Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease

Abstract

In the European LeukemiaNet favourable risk category, allogeneic haematopoietic stem cell transplantation (alloSCT) is not indicated in first complete remission for patients with acute myeloid leukaemia (AML) with NPM1 mutations (ELNfav NPM1 AML), although a proportion of these patients will relapse. Given the prognostic importance of measurable residual disease (MRD), CETLAM-12 considered a pre-emptive intervention in patients with molecular failure (MF). We analyzed 110 ELNfav NPM1 AML patients achieving complete remission (CR) after induction chemotherapy. Two-year cumulative incidence of relapse (CIR), overall survival (OS) and leukaemia-free survival (LFS) were 17%, 81Á5% and 82%, respectively. Fortysix patients required additional therapy for MF (n = 33) or haematological relapse (HemR; n = 13), resulting in a molecular LFS (molLFS) and a cumulative incidence of MF at two years of 61% and 38% respectively. Two-year OS for these 46 patients was 66%, with a different outcome between patients with MF (86%) and HemR (42%) (P = 0Á002). Quantitative NPM1 detection at different timepoints was predictive of molLFS; an MRD ratio (NPM1mut/ ABL1 9 100) cutoff of 0Á05 after first consolidation identified two cohorts with a two-year molLFS of 77% and 40% for patients below and above 0Á05, respectively. In conclusion, MRD-based pre-emptive intervention resulted in a favourable outcome for ELNfav NPM1 AML patients.

Flow cytometric immunophenotypic alterations of persistent clonal haematopoiesis in remission bone marrows of patients with NPM1‐mutated acute myeloid leukaemia

“…To understand the potential clinical importance of these immunophenotypically aberrant cells, and examine their association with persistent CH, we conducted the present study on a cohort of patients with nucleophosmin 1‐mutated ( NPM1 mut ) AML. We chose this specific subtype of AML for the following reasons: i) NPM1 mutations occur in ∼30% of AML and co‐mutations in other genes including FMS‐like tyrosine kinase 3 ( FLT3 ), DNMT3A , IDH1, IDH2, and TET2 , are frequent 23–26 . Several of these mutations have been shown to persist beyond attaining NPM1 mut ‐negative remission 19 , 27,28 ; ii) NPM1 mutation is strongly associated with AML and is particularly rare in the CH setting 3,29 ; iii) NPM1 mut cells are highly sensitive to therapy and NPM1 mutation frequently becomes undetectable in patients who achieve a durable remission; and iv) Most NPM1 mut AML cases show highly aberrant and characteristic immunophenotypic alterations at diagnosis, being frequently negative for CD34, with an acute promyelocytic leukaemia (APL)‐like immunophenotype or monocytic differentiation 30 .…”

MRD Tailored Therapy in AML: What We Have Learned So Far

“…Therefore it can be hypothesized that these patients could benefit from extra pre-emptive treatment before transplantation ( 96 , 97 ). Bataller and colleagues looked into the usage of pre-emptive therapy after molecular failure, classified as the increase of MRD after treatment or failure to achieve molecular response after treatment ( 98 ). They divided the ELN favorable risk NPM1 MRD positive patients into two groups: one where patients proceeded directly to alloSCT and the other where patients received additional therapy before proceeding to alloSCT ( 69 ).…”

“…They divided the ELN favorable risk NPM1 MRD positive patients into two groups: one where patients proceeded directly to alloSCT and the other where patients received additional therapy before proceeding to alloSCT ( 69 ). The choice of additional treatment was based on the individual situation of the patient ( 98 ). No difference in 2-year OS was seen between the molecular failure group receiving extra pre-emptive treatment and the group that directly proceeded to alloSCT (81.5 versus 90%, respectively) ( 98 ).…”

“…The choice of additional treatment was based on the individual situation of the patient ( 98 ). No difference in 2-year OS was seen between the molecular failure group receiving extra pre-emptive treatment and the group that directly proceeded to alloSCT (81.5 versus 90%, respectively) ( 98 ). Compared to the patients that had a morphological relapse and proceeded to alloSCT after receiving salvage therapy, patients classified with molecular failure had a higher 2-year OS (morphological relapse vs. molecular failure, 42 vs. 85.7%, respectively).…”

A stitch in time saves nine… MRD‐based pre‐emptive therapy

“…In work reported in this issue of the journal, Bataller et al 11 . explored the value of pre‐emptive therapy for 157 patients with AML with mutated NPM1 who fell within the ELN favourable risk category at diagnosis and who were treated using the Spanish Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias CETLAM‐12 protocol.…”