AML19
Research type
Research Study
Full title
Adults with acute myeloid leukaemia or high-risk myelodysplastic syndrome (AML19)
IRAS ID
154468
Contact name
Nigel Russell
Contact email
Eudract number
2014-002195-90
Clinicaltrials.gov Identifier
C26822/A16484, Award Ref. Number
Research summary
Research Summary
AML19 will build upon the results of previous trials in acute myeloid leukaemia. It will evaluate several relevant therapeutic questions in patients who are 1860 years old and suitable for intensive chemotherapy. For patients who do not have the APL subtype, the investigators will evaluate the best way of adding mylotarg to induction chemotherapy. After induction, patients will be characterised based upon their prognosis and may enter different randomisations the randomisations allow patients to access different treatments based on their disease profile. The investigators will also evaluate whether continued monitoring of patients can improve outcomes and affects quality of life. Patients with the APL subtype will enter a different part of the trial.
Summary of Results
Cancer Research UK AML19 Trial: Summary of trial findings The AML19 trial opened to patients between the ages of 16 and 60, diagnosed with acute myeloid leukaemia (AML) or high risk myelodysplastic syndrome (MDS). As with previous AML trials supported by the National Cancer Research Institute AML working group, this trial took the form of a platform trial which allowed questions to be asked at different stages of the patient's treatment pathway and build on the results of earlier trials. The trial was Sponsored by Cardiff University and opened in 104 sites across the UK, Denmark and New Zealand, recruiting 2083 patients between 2014 and 2021.
AML is a fast-growing cancer of the blood-forming cells in the bone marrow and is classified as favorable risk, intermediate risk, or adverse risk based on the presence or absence of certain genetic mutations. AML19 tested "risk-adapted" therapy, where different treatments were available depending on the different features of the patient. As risk factors can change based on response to earlier therapy, AML19 was designed to allow patient's treatment options to change through the course of their journey through the trial.
The AML19 trial aimed to answer the following questions:
1. Is the use of a fractionated Mylotarg dose (GO) (2 doses of 3 mg/m2) superior to a single Mylotarg dose (3mg/m2) when combined with either DA or FLAG-Ida induction chemotherapy?
2. Does FLAG-Ida /GO (intensified) induction (best of AML15) improve survival compared to DA /GO (intensified) induction chemotherapy?
3. Does the addition of 1 or 2 courses of HDAC consolidation to 2 courses of FLAG-Ida induction improve survival?
4. In high risk patients or those patients with known poor risk cytogenetics at diagnosis does CPX-351 improve survival compared to FLAG-Ida?
5. Does Molecular Monitoring improve patients long term outcomes versus Standard Clinical Care (no monitoring) in Younger Adults with Acute Myeloid LeukaemiaTrial outcomes - Q1, Q2 +Q3
* This part of the trial set out to determine the optimal induction chemotherapy regimen for younger adults with newly-diagnosed AML without known adverse risk cytogenetics (standard risk).
* 1033 patients were randomly assigned to intensified (FLAG-Ida) or standard(DA) induction chemotherapy with one or two doses of gemtuzumab ozogamicin (GO).
* The results showed no benefit for a fractionated GO dose vs a single dose
* The combination of the treatment regime FLAG-Ida with GO significantly reduced relapse in younger adults with AML and improved event free survival but did not improve overall survival.
* Fewer transplants were performed in patients receiving FLAG-Ida with GO.
* Exploratory analyses showed that of the subgroups patients with NPM1 and FLT3 mutations , (accounting for over 40% of patients) receiving FLAG-ida GO had substantial improvements in overall survival.
* By contrast, in patients with core binding factor AML, outcomes were excellent with DA GO1 with no FLAG-Ida benefit
* The question of what consolidation is required after two courses of FLAG-Ida 1 GO remains open. This randomized comparison showed no overall survival benefit from two courses of HDAC, although there was an increase in relapse risk with one consolidation course.Impact on clinical practice
* For patients with newly diagnosed AML without adverse risk cytogenetics FLAG-ida GO significantly reduces the risk of relapse over current standard of care therefore would be a preferred treatment option as it reduces the requirement for salvage chemotherapy at relapse and reduces the requirement for transplant.
* For the subgroup of patients with NPM1 and FLT3 mutations FLAG-ida GO is the optimal treatment, with exploratory analysis showing substantial improvements in overall survival.
* For patients with core binding factor AML, DA GO is the optimal treatment, with FLAG-ida offering no benefit.Trial Outcomes - Q4 High Risk Patients
* This part of the trial set out to determine the optimal induction chemotherapy regime for younger adults with newly-diagnosed AML with known adverse risk cytogenetics.
* 189 patients were randomly assigned to either CPX-351 or FLAG-Ida chemotherapy
* In high-risk AML and MDS, CPX-351 did not improve response or survival compared with FLAG-Ida but did significantly reduce the chances of relapse
* In the exploratory analysis of a subgroup of patients defined by the presence of myelodysplasia-related gene mutations, CPX-351 did show a significant survival benefit over FLAG-ida.
Impact on clinical practice
* The exploratory analysis suggests secondary AML is better defined by mutational profile than clinical history. To improve outcomes in this group would require rapid availability of next generation sequencing results in a clinical setting to inform treatment decisions, as patients may benefit from treatment with CPX-351 over standard of care.Trial outcome Q5 - Molecular Monitoring Versus Standard Clinical Care
* This part of the trial set out to determine whether sequential molecular MRD monitoring during treatment and for two years after improved patient outcomes over standard clinical care with no molecular monitoring.
* 637 patients (from the AML17 and AML19 trials) were randomly allocated to either the monitor or no-monitor (standard of care) arm.
* Overall there was no difference in survival between patients who received either sequential molecular MRD monitoring or standard clinical care only with no molecular monitoring.
* Importantly in a planned sub-group analysis MRD monitoring coupled with MRD-guided treatment substantially reduced the risk of death in patients with AML with a combination ofNPM1 and FLT3 ITD mutations but had little effect on survival in other genotypes.
Impact in clinical practice
* For patients with NPM1 and FLT3 mutations, MRD monitoring and MRD guided treatment decisions (targeted treatment with FLT3 inhibitors) improved patients survival. Integrating MRD monitoring in to the treatment pathway as part of standard practice for these patients has been established as a standard of care.Does the presence of Measurable Residual Disease( MRD) After Two Chemotherapy Cycles Predict Benefit from Donor Transplant in AML patients with an NPM1 Mutation
* This part of the trial explored if the presence of MRD after two chemotherapy cycles predicted a benefit from donor transplant in patients with AML with genetic mutations, NPM1 and FLT3.
* Data from 737 patients (AML17/19) was analysed exploring patient outcomes based on their mutation status (NPM1 only or both NPM1 and FLT3), whether or not they underwent a donor transplant, and whether they were MRD positive or MRD negative when tested after two rounds of chemotherapy.
* Among patients with acute myeloid leukemia (AML) with genetic mutations NPM1, FLT3, or both, those who had no detectable residual leukemia cells in the blood based on high-sensitivity testing and after two cycles of chemotherapy achieved high rates of overall survival at 3 years and saw no additional survival benefit from undergoing a donor stem cell transplant.
* Among patients who had residual leukemia cells in the blood, those who received a donor stem cell transplant had improved survival compared with those who did not undergo a transplant.Impact in clinical practice
* This is the largest study to examine whether measurable residual disease (MRD) after two cycles of chemotherapy could identify which patients with NPM1 mutated AML would benefit from a transplant. The findings support making MRD status after two rounds of chemotherapy a major part of standard process for selecting patients who are likely to benefit from transplantation and demonstrates for the first time that transplant in first remission can be avoided for a significant number of patientsREC name
Wales REC 3
REC reference
14/WA/1056
Date of REC Opinion
12 Aug 2014
REC opinion
Further Information Favourable Opinion