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

Abstract

Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative stem cell malignancy. Chronic Phase CML (CP) is treatable with overall survival equivalent to general public. Nevertheless, a proportion of CP-CML progresses to the accelerated phase (AP-) and ultimately blast crisis (BC), with the later having an overall survival of 3-23 months, making it almost a fatal manifestation. Therefore, treatment of BC-CML is of the biggest challenges in modern cancer medicine. FDA-approved drugs are available against a large number of mutated genes reported in AML and ALL. As BC-CML resembles AML (myeloid BC) or ALL (lymphoid BC), this study was designed to find out AML-/ALL lineage gene mutations in BC-CML, find their druggability and feasibility of their utilization in patient-tailored treatment of BC-CML. Patients & Methods: The 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 online 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 ethical committee of KAIMRC and carried out per guidelines o of the Helsinki Declaration Results: Overall 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 druggable gene mutations in advanced phase CML. WES showed overall 64 AML-/ALL- associated gene mutated in advanced phase CML patients. 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, which have FDA-approved drug to target them. Conclusions: NGS found druggable mutations in many AML-/ALL-lineage genes. Many of the corresponding drugs are either already approved for BC-CML treatment or in clinical trial phase. 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 to individualize BC-CML patient treatment. Keywords: Blast crisis Chronic Myeloid Leukemia; druggable mutations; pa-tient-tailored treatment; AML lineage genes; ALL lineage genes.