Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries

Abstract

BackgroundChildren with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL.MethodsTo address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period.ResultsAll 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P = 0.026 and P = 0.003, respectively) worse for DS-ALL patients with white blood cell counts ≥50 × 109/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P = 0.029). The platelet counts were lower in the DS-ALL group (P = 0.005). Abnormal karyotypes were more common in non-DS-ALL (P < 0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P < 0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P < 0.001).ConclusionsThe present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL.

Childhood acute lymphoblastic leukemia: Integrating genomics into therapy

“…65 Common childhood ALLassociated translocations occur less frequently in DSassociated ALL (DS-ALL), and the outcomes of children with DS-ALL are inferior to those of children who have ALL without DS. [66][67][68] However, 50% to 60% of children with DS-ALL have rearrangements in the CRLF2 (cytokine receptor-like factor 2) gene, which is located in the pseudoautosomal region (PAR1) of chromosomes X and Y; and these rearrangements most commonly result from interstitial PAR1 deletion, causing purinergic receptor P2Y, G-protein coupled 8 (P2RY8)-cytokine receptorlike factor 2 (CRLF2) fusion (P2RY8-CRLF2). 69,70 Concomitant Janus kinase (JAK) mutations (generally missense point mutations in JAK2) occur in half of patients with CRLF2-rearranged DS-ALL and demonstrate activated JAK/signal transducer and activator of transcription (STAT) pathway and other cytokine receptor pathway signaling.…”

“…Children with trisomy 21 (Down syndrome [DS]) have an increased risk of developing B‐ALL, although the role of germline trisomy 21 in leukemogenesis remains incompletely understood . Common childhood ALL‐associated translocations occur less frequently in DS‐associated ALL (DS‐ALL), and the outcomes of children with DS‐ALL are inferior to those of children who have ALL without DS . However, 50% to 60% of children with DS‐ALL have rearrangements in the CRLF2 (cytokine receptor‐like factor 2) gene, which is located in the pseudoautosomal region (PAR1) of chromosomes X and Y; and these rearrangements most commonly result from interstitial PAR1 deletion, causing purinergic receptor P2Y, G‐protein coupled 8 ( P2RY8 )‐cytokine receptor‐like factor 2 ( CRLF2 ) fusion ( P2RY8‐CRLF2 ) .…”

Etiology of Leukemia in Children with Down Syndrome

“…No cases of infant DS-ALL were registered among 653 DS cases treated in various collaborative group clinical trials (Ponti di Legno Study Group) between (Buitenkamp et al 2014. Similarly, no cases of infant DS-ALL were present in other large treatment cohorts (Whitlock et al 2005 ;Lundin et al 2014 ;Arico et al 2008 ). The reasons for this apparent protection against infant ALL in DS remain unknown.…”

“…Lower frequencies of common cytogenetic abnormalities are also seen among children with DS-ALL. They have a lower incidence of the hyper-diploid karyotype, the ETV6 -RUNX1 t(12;21) fusion protein (Zeller et al 2005 ;Pui et al 1993 ;Lundin et al 2014 ), or other genetic alterations such as t(9;22) (q34;q11) ( BCR / ABL fusion gene), MLL rearrangements, and t(1;19) ( TCF3 -PBX1 fusion gene) (Pui et al 1993 ;Chessells 2001 ;Forestier et al 2008 ).…”

Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome

“…[3][4][5] Although no significant differences have been described in terms of demographic or baseline clinical characteristics, 4,5 the diagnosis of children with DS younger than 1 year is unusual. 4,6 Children with DS-ALL almost exclusively have B-cell precursor immunophenotype; T-cell and mature B-cell immunophenotypes a r e u n c o m m o n . 5 -7 A n o r m a l G-banding karyotype has been observed in 40% of these patients versus 10-20% of those WDS-ALL.…”