Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML

N Engl J Med · 2019371 patients (247 gilteritinib, 124 salvage chemotherapy)

Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. N Engl J Med. 2019. 381:1728-1740

Study type: Clinical trial
Study name: ADMIRAL
Phase: Phase 3
Design: Randomised trial (2:1 ratio), gilteritinib versus salvage chemotherapy
Sample size: 371 patients (247 gilteritinib, 124 salvage chemotherapy)
Source: N Engl J Med · 2019
Trial registration: NCT02421939

In plain words

In some people with acute myeloid leukaemia, the cancer cells carry a mutation called FLT3. When this type of the disease comes back after treatment or does not respond to treatment, more chemotherapy rarely works. In this study, a daily gilteritinib tablet, compared with salvage chemotherapy, raised the median survival from about 5.6 months to 9.3 months and about doubled the proportion of patients in complete remission. During treatment, heart tracings (ECG) and blood tests are done regularly. A side effect called "differentiation syndrome" may occur, which is treated with steroid medicines, so any new symptom should be reported to the care team quickly.

Key results

9.3 vs 5.6 months

Median overall survival

HR for death 0.64 (95% CI 0.49–0.83); P<0.001

34.0% vs 15.3%

Complete remission with full or partial haematological recovery (CR/CRh)

Risk difference 18.6 percentage points (95% CI 9.8–27.4)

21.1% vs 10.5%

Complete remission (CR)

Risk difference 10.6 percentage points (95% CI 2.8–18.4)

2.8 vs 0.7 months

Median event-free survival

HR for treatment failure or death 0.79 (95% CI 0.58–1.09)

Febrile neutropenia 45.9%, anaemia 40.7%, thrombocytopenia 22.8%

Most common grade 3 or higher adverse events with gilteritinib

In the analysis adjusted for treatment duration, grade 3 or higher and serious adverse events were less frequent with gilteritinib than with chemotherapy

Dose and schedule cards

Gilteritinib (ADMIRAL)

Relapsed or refractory FLT3-mutated AML (ITD or TKD) in adultsCycle length: ContinuousOn the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Targeted treatment in relapsed or refractory AML

Relapsed or refractory FLT3-mutated AML (ITD or TKD) in adults

Drug	Dose	Route	Schedule
Gilteritinib	120 mg once a day	Oral, with or without food	Continuous

Cycle length: Continuous
Duration: Until progression or toxicity; at least 6 months to allow time for response

Boxed warning for differentiation syndrome. ECG before starting, on days 8 and 15 of cycle 1 and before the next two cycles; QTc above 500: hold and resume at 80 mg; posterior reversible encephalopathy syndrome: stop permanently. Blood counts and chemistry (including CPK) weekly in the first month, every two weeks in the second month and then monthly.

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Targeted treatment in relapsed or refractory AML

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Gilteritinib

Gilteritinib orally at a dose of 120 mg per day.

According to the FDA label (Xospata): 120 mg orally once daily; continue for at least 6 months in the absence of disease progression or unacceptable toxicity to allow time for a clinical response. ECG before starting, on days 8 and 15 of cycle 1 and before the start of the next two cycles. Differentiation syndrome: systemic corticosteroids and haemodynamic monitoring. QTc over 500 ms: interrupt the drug and resume at a dose of 80 mg.

2Salvage chemotherapy (control group)

Salvage chemotherapy; details of the salvage chemotherapy regimens in the full text of the paper.

Source of the regimen details: Abstract of the paper (N Engl J Med 2019) and the FDA label for gilteritinib (Xospata; DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with relapsed or refractory acute myeloid leukaemia (AML) with an FLT3 mutation. Other inclusion criteria are not stated in the abstract.

Endpoints

Two primary endpoints: overall survival and the percentage of patients with complete remission with full or partial haematological recovery (CR/CRh).

Secondary endpoints: event-free survival (freedom from treatment failure [relapse or failure to achieve remission] or death) and the percentage of patients with complete remission.

Safety and side effects

In an analysis adjusted for treatment duration, grade 3 or higher adverse events and serious adverse events were less frequent in the gilteritinib group than in the chemotherapy group. The most common grade 3 or higher adverse events with gilteritinib: febrile neutropenia 45.9%, anaemia 40.7% and thrombocytopenia 22.8%. According to the FDA label, differentiation syndrome is treated with systemic corticosteroids and haemodynamic monitoring, and the ECG is monitored for QTc prolongation before starting and during the first cycles.

Clinical significance and place in guidelines

ADMIRAL showed that in relapsed or refractory FLT3-mutated AML, single-agent oral gilteritinib, compared with salvage chemotherapy, both prolongs overall survival and brings a higher percentage of patients into remission. According to the FDA label (Xospata), the recommended dose is 120 mg orally once daily, and to allow time for a response, treatment continues for at least 6 months in the absence of disease progression or unacceptable toxicity. These results apply only to patients with an FLT3 mutation, so the mutation status must be known at relapse.

Limitations

The control group received salvage chemotherapy, and no comparison was made with other FLT3 inhibitors or newer combinations. The difference in event-free survival was not statistically significant (the confidence interval of the hazard ratio included 1). Despite a significant benefit, median overall survival was less than one year in both groups. Details of the salvage chemotherapy regimens and of blinding are not given in the abstract. The study was funded by the manufacturer (Astellas Pharma).

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.