Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia
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...
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-06-01
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| Series: | HemaSphere |
| Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000892 |
| _version_ | 1797280322236186624 |
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| author | Chiara Palmi Silvia Bresolin Stefanie Junk Grazia Fazio Daniela Silvestri Marketa Zaliova Athanasios Oikonomou Katerina Scharov Martin Stanulla Anja Moericke Martin Zimmermann Martin Schrappe Barbara Buldini Sanil Bhatia Arndt Borkhardt Claudia Saitta Marta Galbiati Michela Bardini Luca Lo Nigro Valentino Conter Maria Grazia Valsecchi Andrea Biondi Geertruy te Kronnie Gunnar Cario Giovanni Cazzaniga |
| author_facet | Chiara Palmi Silvia Bresolin Stefanie Junk Grazia Fazio Daniela Silvestri Marketa Zaliova Athanasios Oikonomou Katerina Scharov Martin Stanulla Anja Moericke Martin Zimmermann Martin Schrappe Barbara Buldini Sanil Bhatia Arndt Borkhardt Claudia Saitta Marta Galbiati Michela Bardini Luca Lo Nigro Valentino Conter Maria Grazia Valsecchi Andrea Biondi Geertruy te Kronnie Gunnar Cario Giovanni Cazzaniga |
| author_sort | Chiara Palmi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T16:38:29Z |
| format | Article |
| id | doaj.art-8b3553e763074371b4c8f44d90e57a09 |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-03-07T16:38:29Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj.art-8b3553e763074371b4c8f44d90e57a092024-03-03T09:08:00ZengWileyHemaSphere2572-92412023-06-0176e89210.1097/HS9.0000000000000892202306000-00009Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic LeukemiaChiara Palmi0Silvia Bresolin1Stefanie Junk2Grazia Fazio3Daniela Silvestri4Marketa Zaliova5Athanasios Oikonomou6Katerina Scharov7Martin Stanulla8Anja Moericke9Martin Zimmermann10Martin Schrappe11Barbara Buldini12Sanil Bhatia13Arndt Borkhardt14Claudia Saitta15Marta Galbiati16Michela Bardini17Luca Lo Nigro18Valentino Conter19Maria Grazia Valsecchi20Andrea Biondi21Geertruy te Kronnie22Gunnar Cario23Giovanni Cazzaniga241 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy2 Women’s and Children’s Health Department, Hematology-Oncology Clinic and Laboratory, University-Hospital of Padua, Italy4 Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy5 Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy6 Department of Paediatric Oncology, Haematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Düsseldorf, Germany4 Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany7 Pediatrics, Christian-Albrechts-University and University Medical Center Schleswig-Holstein, Kiel, Germany4 Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany7 Pediatrics, Christian-Albrechts-University and University Medical Center Schleswig-Holstein, Kiel, Germany2 Women’s and Children’s Health Department, Hematology-Oncology Clinic and Laboratory, University-Hospital of Padua, Italy6 Department of Paediatric Oncology, Haematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Düsseldorf, Germany6 Department of Paediatric Oncology, Haematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Düsseldorf, Germany1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy8 Center of Pediatric Hematology and Oncology, Azienda Policlinico-San Marco, Catania, Italy1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy9 Statistics, University of Milan Bicocca, Monza, Italy11 Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy2 Women’s and Children’s Health Department, Hematology-Oncology Clinic and Laboratory, University-Hospital of Padua, Italy7 Pediatrics, Christian-Albrechts-University and University Medical Center Schleswig-Holstein, Kiel, Germany1 Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, ItalyChildren 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.http://journals.lww.com/10.1097/HS9.0000000000000892 |
| spellingShingle | Chiara Palmi Silvia Bresolin Stefanie Junk Grazia Fazio Daniela Silvestri Marketa Zaliova Athanasios Oikonomou Katerina Scharov Martin Stanulla Anja Moericke Martin Zimmermann Martin Schrappe Barbara Buldini Sanil Bhatia Arndt Borkhardt Claudia Saitta Marta Galbiati Michela Bardini Luca Lo Nigro Valentino Conter Maria Grazia Valsecchi Andrea Biondi Geertruy te Kronnie Gunnar Cario Giovanni Cazzaniga Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia HemaSphere |
| title | Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia |
| title_full | Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia |
| title_fullStr | Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia |
| title_full_unstemmed | Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia |
| title_short | Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia |
| title_sort | definition and prognostic value of ph like and ikzf1plus status in children with down syndrome and b cell precursor acute lymphoblastic leukemia |
| url | http://journals.lww.com/10.1097/HS9.0000000000000892 |
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