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Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor
Chiara Palmi1, Silvia Bresolin2,3, Stefanie Junk4
1Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
Insights
Children with Down syndrome and acute lymphoblastic leukemia (DS-ALL) have a poorer prognosis. The Philadelphia-like (Ph-like) profile and IKZF1plus pattern are linked to worse outcomes in DS-ALL, necessitating tailored treatments.
Area of Science:
- Pediatric Oncology
- Hematology
- Cancer Genetics
Background:
- Children with Down syndrome (DS) have a higher risk of B-cell acute lymphoblastic leukemia (DS-ALL), often with lower survival rates compared to non-DS ALL.
- DS-ALL typically shows fewer common cytogenetic abnormalities but increased genetic alterations like CRLF2 overexpression and IKZF1 deletions.
Purpose of the Study:
- To investigate the incidence and prognostic impact of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern in DS-ALL.
- To determine if these features contribute to the lower survival observed in DS-ALL patients.
Main Methods:
- Analysis of genetic profiles (Ph-like signature, CRLF2, IKZF1 alterations) in DS-ALL patient cohorts from Italy and Germany.
- Evaluation of the prognostic value of Ph-like signature and IKZF1plus in relation to relapse and survival rates.
- Ex vivo drug screening on IKZF1plus leukemia cells.
Main Results:
- The Ph-like signature was identified in 46/70 DS-ALL patients, predominantly with CRLF2 or IKZF1 alterations.
- The IKZF1plus feature was observed in 18% of a combined cohort.
- Both Ph-like signature and IKZF1 deletion were significantly associated with a poor outcome, with outcomes worsening further when IKZF1 deletion co-occurred with P2RY8::CRLF2 (IKZF1plus).
- IKZF1plus blasts showed sensitivity to drugs targeting Ph-like ALL.
Conclusions:
- The Philadelphia-like (Ph-like) profile and IKZF1plus pattern are significant adverse prognostic factors in Down syndrome acute lymphoblastic leukemia (DS-ALL).
- These findings support the need for tailored therapeutic strategies for DS-ALL patients, particularly those with Ph-like or IKZF1plus features.
- Ex vivo drug sensitivity suggests potential targeted therapies for IKZF1plus DS-ALL.
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.
