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Gilteritinib (Xospata®)

Diller, Elizabeth PharmD; Mann, Janelle E. PharmD, BCOP

doi: 10.1097/01.COT.0000553980.60791.5c
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What is gilteritinib?

Gilteritinib is an oral tyrosine kinase inhibitor FDA approved in 2018 for relapsed or refractory acute myeloid leukemia (AML) with an FMS-like tyrosine kinase 3 (FLT3) mutation.

How does gilteritinib work?

FLT3 is a commonly mutated gene that is known to have a negative impact on prognosis in AML. Gilteritinib is a small molecule that inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3, including FLT3-ITD, tyrosine kinase domain mutations (TKD) FLT3-D835Y and FLT3-ITD-D835Y. Gilteritinib induces apoptosis in FLT3-ITD-expressing leukemic cells.

What is this approved for?

Gilteritinib is approved for adult patients with relapsed or refractory AML with a FLT3 mutation as detected by an FDA-approved test.

What is the basis for this approval?

Gilteritinib was approved based on an interim analysis of the ongoing open-label, multicenter, randomized, phase III ADMIRAL trial that included 138 patients. Patients were randomized to receive gilteritinib 120 mg daily versus salvage chemotherapy.

In this study, 59 percent of patients had relapsed AML and 41 percent of patients had primary refractory AML. Prior stem cell transplantation occurred in 20 percent of patients. Efficacy in the ADMIRAL trial was defined by the rate of complete remission (CR)/complete remission with partial hematologic recovery (CRh), duration of CR/CRh (DOR), and rate to transfusion independence. After a median follow up of 4.6 months, the CR/CRh rate was 21 percent with a median DOR of 4.6 months. CR was achieved in 11.6 percent of patients and CRh was achieved in 9.4 percent of patients. For patients who achieved CR/CRh, the median time to first response was 3.6 months. Among the 106 patients with transfusion dependence, 31.1 percent became transfusion independent.

How do you administer this drug?

Gilteritinib should be initiated at 120 mg orally once daily without regard to meals. Therapy should continue for a minimum of 6 months to allow time for clinical response or until disease progression or unacceptable toxicity.

Are there any premedications needed for gilteritinib?

None required.

What are the common side effects associated with gilteritinib (> or =10%)?

In the clinical trial, the most common toxicities of any grade included fatigue, myalgias, fever, elevated transaminases, dyspnea, edema, pneumonia, renal impairment, and gastrointestinal toxicity. Grade 3 or greater adverse events were less common, but included elevated transaminases, pneumonia, sepsis, and dyspnea. Permanent discontinuation due to adverse reactions occurred in 8 percent of patients.

What are the uncommon side effects associated with gilteritinib (< 10%?)

Less common toxicities include QT prolongation, pericardial effusion, posterior reversible leukoencephalopathy syndrome, differentiation syndrome, pancreatitis, seizure, and anaphylaxis.

Are there any important drug interactions I should be aware of?

Gilteritinib is a substrate of p-glycoprotein and a major substrate of CYP3A4, which metabolize the drug into active metabolites. Concomitant use with strong CYP3A4 inhibitors and inducers should be avoided. Use of agents that target the 5-HT2B receptor or the sigma nonspecific receptor, including escitalopram, fluoxetine, and sertraline, should also be avoided, as gilteritinib may reduce their effect.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

No dose adjustments are required for patients with renal or hepatic insufficiency. Patients with creatinine clearance less than 30 mL/min and severe hepatic impairment were not well-represented in the study.

Practical tips

Gilteritinib dose reductions to 80 mg once daily can be considered for patients with QT prolongation or resolved pancreatitis. Gilteritinib is available through a specialty pharmacy, and most insurances will require a prior authorization before covering the therapy. Patient assistance options are available through the company for qualifying patients.

What should my patients know about gilteritinib?

Patients should be educated on the following:

  • Take gilteritinib with a full glass of water approximately the same time each day.
  • Report any altered mental status, severe stomach pain, or fever while taking gilteritinib.
  • Use effective contraception during therapy and for at least 4 months following the last dose of gilteritinib.
  • Report new medications or updates to current medication to the treatment team.

What useful links are available regarding gilteritinib?

Any ongoing clinical trials related to gilteritinib?

The randomized phase III study ADMIRAL is currently ongoing. Additionally, gilteritinib is being investigated as maintenance therapy in patients with FLT3-ITD AML following the first CR after induction/consolidation therapy and following allogeneic transplantation as well as in combination with azacitidine in newly diagnosed AML with a FLT3 mutation. More information is available at

ELIZABETH DILLER, PHARMD, is PGY2 Oncology Resident at Barnes-Jewish Hospital, St. Louis, Mo. JANELLE E. MANN, PHARMD, BCOP, is an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.

Elizabeth Diller, PharmD
Elizabeth Diller, PharmD:
Elizabeth Diller, PharmD
Janelle E. Mann, PharmD, BCOP
Janelle E. Mann, PharmD, BCOP:
Janelle E. Mann, PharmD, BCOP
Ramaswamy Govindan, MD
Ramaswamy Govindan, MD:
Ramaswamy Govindan, MD
Wolters Kluwer Health, Inc. All rights reserved.
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