Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

• Published in: Cancer Vol. 121; no. 21; pp. 3809 - 3817
• Main Authors: Ribera, Jordi, Morgades, Mireia, Zamora, Lurdes, Montesinos, Pau, Gómez‐Seguí, Inés, Pratcorona, Marta, Sarrà, Josep, Guàrdia, Ramon, Nomdedeu, Josep, Tormo, Mar, Martínez‐Lopez, Joaquin, Hernández‐Rivas, Jesús‐María, González‐Campos, José, Barba, Pere, Escoda, Lourdes, Genescà, Eulàlia, Solé, Francesc, Millá, Fuensanta, Feliu, Evarist, Ribera, Josep‐Maria
• Format: Journal Article
• Language: English
• Published: United States 01.11.2015
• Subjects: Acute Disease; acute lymphoblastic leukemia; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B precursor; copy number alterations; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; DNA Copy Number Variations - genetics; Female; Gene Deletion; Humans; Ikaros Transcription Factor - genetics; Male; Middle Aged; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - diagnosis; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Prognosis; Spain; Survival Rate; Trans-Activators - genetics; Treatment Outcome; Young Adult; Spain; adult; acute lymphoblastic leukemia; B precursor; prognosis; copy number alterations
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.29579

BACKGROUND Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL). METHODS This study analyzed via multiplex ligation–dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B‐cell ALL. RESULTS The cyclin‐dependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)–positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B‐cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph‐negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph‐negative subgroup (hazard ratios, 1.044 and 2.105, respectively). CONCLUSIONS Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B‐precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. Cancer 2015;121:3809–3817. © 2015 American Cancer Society. Deletions of early B‐cell factor 1, cyclin‐dependent kinase inhibitor 2A/B, and Ikaros family zinc finger 1 are independent markers of a poor prognosis for uniformly treated adolescent and adult patients with B precursor acute lymphoblastic leukemia.