PF538 GENETIC EVOLUTION PATTERNS IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA TO SECONDARY ACUTE MYELOID LEUKEMIA: AN ANALYSIS OF 36 PAIRED SAMPLES

Abstract

Background:Chronic myelomonocytic leukemia (CMML) are associated with a tendency to secondary acute myeloid leukemia (sAML) progression.Aims:We sought to examine the patterns of genetic evolution by analyzing a cohort of matched paired samples collected at initial diagnosis and at sAML transformation.Methods:Mutational analyses of 33 genes related to myeloid neoplasms on paired bone marrow samples from 36 patients with CMML at both diagnosis and sAML phase were performed. The samples were analyzed by PCR‐based assays followed by direct sequencing and/or next generation sequencing (NGS). The allele frequency of mutated genes was determined by variant allele frequency with NGS and/or pyrosequencing for validation.Results:Mutational analyses on the 36 paired CMML/sAML samples showed that 92% of patients had at least one mutated gene at initial diagnosis. Gene mutations involving epigenetic regulators (65%), myeloid transcription factors (52%), spliceosome (50 %), and signaling pathway (47%) were frequently detected, followed by BCOR (11%), NPM1 (6%) and SETBP1(6%), mutations of cohesin complex were rare (3%), and none had TP53, WT‐1 or BCORL1 mutations. Co‐existed mutations with different gene classes were present in 78% of CMML patients at diagnosis. The median time from CMML to sAML was 7.2 months (ranged from 1 to 89.6 months). At sAML transformation, 97% of patients had at least one mutated gene, mutation frequencies of epigenetic regulators (62%) and spliceosome (56%) remained mostly unchanged at sAML phase. Acquisition of additional gene mutations was observed in 47% of patients during sAML progression, in which signaling pathway mutations emerged most frequently (RTK/RAS/JAK‐STAT: 5/3/1), followed by transcription factors (3 acquiring RUNX1 mutations and 3 CEBPa). Emergence of new mutant subtypes of the same genes with or without disappearance of pre‐existed mutants was found in 3 RUNX1, and one each for CBL, PTPN11 and TET2 mutated patients during sAML progression. In addition, 8 patients had apparently increase in allele burden (>20%) for 6 genes. Loss of mutations was found in 4 (11%) patients during sAML progression, one each for PTPN11, JAK2V617F, CSF3R and TET2. Eight patients had apparently decrease in allele burden (>20%) for 4 different genes (N‐RAS, PTPN11, CBL and RUNX1).Summary/Conclusion:The present study on a relative large cohort of matched paired CMML/sAML samples showed that genetic evolution from CMML to sAML exhibited different patterns, including stable mutations, acquisition of new mutations, subclone selection or expansion of pre‐existed clones. Loss of mutation might occur but infrequently.