Additional Chromosome Abnormalities Have No Prognostic Value in Acute Promyelocytic Leukemia Patients Treated with Simultaneous ATRA and Anthracycline-Based Chemotherapy: An Update of the APL96 and APL99 Pethema Protocols.
Authors: Cervera Jose , Martin Guillermo , Hernandez Jesus M. , Vellenga Edo , Calasanz Maria J. , Martinez-Climent Jose A. , Luño Elisa , Ferro Maria T. , Rayon Consuelo , Gonzalez Marcos , Tormo Mar , Rivas Concha , Amutio Elena , de la Serna Javier , Gonzalez-San Miguel Jose D. , Bergua Juan , Leon Angel , Diaz-Mediavilla Joaquin , Garcia-Laraña Jose , Esteve Jordi , Sanz Miguel A. ,   on behalf of the PETHEMA Cooperative Group
Published: October 2019

Abstract
Acute promyelocytic leukemia (APL) is genetically characterized by a reciprocal translocation between the long arms of chromosomes 15 and 17, the t(15;17)(q22;q21), which results in the fusion gene PML/RARα. Conventional karyotyping on banded methaphases shows that about one third of APL patients carry additional cytogenetics changes in leukemic cells. The aim of the present study was to compare the clinical and biological characteristics of APL patients with or without chromosomal changes in addition to the t(15;17) and their potential impact on outcome. Between November 1996 and July 2004, a total of 640 de novo genetically confirmed APL patients were enrolled in two consecutive PETHEMA trials (APL96 and APL99). Cytogenetic analysis was available in 418 cases (65%) who disclosed the following features:212 M/206 F; median age 40 yrs. (range, 2–83); median WBC count 2.2 x 109/L (range, 0.3–236); median platelet count 22 x 109/L (range, 1–207); 337 M3 typical/81 M3 variant; relapse risk group (Sanz et al, Blood 2000): 81 (19%) low-risk, 235 (56%) intermediate-risk and 102 (25%) high-risk. Treatment consisted of all-trans-retinoic acid (ATRA) and anthracycline monochemotherapy for induction, followed by three consolidation courses of anthracycline/anthaquinone monochemotherapy with or without ATRA, and maintenance therapy with intermittent ATRA and low dose chemotherapy (methotrexate and 6-mercaptopurine). Additional chromosome aberrations were observed in 95 cases (23%). The most frequent secondary changes were + 8 (n=39), either alone (n=32) or associated with other aberrations (n=7), followed by abn(7q) (n=6), i(17) (n=5), abn(3q) (n=4), abn(1p) (n=3), del(9q) (n=3), abn(8q) (n=3), abn(11q) (n=3), +21 (n=3), +5 (n=2), abn(8p) (n=2), abn(13q) (n=2), and -Y (n=2). No clinical, biological, morphological, immunophenotypic or molecular differences were observed between the group of patients with t(15;17) alone and the group of patients with additional changes. Moreover, no statistical differences were found in terms of complete remission rate, 6-year disease-free survival and relapse-risk (92% vs 91%, 87 vs 90% and 10 vs 10% for patients with t(15;17) alone and patients with additional changes, respectively). In conclusion, patients with APL and additional cytogenetic abnormalities do not show distinct features as compared with patients with t(15;17) alone. Moreover, additional chromosomal changes have no influence in outcome of APL patients receiving state-of-the-art therapeutic protocols.