# Cellular hierarchy for understanding heterogeneity of acute myeloid leukaemia with t(8;21)/RUNX1‐RUNX1T1

## TL;DR

This study shows that the stage of differentiation in t(8;21) AML affects survival and relapse rates, with monocytic-stage arrest linked to worse outcomes.

## Contribution

The study identifies differentiation arrest stage as a key prognostic factor in t(8;21) AML, independent of treatment type.

## Key findings

- Monocytic-stage arrest (Immuno-Mono) is associated with lower survival and higher relapse rates compared to primitive-stage arrest (Immuno-Prim).
- KIT mutations further worsen outcomes in t(8;21) AML patients, regardless of treatment.

## Abstract

Differentiation hierarchies in myeloid malignancies influence therapeutic response and prognosis. Acute myeloid leukaemia (AML) with t(8;21) is one of the most recurrent genetic subtypes of AML and is considered a distinct entity with shared characteristics. However, clinical outcomes remain markedly heterogeneous. This study aimed to investigate the relationship between leukaemic arrest at specific differentiation stages, genomic profiles and clinical outcomes in t(8;21) AML.

We conducted a retrospective study involving 338 patients with t(8;21) AML from three clinical centres in China. Patients received either chemotherapy alone (49.11%, n = 166) or chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo‐HSCT; 41.72%, n = 141). Immunophenotypic profiling classified patients into progenitor subgroups: MPP (20.12%, n = 68), lymphoid‐primed multi‐potent progenitor (14.50%, n = 49), CMP (12.72%, n = 43), GMP (24.85%, n = 84) and GP/MP (10.36%, n = 35). Based on differentiation stage, patients were categorised as primitive (Immuno‐Prim; 47.34%, n = 160) or monocytic (Immuno‐Mono; 35.21%, n = 119).

The Immuno‐Mono group was associated with lower 2‐year overall survival (OS) and a higher 2‐year cumulative incidence of relapse (CIR) compared to the Immuno‐Prim group. Patients with a KIT mutation had poorer 2‐year OS and higher 2‐year CIR than those without the mutation. In the allo‐HSCT cohort, the Immuno‐Mono group continued to show lower 2‐year OS and higher 2‐year CIR relative to the Immuno‐Prim group. Neither gene mutations (aside from KIT) nor chromosomal losses significantly affected OS or CIR.

Leukaemic differentiation stage independently predicts post‐treatment outcomes in t(8;21) AML. Arrest at specific myeloid stages correlates significantly with genetic aberrations, clinical presentation, therapeutic response and survival.

In this multi‐centre study of 338 t(8;21) acute myeloid leukaemia patients, we demonstrate that leukaemic arrest at monocytic differentiation stages (Immuno‐Mono) predicts significantly worse 2‐year survival and higher relapse rates than primitive‐stage arrest (Immuno‐Prim), independent of therapy. We further identify KIT mutations as compounding adverse factors and show that allogeneic transplantation fails to overcome Immuno‐Mono‐associated risk, establishing differentiation arrest as a key prognostic determinant.