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.

Biostatistics and Clinical Epidemiology Fondazione IRCCS San Gerardo dei Tintori Monza Italy

Center of Pediatric Hematology and Oncology Azienda Policlinico San Marco Catania Italy

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Paediatric Oncology Haematology and Clinical Immunology Heinrich Heine University Dusseldorf Medical Faculty Düsseldorf Germany

Istituto di Ricerca Pediatrica Città della Speranza Padua Italy

Medical Genetics School of Medicine and Surgery University of Milan Bicocca Monza Italy

Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Pediatrics Christian Albrechts University and University Medical Center Schleswig Holstein Kiel Germany

Pediatrics Fondazione IRCCS San Gerardo dei Tintori Monza Italy

School of Medicine and Surgery University of Milan Bicocca Italy

Statistics University of Milan Bicocca Monza Italy

Tettamanti Center Fondazione IRCCS San Gerardo dei Tintori Monza Italy

Women's and Children's Health Department Hematology Oncology Clinic and Laboratory University Hospital of Padua Italy

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