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Haematologica 2019 Volume 104(2):312-318
Acute Lymphoblastic Leukemia
Prognostic implications of additional genomic lesions in adult Philadelphia chromosome- positive acute lymphoblastic leukemia
Anna Lucia Fedullo,1* Monica Messina,1* Loredana Elia,1 Alfonso Piciocchi,2 Valentina Gianfelici,1 Alessia Lauretti,1 Stefano Soddu,2 Maria Cristina Puzzolo,1 Clara Minotti,1 Felicetto Ferrara,3 Bruno Martino,4 Patrizia Chiusolo,5 Valeria Calafiore,6 Stefania Paolini,7 Marco Vignetti,1,2 Antonella Vitale,1 Anna Guarini,8 Robin Foà1* and Sabina Chiaretti1*
1Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome; 2GIMEMA Data Center, Rome; 3Division of Hematology and Stem Cell Transplantation Unit, Cardarelli Hospital, Naples; 4Hematology Unit, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria; 5Institute of Hematology, Catholic University, Rome; 6Division of Hematology, AOU Policlinico, University of Catania; 7"L. and A. Seràgnoli" Institute of Hematology, University of Bologna and 8Department of Molecular Medicine, Sapienza University, Rome, Italy
ABSTRACT
To shed light onto the molecular basis of Philadelphia chromo- some-positive acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that patients with Philadelphia chromosome-positive acute lymphoblastic leukemia carry an average of 7.8 lesions/case, with dele- tions outnumbering gains (88% versus 12%). The most common dele- tions were those targeting IKZF1, PAX5 and CDKN2A/B, which were detected in 84%, 36% and 32% of cases, respectively. Patients carrying simultaneous deletions of IKZF1 plus CDKN2A/B and/or PAX5 had a sig- nificantly lower disease-free survival rate (24.9% versus 43.3%; P=0.026). The only IKZF1 isoform affecting prognosis was the dominant negative one (P=0.003). Analysis of copy number aberrations showed that 18% of patients harbored MEF2C deletions, which were of two types, differ- ing in size: the longer deletions were associated with the achievement of a complete molecular remission (P=0.05) and had a favorable impact on disease-free survival (64.3% versus 32.1% at 36 months; P=0.031). These findings retained statistical significance also in multivariate analysis (P=0.057). KRAS deletions, detected in 6% of cases, were associated with the achievement of a complete molecular remission (P=0.009). These results indicate that in adults with Philadelphia chromosome-pos- itive acute lymphoblastic leukemia a detailed evaluation of additional deletions - including CDKN2A/B, PAX5, IKZF1, MEF2C and KRAS - has prognostic implications and should be incorporated in the design of more personalized treatment strategies.
Introduction
The Philadelphia (Ph) chromosome derives from the t(9;22)(q34;q11) and leads to a BCR-ABL1 rearrangement.1 The incidence of this chromosomal change in acute lymphoblastic leukemia (ALL) increases with age, being detected in 25% of adults and in about 50% of elderly patients.2 Prior to the advent of tyrosine kinase inhibitors, the outcome of Ph+ ALL patients was extremely poor,3-5 and the only
*These authors contributed equally to this work
Correspondence:
chiaretti@bce.uniroma1.it or rfoa@bce.uniroma1.it
Received: April 26, 2018. Accepted: August 30, 2018. Pre-published: September 6, 2018.
doi:10.3324/haematol.2018.196055
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