Impact of IKZFplus status and ABL1 kinase domain mutations in patients with newly diagnosed Philadelphia-chromosome positive acute lymphoblastic leukemia receiving imatinib and chemotherapy followed by allogeneic SCT within GMALL07/03

Abstract

Abstract Background Several study groups have demonstrated, that alterations in the IKZF1gene at diagnosis and the presence of ABL1 mutations during treatment have a prognostic impact on the outcome in patients with Philadelphia-Chromosome positive (Ph+) acute lymphoblastic leukemia (ALL).(M. Stanulla et al., JCO 2017; R. Foa et al., JCO 2024) Aim The aim of this retrospective analysis was to evaluate the influence of an IKZFplus status and of ABL1-TKD mutations on the early response in patients treated with imatinib and chemotherapy followed by allogeneic stem cell transplantation (SCT) according to the GMALL protocol 07/03. The trial is an independent study of the Goethe University, funded by the Deutsche Krebshilfe. The analysis was supported by Incyte. Methods A total of 415 patients (pts) with newly diagnosed Ph+ ALL were evaluable within the GMALL07/03 protocol. In the main cohort, Imatinib was given upfront together with start of induction chemotherapy and continued throughout consolidation 1 until SCT. In 193 pts material was available for testing the IKZFplus status (defined as concomitant presence of IKZF1 deletions associated with PAX5 deletions and/or CDKN2A/B deletions) with MLPA P335 (n=104) and/or with single nucleotide polymorphism analysis (n=89). Minimal residual disease (MRD) was measured serially by quantitative real-time PCR for BCR::ABL1. ABL1-mutation analysis at initial diagnosis or during induction was performed with Next-Generation Sequencing (NGS) in n=87 pts. Relapse material was available in 24 pts for which the ABL1-mutation analysis was performed using Sanger sequencing. Results The median age of evaluated pts (N=415) was 43 years (17- 64 y).. After consolidation 1, MRD was available in 44% (N=184) of pts. Of these, 36% (67/184) were in molecular CR (defined as BCR::ABL1 negativity with 1E4 ABL1 copies) or positive below 1E-04 or), 35% (65/184) had a molecular failure with quantitative MRD persistence of 1E-04 or higher, 15% were all others (positive below the quantitative range, low ABL1). At initial diagnosis, an IKZFplus status was found in 46% (88/193) of pts, IKZF deletions alone were found in 26% (51/193) of pts, while 28% (54/193) of pts showed no alterations in the analyzed genes. After consolidation 1, the rate of molecular CR was comparable in pts with IKZFplus signature versus IKZF only and IKZF wildtype (30% [12/39pts] vs. 19% [10/51pts] and 24% [7/29 pts]). At relapse, 9/24 (37.5%) showed an ABL1-TKD mutation (mainly T315I; Y253F/H). At initial diagnosis, no ABL1-TKD mutation was found with a variant allele frequency (VAF) >5% with NGS in any of the analyzed pts (N=89). Conclusion With a variant allelic frequency above >5%, no ABL1-TKD mutations were seen at diagnosis. ABL1-TKD mutations that causes resistance to imatinib were detected at relapse with sanger sequencing and/or NGS. Nevertheless, given the type of mutations, NGS testing should be used in pts with molecular relapse for an earlier detection of ABL1-TKD mutations. Neither IKZF1 deletions alone or IKZF1plus status had a significant impact on the response intial treatment in regard of BCR::ABL1 MRD. Correlation to outcome data in a transplantation based therapy regimen will be demonstrated.