Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia.

Rama Al Hamed,Eleni Tholouli,Arnon Nagler,Hélène Labussière‐Wallet,Goda Choi,Marie‐Thérèse Rubio,Mohamad Mohty,Hans Martin,Anne Huynh,Riitta Niittyvuopio,Ali Bazarbachi,Xavier Poiré,Myriam Labopin,Nicolaus Kröger,Micha Srour,Didier Blaise,Pavel Jindra,Gèrard Socié ,Dietrich W Beelen ,Étienne Daguindau ,Jean Bourhis

doi:10.1002/cam4.4218

Abstract

Nucleophosmin‐1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3‐internal tandem duplication (FLT3‐ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo‐HCT). We identified 1572 adult (age ≥ 18 year) patients with NPM1‐mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow‐up for survivors was 23.7 months. FLT3‐ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia‐free survival (LFS) were negatively affected by concomitant FLT3‐ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10−5 and HR 1.71, p < 10−5, respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score ≥90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3‐ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10−5), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score ≥90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3‐ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1‐mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.

Highlights

Acute myeloid leukemia (AML) is a heterogenous disease with a highly variable prognosis and high overall mortality
Nucleophosmin-1 (NPM1) is an essential gene encoding a protein that physiologically shuttles between the nucleus and cytoplasm to establish multiple protein–p rotein interactions involving critical cell functions such as formation and export of ribosomes, stabilization of the oncosuppressor p14Arf protein, and regulation of centrosome duplication.3–5 NPM1 mutations occur in approximately 30% of adult AML cases and in 50%–60% of normal karyotype AML, representing one of the most frequently encountered molecular abnormalities in AML.5–7 In normal karyotype AML, and in the absence of FLT3-internal tandem duplication (FLT3-ITD), NPM1 mutation reduces the risk of relapse and confers a survival advantage
| 3 (EBMT) registry, we investigated the predictive factors of posttransplant outcomes in patients with normal karyotype NPM1-m utated AML with specific emphasis on the individual and aggregate roles of measurable residual disease (MRD) status before transplant, FLT3-I TD mutation status, and disease status at transplant

Summary

| INTRODUCTION

Acute myeloid leukemia (AML) is a heterogenous disease with a highly variable prognosis and high overall mortality. Allogeneic hematopoietic stem cell transplant (allo-HCT) is deferred in these patients in first complete remission (CR1) unless in the setting of minimal/ measurable residual disease (MRD) positivity or disease relapse.[10] when NPM1 is present in the setting of FLT3-ITD at high allelic burden, disease prognosis significantly decreases and patients are referred for allo-HCT in CR1 irrespective of MRD status.[10] Transplant indication in CR1 remains controversial in patients with NPM1-mutated AML and low allelic burden of FLT3-ITD. Current data suggest that the concomitant presence of FLT3-ITD and NPM1, MRD positivity before or after transplant, and disease status at the time of transplant influence the risk of posttransplant relapse and affect outcome.10–13 the respective and independent contributions of these factors remain largely unknown. (EBMT) registry, we investigated the predictive factors of posttransplant outcomes in patients with normal karyotype NPM1-m utated AML with specific emphasis on the individual and aggregate roles of MRD status before transplant, FLT3-I TD mutation status, and disease status at transplant

| Study design and data collection

| RESULTS

| DISCUSSION

| LIMITATIONS

Findings

| CONCLUSION