Abstract 5994: Investigating druggability of myeloid and lymphoid lineage gene mutations in advanced phase CML by employing drug discovery tools: Implications in fatal blast crisis CML precision oncology

Abstract Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative stem cell malignancy. Chronic Phase CML (CP-CML) is treatable with overall survival equivalent to the general population. Nevertheless, a proportion of CP-CML progresses to the accelerated phase (AP-CML) and ultimately blast crisis (BC-CML), with the latter having an overall survival (OS) of 3-23 months, making it almost a fatal manifestation. Although BC-CML is a different clinical entity than acute leukemias, it resembles AML (as myeloid BC-CML) or ALL (lymphoid BC-CML). Therefore, this study was designed to find out druggable AML-/ALL-lineage gene mutations in BC-CML Methods: The study included 141 CML patients. All response criteria were per European LeukemiaNet (ELN) guidelines 2020. Whole exome sequencing (WES) was carried out to find out druggable gene mutations and the druggability of the mutated genes was determined using the online artificial intelligence (AI) tool (https://www.pandrugs.org/#!/query/). SAS/STAT software version 9.4 was used for data analysis (SAS Institute Inc., Cary, NC, USA). For statistical computing, the R package was employed. Results: Out of 141, 18 (12.8%) patients progressed to AP-CML while 12 (8.5%) to BC-CML. BC-CML patients had poorer response to TKIs and higher mortality rate (75%). WES showed 64 AML-/ALL-associated genes mutated in advanced phase CML patients. Overall WES coverage was about 110X. AP-CML had 1644 variants, whereas BC-CML had 2531 variants, with a 54% gain in mutations from AP-CML to BC-CML (P< 0.000001). Among AML-/ALL- related mutated genes were NPM1 (%1.98), DNMT3A (%1.86), PML (%1.82), AKT1 (%1.62), CBL (%1.30), JAK2 (%0.71), TET2 (%0.59), IDH1 (%0.32), and BCL2. We also found that some FDA-approved drugs for different hematological malignancies (e.g. VENETOCLAX, DECITABINE, AZACITIDINE, BORTEZOMIB, ZANUBRUTINIB, IVOSIDENIB, TAZEMETOSTAT, RUXOLITINIB, PACRITINIB, ARSENIC TRIOXIDE etc.) can effectively target multiple gene groups mutated in our advanced phase CML patients. Conclusions: NGS analysis of AP- & BC-CML found mutations in many AML-/ALL-lineage genes, which is much higher than previously reported. This shows a huge genetic similarity between BC-CML and AML/ALL. FDA-approved and various novel experimental drugs under clinical trials are available against some of the genes we reported. We conclude that our approach can help in finding drug-targetable gene mutations related to AML-/ALL-lineage & other hematological malignancies in almost every BC-CML patient and provides practical guidance for drug repurposing as well as a gateway for under-trial novel experimental drugs to individualize BC-CML patient treatment. Citation Format: Fatimah Alabdullah, Nawaf Alanazi, Abdulkareem AlGarni, Kanza Adeel, Yaqob Samir Taleb, Amer Mahmood, Sabreen Alanazi, Aamer Aleem, Zafar Iqbal. Investigating druggability of myeloid and lymphoid lineage gene mutations in advanced phase CML by employing drug discovery tools: Implications in fatal blast crisis CML precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5994.