Clinical trialPhase 3Leukaemia

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial

Lancet · 2023539 patients (268 quizartinib, 271 placebo)

Erba HP, Montesinos P, Kim HJ, et al. Lancet. 2023. 401:1571-1583

Study type: Clinical trial
Study name: QuANTUM-First
Phase: Phase 3
Design: Randomised (1:1), double-blind, placebo-controlled trial at 193 centres in 26 countries
Sample size: 539 patients (268 quizartinib, 271 placebo)
Source: Lancet · 2023
Trial registration: NCT02668653

In plain words

The FLT3-ITD mutation is one of the high-risk mutations in acute myeloid leukaemia. In this study, adding quizartinib tablets to chemotherapy and continuing them for up to three years raised the median survival from about 15 months to about 32 months. This drug can affect the heart rhythm, so heart tracings (ECGs) and blood salt tests are done regularly.

Key results

31.9 vs 15.1 months

Median overall survival

HR 0.78 (95% CI 0.62–0.98); p=0.032; median follow-up 39.2 months

92% vs 90%

Grade 3 or higher adverse events

244 of 265 vs 240 of 268 patients

Dose and schedule cards

7+3 + quizartinib (QuANTUM-First)

Newly diagnosed FLT3-ITD-positive AML (patients up to 75 years of age in the trial), only if QTcF ≤450 msCycle length: 28-day cyclesOn the page “Leukaemia” · Regimens and dosing in newly diagnosed AML (induction, consolidation and maintenance)

Newly diagnosed FLT3-ITD-positive AML (patients up to 75 years of age in the trial), only if QTcF ≤450 ms

Drug	Dose	Route	Schedule
Induction (up to 2 cycles)
Cytarabine + daunorubicin or idarubicin	Cytarabine 100 or 200 mg/m²; daunorubicin 60 or idarubicin 12 mg/m²	IV	Cytarabine Days 1–7; anthracycline Days 1–3
Quizartinib	35.4 mg once daily	Oral	Days 8–21 (in a second 5+2 induction: Days 6–19)
Consolidation (up to 4 cycles)
High-dose cytarabine	1.5 to 3 g/m² every 12 hours	IV	Days 1, 3 and 5
Quizartinib	35.4 mg once daily	Oral	Days 6–19
Maintenance
Quizartinib	26.5 mg once daily, then 53 mg once daily	Oral	Days 1–14 of the first cycle at 26.5 mg; from Day 15, 53 mg if QTcF ≤450 ms, continuous

Cycle length: 28-day cycles
Duration: Up to 2 induction cycles, up to 4 consolidation cycles and up to 36 maintenance cycles (or until progression/unacceptable toxicity)

ECG before starting and weekly during induction and consolidation; during maintenance, weekly for at least one month after starting or after a dose increase. Discontinue QT-prolonging drugs as far as possible. QTcF 481–500 ms: reduce the dose without interrupting; above 500: interrupt and resume at a lower dose once below 450; if QTcF above 500 occurred during induction or consolidation, maintenance should continue at 26.5 mg; recurrent QTcF above 500 or torsades de pointes: discontinue permanently. Maintenance starts after count recovery (neutrophils above 500 and platelets above 50,000 per microliter); stop 7 days before the transplant conditioning regimen, and in the trial, transplanted patients started maintenance after recovering from the transplant.

On the page “Leukaemia” · Regimens and dosing in newly diagnosed AML (induction, consolidation and maintenance)

7+3 + quizartinib (QuANTUM-First)

Newly diagnosed FLT3-ITD-positive AML (age 18 to 75 in the trial), only if QTcF ≤450 msCycle length: 28-day cyclesOn the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Induction and consolidation in patients fit for intensive treatment

Newly diagnosed FLT3-ITD-positive AML (age 18 to 75 in the trial), only if QTcF ≤450 ms

Drug	Dose	Route	Schedule
Induction (up to 2 cycles)
Cytarabine + daunorubicin or idarubicin	Cytarabine 100 or 200 mg/m² a day; daunorubicin 60 or idarubicin 12 mg/m² a day	IV	Cytarabine days 1 to 7; anthracycline days 1 to 3
Quizartinib	35.4 mg once a day	Oral	Days 8 to 21 (in a second 5+2 induction: days 6 to 19)
Consolidation (up to 4 cycles)
Cytarabine	1.5 to 3 g/m² every 12 hours	IV	Days 1, 3 and 5
Quizartinib	35.4 mg once a day	Oral	Days 6 to 19
Maintenance (up to 36 cycles)
Quizartinib	26.5 mg once a day, then 53 mg	Oral	Days 1 to 14 of the first cycle 26.5 mg; from day 15, 53 mg if QTcF ≤450 ms, continuously

Cycle length: 28-day cycles
Duration: Up to 2 induction cycles, 4 consolidation cycles and 36 maintenance cycles

ECG before starting and weekly during induction and consolidation; in maintenance, weekly for at least one month after starting or increasing the dose. QTcF 481 to 500: reduce the dose without stopping; above 500: stop and resume at a lower dose after it falls below 450; if QTcF above 500 occurred during induction or consolidation, maintenance stays at 26.5 mg. With a strong CYP3A inhibitor, reduce 53 to 26.5, 35.4 to 17.7 and 26.5 to 17.7 mg, and if the current dose is 17.7 mg, stop the drug while the inhibitor is used. Start maintenance after count recovery (neutrophils above 500 and platelets above 50,000/µL), and stop it 7 days before transplant conditioning.

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Induction and consolidation in patients fit for intensive treatment

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

1Chemotherapy + quizartinib

Induction (up to 2 cycles): "7+3" with cytarabine 100 mg/m² per day (or 200 mg/m² if the centre's standard) as a continuous IV infusion on days 1 to 7 and daunorubicin 60 mg/m² or idarubicin 12 mg/m² IV on days 1 to 3; quizartinib 40 mg (dihydrochloride salt; equivalent to 35.4 mg quizartinib) orally once daily from day 8 for 14 days (in a second 5+2 induction: days 6 to 19).

Consolidation (up to 4 cycles): high-dose cytarabine 1.5 to 3 g/m² every 12 hours on days 1, 3 and 5 with quizartinib 40 mg (35.4 mg) on days 6 to 19, and/or allogeneic transplantation.

Continuation (maintenance): single-agent quizartinib for up to 3 years (36 cycles of 28 days); per the FDA label, 26.5 mg on days 1 to 14 of the first cycle, then 53 mg once daily if QTcF ≤450 ms. Transplanted patients started maintenance after recovery from transplantation.

2Chemotherapy + placebo

The same induction and consolidation regimen with placebo on the same schedule, then continued placebo for up to 3 years.

Source of the regimen details: Abstract of the paper (Lancet 2023) and the FDA label for quizartinib (DailyMed; section 14: consolidation cytarabine dose and dosing days; 20 and 30 mg tablets of the salt equivalent to 17.7 and 26.5 mg quizartinib)

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 aged 18 to 75 with newly diagnosed AML with an FLT3-ITD mutation. Median age 56 years (range 20 to 75).

Endpoints

Primary outcome: overall survival in the intention-to-treat population.

Secondary outcomes: event-free survival, complete remission rate and safety.

Safety and side effects

Grade 3 or higher adverse events occurred in 92% of the quizartinib group and 90% of the placebo group. The most common grade 3 or 4 adverse events in both groups were febrile neutropenia, hypokalaemia and pneumonia, and in the quizartinib group neutropenia. Quizartinib can prolong the QT interval, and ECG and electrolyte monitoring is required.

Clinical significance and place in guidelines

Quizartinib was approved in 2023 by the FDA and then the EMA for newly diagnosed FLT3-ITD-positive AML with standard induction and consolidation and as maintenance. For patients with FLT3-ITD, quizartinib or midostaurin (based on the RATIFY study) are now first-line options with intensive chemotherapy; unlike RATIFY, this study also included patients up to 75 years, but it studied only FLT3-ITD patients (not TKD).

Limitations

Only FLT3-ITD patients were enrolled, and the results cannot be generalised to TKD mutations. There was no direct comparison with midostaurin. The overall survival benefit was statistically significant but with a relatively wide confidence interval, and the independent role of post-transplant maintenance was not tested separately.

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.