PLZF-RAR_α, NPM1-RAR_α, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review

• Main Authors: Marta Sobas, Maria Carme Talarn-Forcadell, David Martínez-Cuadrón, Lourdes Escoda, María J. García-Pérez, Jose Mariz, María J. Mela-Osorio, Isolda Fernández, Juan M. Alonso-Domínguez, Javier Cornago-Navascués, Gabriela Rodríguez-Macias, María E. Amutio, Carlos Rodríguez-Medina, Jordi Esteve, Agnieszka Sokół, Thais Murciano-Carrillo, María J. Calasanz, Manuel Barrios, Eva Barragán, Miguel A. Sanz, Pau Montesinos
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: Cancers
• Subjects: variant; acute promyelocytic leukemia; systematic review; characteristics; outcomes
• Online Access: https://www.mdpi.com/2072-6694/12/5/1313

It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RAR_α being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RAR_α and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RAR_α and 2 NPM1-RAR_α), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 10⁹/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.