BCR-ABL1-Positive Acute Lymphoblastic Leukemia Patients Treated with Only TKI Vs Conventional Chemo Plus TKI Therapy Show Similar DNA Alterations At Relapse Targeting Key Regulators of Tumor Suppression, Cell Cycle Control, and Lymphoid/B-Cell Development,
Authors: Iacobucci Ilaria , Pfifer Heike , Lonetti Annalisa , Papayannidis Cristina , Ferrari Anna , Trino Stefania , Abbenante Maria Chiara , Parisi Sarah , Soverini Simona , Vitale Antonella , Paolini Stefania , Ottaviani Emanuela , Baldazzi Carmen , Pane Fabrizio , Baccarani Michele , Ottmann Oliver G. , Martinelli Giovanni 
Published: October 2019

Abstract 3580

Introduction:

Although treatment with tyrosine kinase inhibitors (TKIs) has revolutionized the management of adult patients with BCR-ABL1 -positive acute lymphoblastic leukemia (ALL) and significantly improved response rates, relapse is still an expected and early event in the majority of them. It is usually attributed to the emergence of resistant clones with mutations in BCR-ABL1 kinase domain or to BCR-ABL1 -independent pathways but many questions remain unresolved about the genetic abnormalities responsible for relapse after TKI and chemotherapy-based regimens. Patients and methods: In an attempt to better understand the genetic mechanisms responsible for this phenomenon, we have analyzed matched diagnosis-relapse samples from 30 adult BCR-ABL1 -positive ALL patients using high resolution Affymetrix single nucleotide polymorphism (SNP) arrays (GeneChip® Human Mapping 250K NspI, n=15 pairs and Genome-Wide Human SNP 6.0, n= 15 pairs). Genetic differences were analyzed in terms of copy number changes and loss of heterozygosity (LOH) events. 20 patients were enrolled in clinical trials of GIMEMA AL Working Party and treated with imatinib alone or in combination with conventional chemotherapy (40%) or dasatinib as frontline therapy (60%). The median age at diagnosis was 54 years (range 23–74) and the median blast cell count was 97% (range 60–99). The median time to relapse was 27 months (range, 9–104). 10 patients were treated according to the GMALL trials, a high-dose chemotherapy based protocol in combination with imatinib. The median age at diagnosis was 65 years (range 19–79) and the median leucocyte count was 37300/μl (range 5000 – 220000/μl). The median time to relapse was 9.8 months (range, 3 – 25). Results: First, we compared diagnosis and relapse samples for the presence of macroscopic (> 1.5 MB) copy number alterations (CNA). Novel acquired macroscopic CNAs were detected in 7/20 (35%) TKI relapse cases and included losses of 3p12-p14, 5q34, 9q34, 10q24 and 12p13-p12 and gains of 1q, 9q34-q33 and 22q and in 4/10 (40%) chemotherapy-relapse cases and included losses of 9p21 and 12q21–22 and gains of all chromosome 8 or part of it in 2 patients. Since no common patterns of acquired alterations were observed, it is likely that relapse may be due to a more generalized genetic instability rather than to specific mechanisms. Moreover, chemotherapy did not select resistant clones with higher number of alterations. 8/20 (40%) TKI resistant cases and 4/10 chemotherapy resistant patients harbored the same CNAs present in the matched diagnosis sample (losses of 9p21 in 7 cases, 7p and 22q11 in single cases and gains of chromosomes 1q, 4, 8q, 17q and 21), indicating a common clonal origin. In contrast, in 5/20 (25%) TKI resistant cases and 4/10 (40%) chemotherapy resistant patients macroscopic CNAs present at diagnosis were lost at relapse (losses of chromosomes 7, 11q, 14q, 15q, 16q and 19p and gains of 5q, 8q, 9q34 and 22q11). Thereafter, we compared diagnosis and relapse samples for microscopic CNAs (< 1.5 MB). The alteration most frequently acquired at relapse was loss of the tumor suppressor CDKN2A (53% vs 33 % of diagnosis). Other common acquired CNAs at relapse included gains of ABC transporter genes, such as ABCC1, ABCC6 (1q41) and BCL8 (15q11); losses affected EBF1 (5q33) and IGLL3 (22q11) genes involved in B-cell development, BTG1 (12q21) involved in cell cycle regulation and CHEK2 (22q12) involved in DNA repair. Interestingly, for all relapse cases analysis of IKZF1 deletions, identified in 80% of patients, demonstrated a clonal relationship between diagnostic and relapse samples, suggesting that this alteration is not acquired with relapse but it is maintained with fidelity from diagnosis working as a marker of disease. The majority (92%) of relapse samples harbored at least some of the CNAs present in the matched diagnosis sample, indicating a common clonal origin. Conclusions: Genomic copy number changes evolving from diagnosis to relapse have been identified demonstrating that a diversity of alterations contributes to relapse and with the most common alterations targeting key regulators of tumor suppression, cell cycle control, and lymphoid/B cell development. Supported by European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2009, Ateneo RFO grants, PIO program, Programma di Ricerca Regione – Università 2007 – 2009.

Disclosures:

Soverini: Novartis: Consultancy; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy. Baccarani:Pfizer Oncology: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy; Novartis: Research Funding; Pfizer Oncology: Honoraria; Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Ottmann:Novartis Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy.