IDH1 and 2 inhibitors as well. CRh has been associated with transfusion independence and lower risk of infections. Thus, it is a clinically relevant endpoint.

  6. MRD analysis: Polymerase chain reaction (PCR) is insufficient to analyze MRD in FLT3-mutated AML due to the template bias issue. Hence, a high sensitivity PCR-next-generation sequencing combination method is utilized to test MRD. This is currently not available in India.


 

 

Molecular Spectrum of Action[16]

Analysis of the molecular makeup of good responders to gilteritinib demonstrates that:

  • Good response was seen with those with concomitant DNMT3A, IDH1/2, and WT-1 mutations.

  • While the best response was seen with dual-mutated DNMT3A and NPM1.

The impact of FLT3 mutations on response was also assessed:

  • Presence of multiple FLT3-ITD mutations had no impact on response.

  • Longer FLT3 ITD length responded better than shorter ITD length.

  • High allele ratio FLT3 (↑allele burden) is known to have poorer prognosis—gilteritinib was superior to chemotherapy. However, it was not able to fully abrogate the poor risk.

Treatment resistance to gilteritinib:

  • Failure of gilteritinib therapy can be caused by primary and secondary mechanisms.

  • F691L gatekeeper mutations and RAS/MAPK pathway gene mutations constitute the most common resistance pathway. They both are mutually exclusive.

  • On-target point mutations: D835, F691 (gatekeeper mutation), N676, and FLT-3 juxtamembrane (JMD) E598D mutations.

  • Off-target mutations in Ras/MAPK pathway: NRAS, PTPN11, and KRAS.

  • Nongenetic mechanisms like FGF2-activated FGF1 receptor 1 can also contribute.


 

Conclusion

Gilteritinib is the first oral tyrosine kinase inhibitor approved for the management of AML in the R/R setting. Its tolerance and lack of marrow aplasia makes it an ideal agent for managing AML patients in an outpatient setting. Ongoing clinical trials in combination therapy and in upfront setting will open broader avenues in the management of FLT-3-mutated AML.


 

 

Conflict of Interest

None declared.

Patient Consent

Patient consent is not required.



Address for correspondence

Parathan Karunakaran, MD, DM
Cancer Institute (WIA)
38, Sardar Patel Road, Chennai 600 036, Tamil Nadu
India   

Publication History

Article published online:
10 July 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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