Mutually-Exclusive Pathways between IKZF1plus and RAS Mutations and TP53 double-Hit Alterations Lead Relapse in B-Other, Ph-like and Hyperdiploidy Genetic Groups in Adult B-Cell Acute Lymphoblastic Leukemia

• Published in: Blood 2023-11, Vol.142, p.1616-1616
• Main Authors: Navas Acosta, Josgrey Del Valle Del Valle, González, Teresa, Serramito-Gómez, Inmaculada, Villaverde Ramiro, Angela, Miguel-García, Cristina, Santos-Mínguez, Sandra, Ribera, Jordi, Granada, Isabel, Morgades, Mireia, Sanchez, Ricardo, Such, Esperanza, Barrera, Susana, Ciudad, Juana, Orfao, Alberto, Valls, Julio Davila, De Las Heras, Natalia, Fuster, José, Garcia de Coca, Alfonso, Labrador, Jorge, Queizan Hernandez, Jose Antonio, Mendoza, María Carmen, Riesco, Susana, Martín, Sandra, Ribera, Josep-Maria, Benito Sanchez, Maria Rocio, Hernández-Rivas, Jesús María
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2023-182163

Introduction: Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a hematologic malignancy characterized by a high genetic heterogeneity and high relapse rate. Despite treatment advances have led to high cure rates in pediatric BCP-ALL (90%), improving survival in adults remains a challenge. Identification of genetic alterations driving relapse and both new prognostic and therapeutic biomarkers are important to improve survival in adults with BCP-ALL. Aim: To identify genetic alterations that lead to relapse in adult BCP-ALL patients (18-72 years) based on the tumor genetic landscape. Methods: Forty-five adult BCP-ALL patients (median age: 43 years; range 18-72 years) were studied at diagnosis and relapse by massive sequencing using a custom panel that allows detection of single nucleotide variants (SNVs) and insertions/deletions (INDELs) in 150 genes involved in BCP-ALL, in addition to copy number variations (CNVs), gene fusions and aneuploidy. Thirty-eight percent of patients belonged to the BCP-other ALL group, 16% were Philadelphia-positive (Ph+), 16% were classified as Philadelphia-like (Ph-like), 11% belonged to the high hyperdiploidy group, 8% had KMT2A rearrangements ( KMT2Ar), 4% TCF3::PBX1 fusion, 3% showed hypodiploidy, 2% low hyperdiploidy and 2% de novo MYC and BCL2 double-hit. Patients were treated according to the Spanish Adult-PETHEMA high-risk ALL protocols. Results: The most frequently deleted gene at diagnosis was IKZF1 (25/45, 56%). Among these cases, 72% (20/25) had IKZF1plus genetic profile, characterized by co-occurrence of IKZF1 deletions with at least one deletion in CDKN2A/B, PAX5 or PAR1, without ERG deletion. The IKZF1plus genetic profile was associated with specific genetic subgroups: Ph+ (5/7, 71%), Ph-like (5/7, 71%) and B-other (10/17, 59%). Moreover, it was significantly related with the presence of minimal/measurable residual disease (MRD) after induction (16/18, 89%) p < 0.001 and persistence at relapse in most patients (18/20, 90%; p < 0.001). Interestingly, among those 5 patients initially diagnosed with IKZF1 deletion but who did not meet the criteria for the IKZF1plus profile, 2 of them acquired the IKZF1plus profile at relapse. This suggests a possible cooperation of these genetic deletions contributing to therapy resistance and disease progression in these genetic subgroups. Eighty-six percent (6/7) of Ph+ patients who received imatinib treatment presented ABL1 mutations that were detected exclusively a