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

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation

N Engl J Med · 2017717 patients (360 midostaurin, 357 placebo) of 3277 patients screened

Stone RM, Mandrekar SJ, Sanford BL, et al. N Engl J Med. 2017. 377:454-464

Study type: Clinical trial
Study name: RATIFY (CALGB 10603)
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled, international trial (stratified by FLT3 mutation subtype)
Sample size: 717 patients (360 midostaurin, 357 placebo) of 3277 patients screened
Source: N Engl J Med · 2017
Trial registration: NCT00651261

In plain words

About a third of patients with acute myeloid leukaemia have a genetic change called an FLT3 mutation, which makes the disease more aggressive. This study showed that adding midostaurin capsules, taken by mouth, to standard chemotherapy lowers the risk of death by about 22%. That is why FLT3 testing at diagnosis is now essential for all patients, so that this drug can be added to treatment if the mutation is present.

Key results

HR for death 0.78

Overall survival

95% CI 0.63–0.96; one-sided P=0.009; median OS 74.7 vs 25.6 months (full text)

51.4% vs 44.3%

4-year overall survival

Full text of the paper

HR 0.78

Event-free survival

95% CI 0.66–0.93; one-sided P=0.002; 4-year EFS 28.2% vs 20.6%

Dose and schedule cards

7+3 (cytarabine + daunorubicin or idarubicin) followed by high-dose cytarabine

Newly diagnosed AML (non-APL) in patients fit for intensive chemotherapyOn the page “Leukaemia” · Regimens and dosing in newly diagnosed AML (induction, consolidation and maintenance)

Newly diagnosed AML (non-APL) in patients fit for intensive chemotherapy

Drug	Dose	Route	Schedule
Induction
Cytarabine	100 or 200 mg/m² per day	IV, continuous infusion	Days 1–7
Daunorubicin	60 mg/m² per day	IV	Days 1–3
Induction (instead of daunorubicin)
Idarubicin	12 mg/m² per day	IV	Days 1–3
Consolidation
High-dose cytarabine	1.5 to 3 g/m² every 12 hours	IV	Days 1, 3 and 5

Cycle length: Induction: 1 cycle and, if needed, a second cycle (7+3 or 5+2); consolidation: 28-day cycles
Duration: Up to 2 induction cycles, then up to 4 consolidation cycles or allogeneic transplantation according to ELN risk

These doses are the chemotherapy backbone of the RATIFY trial (daunorubicin 60 + cytarabine 200 mg/m²; consolidation with cytarabine 3 g/m²) and the QuANTUM-First trial (cytarabine 100 or 200, daunorubicin 60 or idarubicin 12; consolidation 1.5 to 3 g/m²). In FLT3-mutated AML, midostaurin or (in FLT3-ITD) quizartinib is added to this same backbone (following regimens). The decision between continued consolidation and allogeneic transplantation in first remission is based on ELN 2022 genetic risk.

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

7+3 + midostaurin (RATIFY)

Newly diagnosed AML with a FLT3 mutation (ITD or TKD) detected by an approved test, fit for intensive chemotherapy (patients aged 18 to 60 years in RATIFY)On the page “Leukaemia” · Regimens and dosing in newly diagnosed AML (induction, consolidation and maintenance)

Newly diagnosed AML with a FLT3 mutation (ITD or TKD) detected by an approved test, fit for intensive chemotherapy (patients aged 18 to 60 years in RATIFY)

Drug	Dose	Route	Schedule
Induction (up to 2 cycles)
Daunorubicin	60 mg/m² per day	IV	Days 1–3
Cytarabine	200 mg/m² per day	IV, continuous infusion	Days 1–7
Midostaurin	50 mg twice daily with food	Oral	Days 8–21
Consolidation (up to 4 cycles)
High-dose cytarabine	3 g/m² every 12 hours	IV	Days 1, 3 and 5
Midostaurin	50 mg twice daily with food	Oral	Days 8–21
Maintenance in RATIFY
Midostaurin	50 mg twice daily	Oral	Continuous, up to 12 cycles of 28 days

Cycle length: 28-day induction and consolidation cycles
Duration: Up to 2 induction cycles + up to 4 consolidation cycles (12-cycle maintenance only in the trial protocol)

Give prophylactic antiemetics before each dose; take the drug with food, approximately 12 hours apart. The FDA label approves midostaurin only in combination with induction and consolidation; single-agent maintenance was part of the RATIFY protocol, and patients who proceeded to transplantation discontinued study treatment.

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

7+3

AML, first inductionOn the page “7+3 regimen (AML induction) and high-dose cytarabine”

AML, first induction

Drug	Dose	Route	Schedule
Cytarabine	100 mg/m² a day	Continuous infusion	Days 1 to 7
Daunorubicin (or idarubicin 12 mg/m²)	60 to 90 mg/m²	IV	Days 1 to 3
Midostaurin (FLT3-positive only)	50 mg twice a day	Oral, with food	Days 8 to 21

Cycle length: One cycle; bone marrow assessment around day 14 and after count recovery
Duration: One to two induction cycles

Daunorubicin 90 as in E1900; midostaurin as in RATIFY.

Dose source:.

On the page “7+3 regimen (AML induction) and high-dose cytarabine”

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

1Standard chemotherapy + midostaurin

Induction: daunorubicin 60 mg/m² by rapid IV injection on days 1 to 3 and cytarabine 200 mg/m² by continuous IV infusion on days 1 to 7; midostaurin 50 mg orally twice daily on days 8 to 21 (a second identical induction cycle if needed).

Consolidation: four 28-day cycles of high-dose cytarabine 3000 mg/m² over 3 hours every 12 hours on days 1, 3 and 5, with midostaurin 50 mg twice daily on days 8 to 21.

Maintenance: midostaurin 50 mg orally twice daily for 12 cycles of 28 days.

2Standard chemotherapy + placebo

The same induction and consolidation regimen (daunorubicin/cytarabine, then high-dose cytarabine) with oral placebo on the same schedule, and placebo in the maintenance phase for 12 cycles.

Source of the regimen details: Full text of the paper in PMC (PMC5754190), Methods section

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 59 with newly diagnosed acute myeloid leukaemia (AML) with an FLT3 mutation (tyrosine kinase domain [TKD] point mutation or internal tandem duplication [ITD] with a high or low allelic ratio). Allogeneic transplantation was allowed.

Endpoints

Primary outcome: overall survival (OS).

Secondary outcomes: event-free survival (EFS), complete remission rate, disease-free survival and safety.

Safety and side effects

The rate of severe adverse events was similar in the two groups. Grade 3 to 5 anaemia (92.7% versus 87.8%) and grade 3 to 5 rash (14.1% versus 7.6%) were more frequent in the midostaurin group, and nausea was more frequent in the placebo group (9.6% versus 5.6%).

Clinical significance and place in guidelines

The first targeted drug in several decades to improve AML survival in a phase 3 trial. Midostaurin was approved in 2017 by the FDA and EMA for newly diagnosed FLT3-mutated AML with standard induction and consolidation chemotherapy. The ELN 2022 recommendations advise adding midostaurin to the "7+3" regimen for patients fit for intensive therapy with an FLT3 mutation (ITD or TKD).

Limitations

Only patients younger than 60 were enrolled. A large proportion of patients underwent allogeneic transplantation, and the independent role of maintenance therapy could not be assessed in the study design. At the time of the study, today's genetic classification (for example NPM1 status) was not fully incorporated into the analyses.

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.