sábado, 15 de septiembre de 2018

Prognostic implications of additional genomic lesions in adult Ph+ acute lymphoblastic leukemia. - PubMed - NCBI

2018 Sep 6. pii: haematol.2018.196055. doi: 10.3324/haematol.2018.196055. [Epub ahead of print]

Prognostic implications of additional genomic lesions in adult Ph+ acute lymphoblastic leukemia.

Fedullo AL1, Messina M1, Elia L1, Piciocchi A2, Gianfelici V1, Lauretti A1, Soddu S2, Puzzolo MC1, Minotti C1, Ferrara F3, Martino B4, Chiusolo P5, Calafiore V6, Paolini S7, Vignetti M2, Vitale A1, Guarini A8, Foà R1, Chiaretti S9.

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Abstract

To shed light into the molecular basis of Ph+ 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 Ph+ acute lymphoblastic leukemia patients enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that Ph+ acute lymphoblastic leukemia patients carry 7.8 lesions/case on average, with deletions outnumbering gains (88% vs 12%). The most common deletions were those targeting IKZF1, PAX5 and CDKN2A/B detected in 84%, 36% and 32% of cases, respectively. Patients carrying simultaneous deletions of IKZF1 plus CDKN2A/B and/or PAX5 had a significantly worse disease-free survival (24.9% vs 43.3%, p=0.026). The only IKZF1 isoform impacting on prognosis was the dominant negative (p=0.003). Copy number aberrations analysis showed that 18% of patients harbored MEF2C deletions, which were of two types, differing 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% vs 32.1% at 36 months, p=0.031). These findings retain 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 adult Ph+ 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 always more personalized treatment strategies.