Originally published as JCO Early Release 10.1200/JCO.2008.21.6408 on September 21 2009

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IKZF1 (Ikaros) Deletions in BCR-ABL1–Positive Acute Lymphoblastic Leukemia Are Associated With Short Disease-Free Survival and High Rate of Cumulative Incidence of Relapse: A GIMEMA AL WP Report

From the Department of Hematology and Oncology "L. and A. Seràgnoli," University of Bologna, Bologna; Department of Genetics and Microbiology, University of Bari, Bari; Department of Biotechnological Sciences and Hematology, "La Sapienza" University; Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Data Center, GIMEMA Foundation; Department of Hematology, Tor Vergata University Hospital, Rome; Department of Clinical and Biological Science, University of Turin at Orbassano, Orbassano; and University of Naples Federico II, Naples, Italy.

Corresponding author: Giovanni Martinelli, MD, Molecular Biology Unit, Department of Hematology and Oncology "L. and A. Seràgnoli," University of Bologna, Via Massarenti, 9-40138 Bologna, Italy; e-mail: giovanni.martinelli2{at}unibo.it.

Purpose The causes of the aggressive nature of BCR-ABL1–positive adult acute lymphoblastic leukemia (ALL) are unknown. To identify, at the submicroscopic level, oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed an investigation of genomic copy number alterations using single nucleotide polymorphism array, genomic polymerase chain reaction, and sequencing of candidate genes.

Patients and Methods Eighty-three patients with de novo adult Philadelphia chromosome (Ph) –positive ALL were enrolled onto institutional (n = 17) or Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Working Party delle Leucemia Acute (n = 66) clinical trials. Treatments included tyrosine kinase inhibitor (TKI) alone, conventional chemotherapy, or a combination of TKI and chemotherapy.

Results A 7p12 deletion of IKZF1 (Ikaros) was identified in 52 (63%) of 83 patients. The pattern of deletion varied among different patients, but the two most common deletion types were loss of exons 4 to 7 in 31 (37%) of 83 patients and loss of exons 2 to 7 in 17 (20%) of 83 patients. Disease-free survival (DFS) was shorter in patients with IKZF1 deletion versus patients with IKZF1 wild type (10 v 32 months, respectively; P = .02). Furthermore, a significantly shorter cumulative incidence of relapse was recorded in patients with IKZF1 deletion versus patients with IKZF1 wild type (10.1 v 56.1 months, respectively; P = .001). Multivariate analysis confirmed the negative prognostic impact of IKZF1 deletion on DFS (P = .04).

Conclusion We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.

Supported by European LeukemiaNet, Associazione Italiana per la Ricerca sul Cancro, Associazione Italiana Contro Le Leucemie, Linfomi E Mieloma, Fondazione Del Monte di Bologna e Ravenna, Fondo per Investimenti della Ricerca di Base 2006, Ateneo 60% grants, and GIMEMA Onlus Working Party Acute Leukemia and Chronic Myeloid Leukemia.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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