Impact of clinical features, cytogenetics, genetic mutations, and methylation dynamics of CDKN2B and DLC-1 promoters on treatment response to azacitidine

• Published in: Annals of hematology Vol. 99; no. 3; pp. 527 - 537
• Main Authors: Martín, Iván, Navarro, Blanca, Serrano, Alicia, Villamón, Eva, Calabuig, Marisa, Solano, Carlos, Chaves, Felipe Javier, Yagüe, Nuria, Orts, Maribel, Amat, Paula, Fuentes, Azahara, Seda, Enrique, García, Francisca, Hernández-Boluda, Juan Carlos, Tormo, Mar
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2020; Springer Nature B.V
• Subjects: Aged; Aged, 80 and over; Azacitidine - administration & dosage; Chromosome Deletion; Chromosomes, Human, Pair 7 - genetics; Chromosomes, Human, Pair 7 - metabolism; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Cytogenetics; Disease-Free Survival; DNA Methylation - drug effects; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Female; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Hematology; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation; Myelodysplastic syndromes; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - mortality; Oncology; Original Article; Promoter Regions, Genetic; Survival Rate; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Promoter methylation; Gene mutations; Azacitidine; Platelet doubling; Acute myeloid leukemia; Myelodysplastic syndromes
• ISSN: 0939-5555; 1432-0584; 1432-0584
• DOI: 10.1007/s00277-020-03932-8

Azacitidine (AZA) is a DNA hypomethylation agent administered in myeloid neoplasms; however, there is still a lack of established predictors of response. We studied 113 patients with myelodysplastic syndromes ( n  = 85) or acute myeloid leukemia ( n  = 28) who received AZA to assess the predictive value on response of clinical features, cytogenetics, and molecular markers. Overall, 46 patients (41%) responded to AZA. Platelet doubling after the first AZA cycle was associated with a better response (68% vs. 32% responders, P  = 0.041). Co-occurrence of chromosome 7 abnormalities and 17p deletion was associated with a worse response ( P  = 0.039). Pre-treatment genetic mutations were detected in 98 patients (87%) and methylation of CDKN2B and DLC-1 promoters were detected in 50 (44%) and 37 patients (33%), respectively. Patients with SF3B1 mutations showed a better response to AZA (68% vs. 35% responders, P  = 0.008). In contrast, subjects with mutations in transcription factors ( RUNX1 , SETBP1 , NPM1 ) showed a worse response (20% vs. 47% responders, P  = 0.014). DLC-1 methylation pre-treatment was associated with poor clinical features and its reduction post-treatment resulted in a better response to AZA in MDS patients ( P  = 0.037). In conclusion, we have identified several predictors of response to AZA that could help select the best candidates for this treatment.