Molecular relapse after first-line intensive therapy in patients with CBF or NPM1-mutated acute myeloid leukemia - a FILO study

Abstract

Patients with Core-Binding Factor (CBF) and NPM1-mutated acute myeloid leukemia (AML) can be monitored by quantitative PCR after having achieved first complete remission (CR) to detect morphologic relapse and drive preemptive therapy. How to best manage these patients is unknown. We retrospectively analyzed 303 patients with CBF and NPM1-mutated AML, aged 18-60 years, without allogeneic hematopoietic cell transplantation (HCT) in first CR, with molecular monitoring after first-line intensive therapy. Among these patients, 153 (51%) never relapsed, 95 (31%) had molecular relapse (53 received preemptive therapy and 42 progressed to morphologic relapse at salvage therapy), and 55 (18%) had upfront morphologic relapse. Patients who received preemptive therapy had higher OS than those who received salvage therapy after having progressed from molecular to morphologic relapse and those with upfront morphologic relapse (three-year OS: 78% vs. 51% vs. 51%, respectively, P = 0.01). Preemptive therapy included upfront allogeneic HCT (n = 19), intensive chemotherapy (n = 21), and non-intensive therapy (n = 13; three-year OS: 92% vs. 79% vs. 58%, respectively, P = 0.09). Although not definitive due to the non-randomized allocation of patients to different treatment strategies at relapse, our study suggests that molecular monitoring should be considered during follow-up to start preemptive therapy before overt morphologic relapse.

Fig. 1. Description of states and transitions in the multistate model.

A Flow chart of patients with CBF and NPM1-mutated AML included in the study cohort with description of states and transitions used in the multistate model. B Predicted probabilities of being in a specific state over time, from initial diagnosis.

Fig. 2

Cumulative incidence of molecular and morphologic relapses in the study cohort (n = 303).

Fig. 3

Overall survival of 150 patients with CBF or NPM1-mutated AML who relapsed during follow-up, stratified by the type of relapse (molecular relapse with preemptive therapy vs. molecular relapse with morphologic relapse at the time of salvage therapy vs. upfront morphologic relapse), calculated from the time of first detected relapse.

Fig. 4

Overall survival of 53 patients with CBF or NPM1-mutated AML with molecular relapse who received preemptive therapy, stratified by the type of salvage therapy (upfront allogeneic hematopoietic cell transplantation (HCT) vs. intensive chemotherapy vs. non-intensive chemotherapy), calculated from the time of first detected relapse.