P397: ikzf1 alterations have a negative impact on early molecular response and survival of adult patients with b-cell precursor acute lymphoblastic leukemia treated with gmall 07/2003 protocol in czechia

Background: Alterations of IKZF1 encoding IKAROS are associated with poor outcome of high risk B-progenitor acute lymphoblastic leukemia (ALL) including BCR::ABL1-positive (Ph+) and Ph-like ALL patients (review Churchman and Mullighan 2017). Co-occurrence of IKZF1 deletions (IKZF1del) with at least one other gene deletion (CDKN2A, CDKN2B, PAX5 or PAR1) in the absence of ERG deletion was defined as IKZF1plus. Presence of IKZF1plus represented a very-poor prognostic factor of outcome in pediatric ALL (Stanulla et al 2018). Aims: This work of the Czech Leukemia Study Group for Life is focused on 79 adult B-ALL patients treated with GMALL 07/2003 protocol (and with imatinib in Ph+ ALL). The aim is to analyse prognostic significance of IKZF1 alterations on molecular response at week 11 (W11) and overall survival (OS). Methods: MLPA was performed in 38 Ph+ and 41 Ph-negative (Ph-) ALL patients using kits P335, P202 and Coffalyser software (MRC Holland). Patients were divided into 4 groups: IKZF1plus, IKZF1del, MLPA positive excluding IKZF1 (MLPApos) and MLPA negative (MLPAneg). Molecular response was evaluated by quantification of clone-specific IG/TCR rearrangements or BCR::ABL1 transcript. Measurable residual disease (MRD) achievement was defined as negative or positive quantifiable. Log-rank test, Kaplan-Meiers survival curves and Chi-square test were used for statistical evaluations. Results:IKZF1del and IKZF1plus had higher frequency in Ph+ ALL patients (42% and 34%, respectively) compared to Ph- ALL (7% and 7%, respectively). MLPAplus was detected more frequently in Ph- (29%) compared to Ph+ patients (11%). OS was significantly shorter in Ph+ patients with IKZF1plus compared to other groups (P=0.04). All five MLPAneg patients are alive. The probability to achieve MRD at W11 was not significantly decreased in Ph+ patients with IKZF1plus and IKZF1del compared to MLPApos and MLPAneg. OS of patients not achieving MRD at W11 was reduced in IKZF1plus and IKZF1del group compared to MLPApos and MLPAneg (P=0.07 and 0.08, respectively). However, despite achieving MRD at W11, IKZF1plus and IKZF1del patients had low probability of OS with a worse trend in IKZF1plus. Despite low numbers of Ph- patients with IKZF1plus (n=3) and IKZF1del (n=3), there was a clear trend to worse outcome in this group that is comparable to MLPApos and contrasting with MLPAneg patients. A significant difference was found between IKZF1plus and MLPAneg patients (P=0.003). The probability to reach MRD at W11 was significantly lower in patients with IKZF1plus and MLPApos (P=0.003). Irrespective of IKZF1 status, all Ph- patients who did not achieve MRD at W11 had low probability of OS. Patients with IKZF1 alterations and MRD response had lower probability of OS. Summary/Conclusion:IKZF1 alterations were more frequent in Ph+ ALL. Their detection correlated with shorter OS in both Ph+ and Ph- ALL adults treated with GMALL 07/2003 protocol. Individuals with IKZFplus had the worse outcome. Importantly, IKZF1 alterations were proven as a poor prognostic factor for OS despite the achievement of MRD at W11. IKZF1 profiling should be performed regularly in B-ALL as there is a room for treatment intensification in IKZF1-altered patients. Supported by AZV CR NU22-03-00210. Keywords: Ph+ ALL, B cell acute lymphoblastic leukemia, ALL, Ikaros