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1616 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

Program: Oral and Poster Abstracts
Session: 618. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Translational Research, Diseases, Lymphoid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Josgrey Del Valle Del Valle Navas Acosta1*, Teresa González, PhD2*, Inmaculada Serramito-Gómez, PhD2*, Angela Villaverde Ramiro2*, Cristina Miguel-García2*, Sandra Santos-Mínguez2*, Jordi Ribera3*, Isabel Granada, MD3*, Mireia Morgades3*, Ricardo Sanchez, PhD, MD4*, Esperanza Such, PhD5*, Susana Barrera6,7*, Juana Ciudad6,7*, Alberto Orfao, MD, PhD6,7*, Julio Davila Valls8*, Natalia De Las Heras, MD9*, José Fuster10*, Alfonso Garcia de Coca11*, Jorge Labrador12*, Jose Antonio Queizan Hernandez, MD13*, María Carmen Mendoza14*, Susana Riesco14*, Sandra Martín15*, Josep-Maria Ribera, MD, PhD3, Maria Rocio Benito Sanchez, PhD2* and Jesús María Hernández-Rivas, PhD2

1University of Salamanca, IBSAL, IBMCC, CSIC, Cancer Research Center, Department of Hematology - Hospital Universitario de Salamanca, SALAMANCA, AL, Spain
2University of Salamanca, IBSAL, IBMCC, CSIC, Cancer Research Center, Department of Hematology - Hospital Universitario de Salamanca, Salamanca, Spain
3ICO-Hospital Germans Trias i Pujol, Institut de Recerca contra la Leucèmia Josep Carreras (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
4Doce de Octubre Hospital, Madrid, Spain
5Department of Hematology, Hospital Universitari i Politecnic La Fe, Valencia, Spain
6Cancer Research Center (IBMCC-CSIC/USAL-IBSAL), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca, Salamanca, Spain
7Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC) CB16/12/00400, Instituto de Salud Carlos III, Madrid, Spain
8Hematology Service-Hospital Nuestra Señora de Sonsoles, Ávila, Spain
9Hospital Universitario de León, Leon, Spain
10Section of Pediatric Oncohematology, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain
11Hematology Department - Hospital Clínico de Valladolid, Valladolid, Spain
12Department of Hematology-Hospital Universitario Burgos, Burgos, Spain
13Hematology Department - Hospital General de Segovia, Segovia, Spain
14Pediatric Service - Hospital Universitario de Salamanca, Salamanca, Spain
15Molecular Biology Unit - Hospital Regional Universitario de Málaga, Málaga, Spain

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 at relapse. Of these cases, 67% (4/6) were also associated with IKZF1plus at relapse (Figure 1A).

Two mutually exclusive genetic patterns were identified at relapse in adult B-other and Ph-like patients. Thus, patients with IKZF1plus profile did not show RAS pathway mutations (59% and 57%, respectively), while patients with RAS pathway mutations lack in IKZF1plus profile (18% and 29%, respectively) (Figure 1B). Moreover age-related differences in the adult B-other ALL patient group were observed. The presence of mutations in RAS pathway was associated with younger age (<40 years) (3/10, 30% vs. 0/7, 0%), whereas older patients (≥40 years) predominated in the IKZF1plus profile (6/7, 86% vs. 3/10, 30%).

TP53 alterations were detected at diagnosis and/or relapse in 11 patients (24%), most of which (9/11, 82%) had a heterozygous mutation plus a deletion or a homozygous mutation (double-hit). The high hyperdiploidy subgroup was enriched in TP53 mutations (4/5, 80%), most of which were already present at diagnosis (3/4, 75%). These findings indicate that genetic biomarkers usually linked to a favorable prognosis, such as high hyperdiploidy, can be associated with unfavorable genetic markers, leading to poorer outcomes in this group of patients (Figure 1C). Both the IKZF1plus profile and TP53 alterations were associated with poorer overall survival (OS) rates (P=0.034 and P=0.040, respectively) in adult BCP-ALL (Figure 2).

Conclusion: Our results highlight the clinical importance of the TP53 alterations and the IKZF1plus profile as prognostic factors in adult BCP-ALL, suggesting they might help guiding more personalized therapeutic strategies to improve outcomes in this group of BCP-ALL patients.

Grants: SACYL(GRS2386/A/21,GRS2385/A/21,GRS2527/A/22,GRS2506/A/22), JCyL SA118P20, FMM21/002 AP176752021, Pfizer 69383919.

Disclosures: Ribera: Takeda: Consultancy; Novartis: Consultancy; Incyte: Consultancy, Research Funding; AMGEN: Research Funding; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding. Hernández-Rivas: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau.

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