Late in 2018, the FLT3 inhibitor gilteritinib was approved for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation, as detected by a U.S. Food and Drug Administration (FDA)-approved test.^1,2 The FDA also approved an expanded indication for a companion diagnostic to include its use with gilteritinib. The LeukoStrat CDx FLT3 Mutation Assay is used to detect the FLT3 mutations in AML.

Supporting Efficacy Data

Approval of gilteritinib was based on an interim analysis of the ADMIRAL trial (ClinicalTrials.gov identifier NCT02421939), which included 138 adult patients with relapsed or refractory AML having a FLT3 internal tandem duplication or D835 or I836 mutation detected by the LeukoStrat CDx FLT3 Mutation Assay.² Gilteritinib was given orally at a dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit. Dose reductions were allowed to manage adverse events, and dose increases were allowed to increase clinical benefit.

Patients had a median age of 60 years (38% ≥ 65 years), 54% were female, 60% were white and 27% were Asian, and 18% had an Eastern Cooperative Oncology Group performance status of ≥ 2. Approximately 59% had untreated relapsed AML, and 41% had primary refractory disease. The median number of relapses was one, 20% of patients had undergone prior stem cell transplantation, and 77% were transfusion-dependent at baseline. FLT3 mutation status was internal tandem duplication alone in 88%, tyrosine kinase domain D835/I836 point mutation alone in 9%, and both in 4%.

The median follow-up was 4.6 months. Complete remission with partial hematologic recovery was observed in 29 patients (21.0%). The median duration of response was 4.6 months (range = 0.1–15.9+ months), and 14 patients were still in remission at the time of the first interim duration-of-response analysis. The median time to first response was 3.6 months (range = 0.9–9.6 months).

Complete remission or partial hematologic recovery was achieved in 29 of 126 patients (23.0%) with a FLT3 internal tandem duplication or FLT3 internal tandem duplication/tyrosine kinase domain mutation and 0 of 12 patients with a FLT3 tyrosine kinase domain mutation alone.

Among 106 patients who were dependent on red blood cell or platelet transfusions at baseline, 33 (31.1%) became independent of those transfusions during any 56-day postbaseline period. Among 32 patients independent of both red blood cell and platelet transfusions at baseline, 17 (53.1%) remained transfusion-independent during any 56-day postbaseline period.

How It Works

Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3). Gilteritinib demonstrated the ability to inhibit FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3 internal tandem duplication and tyrosine kinase domain mutations FLT3-D835Y and FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells expressing FLT3 internal tandem duplication.

How It Is Used

Patients should be selected for the treatment of AML with gilteritinib based on the presence of FLT3 mutations in the blood or bone marrow as detected by an FDA-approved test.

The recommended starting dose of gilteritinib is 120 mg orally once daily. Response may be delayed. In the absence of disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response.

Blood cell counts and blood chemistries, including creatine phosphokinase, should be assessed prior to the initiation of gilteritinib, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. ECGs should be performed prior to the initiation of treatment, on days 8 and 15 of cycle 1, and prior to the start of the next two cycles.

Dose modifications for adverse reactions include the following:

• For posterior reversible encephalopathy syndrome, discontinue gilteritinib.
• For a QTc interval > 500 msec, interrupt treatment and resume at 80 mg/d when the QTc interval returns to within 30 msec of baseline or ≤ 480 msec.
• For a QTc interval increased by > 30 msec on ECG on day 8 of cycle 1, confirm with ECG on day 9; if confirmed, consider dose reduction to 80 mg/d.
• For pancreatitis, interrupt treatment until pancreatitis is resolved and resume treatment at 80 mg/d. For other grade 3 or higher toxicities considered related to treatment, interrupt treatment until toxicity resolves or improves to grade 1, and resume gilteritinib at 80 mg/d.

Concomitant use of gilteritinib with a combined P-glycoprotein and strong CYP3A inducer (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) should be avoided. Concomitant use decreases gilteritinib exposure, which may decrease its efficacy. Concomitant use of gilteritinib with a strong CYP3A inhibitor (eg, ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole) increases gilteritinib exposure, which may increase the risk of gilteritinib adverse reactions. Alternative therapies that are not strong CYP3A inhibitors should be considered. If concomitant use cannot be avoided, patients should be monitored more frequently for gilteritinib adverse reactions.

Safety Profile

The safety evaluation of gilteritinib is based on 292 patients with relapsed or refractory AML treated with gilteritinib at 120 mg daily.

The most common adverse reactions of any grade (≥ 20%) were myalgia/arthralgia (42%), transaminase increase (41%), fatigue/malaise (40%), fever (35%), noninfectious diarrhea (34%), dyspnea (34%), edema (34%), rash (30%), pneumonia (30%), nausea (27%), stomatitis (26%), cough (25%), headache (21%), hypotension (21%), dizziness (20%), and vomiting (20%). The most common grade ≥ 3 adverse events included pneumonia (23%), transaminase increase (16%), sepsis (14%), and dyspnea (12%). The most common grade ≥ 3 laboratory abnormalities were increased alanine aminotransferase (12%), hypophosphatemia (12%), hyponatremia (12%), and increased aspartate aminotransferase (10%).

The most common nonhematologic serious adverse events (≥ 5%) were pneumonia (19%), sepsis (13%), fever (13%), dyspnea (7%), and renal impairment (5%). Adverse events led to permanent discontinuation of treatment in 8% of patients, with the most common causes being pneumonia (2%), sepsis (2%), and dyspnea (1%).

Other clinically significant adverse events occurring in ≤ 10% of patients included prolonged QT interval (7%), cardiac failure (4%), pericardial effusion (3%), pericarditis (2%), differentiation syndrome (1%), anaphylactic reaction (1%), and posterior reversible encephalopathy syndrome (1%).

The full prescribing information for gilteritinib includes warnings and precautions for posterior reversible encephalopathy syndrome, prolonged QT interval, pancreatitis, and embryofetal toxicity. Hypokalemia and hypomagnesemia should be corrected prior to and during gilteritinib administration. Patients should be advised not to breastfeed during gilteritinib therapy. Gilteritinib is contraindicated in patients with hypersensitivity to the drug or any of the excipients; anaphylactic reactions have been observed in clinical trials.■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. December 14, 2018. Available at htpps://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627045.htm. Accessed December 10, 2019.

2. Xospata (gilteritinib) tablets prescribing information, Astellas Pharma US Inc, November 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/-label/2018/211349s000lbl.pdf. Accessed December 10, 2019.