Investigations on druggable gene mutations related to AML/ALL lineage genes in Advanced Phases of CML: Implications in patient-tailored therapy of blast crisis CML in TKI era

BackgroundChronic 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. Therefore, the treatment of BC-CML is one of the biggest challenges in modern cancer medicine. Moreover, the OS of BC-CML is very variable indicating its heterogeneity. 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 AML-/ALL lineage gene mutations in BC-CML using very sensitive next-generation sequencing. Patients & MethodsThe study included 141 CML patients (123 CP-CML as control groups; 6 AP-CML and 12 BC-CML as experimental groups). Most of the patients received imatinib mesylate (IM) as first-line treatment. 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 www.pandrugs.com. 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 (Vienna, Austria). The study was approved by the ethical committee of KAIMRC and carried out per the guidelines of the Helsinki Declaration ResultsOverall male-to-female ratio was 1.6:1 and the mean age was 36.4 (range: 9-67) years. Eighteen (12.8%) patients progressed to AP-CML while 12 (8.5%) to BC-CML finally. BC-ML patients had overall poorer response to TKIs and higher mortality rate (75%) that prompted to look for additional gene mutations. WES showed overall 64 AML-/ALL-associated gene 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. ConclusionsNGS 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 for some of these genes we reported in this study. We conclude that our approach can help in finding druggable gene mutations related to AML-/ALL-lineage genes in almost every BC-CML patients and provide a practical guidance for drug repurposing as well as gateway to in-trail novel experimental drugs to individualize BC-CML patient treatment. Tweetable AbstractBlast crisis Chronic Myeloid Leukemia (BC-CML) is fatal due to its limited number of therapeutic options due to its clinical and genetic heterogeneity. In this study, we report AML-/ALL-lineage gene mutations associated with BC-CML, their implications in further comprehending BC-CML biology in clinical management.