Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non‐Down syndrome

Abstract

Pediatric acute megakaryoblastic leukemia in non-Down syndrome (AMKL) is a unique subtype of acute myeloid leukemia (AML). Novel CBFA2T3-GLIS2 and NUP98-KDM5A fusions recurrently found in AMKL were recently reported as poor prognostic factors. However, their detailed clinical and molecular characteristics in patients treated with recent improved therapies remain uncertain. We analyzed molecular features of 44 AMKL patients treated on two recent Japanese AML protocols, the AML99 and AML-05 trials. We identified CBFA2T3-GLIS2, NUP98-KDM5A, RBM15-MKL1, and KMT2A rearrangements in 12 (27%), 4 (9%), 2 (5%), and 3 (7%) patients, respectively. Among 459 other AML patients, NUP98-KDM5A was identified in 3 patients, whereas CBFA2T3-GLIS2 and RBM15-MKL1 were only present in AMKL. GATA1 mutations were found in 5 patients (11%). Four-year overall survival (OS) and event-free survival (EFS) rates of CBFA2T3-GLIS2-positive patients in AMKL were 41.7% and 16.7%, respectively. Three-year cumulative incidence of relapse in CBFA2T3-GLIS2-positive patients was significantly higher than that of CBFA2T3-GLIS2-negative patients (75.0% vs. 35.7%, P = 0.024). In multivariate analyses, CBFA2T3-GLIS2 was an independent poor prognostic factor for OS (HR, 4.34; 95% CI, 1.31-14.38) and EFS (HR, 2.95; 95% CI, 1.20-7.23). Furthermore, seven (54%) of 13 infant AMKL patients were CBFA2T3-GLIS2-positive. Notably, out of 7 CBFA2T3-GLIS2-positive infants, six (86%) relapsed and five (71%) died. Moreover, all of CBFA2T3-GLIS2-positive patients who experienced induction failure (n = 3) were infants, indicating worse prognosis of CBFA2T3-GLIS2-positive infants. These findings indicated the significance of CBFA2T3-GLIS2 as a poor prognostic factor in AMKL patients, particularly in infants.

CBFA2T3‐GLIS2‐positive acute myeloid leukaemia. A peculiar paediatric entity

“…Indeed, genetic mutations involving GATA1 , KIT and FLT3 genes are less frequent in CBFA2T3‐GLIS2 ‐positive than in negative patients, being detected only in few cases. In the study reported by Hara et al (), genetic mutations were found in 14% of AMKL CBFA2T3‐GLIS2 ‐positive patients as compared to 35% of negative patients. The genes commonly involved are FLT3 , GATA1 and KIT (Hara et al , ) as well as RAS mutations and mutations in the JAK/STAT pathway (Table ) (Gruber et al , ; De Rooij et al , ).…”

“…In the study reported by Hara et al (), genetic mutations were found in 14% of AMKL CBFA2T3‐GLIS2 ‐positive patients as compared to 35% of negative patients. The genes commonly involved are FLT3 , GATA1 and KIT (Hara et al , ) as well as RAS mutations and mutations in the JAK/STAT pathway (Table ) (Gruber et al , ; De Rooij et al , ). So far, an impact of the mutation burden on the outcome of CBFA2T3‐GLIS2 positive AML has not been demonstrated.…”

“…In the two largest cohorts of paediatric AMKL screened by deep‐sequencing approaches and collected thanks to international collaborative efforts, the presence of the CBFA2T3‐GLIS2 fusion gene was detected in 16% and 18·6% of cases (De Rooij et al , , ). Recently, a higher percentage (27%) of transcript‐positive patients was reported in paediatric non‐DS‐AMKL enrolled in two Japanese clinical trials, whilst it was not identified in any of the other paediatric AML cases studied (Hara et al , ).…”

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

“…In addition, haematopoietic stem cell transplantation (SCT) is generally not performed in infants with AML in the low‐ or intermediate‐risk group owing to its late side effects (Niewerth et al , ). However, CBFA2T3‐GLIS2 and NUP98‐KDM5A have been recently found to be poor prognostic markers (de Rooij et al , ; Hara et al , ). Thus, the establishment of a revised risk‐stratified therapy specific for infants with AML may improve treatment outcomes and reduce late side effects.…”

Leucémies à mégacaryoblastes de l’enfant

“…Répartition des oncogènes de fusions les plus fréquents dans les LAM7 de novo. (selon [39] et [20]). B. Fréquences des mutations additionnelles observées dans les différents sous-groupes de LAM7 pédiatriques.…”