Correlation between MRD-positivity and benefit of allogeneic transplant in NPM1-mutated AML, regardless of FLT3 ITD

Results from a pooled dataset from the AML17 and AML19 trials demonstrated that the presence of molecular minimal residual disease (MRD) following induction chemotherapy can be used to determine patients with NPM1-mutated acute myeloid leukaemia (AML) who may benefit from allogeneic transplant in first remission, regardless of whether FLT3 internal tandem duplication (ITD) mutations are present as well.

NPM1 is the most commonly mutated gene in AML and is generally considered as a favourable-risk marker. However, according to the latest ELN classification, patients are considered intermediate-risk if they also have FLT3 internal tandem duplication (ITD) mutations and adverse-risk if a rare adverse karyotype is present. The role of allogeneic transplant in first remission (CR1-allo) in NPM1-mutated AML remains controversial, with significant variation in practice worldwide. Early studies demonstrated no benefit to CR1-allo in NPM1-mutated AML with wild-type or low allelic ratio FLT3 ITD. Furthermore, MRD has been shown to be associated with large survival differences in patients with NPM1 mutations. In order to determine whether molecular MRD can be used to stratify decision making regarding post-remission therapy in patients with NPM1-mutated AML, data were compared from two large studies conducted in the United Kingdom, AML17 and AML19.

Study design

NCRI AML17 (April 2009 to December 2014) and AML19 (November 2015 to November 2020) were sequential prospective randomised trials for younger adults (18 – 60 years) with newly diagnosed AML. In AML17, decisions regarding CR1-allo were made using a validated risk score incorporating baseline factors and response to induction. In AML19, for patients with NPM1-mutated AML, the protocol recommended CR1-allo only in patients testing MRD-positive in the peripheral blood (PB) post cycle 2 (PC2), regardless of other baseline risk factors such as FLT3 ITD. Importantly, both trials were performed prior to the availability of midostaurin and FLT3 ITD MRD assays. Molecular relapses were included as relapse events, and alloSCT performed after molecular relapse was not considered as CR1. At ASH 2023, Dr. Othman compared the outcomes of patients with NPM1-mutations in these trials and assessed the benefit of CR1-allo according to FLT3 ITD and molecular MRD status.

Results

In total, 737 patients with NPM1-mutated AML who achieved CR/CRi and had a valid PC2 PB MRD result were included in the analysis. In AML17 (N= 348), 17% of patients tested PB PC2 MRD-positive, as compared to 21% of patients in AML19 (N= 389). Median age of the patients was 52 years old, 39% had FLT3 ITD and 40% of patients received a transplant at one point in their disease course. In AML17, MRD-positive patients generally had poor outcomes, with a 3-year cumulative incidence of relapse (CIR) of 84% and overall survival (OS) of 25%. These outcomes were improved in AML19, with 3-year CIR of 50% and 3-year OS of 51%.

A significant survival advantage (HR[95%CI]: 0.39[0.24-0.64]) was observed in patients who had detectable MRD after the first two courses of chemotherapy if they received a transplant in their first remission compared with patients who were MRD-negative (HR[95%CI]: 0.82[0.50-1.33]) after chemotherapy. Furthermore, there was no subgroup heterogeneity and transplantation benefitted all patients with MRD-negative status. Conversely, the study identified no subgroup in the MRD-negative population with a survival advantage from allogeneic transplant.

Interestingly, the MRD-status also predicts the benefit of transplantation in patients with NPM1-mutated AML and FLT3 ITD. In this patient population (N= 286), patients who were MRD-positive (N= 81) benefitted more from transplant vs. no transplant (HR[95%CI]: 0.52[0.29-0.93]), as compared to the patients who were MRD-negative (N= 205, HR[95%CI]: 0.80[0.37-1.72]).

Conclusion

Molecular MRD after induction chemotherapy identifies patients with NPM1-mutated AML who benefit from allogeneic transplant in first remission. Patients achieving MRD negativity in blood after second induction show no survival benefit from CR1 transplant, even if they are FLT3 ITD co-mutated.

Reference

Othman J, et al. The Benefit of Allogeneic Transplant in 1st Complete Remission in NPM1 Mutated AML with or without FLT3 ITD Is Restricted to Those Testing MRD Positive after Induction – an Analysis of the UK NCRI AML17 and AML19 Studies. Presented at ASH 2023; Abstract 425.