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.
OBJECTIVE
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.


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).


CONCLUSIONS
We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.
Martinelli
Giovanni
G
Molecular Biology Unit, Department of Hematology and Oncology L. and A. Seràgnoli, University of Bologna, Via Massarenti, 9-40138 Bologna, Italy. giovanni.martinelli2@unibo.it
Iacobucci
Ilaria
I
Storlazzi
Clelia Tiziana
CT
Vignetti
Marco
M
Paoloni
Francesca
F
Cilloni
Daniela
D
Soverini
Simona
S
Vitale
Antonella
A
Chiaretti
Sabina
S
Cimino
Giuseppe
G
Papayannidis
Cristina
C
Paolini
Stefania
S
Elia
Loredana
L
Fazi
Paola
P
Meloni
Giovanna
G
Amadori
Sergio
S
Saglio
Giuseppe
G
Pane
Fabrizio
F
Baccarani
Michele
M
Foà
Robin
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D010677:Philadelphia Chromosome; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D000970:Antineoplastic Agents; C497239:IKZF1 protein, human; D047428:Protein Kinase Inhibitors; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl