Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia

Abstract

Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, CRLF2 overexpression and IKZF1 deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern. These features have been associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols. Forty-six out of 70 DS-ALL patients treated in Italy from 2000 to 2014 displayed Ph-like signature, mostly characterized by CRLF2 (n = 33) and IKZF1 (n = 16) alterations; only 2 cases were positive for ABL-class or PAX5-fusion genes. Moreover, in an Italian and German joint cohort of 134 DS-ALL patients, we observed 18% patients positive for IKZF1plus feature. Ph-like signature and IKZF1 deletion were associated with poor outcome (cumulative incidence of relapse: 27.7 ± 6.8% versus 13 ± 7%; P = 0.04 and 35.2 ± 8.6% versus 17 ± 3.9%; P = 0.007, respectively), which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition (13/15 patients had an event of relapse or treatment-related death). Notably, ex vivo drug screening revealed sensitivity of IKZF1plus blasts for drugs active against Ph-like ALL such as Birinapant and histone deacetylase inhibitors. We provided data in a large setting of a rare condition (DS-ALL) supporting that these patients, not associated with other high-risk features, need tailored therapeutic strategies.

Multifaceted roles of IKZF1 gene, perspectives from bench to bedside

“…Buitenkamp T et al showed that DS-ALL patients had a similar frequency of IKZF1 deletions to that of high-risk (HR) non-DS-ALL patients (~30%) (81). Palmi C et al discovered that the IKZF1 plus feature in DS-ALL was 3 times more frequent than in non-DS-ALL (18% versus 6%), and IKZF1 plus patients had even worse outcome as well as higher relapse (82). Furthermore, they also found that the blasts of IKZF1 plus DS-ALL patients were particularly sensitive to drugs which had been described to be effective in Ph-like cases, such as HDAC inhibitors.…”

“…Song C et al demonstrated that TBB and CX-4945, different kinds of casein kinase II inhibitors, restored IKAROS activity and showed an antileukemia effect by inhibiting the transcription of the genes involved in the PI3K pathway (105). Palmi C et al studied some compounds in vitro cell culture that show one of histone deacetylase inhibitors, Givinostat, has the highest efficacy on IKZF1 plus blasts in comparison to controls (82). In the clinical setting, the direct targeting of IKZF1 to restore its function have not been yet.…”

“…Palmi C et al. studied some compounds in vitro cell culture that show one of histone deacetylase inhibitors, Givinostat, has the highest efficacy on IKZF1 plus blasts in comparison to controls ( 82 ). In the clinical setting, the direct targeting of IKZF1 to restore its function have not been yet.…”