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
Year: 2025
Type: conference-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.
Source: Blood
Authors: Heike Pfeifer, Maher Hanoun, Ahmet Elmaagacli, Simon Raffel, Boris Böll, Klaus Wethmar, Andreas Viardot, Björn Steffen, Sonja Martin, Veit Buecklein, Stefan Schwartz, Knut Wendelin, Hendrik Poeck, Doris Kraemer, Mathias Hänel, Lisa Heberling, Thomas Burmeister, Monika Brüggemann, Thomas Oellerich, Hubert Serve, Nicola Gökbuget, Fabian Lang
Institutions: Goethe University Frankfurt, University Hospital Frankfurt, Essen University Hospital, Stiftung Universitätsmedizin Essen, Asklepios Klinik St. Georg, Heidelberg University, University of Cologne, University of Münster, University Hospital Münster, Universität Ulm, University Hospital Ulm, Robert Bosch Hospital, LMU Klinikum, Ludwig-Maximilians-Universität München, Charité - Universitätsmedizin Berlin, University Hospital Regensburg, University of Regensburg, Klinikum Chemnitz, University Hospital Carl Gustav Carus, Christian-Albrechts-Universität zu Kiel, University Hospital Schleswig-Holstein
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7108450793
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