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Combining gene mutation with gene expression analysis improves outcomes prediction in acute promyelocytic leukemia

Antonio R. Lucena-Araujo, Juan L. Coelho-Silva, Diego A Pereira-Martins, Douglas R. Silveira MD, Luisa Corrêa de Araujo Koury, Raul A. M. Melo, Rosane Bittencourt, Katia Pagnano, Ricardo Pasquini, Elenaide C. Nunes, Evandro M. Fagundes, Ana B. Gloria, Fabio R Kerbauy, Maria de Lourdes Chauffaille, Israel Bendit, Vanderson Rocha, Armand Keating, Martin S. Tallman, Raul C. Ribeiro, Richard Dillon, Arnold Ganser, Bob Löwenberg, Peter Valk, Francesco Lo Coco, Miguel A. Sanz, Nancy Berliner and Eduardo M. Rego

Key Points

  • ISAPL modeling identified two distinct groups of patients with APL with significant differences in clinical outcomes.

  • ISAPL modeling might be a viable alternative for identifying patients that should be monitored and treated differently.

Abstract

Combining the analysis of mutations with aberrant expression of genes previously related to poorer prognosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we propose an integrative score in APL (ISAPL) and demonstrate its relationship with clinical outcomes of patients treated with all-trans retinoic acid (ATRA) in combination with anthracycline-based chemotherapy. Based on FLT3-ITD mutational status, ΔNp73/TAp73 expression ratio, ID1, BAALC, ERG, and KMT2E gene expression levels, we modeled ISAPL in 159 patients (median ISAPL score: 3, range: 0-10). ISAPL modeling identified two distinct groups of patients, with significant differences in early mortality (P<0.001), remission (P=0.004), overall survival (P<0.001), cumulative incidence of relapse (P=0.028), disease-free survival (P=0.03), and event-free survival (P<0.001). These data were internally validated using a bootstrap resampling procedure. At least for patients treated with ATRA and anthracycline-based chemotherapy, ISAPL modeling may identify those who need to be treated differently to maximize their chances of cure.

  • Submitted February 19, 2019.
  • Revision received July 9, 2019.
  • Accepted May 23, 2019.