Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup

Abstract

Summary Although infants (age <1 year) with acute myeloid leukaemia (AML) have unique characteristics and are vulnerable to chemotherapy, children aged 1–2 years with AML may have characteristics similar to that of infants. Thus, we analysed 723 paediatric AML patients treated on the Japanese AML99 and AML‐05 trials to identify characteristics of younger children. We identified patients aged <3 years (the younger group) as a distinct subgroup. KMT2A‐rearrangement (KMT2A‐R), CBFA2T3‐GLIS2, CBFB‐MYH11 and NUP98‐KDM5A were frequently found in the younger group. Prognostic analyses revealed poor 5‐year overall survival (OS), event‐free survival (EFS) and cumulative incidence of relapse (CIR) in patients with CBFA2T3‐GLIS2 (42%, 17% and 83%, respectively) and those with NUP98‐KDM5A (33%, 17% and 83%, respectively). Additionally, we identified KMT2A‐R and CBFB‐MYH11 as age‐specific prognostic markers. Regarding KMT2A‐R, the younger group had significantly better OS, EFS and CIR than the older group (aged 3 to <18 years) (P = 0·023, 0·011 and <0·001, respectively). Conversely, concerning CBFB‐MYH11, the younger group had significantly poor EFS and CIR than the older group (each P < 0·001), suggesting that certain molecular markers are linked to different prognoses according to age. Therefore, we characterized patients <3 years as a distinct subgroup of paediatric AML.

Prognostic stratification of molecularly and clinically distinct subgroup in children with acute monocytic leukemia

“…Although the high incidence of MLL‐R in the case of children AML, the relationship between MLL‐R and outcome in AML is less straightforward than in ALL 29 . Hara et al reported that MLL‐R has age‐specific prognostic effect, and the children ≤3 years with this fusion gene had a better prognosis than the older ones 30 . Conversely, when analyzing a large cohort of pediatric AMLs with MLL‐R , 5‐year EFS and OS were poorer, when compared with all pediatric AML 31 .…”

Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity

“…Infant acute myeloid leukemia (AML) has been conventionally defined as AML in patients aged <1 year [1,2,8]. If infant specific features can be seen up to 3 years, they are more prominent up to 2 years of age and many groups agree to define the infant group by children less than 2 years of age [1,9].…”

“…The incidence of pediatric AML is estimated to be between 5 and 7 cases per million people per year, with a peak of incidence at 11 cases per million people per year at 2 years of age [10]. Infant AML is a distinct entity, representing 10-25% of pediatric AML, depending on age limits: 32% of children if the cut off is set at 3 years old in a Japanese cohort, 12% of children if <1 or 24% <2 years old in a ELAM02 French cohort [1,2]. Overall AML in children less than 2 years of age represent a fourth of childhood AML with unique features.…”

“…Typical leukemia presentations with anemia, bleeding, febrile neutropenia, bone pain and organomegaly are not uncommon but some specific aspects need to be underlined. AML in infants is more frequently associated with higher white blood cell counts and extra-medullary symptoms than in older children, notably skin lesions and central nervous system (CNS) involvement [1,2,8,12,13].…”

“…AMKL is highly associated with this subgroup and is rare in other age groups. This intriguing feature has prompted interest by different groups and recent in-depth molecular studies have been reported in the literature [2][3][4]. These research groups have been able to decipher the genomic landscape of AML and more specifically AMKL, by identifying recurrent fusions either unique to infant AML or strongly associated with this age group.…”