Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols

Simple Summary Recent advances in genomic analyses of acute lymphoblastic leukemia (ALL) have identified novel prognostic markers associated with patient outcome. In this frame, copy number alterations (CNAs) are constantly gaining relevance as potential risk stratification markers. Herein, we present our data of a proposed CNA-profile risk-index applied on a Greek ALLIC-BFM cohort. The results of our study demonstrate that EFS for GR(good-risk)-CNA-profile patients was 96.0% versus 57.6% of PR(poor-risk)-CNA-profile ones (p < 0.001) in the whole cohort. EFS within the IR-group for the GR-CNA vs. PR-CNA subgroups was 100.0% vs. 60.0% (p < 0.001), and within the HR-group, 88.2% vs. 55.6% (p = 0.047), respectively. The above results indicate that the application of the proposed CNA-profile classifier is feasible in BFM-based protocols, adding prognostic value to the existing prognostic markers and successfully stratifying patients within prognostic subgroups. This novel genomic risk index can be incorporated in future risk-stratification algorithms, further refining MRD-based stratification and possibly reassigning optimal treatment strategies. We present our data of a novel proposed CNA-profile risk-index, applied on a Greek ALLIC-BFM-treated cohort, aiming at further refining genomic risk-stratification. Eighty-five of 227 consecutively treated ALL patients were analyzed for the copy-number-status of eight genes (IKZF1/CDKN2A/2B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1). Using the MLPA-assay, patients were stratified as: (1) Good-risk(GR)-CNA-profile (n = 51), with no deletion of IKZF1/CDKN2A/B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1 or isolated deletions of ETV6/PAX5/BTG1 or ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. (2) Poor-risk(PR)-CNA-profile (n = 34), with any deletion of Iota Kappa Zeta F1/PAR1/EBF1/RB1 or any other CNA. With a median follow-up time of 49.9 months, EFS for GR-CNA-profile and PR-CNA-profile patients was 96.0% vs. 57.6% (p < 0.001). For IR-group and HR-group patients, EFS for the GR-CNA/PR-CNA subgroups was 100.0% vs. 60.0% (p < 0.001) and 88.2% vs. 55.6% (p = 0.047), respectively. Among FC-MRDd15 + patients (MRDd15 >= 10(-4)), EFS rates were 95.3% vs. 51.7% for GR-CNA/PR-CNA subjects (p < 0.001). Similarly, among FC-MRDd33 + patients (MRDd33 >= 10(-4)), EFS was 92.9% vs. 27.3% (p < 0.001) and for patients FC-MRDd33 - (MRDd33 < 10(-4)), EFS was 97.2% vs. 72.7% (p = 0.004), for GR-CNA/PR-CNA patients, respectively. In a multivariate analysis, the CNA-profile was the most important outcome predictor. In conclusion, the CNA-profile can establish a new genomic risk-index, identifying a distinct subgroup with increased relapse risk among the IR-group, as well as a subgroup of patients with superior prognosis among HR-patients. The CNA-profile is feasible in BFM-based protocols, further refining MRD-based risk-stratification.

Automated summary

Recent genomic analyses in acute lymphoblastic leukemia have identified CNAs as potential risk stratification markers, with novel prognostic value in patient outcome. The proposed CNA-profile risk index demonstrates significant differences in event-free survival rates, showing feasibility in BFM-based protocols to refine risk stratification and predict patient outcomes.